G. David Adamson, MD

Total fertility rate and fertility care: Demographic shifts and changing demands

Vollset SE, Goren E, Yuan C-W, et al. Fertility, mortality, migration, and population scenarios for 195 countries and territories from 2017 to 2100: a forecasting analysis for the Global Burden of Disease Study. Lancet. 2020;396:1285-1306.

The total fertility rate (TFR) globally is decreasing rapidly, and in the United States it is now 1.8 births per woman, well below the required replacement rate of 2.1 that maintains the population.¹ These reduced TFRs result in significant demographic shifts that affect the economy, workforce, society, health care needs, environment, and geopolitical standing of every country. These changes also will shift demands for the volume and type of services delivered by women’s health care clinicians.

In addition to the TFR, mortality rates and migration rates play essential roles in determining a country’s population.² Anticipation and planning for these population and health care service changes by each country’s government, business, professionals, and other stakeholders are imperative to manage their impact and optimize quality of life.

Illustration: Kimberly Martens for OBG Management

US standings in projected population and economic growth

The US population is predicted to peak at 364 million in 2062 and decrease to 336 million in 2100, at which time it will be the fourth largest country in the world, according to a forecasting analysis by Vollset and colleagues.¹ China is expected to become the biggest economy in the world in 2035, but this is predicted to change because of its decreasing population so that by 2098 the United States will again be the country with the largest economy (FIGURE 1).¹

For the United States to maintain its economic and geopolitical standing, it is important to have policies that promote families. Other countries, especially in northern Europe, have implemented such policies. These include education of the population,economic incentives to create families, extended day care, and favorable tax policies.³ They also include increased access to family-forming fertility care. Such policies in Denmark have resulted in approximately 10% of all children being born from assisted reproductive technology (ART), compared with about 1.5% in the United States. Other countries have similar policies and success in increasing the number of children born from ART.

In the United States, the American Society for Reproductive Medicine (ASRM), RESOLVE: the National Infertility Association, the American Medical Women’s Association (AMWA), and others are promoting the need for increased access to fertility care and family-forming resources, primarily through family-forming benefits provided by companies.⁴ Such benefits are critical since the primary reason most people do not undergo fertility care is a lack of affordability. Only 1 person in 4 in the United States who needs fertility care receives treatment. Increased access would result in more babies being born to help address the reduced TFR.

Educational access, contraceptive goals, and access to fertility care

Continued trends in women’s educational attainment and access to contraception will hasten declines in the fertility rate and slow population growth (TABLE).¹ These educational and contraceptive goals also must be pursued so that every person can achieve their individual reproductive life goals of having a family if and when they want to have a family. In addition to helping address the decreasing TFR, there is a fundamental right to found a family, as stated in the United Nations charter. It is a matter of social justice and equity that everyone who wants to have a family can access reproductive care on a nondiscriminatory basis when needed.

While the need for more and better insurance coverage for infertility has been well documented for many years, the decreasing TFR in the United States is an additional compelling reason that government, business, and other stakeholders should continue to increase access to fertility benefits and care. Women’s health care clinicians are encouraged to support these initiatives that also improve quality of life, equity, and social justice.

Continue to: A new comprehensive ovulatory disorders classification system developed by FIGO...

Munro MG, Balen AH, Cho S, et al; FIGO Committee on Menstrual Disorders and Related Health Impacts, and FIGO Committee on Reproductive Medicine, Endocrinology, and Infertility. The FIGO ovulatory disorders classification system. Fertil Steril. 2022;118:768-786.

Ovulatory disorders are well-recognized and common causes of infertility and abnormal uterine bleeding (AUB). Ovulatory disorders occur on a spectrum, with the most severe form being anovulation, and comprise a heterogeneous group that has been classically categorized based on an initial monograph published by the World Health Organization (WHO) in 1973. That classification was based on gonadotropin levels and categorized these disorders into 3 groups: 1) hypogonadotropic (such as hypothalamic amenorrhea), 2) eugonadotropic (such as polycystic ovary syndrome [PCOS]), and 3) hypergonadotropic (such as primary ovarian insufficiency). This initial classification was the subject of several subsequent iterations and modifications over the past 50 years; for example, at one point, ovulatory disorder caused by hyperprolactinemia was added as a separate fourth category. However, due to advances in endocrine assays, imaging technology, and genetics, our understanding of ovulatory disorders has expanded remarkably over the past several decades.

Previous FIGO classifications

Considering the emergent complexity of these disorders and the limitations of the original WHO classification to capture these subtleties adequately, the International Federation of Gynecology and Obstetrics (FIGO) recently developed and published a new classification system for ovulatory disorders.⁵ This new system was designed using a meticulously followed Delphi process with inputs from a diverse group of national and international professional organizations, subspecialty societies, specialty journals, recognized experts in the field, and lay individuals interested in the subject matter.

Of note, FIGO had previously published classification systems for nongestational normal and abnormal uterine bleeding in the reproductive years (FIGO AUB System 1),as well as a subsequent classification system that described potential causes of AUB symptoms (FIGO AUB System 2), with the 9 categories arranged under the acronym PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy–Coagulopathy, Ovulatory dysfunction, Endometrial disorders, Iatrogenic, and Not otherwise classified). This new FIGO classification of ovulatory disorders can be viewed as a continuation of the previous initiatives and aims to further categorize the subgroup of AUB-O (AUB with ovulatory disorders). However, it is important to recognize that while most ovulatory disorders manifest with the symptoms of AUB, the absence of AUB symptoms does not necessarily preclude ovulatory disorders.

New system uses a 3-tier approach

The new FIGO classification system for ovulatory disorders has adopted a 3-tier system.

The first tier is based on the anatomic components of the hypothalamic-pituitary-ovarian (HPO) axis and is referred to with the acronym HyPO, for Hypothalamic-Pituitary-Ovarian. Recognizing that PCOS refers to a distinct spectrum of conditions that share a variable combination of signs and symptoms caused to varying degrees by different pathophysiologic mechanisms that involve inherent ovarian follicular dysfunction, neuroendocrine dysfunction, insulin resistance, and androgen excess, it is categorized in a separate class of its own in the first tier, referred to with the letter P.

Adding PCOS to the anatomical categories referred to by HyPO, the first tier is overall referred to with the acronym HyPO-P (FIGURE 2).⁵

The second tier of stratification provides further etiologic details for any of the primary 3 anatomic classifications of hypothalamic, pituitary, and ovarian. These etiologies are arranged in 10 distinct groups under the mnemonic GAIN-FIT-PIE, which stands for Genetic, Autoimmune, Iatrogenic, Neoplasm; Functional, Infectious/inflammatory, Trauma and vascular; and Physiological, Idiopathic, Endocrine.

The third tier of the system refers to the specific clinical diagnosis. For example, an individual with Kallmann syndrome would be categorized as having type I (hypothalamic), Genetic, Kallmann syndrome, and an individual with PCOS would be categorized simply as having type IV, PCOS.

Continue to: Live birth rate with conventional IVF shown noninferior to that with PGT-A...

Yan J, Qin Y, Zhao H, et al. Live birth with or without preimplantation genetic testing for aneuploidy. N Engl J Med. 2021;385:2047-2058.

Preimplantation genetic testing for aneuploidy (PGT-A) is increasingly used in many in vitro fertilization (IVF) cycles in the United States. Based on data from the Centers for Disease Control and Prevention, 43.8% of embryo transfers in the United States in 2019 included at least 1 PGT-A–tested embryo.⁶ Despite this widespread use, however, there are still no robust clinical data for PGT-A’s efficacy and safety, and the guidelines published by the ASRM do not recommend its routine use in all IVF cycles.⁷ In the past 2 to 3 years, several large studies have raised questions about the reported benefit of this technology.^8,9

Details of the trial

In a multicenter, controlled, noninferiority trial conducted by Yan and colleagues, 1,212 subfertile women were randomly assigned to either conventional IVF with embryo selection based on morphology or embryo selection based on PGT-A with next-generation sequencing. Inclusion criteria were the diagnosis of subfertility, undergoing their first IVF cycle, female age of 20 to 37, and the availability of 3 or more good-quality blastocysts.

On day 5 of embryo culture, patients with 3 or more blastocysts were randomly assigned in a 1:1 ratio to either the PGT-A group or conventional IVF. All embryos were then frozen, and patients subsequently underwent frozen embryo transfer of a single blastocyst, selected based on either morphology or euploid result by PGT-A. If the initial transfer did not result in a live birth, and there were remaining transferable embryos (either a euploid embryo in the PGT-A group or a morphologically transferable embryo in the conventional IVF group), patients underwent successive frozen embryo transfers until either there was a live birth or no more embryos were available for transfer.

The study’s primary outcome was the cumulative live birth rate per randomly assigned patient that resulted from up to 3 frozen embryo transfer cycles within 1 year. There were 606 patients randomly assigned to the PGT-A group and 606 randomly assigned to the conventional IVF group.

In the PGT-A group, 468 women (77.2%) had live births; in the conventional IVF group, 496 women (81.8%) had live births. Women in the PGT-A group had a lower incidence of pregnancy loss compared with the conventional IVF group: 8.7% versus 12.6% (absolute difference of -3.9%; 95% confidence interval [CI], -7.5 to -0.2). There was no difference in obstetric and neonatal outcomes between the 2 groups. The authors concluded that among women with 3 or more good-quality blastocysts, conventional IVF resulted in a cumulative live birth rate that was noninferior to that of the PGT-A group.

Some benefit shown with PGT-A

Although the study by Yan and colleagues did not show any benefit, and even a possible reduction, with regard to cumulative live birth rate for PGT-A, it did show a 4% reduction in clinical pregnancy loss when PGT-A was used. Furthermore, the study design has been criticized for performing PGT-A on only 3 blastocysts in the PGT-A group. It is quite conceivable that the PGT-A group would have had more euploid embryos available for transfer if the study design had included all the available embryos instead of only 3. On the other hand, one could argue that if the authors had extended the study to include all the available embryos, the conventional group would have also had more embryos for transfer and, therefore, more chances for pregnancy and live birth.

It is also important to recognize that only patients who had at least 3 embryos available for biopsy were included in this study, and therefore the results of this study cannot be extended to patients with fewer embryos, such as those with diminished ovarian reserve.

In summary, based on this study’s results, we may conclude that for the good-prognosis patients in the age group of 20 to 37 who have at least 3 embryos available for biopsy, PGT-A may reduce the miscarriage rate by about 4%, but this benefit comes at the expense of about a 4% reduction in the cumulative live birth rate. ●

Total fertility rate and fertility care: Demographic shifts and changing demands

Vollset SE, Goren E, Yuan C-W, et al. Fertility, mortality, migration, and population scenarios for 195 countries and territories from 2017 to 2100: a forecasting analysis for the Global Burden of Disease Study. Lancet. 2020;396:1285-1306.

The total fertility rate (TFR) globally is decreasing rapidly, and in the United States it is now 1.8 births per woman, well below the required replacement rate of 2.1 that maintains the population.¹ These reduced TFRs result in significant demographic shifts that affect the economy, workforce, society, health care needs, environment, and geopolitical standing of every country. These changes also will shift demands for the volume and type of services delivered by women’s health care clinicians.

In addition to the TFR, mortality rates and migration rates play essential roles in determining a country’s population.² Anticipation and planning for these population and health care service changes by each country’s government, business, professionals, and other stakeholders are imperative to manage their impact and optimize quality of life.

Illustration: Kimberly Martens for OBG Management

US standings in projected population and economic growth

The US population is predicted to peak at 364 million in 2062 and decrease to 336 million in 2100, at which time it will be the fourth largest country in the world, according to a forecasting analysis by Vollset and colleagues.¹ China is expected to become the biggest economy in the world in 2035, but this is predicted to change because of its decreasing population so that by 2098 the United States will again be the country with the largest economy (FIGURE 1).¹

For the United States to maintain its economic and geopolitical standing, it is important to have policies that promote families. Other countries, especially in northern Europe, have implemented such policies. These include education of the population,economic incentives to create families, extended day care, and favorable tax policies.³ They also include increased access to family-forming fertility care. Such policies in Denmark have resulted in approximately 10% of all children being born from assisted reproductive technology (ART), compared with about 1.5% in the United States. Other countries have similar policies and success in increasing the number of children born from ART.

In the United States, the American Society for Reproductive Medicine (ASRM), RESOLVE: the National Infertility Association, the American Medical Women’s Association (AMWA), and others are promoting the need for increased access to fertility care and family-forming resources, primarily through family-forming benefits provided by companies.⁴ Such benefits are critical since the primary reason most people do not undergo fertility care is a lack of affordability. Only 1 person in 4 in the United States who needs fertility care receives treatment. Increased access would result in more babies being born to help address the reduced TFR.

Educational access, contraceptive goals, and access to fertility care

Continued trends in women’s educational attainment and access to contraception will hasten declines in the fertility rate and slow population growth (TABLE).¹ These educational and contraceptive goals also must be pursued so that every person can achieve their individual reproductive life goals of having a family if and when they want to have a family. In addition to helping address the decreasing TFR, there is a fundamental right to found a family, as stated in the United Nations charter. It is a matter of social justice and equity that everyone who wants to have a family can access reproductive care on a nondiscriminatory basis when needed.

While the need for more and better insurance coverage for infertility has been well documented for many years, the decreasing TFR in the United States is an additional compelling reason that government, business, and other stakeholders should continue to increase access to fertility benefits and care. Women’s health care clinicians are encouraged to support these initiatives that also improve quality of life, equity, and social justice.

Continue to: A new comprehensive ovulatory disorders classification system developed by FIGO...

Munro MG, Balen AH, Cho S, et al; FIGO Committee on Menstrual Disorders and Related Health Impacts, and FIGO Committee on Reproductive Medicine, Endocrinology, and Infertility. The FIGO ovulatory disorders classification system. Fertil Steril. 2022;118:768-786.

Ovulatory disorders are well-recognized and common causes of infertility and abnormal uterine bleeding (AUB). Ovulatory disorders occur on a spectrum, with the most severe form being anovulation, and comprise a heterogeneous group that has been classically categorized based on an initial monograph published by the World Health Organization (WHO) in 1973. That classification was based on gonadotropin levels and categorized these disorders into 3 groups: 1) hypogonadotropic (such as hypothalamic amenorrhea), 2) eugonadotropic (such as polycystic ovary syndrome [PCOS]), and 3) hypergonadotropic (such as primary ovarian insufficiency). This initial classification was the subject of several subsequent iterations and modifications over the past 50 years; for example, at one point, ovulatory disorder caused by hyperprolactinemia was added as a separate fourth category. However, due to advances in endocrine assays, imaging technology, and genetics, our understanding of ovulatory disorders has expanded remarkably over the past several decades.

Previous FIGO classifications

Considering the emergent complexity of these disorders and the limitations of the original WHO classification to capture these subtleties adequately, the International Federation of Gynecology and Obstetrics (FIGO) recently developed and published a new classification system for ovulatory disorders.⁵ This new system was designed using a meticulously followed Delphi process with inputs from a diverse group of national and international professional organizations, subspecialty societies, specialty journals, recognized experts in the field, and lay individuals interested in the subject matter.

Of note, FIGO had previously published classification systems for nongestational normal and abnormal uterine bleeding in the reproductive years (FIGO AUB System 1),as well as a subsequent classification system that described potential causes of AUB symptoms (FIGO AUB System 2), with the 9 categories arranged under the acronym PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy–Coagulopathy, Ovulatory dysfunction, Endometrial disorders, Iatrogenic, and Not otherwise classified). This new FIGO classification of ovulatory disorders can be viewed as a continuation of the previous initiatives and aims to further categorize the subgroup of AUB-O (AUB with ovulatory disorders). However, it is important to recognize that while most ovulatory disorders manifest with the symptoms of AUB, the absence of AUB symptoms does not necessarily preclude ovulatory disorders.

New system uses a 3-tier approach

The new FIGO classification system for ovulatory disorders has adopted a 3-tier system.

The first tier is based on the anatomic components of the hypothalamic-pituitary-ovarian (HPO) axis and is referred to with the acronym HyPO, for Hypothalamic-Pituitary-Ovarian. Recognizing that PCOS refers to a distinct spectrum of conditions that share a variable combination of signs and symptoms caused to varying degrees by different pathophysiologic mechanisms that involve inherent ovarian follicular dysfunction, neuroendocrine dysfunction, insulin resistance, and androgen excess, it is categorized in a separate class of its own in the first tier, referred to with the letter P.

Adding PCOS to the anatomical categories referred to by HyPO, the first tier is overall referred to with the acronym HyPO-P (FIGURE 2).⁵

The second tier of stratification provides further etiologic details for any of the primary 3 anatomic classifications of hypothalamic, pituitary, and ovarian. These etiologies are arranged in 10 distinct groups under the mnemonic GAIN-FIT-PIE, which stands for Genetic, Autoimmune, Iatrogenic, Neoplasm; Functional, Infectious/inflammatory, Trauma and vascular; and Physiological, Idiopathic, Endocrine.

The third tier of the system refers to the specific clinical diagnosis. For example, an individual with Kallmann syndrome would be categorized as having type I (hypothalamic), Genetic, Kallmann syndrome, and an individual with PCOS would be categorized simply as having type IV, PCOS.

Continue to: Live birth rate with conventional IVF shown noninferior to that with PGT-A...

Yan J, Qin Y, Zhao H, et al. Live birth with or without preimplantation genetic testing for aneuploidy. N Engl J Med. 2021;385:2047-2058.

Preimplantation genetic testing for aneuploidy (PGT-A) is increasingly used in many in vitro fertilization (IVF) cycles in the United States. Based on data from the Centers for Disease Control and Prevention, 43.8% of embryo transfers in the United States in 2019 included at least 1 PGT-A–tested embryo.⁶ Despite this widespread use, however, there are still no robust clinical data for PGT-A’s efficacy and safety, and the guidelines published by the ASRM do not recommend its routine use in all IVF cycles.⁷ In the past 2 to 3 years, several large studies have raised questions about the reported benefit of this technology.^8,9

Details of the trial

In a multicenter, controlled, noninferiority trial conducted by Yan and colleagues, 1,212 subfertile women were randomly assigned to either conventional IVF with embryo selection based on morphology or embryo selection based on PGT-A with next-generation sequencing. Inclusion criteria were the diagnosis of subfertility, undergoing their first IVF cycle, female age of 20 to 37, and the availability of 3 or more good-quality blastocysts.

On day 5 of embryo culture, patients with 3 or more blastocysts were randomly assigned in a 1:1 ratio to either the PGT-A group or conventional IVF. All embryos were then frozen, and patients subsequently underwent frozen embryo transfer of a single blastocyst, selected based on either morphology or euploid result by PGT-A. If the initial transfer did not result in a live birth, and there were remaining transferable embryos (either a euploid embryo in the PGT-A group or a morphologically transferable embryo in the conventional IVF group), patients underwent successive frozen embryo transfers until either there was a live birth or no more embryos were available for transfer.

The study’s primary outcome was the cumulative live birth rate per randomly assigned patient that resulted from up to 3 frozen embryo transfer cycles within 1 year. There were 606 patients randomly assigned to the PGT-A group and 606 randomly assigned to the conventional IVF group.

In the PGT-A group, 468 women (77.2%) had live births; in the conventional IVF group, 496 women (81.8%) had live births. Women in the PGT-A group had a lower incidence of pregnancy loss compared with the conventional IVF group: 8.7% versus 12.6% (absolute difference of -3.9%; 95% confidence interval [CI], -7.5 to -0.2). There was no difference in obstetric and neonatal outcomes between the 2 groups. The authors concluded that among women with 3 or more good-quality blastocysts, conventional IVF resulted in a cumulative live birth rate that was noninferior to that of the PGT-A group.

Some benefit shown with PGT-A

Although the study by Yan and colleagues did not show any benefit, and even a possible reduction, with regard to cumulative live birth rate for PGT-A, it did show a 4% reduction in clinical pregnancy loss when PGT-A was used. Furthermore, the study design has been criticized for performing PGT-A on only 3 blastocysts in the PGT-A group. It is quite conceivable that the PGT-A group would have had more euploid embryos available for transfer if the study design had included all the available embryos instead of only 3. On the other hand, one could argue that if the authors had extended the study to include all the available embryos, the conventional group would have also had more embryos for transfer and, therefore, more chances for pregnancy and live birth.

It is also important to recognize that only patients who had at least 3 embryos available for biopsy were included in this study, and therefore the results of this study cannot be extended to patients with fewer embryos, such as those with diminished ovarian reserve.

In summary, based on this study’s results, we may conclude that for the good-prognosis patients in the age group of 20 to 37 who have at least 3 embryos available for biopsy, PGT-A may reduce the miscarriage rate by about 4%, but this benefit comes at the expense of about a 4% reduction in the cumulative live birth rate. ●

Total fertility rate and fertility care: Demographic shifts and changing demands

Vollset SE, Goren E, Yuan C-W, et al. Fertility, mortality, migration, and population scenarios for 195 countries and territories from 2017 to 2100: a forecasting analysis for the Global Burden of Disease Study. Lancet. 2020;396:1285-1306.

The total fertility rate (TFR) globally is decreasing rapidly, and in the United States it is now 1.8 births per woman, well below the required replacement rate of 2.1 that maintains the population.¹ These reduced TFRs result in significant demographic shifts that affect the economy, workforce, society, health care needs, environment, and geopolitical standing of every country. These changes also will shift demands for the volume and type of services delivered by women’s health care clinicians.

In addition to the TFR, mortality rates and migration rates play essential roles in determining a country’s population.² Anticipation and planning for these population and health care service changes by each country’s government, business, professionals, and other stakeholders are imperative to manage their impact and optimize quality of life.

Illustration: Kimberly Martens for OBG Management

US standings in projected population and economic growth

The US population is predicted to peak at 364 million in 2062 and decrease to 336 million in 2100, at which time it will be the fourth largest country in the world, according to a forecasting analysis by Vollset and colleagues.¹ China is expected to become the biggest economy in the world in 2035, but this is predicted to change because of its decreasing population so that by 2098 the United States will again be the country with the largest economy (FIGURE 1).¹

For the United States to maintain its economic and geopolitical standing, it is important to have policies that promote families. Other countries, especially in northern Europe, have implemented such policies. These include education of the population,economic incentives to create families, extended day care, and favorable tax policies.³ They also include increased access to family-forming fertility care. Such policies in Denmark have resulted in approximately 10% of all children being born from assisted reproductive technology (ART), compared with about 1.5% in the United States. Other countries have similar policies and success in increasing the number of children born from ART.

In the United States, the American Society for Reproductive Medicine (ASRM), RESOLVE: the National Infertility Association, the American Medical Women’s Association (AMWA), and others are promoting the need for increased access to fertility care and family-forming resources, primarily through family-forming benefits provided by companies.⁴ Such benefits are critical since the primary reason most people do not undergo fertility care is a lack of affordability. Only 1 person in 4 in the United States who needs fertility care receives treatment. Increased access would result in more babies being born to help address the reduced TFR.

Educational access, contraceptive goals, and access to fertility care

Continued trends in women’s educational attainment and access to contraception will hasten declines in the fertility rate and slow population growth (TABLE).¹ These educational and contraceptive goals also must be pursued so that every person can achieve their individual reproductive life goals of having a family if and when they want to have a family. In addition to helping address the decreasing TFR, there is a fundamental right to found a family, as stated in the United Nations charter. It is a matter of social justice and equity that everyone who wants to have a family can access reproductive care on a nondiscriminatory basis when needed.

While the need for more and better insurance coverage for infertility has been well documented for many years, the decreasing TFR in the United States is an additional compelling reason that government, business, and other stakeholders should continue to increase access to fertility benefits and care. Women’s health care clinicians are encouraged to support these initiatives that also improve quality of life, equity, and social justice.

Continue to: A new comprehensive ovulatory disorders classification system developed by FIGO...

Munro MG, Balen AH, Cho S, et al; FIGO Committee on Menstrual Disorders and Related Health Impacts, and FIGO Committee on Reproductive Medicine, Endocrinology, and Infertility. The FIGO ovulatory disorders classification system. Fertil Steril. 2022;118:768-786.

Ovulatory disorders are well-recognized and common causes of infertility and abnormal uterine bleeding (AUB). Ovulatory disorders occur on a spectrum, with the most severe form being anovulation, and comprise a heterogeneous group that has been classically categorized based on an initial monograph published by the World Health Organization (WHO) in 1973. That classification was based on gonadotropin levels and categorized these disorders into 3 groups: 1) hypogonadotropic (such as hypothalamic amenorrhea), 2) eugonadotropic (such as polycystic ovary syndrome [PCOS]), and 3) hypergonadotropic (such as primary ovarian insufficiency). This initial classification was the subject of several subsequent iterations and modifications over the past 50 years; for example, at one point, ovulatory disorder caused by hyperprolactinemia was added as a separate fourth category. However, due to advances in endocrine assays, imaging technology, and genetics, our understanding of ovulatory disorders has expanded remarkably over the past several decades.

Previous FIGO classifications

Considering the emergent complexity of these disorders and the limitations of the original WHO classification to capture these subtleties adequately, the International Federation of Gynecology and Obstetrics (FIGO) recently developed and published a new classification system for ovulatory disorders.⁵ This new system was designed using a meticulously followed Delphi process with inputs from a diverse group of national and international professional organizations, subspecialty societies, specialty journals, recognized experts in the field, and lay individuals interested in the subject matter.

Of note, FIGO had previously published classification systems for nongestational normal and abnormal uterine bleeding in the reproductive years (FIGO AUB System 1),as well as a subsequent classification system that described potential causes of AUB symptoms (FIGO AUB System 2), with the 9 categories arranged under the acronym PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy–Coagulopathy, Ovulatory dysfunction, Endometrial disorders, Iatrogenic, and Not otherwise classified). This new FIGO classification of ovulatory disorders can be viewed as a continuation of the previous initiatives and aims to further categorize the subgroup of AUB-O (AUB with ovulatory disorders). However, it is important to recognize that while most ovulatory disorders manifest with the symptoms of AUB, the absence of AUB symptoms does not necessarily preclude ovulatory disorders.

New system uses a 3-tier approach

The new FIGO classification system for ovulatory disorders has adopted a 3-tier system.

The first tier is based on the anatomic components of the hypothalamic-pituitary-ovarian (HPO) axis and is referred to with the acronym HyPO, for Hypothalamic-Pituitary-Ovarian. Recognizing that PCOS refers to a distinct spectrum of conditions that share a variable combination of signs and symptoms caused to varying degrees by different pathophysiologic mechanisms that involve inherent ovarian follicular dysfunction, neuroendocrine dysfunction, insulin resistance, and androgen excess, it is categorized in a separate class of its own in the first tier, referred to with the letter P.

Adding PCOS to the anatomical categories referred to by HyPO, the first tier is overall referred to with the acronym HyPO-P (FIGURE 2).⁵

The second tier of stratification provides further etiologic details for any of the primary 3 anatomic classifications of hypothalamic, pituitary, and ovarian. These etiologies are arranged in 10 distinct groups under the mnemonic GAIN-FIT-PIE, which stands for Genetic, Autoimmune, Iatrogenic, Neoplasm; Functional, Infectious/inflammatory, Trauma and vascular; and Physiological, Idiopathic, Endocrine.

The third tier of the system refers to the specific clinical diagnosis. For example, an individual with Kallmann syndrome would be categorized as having type I (hypothalamic), Genetic, Kallmann syndrome, and an individual with PCOS would be categorized simply as having type IV, PCOS.

Continue to: Live birth rate with conventional IVF shown noninferior to that with PGT-A...

Yan J, Qin Y, Zhao H, et al. Live birth with or without preimplantation genetic testing for aneuploidy. N Engl J Med. 2021;385:2047-2058.

Preimplantation genetic testing for aneuploidy (PGT-A) is increasingly used in many in vitro fertilization (IVF) cycles in the United States. Based on data from the Centers for Disease Control and Prevention, 43.8% of embryo transfers in the United States in 2019 included at least 1 PGT-A–tested embryo.⁶ Despite this widespread use, however, there are still no robust clinical data for PGT-A’s efficacy and safety, and the guidelines published by the ASRM do not recommend its routine use in all IVF cycles.⁷ In the past 2 to 3 years, several large studies have raised questions about the reported benefit of this technology.^8,9

Details of the trial

In a multicenter, controlled, noninferiority trial conducted by Yan and colleagues, 1,212 subfertile women were randomly assigned to either conventional IVF with embryo selection based on morphology or embryo selection based on PGT-A with next-generation sequencing. Inclusion criteria were the diagnosis of subfertility, undergoing their first IVF cycle, female age of 20 to 37, and the availability of 3 or more good-quality blastocysts.

On day 5 of embryo culture, patients with 3 or more blastocysts were randomly assigned in a 1:1 ratio to either the PGT-A group or conventional IVF. All embryos were then frozen, and patients subsequently underwent frozen embryo transfer of a single blastocyst, selected based on either morphology or euploid result by PGT-A. If the initial transfer did not result in a live birth, and there were remaining transferable embryos (either a euploid embryo in the PGT-A group or a morphologically transferable embryo in the conventional IVF group), patients underwent successive frozen embryo transfers until either there was a live birth or no more embryos were available for transfer.

The study’s primary outcome was the cumulative live birth rate per randomly assigned patient that resulted from up to 3 frozen embryo transfer cycles within 1 year. There were 606 patients randomly assigned to the PGT-A group and 606 randomly assigned to the conventional IVF group.

In the PGT-A group, 468 women (77.2%) had live births; in the conventional IVF group, 496 women (81.8%) had live births. Women in the PGT-A group had a lower incidence of pregnancy loss compared with the conventional IVF group: 8.7% versus 12.6% (absolute difference of -3.9%; 95% confidence interval [CI], -7.5 to -0.2). There was no difference in obstetric and neonatal outcomes between the 2 groups. The authors concluded that among women with 3 or more good-quality blastocysts, conventional IVF resulted in a cumulative live birth rate that was noninferior to that of the PGT-A group.

Some benefit shown with PGT-A

Although the study by Yan and colleagues did not show any benefit, and even a possible reduction, with regard to cumulative live birth rate for PGT-A, it did show a 4% reduction in clinical pregnancy loss when PGT-A was used. Furthermore, the study design has been criticized for performing PGT-A on only 3 blastocysts in the PGT-A group. It is quite conceivable that the PGT-A group would have had more euploid embryos available for transfer if the study design had included all the available embryos instead of only 3. On the other hand, one could argue that if the authors had extended the study to include all the available embryos, the conventional group would have also had more embryos for transfer and, therefore, more chances for pregnancy and live birth.

It is also important to recognize that only patients who had at least 3 embryos available for biopsy were included in this study, and therefore the results of this study cannot be extended to patients with fewer embryos, such as those with diminished ovarian reserve.

In summary, based on this study’s results, we may conclude that for the good-prognosis patients in the age group of 20 to 37 who have at least 3 embryos available for biopsy, PGT-A may reduce the miscarriage rate by about 4%, but this benefit comes at the expense of about a 4% reduction in the cumulative live birth rate. ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, we discuss several aspects of infertility and emerging technologic advances in treatment. We review an important infertility fact sheet recently issued by the World Health Organization (WHO) that provides a succinct overview of infertility causes, the rights of infertility patients, treatment challenges, and advocacy efforts. In addition, we discuss what the infertility literature reveals about reducing multiple birth rates and the technologic, financial, and social factors involved. Finally, we look at the molecular progress made in germline-editing technology and the myriad complications involved in its potential future translation to clinical phenotyping.

WHO recognizes the burden of infertility and addresses fertility care needs

World Health Organization (WHO). Infertility fact sheet. September 14, 2020. https://www.who.int/news-room/fact-sheets/detail/infertility. Accessed January 24, 2021.

The WHO published its first comprehensive infertility fact sheet in September 2020. This document is important because it validates infertility as a high-burden disease and disability that diminishes quality of life for up to 186 million individuals globally. The infertility fact sheet is a comprehensive yet focused quick read that addresses the causes of infertility, why infertility is important, challenges, and the WHO response.

Factors in infertility

Infertility is caused by different factors in women and men, yet sometimes it is unexplained, and its relative importance can vary from country to country. For women, tubal disorders (for example, postinfectious), uterine problems (fibroids, congenital), endometriosis, ovarian disorders (polycystic ovary syndrome, ovulation disorders), and endocrine imbalances are the most common factors.

For men, causes of infertility include obstruction of the reproductive tract (as after injuries or infection); hormonal disorders in the hypothalamus, pituitary, and/or testicles (for example, low testosterone); testicular failure to produce sperm (such as after cancer treatment); and abnormal sperm function and quality (low count, motility, or morphology).

Environmental and lifestyle factors— including smoking, obesity, alcohol, or toxins—can affect fertility.

Continue to: Recognizing all individuals’ fertility rights...

The WHO infertility fact sheet makes strong statements, recognizing that individuals and couples have the right to decide the number, timing, and spacing of their children. Addressing infertility is therefore an important part of realizing the right of individuals and couples to found a family. This includes heterosexual couples, same-sex partners, older persons, individuals not in sexual relationships who might require infertility management and fertility care services, and notably marginalized populations.

Addressing infertility also can help mitigate gender inequality, which has significant negative social impacts on the lives of infertile individuals, especially women. Fertility education is important to reduce the fear of infertility and contraception use in those wanting pregnancy in the future.

In most countries the biggest challenges are availability, access, and quality of interventions to address infertility. This includes the United States, where only 1 in 4 individuals receive the fertility care they need. Lack of prioritization, ineffective public health strategies, inadequate funding, and costs are barriers. Health policies need to recognize that infertility is a disease that often can be prevented, thereby reducing future costs. Comprehensive awareness and education programs, laws and policies that regulate and ensure access and the human rights of all involved, are essential.

Advocacy efforts

To address infertility and fertility care, the WHO is committed to:

• collaborate with partners on epidemiologic and etiologic research
• facilitate policy dialogue globally to frame infertility within a legal and policy framework
• support generation of data on the burden of infertility
• develop guidelines
• produce other documents of standards
• collaborate with all stakeholders to strengthen political commitment and health system capacity, and
• provide country-level technical support to develop or strengthen policies and services.

For your practice, this means that infertility is recognized as a disease that should receive its appropriate share of health care resources. Infertility and fertility care are the right of every individual according to their desires to found a family. Besides providing the best care you can to all your patients, including referring them when necessary, all health care clinicians should advocate on behalf of their patients to payors, policy makers, and the public the need to provide equitable laws, resources, and funding for infertility and fertility care.

Continue to: Lessons learned in reducing multiple pregnancy rates in infertility treatment...

Lessons learned in reducing multiple pregnancy rates in infertility treatment

Views and reviews section. Fertil Steril. 2020;114:671- 672; 673-679; 680-689; 690-714; 715-721.

In the October 2020 issue of Fertility and Sterility, the Views and Reviews section included 5 articles on avoiding multiple live birth rates (LBRs) in assisted reproductive technologies (ART).^1-5 International experts provided a comprehensive review of global multiple LBRs and their associated negative impact on maternal and perinatal outcomes, reasons for global variability, strategies to reduce multiples, single embryo transfer, and implications of funding and reporting. These international comparisons and recommendations are helpful and applicable to infertility care in the United States.³

The rise of multiple birth rates

During the first decade of in vitro fertilization (IVF), live birth rates were low, increasing to 14% in 1990. Multiple embryos needed to be transferred so that even these LBRs could be obtained. In the 1990s, however, laboratory technology improved rapidly, with increased implantation rates and subsequent rapid increases in LBR, but also with increased multiple birth rates (MBRs).

In the United States, clinic-specific reporting helped create competition among clinics for the best LBRs, and this led to MBRs of 30% and higher. Numerous studies documented the associated significantly increased morbidity and mortality of both mothers and babies. Similar situations occurred in many other countries while some, especially Nordic nations, Australia, New Zealand, and Japan, had twin rates of less than 10% or even 5% since the early 2000s. So why the difference?

The higher MBR is due largely to the transfer of more than one embryo. The immediate solution is therefore always to perform elective single embryo transfer (eSET). However, numerous factors affect the decision to perform eSET or not, and this ideal is far from being achieved. Older women, those with longer duration of infertility and/or failed treatment, often feel a time pressure and want to transfer more embryos. Of course, biologically this is reasonable because the number and quality of their embryos is lower. While attempts have been made to assess embryo quality with preimplantation genetic testing for aneuploidy, evidence that this increases the LBR is controversial except possibly in women aged 35 to 38 years. This is especially true when the cumulative LBR, that is, the number of live births after transfer of all embryos from an egg retrieval cycle, is the measured outcome.

The major factor that determines the frequency of eSET is financial. Affordability is the out-of-pocket cost (after insurance or other subsidy) as a percentage of disposable income, and it is the most important factor that determines whether eSET is performed. Less affordable treatment creates a financial incentive to transfer more than one embryo to maximize the pregnancy rates in fewer cycles.⁵ Other factors include whether the effectiveness of treatment, that is, LBR, is emphasized over safety, that is, MBR. In the United States, the Society for Assisted Reproductive Technology now reports cumulative LBR, singleton and multiple LBR, and preterm births as outcomes, thereby increasing the emphasis on eSET.

Sociologic, cultural, and religious factors also can affect the frequency of eSET. Even within the United States, great variation exists in values and beliefs regarding infertility treatment. It can be challenging to determine who makes decisions: the patient alone, the physician, the payor, professional guidelines, or laws. In many countries, including the United States, it is an amalgam of these.

Setting new goals

If the goal is to reduce the MBR, what should that rate be? In the past few years, the MBR in the United States has been reduced to approximately 10%. It is reasonable now to set a goal of 5% in the next several years. To do this, we can learn from countries that have been successful. The United States already has very high-quality clinical and laboratory services, knowledgeable physicians, and a reasonable regulatory environment. Improved technology, specifically embryo selection for transfer, and focus on adherence to established embryo transfer guidelines could help.

Many would argue that eSET essentially should be performed always in women younger than age 40 and in all women of any age with a known euploid embryo. The major problem that drives multiples is the lack of affordability, which can be addressed by increased subsidies from payors. Increased subsidies can result from legislative mandates or societal pressures on employers, either of which could be associated with requirements for eSET and/or reduced MBRs.

In your practice, you can now reassure your infertility patients that cumulative LBRs are excellent in the United States and that the risk of multiple pregnancy has been reduced dramatically. This should encourage more patients to accept and take advantage of this successful technology that has resulted in the birth of millions of babies globally. Further reduction of the MBR to 5% should be possible within a few years through education and advocacy by women’s health care clinicians that results in increased subsidies and more affordable IVF.

Continue to: Genetics and ART...

Genetics and ART: Selection versus correction

Adashi EY, Cohen IG. The case for remedial germline editing—the long-term view. JAMA. 2020;323:1762-1763.

Rosenbaum L. The future of gene editing—toward scientific and social consensus. N Engl J Med. 2019;380:971-975.

Cyranoski D. The CRISPR-baby scandal: what’s next for human gene-editing. Nature. 2019;566:440-442.

de Wert G, Pennings G, Clarke A, et al; European Society of Human Genetics and European Society of Human Reproduction and Embryology. Human germline gene editing: recommendations of ESHG and ESHRE. Hum Reprod Open. 2018;hox025.

Following the completion of the Human Genome Project in 2003 and major technologic advancements in the subsequent years, the field of human genetics became the focal point of convergence for several distinct but interrelated disciplines: bioinformatics, computational biology, and sequencing technologies. As the result, individual human genomes can now be sequenced at a single base pair level, and with higher fidelity, at a fraction of the original cost and at a much faster speed.

This molecular progress, however, has not been accompanied by an equivalent clinical progress, because in a significant number of cases a defined and predictable clinical phenotype cannot be attributed to a detected molecular genotype. This has resulted in an overabundance of variants of uncertain significance. Variable expressivity, incomplete penetrance, epigenetics, mosaicism, and the polygenic nature of many human traits further complicate reliable interpretation and prognostication of the colossal amount of molecular genetic data that are being generated by the above-mentioned technologic advances.

Considering these limitations, at this juncture it is crucial to acknowledge that any attempts to prematurely commercialize these preclinical and research studies (such as polygenic risk scores for embryos) are perilous and have the potential to cause significant harm in terms of unnecessary stress and anxiety for intended parents as well as the potential for yet-unmapped societal and legal implications.

However, it is just a matter of time until more accurate clinical phenotyping catches up with molecular genotyping. As we get closer to this next historic milestone, precision medicine in the postnatal life (with regard to both diagnostics and therapeutics) and preimplantation genetic testing (PGT) at the prenatal stage for a much wider spectrum of conditions—including both monogenic and polygenic traits—may indeed become a reality.

The potential of germline editing

Specifically regarding PGT (which requires IVF), it is important to recognize that due to the limited and nonrenewable endowment of human oocytes (ovarian reserve), combined with the detrimental impact of advancing age on the quality of the remaining cohort as manifested by a higher risk of aneuploidy, the current clinical practice of trying to “select” a nonaffected embryo can be very inefficient. As a result, the intended parents pursuing such treatments may need to undergo multiple cycles of ovarian stimulation and oocyte retrieval.

A potential solution for genes associated with known diseases is the prospect of remedial germline editing by CRISPR–Cas9 technology or its future descendants. This would take advantage of the existing embryos to try to “correct” the defective gene instead of trying to “select” a normal embryo. These technologies are still in the early stages of development and are remotely distant from clinical applications. On the other hand, although germline gene editing, if actualized, would be a monumental breakthrough in the history of genetics and medicine, we must be cognizant of its serious legal, societal, and ethical ramifications, which are currently unknown. Furthermore, even at the biologic and technical level, the technology still is not advanced enough to reliably rule out off-target modifications, and the unintended clinical consequences of the on-target corrections have not been studied either.

Regulation of genetic modifications

Due to these myriad concerns and the lack of an existing appropriate regulatory framework and oversight for such interventions, current US law (since December 2015, through provisions in annual federal appropriations laws passed by Congress and renewed annually thereafter) bars the US Food and Drug Administration from considering any clinical trial application “in which a human embryo is intentionally created or modified to include a heritable genetic modification.” Notably, this moratorium also prohibits mitochondrial replacement technology (MRT), which is a less controversial and relatively better-studied innovation.

Mitochondrial genetic disorders caused by the mutations in mitochondrial DNA (versus nuclear DNA) are amenable to a specific treatment strategy aimed at substituting the defective maternal mitochondrial genome with the mitochondrial genome of an unaffected donor oocyte. This can be achieved via either pronuclear transfer, which involves isolation and transfer of the male and female pronuclei from an affected embryo to an enucleated normal donor embryo, or maternal spindle transfer, which involves isolation and transfer of the metaphase II spindle complex of an affected oocyte to an enucleated disease-free donor egg. It is noteworthy that in 2015 in the United Kingdom, Parliament expanded the definition of “permitted eggs and embryos” to include those “where unhealthy mitochondrial DNA is replaced by healthy mitochondrial DNA from a donor.” This thereby allows the UK Human Fertilisation and Embryology Authority to formally direct and oversee clinical trials in MRT.

Summing up

Although the future of assisted human reproduction cannot be clearly outlined at this time, it is likely to be radically different from the current state given these emerging applications at the intersection of ART and diagnostic and therapeutic genetics. To ensure that exploring this uncharted territory will ultimately be in the interest of humankind and civilization, proper regulatory oversight—after careful consideration of all ethical, societal, and legal implications—needs to be developed for all preclinical and clinical research in this field. Participatory public engagement must be an integrated part of this process. ●

In this Update, we discuss several aspects of infertility and emerging technologic advances in treatment. We review an important infertility fact sheet recently issued by the World Health Organization (WHO) that provides a succinct overview of infertility causes, the rights of infertility patients, treatment challenges, and advocacy efforts. In addition, we discuss what the infertility literature reveals about reducing multiple birth rates and the technologic, financial, and social factors involved. Finally, we look at the molecular progress made in germline-editing technology and the myriad complications involved in its potential future translation to clinical phenotyping.

WHO recognizes the burden of infertility and addresses fertility care needs

World Health Organization (WHO). Infertility fact sheet. September 14, 2020. https://www.who.int/news-room/fact-sheets/detail/infertility. Accessed January 24, 2021.

The WHO published its first comprehensive infertility fact sheet in September 2020. This document is important because it validates infertility as a high-burden disease and disability that diminishes quality of life for up to 186 million individuals globally. The infertility fact sheet is a comprehensive yet focused quick read that addresses the causes of infertility, why infertility is important, challenges, and the WHO response.

Factors in infertility

Infertility is caused by different factors in women and men, yet sometimes it is unexplained, and its relative importance can vary from country to country. For women, tubal disorders (for example, postinfectious), uterine problems (fibroids, congenital), endometriosis, ovarian disorders (polycystic ovary syndrome, ovulation disorders), and endocrine imbalances are the most common factors.

For men, causes of infertility include obstruction of the reproductive tract (as after injuries or infection); hormonal disorders in the hypothalamus, pituitary, and/or testicles (for example, low testosterone); testicular failure to produce sperm (such as after cancer treatment); and abnormal sperm function and quality (low count, motility, or morphology).

Environmental and lifestyle factors— including smoking, obesity, alcohol, or toxins—can affect fertility.

Continue to: Recognizing all individuals’ fertility rights...

The WHO infertility fact sheet makes strong statements, recognizing that individuals and couples have the right to decide the number, timing, and spacing of their children. Addressing infertility is therefore an important part of realizing the right of individuals and couples to found a family. This includes heterosexual couples, same-sex partners, older persons, individuals not in sexual relationships who might require infertility management and fertility care services, and notably marginalized populations.

Addressing infertility also can help mitigate gender inequality, which has significant negative social impacts on the lives of infertile individuals, especially women. Fertility education is important to reduce the fear of infertility and contraception use in those wanting pregnancy in the future.

In most countries the biggest challenges are availability, access, and quality of interventions to address infertility. This includes the United States, where only 1 in 4 individuals receive the fertility care they need. Lack of prioritization, ineffective public health strategies, inadequate funding, and costs are barriers. Health policies need to recognize that infertility is a disease that often can be prevented, thereby reducing future costs. Comprehensive awareness and education programs, laws and policies that regulate and ensure access and the human rights of all involved, are essential.

Advocacy efforts

To address infertility and fertility care, the WHO is committed to:

• collaborate with partners on epidemiologic and etiologic research
• facilitate policy dialogue globally to frame infertility within a legal and policy framework
• support generation of data on the burden of infertility
• develop guidelines
• produce other documents of standards
• collaborate with all stakeholders to strengthen political commitment and health system capacity, and
• provide country-level technical support to develop or strengthen policies and services.

For your practice, this means that infertility is recognized as a disease that should receive its appropriate share of health care resources. Infertility and fertility care are the right of every individual according to their desires to found a family. Besides providing the best care you can to all your patients, including referring them when necessary, all health care clinicians should advocate on behalf of their patients to payors, policy makers, and the public the need to provide equitable laws, resources, and funding for infertility and fertility care.

Continue to: Lessons learned in reducing multiple pregnancy rates in infertility treatment...

Lessons learned in reducing multiple pregnancy rates in infertility treatment

Views and reviews section. Fertil Steril. 2020;114:671- 672; 673-679; 680-689; 690-714; 715-721.

In the October 2020 issue of Fertility and Sterility, the Views and Reviews section included 5 articles on avoiding multiple live birth rates (LBRs) in assisted reproductive technologies (ART).^1-5 International experts provided a comprehensive review of global multiple LBRs and their associated negative impact on maternal and perinatal outcomes, reasons for global variability, strategies to reduce multiples, single embryo transfer, and implications of funding and reporting. These international comparisons and recommendations are helpful and applicable to infertility care in the United States.³

The rise of multiple birth rates

During the first decade of in vitro fertilization (IVF), live birth rates were low, increasing to 14% in 1990. Multiple embryos needed to be transferred so that even these LBRs could be obtained. In the 1990s, however, laboratory technology improved rapidly, with increased implantation rates and subsequent rapid increases in LBR, but also with increased multiple birth rates (MBRs).

In the United States, clinic-specific reporting helped create competition among clinics for the best LBRs, and this led to MBRs of 30% and higher. Numerous studies documented the associated significantly increased morbidity and mortality of both mothers and babies. Similar situations occurred in many other countries while some, especially Nordic nations, Australia, New Zealand, and Japan, had twin rates of less than 10% or even 5% since the early 2000s. So why the difference?

The higher MBR is due largely to the transfer of more than one embryo. The immediate solution is therefore always to perform elective single embryo transfer (eSET). However, numerous factors affect the decision to perform eSET or not, and this ideal is far from being achieved. Older women, those with longer duration of infertility and/or failed treatment, often feel a time pressure and want to transfer more embryos. Of course, biologically this is reasonable because the number and quality of their embryos is lower. While attempts have been made to assess embryo quality with preimplantation genetic testing for aneuploidy, evidence that this increases the LBR is controversial except possibly in women aged 35 to 38 years. This is especially true when the cumulative LBR, that is, the number of live births after transfer of all embryos from an egg retrieval cycle, is the measured outcome.

The major factor that determines the frequency of eSET is financial. Affordability is the out-of-pocket cost (after insurance or other subsidy) as a percentage of disposable income, and it is the most important factor that determines whether eSET is performed. Less affordable treatment creates a financial incentive to transfer more than one embryo to maximize the pregnancy rates in fewer cycles.⁵ Other factors include whether the effectiveness of treatment, that is, LBR, is emphasized over safety, that is, MBR. In the United States, the Society for Assisted Reproductive Technology now reports cumulative LBR, singleton and multiple LBR, and preterm births as outcomes, thereby increasing the emphasis on eSET.

Sociologic, cultural, and religious factors also can affect the frequency of eSET. Even within the United States, great variation exists in values and beliefs regarding infertility treatment. It can be challenging to determine who makes decisions: the patient alone, the physician, the payor, professional guidelines, or laws. In many countries, including the United States, it is an amalgam of these.

Setting new goals

If the goal is to reduce the MBR, what should that rate be? In the past few years, the MBR in the United States has been reduced to approximately 10%. It is reasonable now to set a goal of 5% in the next several years. To do this, we can learn from countries that have been successful. The United States already has very high-quality clinical and laboratory services, knowledgeable physicians, and a reasonable regulatory environment. Improved technology, specifically embryo selection for transfer, and focus on adherence to established embryo transfer guidelines could help.

Many would argue that eSET essentially should be performed always in women younger than age 40 and in all women of any age with a known euploid embryo. The major problem that drives multiples is the lack of affordability, which can be addressed by increased subsidies from payors. Increased subsidies can result from legislative mandates or societal pressures on employers, either of which could be associated with requirements for eSET and/or reduced MBRs.

In your practice, you can now reassure your infertility patients that cumulative LBRs are excellent in the United States and that the risk of multiple pregnancy has been reduced dramatically. This should encourage more patients to accept and take advantage of this successful technology that has resulted in the birth of millions of babies globally. Further reduction of the MBR to 5% should be possible within a few years through education and advocacy by women’s health care clinicians that results in increased subsidies and more affordable IVF.

Continue to: Genetics and ART...

Genetics and ART: Selection versus correction

Adashi EY, Cohen IG. The case for remedial germline editing—the long-term view. JAMA. 2020;323:1762-1763.

Rosenbaum L. The future of gene editing—toward scientific and social consensus. N Engl J Med. 2019;380:971-975.

Cyranoski D. The CRISPR-baby scandal: what’s next for human gene-editing. Nature. 2019;566:440-442.

de Wert G, Pennings G, Clarke A, et al; European Society of Human Genetics and European Society of Human Reproduction and Embryology. Human germline gene editing: recommendations of ESHG and ESHRE. Hum Reprod Open. 2018;hox025.

Following the completion of the Human Genome Project in 2003 and major technologic advancements in the subsequent years, the field of human genetics became the focal point of convergence for several distinct but interrelated disciplines: bioinformatics, computational biology, and sequencing technologies. As the result, individual human genomes can now be sequenced at a single base pair level, and with higher fidelity, at a fraction of the original cost and at a much faster speed.

This molecular progress, however, has not been accompanied by an equivalent clinical progress, because in a significant number of cases a defined and predictable clinical phenotype cannot be attributed to a detected molecular genotype. This has resulted in an overabundance of variants of uncertain significance. Variable expressivity, incomplete penetrance, epigenetics, mosaicism, and the polygenic nature of many human traits further complicate reliable interpretation and prognostication of the colossal amount of molecular genetic data that are being generated by the above-mentioned technologic advances.

Considering these limitations, at this juncture it is crucial to acknowledge that any attempts to prematurely commercialize these preclinical and research studies (such as polygenic risk scores for embryos) are perilous and have the potential to cause significant harm in terms of unnecessary stress and anxiety for intended parents as well as the potential for yet-unmapped societal and legal implications.

However, it is just a matter of time until more accurate clinical phenotyping catches up with molecular genotyping. As we get closer to this next historic milestone, precision medicine in the postnatal life (with regard to both diagnostics and therapeutics) and preimplantation genetic testing (PGT) at the prenatal stage for a much wider spectrum of conditions—including both monogenic and polygenic traits—may indeed become a reality.

The potential of germline editing

Specifically regarding PGT (which requires IVF), it is important to recognize that due to the limited and nonrenewable endowment of human oocytes (ovarian reserve), combined with the detrimental impact of advancing age on the quality of the remaining cohort as manifested by a higher risk of aneuploidy, the current clinical practice of trying to “select” a nonaffected embryo can be very inefficient. As a result, the intended parents pursuing such treatments may need to undergo multiple cycles of ovarian stimulation and oocyte retrieval.

A potential solution for genes associated with known diseases is the prospect of remedial germline editing by CRISPR–Cas9 technology or its future descendants. This would take advantage of the existing embryos to try to “correct” the defective gene instead of trying to “select” a normal embryo. These technologies are still in the early stages of development and are remotely distant from clinical applications. On the other hand, although germline gene editing, if actualized, would be a monumental breakthrough in the history of genetics and medicine, we must be cognizant of its serious legal, societal, and ethical ramifications, which are currently unknown. Furthermore, even at the biologic and technical level, the technology still is not advanced enough to reliably rule out off-target modifications, and the unintended clinical consequences of the on-target corrections have not been studied either.

Regulation of genetic modifications

Due to these myriad concerns and the lack of an existing appropriate regulatory framework and oversight for such interventions, current US law (since December 2015, through provisions in annual federal appropriations laws passed by Congress and renewed annually thereafter) bars the US Food and Drug Administration from considering any clinical trial application “in which a human embryo is intentionally created or modified to include a heritable genetic modification.” Notably, this moratorium also prohibits mitochondrial replacement technology (MRT), which is a less controversial and relatively better-studied innovation.

Mitochondrial genetic disorders caused by the mutations in mitochondrial DNA (versus nuclear DNA) are amenable to a specific treatment strategy aimed at substituting the defective maternal mitochondrial genome with the mitochondrial genome of an unaffected donor oocyte. This can be achieved via either pronuclear transfer, which involves isolation and transfer of the male and female pronuclei from an affected embryo to an enucleated normal donor embryo, or maternal spindle transfer, which involves isolation and transfer of the metaphase II spindle complex of an affected oocyte to an enucleated disease-free donor egg. It is noteworthy that in 2015 in the United Kingdom, Parliament expanded the definition of “permitted eggs and embryos” to include those “where unhealthy mitochondrial DNA is replaced by healthy mitochondrial DNA from a donor.” This thereby allows the UK Human Fertilisation and Embryology Authority to formally direct and oversee clinical trials in MRT.

Summing up

Although the future of assisted human reproduction cannot be clearly outlined at this time, it is likely to be radically different from the current state given these emerging applications at the intersection of ART and diagnostic and therapeutic genetics. To ensure that exploring this uncharted territory will ultimately be in the interest of humankind and civilization, proper regulatory oversight—after careful consideration of all ethical, societal, and legal implications—needs to be developed for all preclinical and clinical research in this field. Participatory public engagement must be an integrated part of this process. ●

In this Update, we discuss several aspects of infertility and emerging technologic advances in treatment. We review an important infertility fact sheet recently issued by the World Health Organization (WHO) that provides a succinct overview of infertility causes, the rights of infertility patients, treatment challenges, and advocacy efforts. In addition, we discuss what the infertility literature reveals about reducing multiple birth rates and the technologic, financial, and social factors involved. Finally, we look at the molecular progress made in germline-editing technology and the myriad complications involved in its potential future translation to clinical phenotyping.

WHO recognizes the burden of infertility and addresses fertility care needs

World Health Organization (WHO). Infertility fact sheet. September 14, 2020. https://www.who.int/news-room/fact-sheets/detail/infertility. Accessed January 24, 2021.

The WHO published its first comprehensive infertility fact sheet in September 2020. This document is important because it validates infertility as a high-burden disease and disability that diminishes quality of life for up to 186 million individuals globally. The infertility fact sheet is a comprehensive yet focused quick read that addresses the causes of infertility, why infertility is important, challenges, and the WHO response.

Factors in infertility

Infertility is caused by different factors in women and men, yet sometimes it is unexplained, and its relative importance can vary from country to country. For women, tubal disorders (for example, postinfectious), uterine problems (fibroids, congenital), endometriosis, ovarian disorders (polycystic ovary syndrome, ovulation disorders), and endocrine imbalances are the most common factors.

For men, causes of infertility include obstruction of the reproductive tract (as after injuries or infection); hormonal disorders in the hypothalamus, pituitary, and/or testicles (for example, low testosterone); testicular failure to produce sperm (such as after cancer treatment); and abnormal sperm function and quality (low count, motility, or morphology).

Environmental and lifestyle factors— including smoking, obesity, alcohol, or toxins—can affect fertility.

Continue to: Recognizing all individuals’ fertility rights...

The WHO infertility fact sheet makes strong statements, recognizing that individuals and couples have the right to decide the number, timing, and spacing of their children. Addressing infertility is therefore an important part of realizing the right of individuals and couples to found a family. This includes heterosexual couples, same-sex partners, older persons, individuals not in sexual relationships who might require infertility management and fertility care services, and notably marginalized populations.

Addressing infertility also can help mitigate gender inequality, which has significant negative social impacts on the lives of infertile individuals, especially women. Fertility education is important to reduce the fear of infertility and contraception use in those wanting pregnancy in the future.

In most countries the biggest challenges are availability, access, and quality of interventions to address infertility. This includes the United States, where only 1 in 4 individuals receive the fertility care they need. Lack of prioritization, ineffective public health strategies, inadequate funding, and costs are barriers. Health policies need to recognize that infertility is a disease that often can be prevented, thereby reducing future costs. Comprehensive awareness and education programs, laws and policies that regulate and ensure access and the human rights of all involved, are essential.

Advocacy efforts

To address infertility and fertility care, the WHO is committed to:

• collaborate with partners on epidemiologic and etiologic research
• facilitate policy dialogue globally to frame infertility within a legal and policy framework
• support generation of data on the burden of infertility
• develop guidelines
• produce other documents of standards
• collaborate with all stakeholders to strengthen political commitment and health system capacity, and
• provide country-level technical support to develop or strengthen policies and services.

For your practice, this means that infertility is recognized as a disease that should receive its appropriate share of health care resources. Infertility and fertility care are the right of every individual according to their desires to found a family. Besides providing the best care you can to all your patients, including referring them when necessary, all health care clinicians should advocate on behalf of their patients to payors, policy makers, and the public the need to provide equitable laws, resources, and funding for infertility and fertility care.

Continue to: Lessons learned in reducing multiple pregnancy rates in infertility treatment...

Lessons learned in reducing multiple pregnancy rates in infertility treatment

Views and reviews section. Fertil Steril. 2020;114:671- 672; 673-679; 680-689; 690-714; 715-721.

In the October 2020 issue of Fertility and Sterility, the Views and Reviews section included 5 articles on avoiding multiple live birth rates (LBRs) in assisted reproductive technologies (ART).^1-5 International experts provided a comprehensive review of global multiple LBRs and their associated negative impact on maternal and perinatal outcomes, reasons for global variability, strategies to reduce multiples, single embryo transfer, and implications of funding and reporting. These international comparisons and recommendations are helpful and applicable to infertility care in the United States.³

The rise of multiple birth rates

During the first decade of in vitro fertilization (IVF), live birth rates were low, increasing to 14% in 1990. Multiple embryos needed to be transferred so that even these LBRs could be obtained. In the 1990s, however, laboratory technology improved rapidly, with increased implantation rates and subsequent rapid increases in LBR, but also with increased multiple birth rates (MBRs).

In the United States, clinic-specific reporting helped create competition among clinics for the best LBRs, and this led to MBRs of 30% and higher. Numerous studies documented the associated significantly increased morbidity and mortality of both mothers and babies. Similar situations occurred in many other countries while some, especially Nordic nations, Australia, New Zealand, and Japan, had twin rates of less than 10% or even 5% since the early 2000s. So why the difference?

The higher MBR is due largely to the transfer of more than one embryo. The immediate solution is therefore always to perform elective single embryo transfer (eSET). However, numerous factors affect the decision to perform eSET or not, and this ideal is far from being achieved. Older women, those with longer duration of infertility and/or failed treatment, often feel a time pressure and want to transfer more embryos. Of course, biologically this is reasonable because the number and quality of their embryos is lower. While attempts have been made to assess embryo quality with preimplantation genetic testing for aneuploidy, evidence that this increases the LBR is controversial except possibly in women aged 35 to 38 years. This is especially true when the cumulative LBR, that is, the number of live births after transfer of all embryos from an egg retrieval cycle, is the measured outcome.

The major factor that determines the frequency of eSET is financial. Affordability is the out-of-pocket cost (after insurance or other subsidy) as a percentage of disposable income, and it is the most important factor that determines whether eSET is performed. Less affordable treatment creates a financial incentive to transfer more than one embryo to maximize the pregnancy rates in fewer cycles.⁵ Other factors include whether the effectiveness of treatment, that is, LBR, is emphasized over safety, that is, MBR. In the United States, the Society for Assisted Reproductive Technology now reports cumulative LBR, singleton and multiple LBR, and preterm births as outcomes, thereby increasing the emphasis on eSET.

Sociologic, cultural, and religious factors also can affect the frequency of eSET. Even within the United States, great variation exists in values and beliefs regarding infertility treatment. It can be challenging to determine who makes decisions: the patient alone, the physician, the payor, professional guidelines, or laws. In many countries, including the United States, it is an amalgam of these.

Setting new goals

If the goal is to reduce the MBR, what should that rate be? In the past few years, the MBR in the United States has been reduced to approximately 10%. It is reasonable now to set a goal of 5% in the next several years. To do this, we can learn from countries that have been successful. The United States already has very high-quality clinical and laboratory services, knowledgeable physicians, and a reasonable regulatory environment. Improved technology, specifically embryo selection for transfer, and focus on adherence to established embryo transfer guidelines could help.

Many would argue that eSET essentially should be performed always in women younger than age 40 and in all women of any age with a known euploid embryo. The major problem that drives multiples is the lack of affordability, which can be addressed by increased subsidies from payors. Increased subsidies can result from legislative mandates or societal pressures on employers, either of which could be associated with requirements for eSET and/or reduced MBRs.

In your practice, you can now reassure your infertility patients that cumulative LBRs are excellent in the United States and that the risk of multiple pregnancy has been reduced dramatically. This should encourage more patients to accept and take advantage of this successful technology that has resulted in the birth of millions of babies globally. Further reduction of the MBR to 5% should be possible within a few years through education and advocacy by women’s health care clinicians that results in increased subsidies and more affordable IVF.

Continue to: Genetics and ART...

Genetics and ART: Selection versus correction

Adashi EY, Cohen IG. The case for remedial germline editing—the long-term view. JAMA. 2020;323:1762-1763.

Rosenbaum L. The future of gene editing—toward scientific and social consensus. N Engl J Med. 2019;380:971-975.

Cyranoski D. The CRISPR-baby scandal: what’s next for human gene-editing. Nature. 2019;566:440-442.

de Wert G, Pennings G, Clarke A, et al; European Society of Human Genetics and European Society of Human Reproduction and Embryology. Human germline gene editing: recommendations of ESHG and ESHRE. Hum Reprod Open. 2018;hox025.

Following the completion of the Human Genome Project in 2003 and major technologic advancements in the subsequent years, the field of human genetics became the focal point of convergence for several distinct but interrelated disciplines: bioinformatics, computational biology, and sequencing technologies. As the result, individual human genomes can now be sequenced at a single base pair level, and with higher fidelity, at a fraction of the original cost and at a much faster speed.

This molecular progress, however, has not been accompanied by an equivalent clinical progress, because in a significant number of cases a defined and predictable clinical phenotype cannot be attributed to a detected molecular genotype. This has resulted in an overabundance of variants of uncertain significance. Variable expressivity, incomplete penetrance, epigenetics, mosaicism, and the polygenic nature of many human traits further complicate reliable interpretation and prognostication of the colossal amount of molecular genetic data that are being generated by the above-mentioned technologic advances.

Considering these limitations, at this juncture it is crucial to acknowledge that any attempts to prematurely commercialize these preclinical and research studies (such as polygenic risk scores for embryos) are perilous and have the potential to cause significant harm in terms of unnecessary stress and anxiety for intended parents as well as the potential for yet-unmapped societal and legal implications.

However, it is just a matter of time until more accurate clinical phenotyping catches up with molecular genotyping. As we get closer to this next historic milestone, precision medicine in the postnatal life (with regard to both diagnostics and therapeutics) and preimplantation genetic testing (PGT) at the prenatal stage for a much wider spectrum of conditions—including both monogenic and polygenic traits—may indeed become a reality.

The potential of germline editing

Specifically regarding PGT (which requires IVF), it is important to recognize that due to the limited and nonrenewable endowment of human oocytes (ovarian reserve), combined with the detrimental impact of advancing age on the quality of the remaining cohort as manifested by a higher risk of aneuploidy, the current clinical practice of trying to “select” a nonaffected embryo can be very inefficient. As a result, the intended parents pursuing such treatments may need to undergo multiple cycles of ovarian stimulation and oocyte retrieval.

A potential solution for genes associated with known diseases is the prospect of remedial germline editing by CRISPR–Cas9 technology or its future descendants. This would take advantage of the existing embryos to try to “correct” the defective gene instead of trying to “select” a normal embryo. These technologies are still in the early stages of development and are remotely distant from clinical applications. On the other hand, although germline gene editing, if actualized, would be a monumental breakthrough in the history of genetics and medicine, we must be cognizant of its serious legal, societal, and ethical ramifications, which are currently unknown. Furthermore, even at the biologic and technical level, the technology still is not advanced enough to reliably rule out off-target modifications, and the unintended clinical consequences of the on-target corrections have not been studied either.

Regulation of genetic modifications

Due to these myriad concerns and the lack of an existing appropriate regulatory framework and oversight for such interventions, current US law (since December 2015, through provisions in annual federal appropriations laws passed by Congress and renewed annually thereafter) bars the US Food and Drug Administration from considering any clinical trial application “in which a human embryo is intentionally created or modified to include a heritable genetic modification.” Notably, this moratorium also prohibits mitochondrial replacement technology (MRT), which is a less controversial and relatively better-studied innovation.

Mitochondrial genetic disorders caused by the mutations in mitochondrial DNA (versus nuclear DNA) are amenable to a specific treatment strategy aimed at substituting the defective maternal mitochondrial genome with the mitochondrial genome of an unaffected donor oocyte. This can be achieved via either pronuclear transfer, which involves isolation and transfer of the male and female pronuclei from an affected embryo to an enucleated normal donor embryo, or maternal spindle transfer, which involves isolation and transfer of the metaphase II spindle complex of an affected oocyte to an enucleated disease-free donor egg. It is noteworthy that in 2015 in the United Kingdom, Parliament expanded the definition of “permitted eggs and embryos” to include those “where unhealthy mitochondrial DNA is replaced by healthy mitochondrial DNA from a donor.” This thereby allows the UK Human Fertilisation and Embryology Authority to formally direct and oversee clinical trials in MRT.

Summing up

Although the future of assisted human reproduction cannot be clearly outlined at this time, it is likely to be radically different from the current state given these emerging applications at the intersection of ART and diagnostic and therapeutic genetics. To ensure that exploring this uncharted territory will ultimately be in the interest of humankind and civilization, proper regulatory oversight—after careful consideration of all ethical, societal, and legal implications—needs to be developed for all preclinical and clinical research in this field. Participatory public engagement must be an integrated part of this process. ●

Although we are not able to cover all of the important developments in fertility medicine over the past year, there were 3 important articles published in the past 12 months that we highlight here. First, we discuss an American College of Obstetricians and Gynecologists (ACOG) committee opinion on genetic carrier screening that was reaffirmed in 2019. Second, we explore an interesting retrospective analysis of time-lapse videos and clinical outcomes of more than 10,000 embryos from 8 IVF clinics, across 4 countries. The authors assessed whether a deep learning model could predict the probability of pregnancy with fetal heart from time-lapse videos in the hopes that their research can improve prioritization of the most viable embryo for single embryo transfer. Last, we consider a review of the data on obstetric and reproductive health effects of preconception and prenatal exposure to several environmental toxicants, including heavy metals, endocrine-disrupting chemicals, pesticides, and air pollution.

Preconception genetic carrier screening: Standardize your counseling approach 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129:e35-e40. 

With the rapid development of advanced and high throughput platforms for DNA sequencing in the past several years, the cost of genetic testing has decreased dramatically. Women's health care providers in general, and fertility specialists in particular, are uniquely positioned to take advantage of these novel and yet affordable technologies by counseling prospective parents during the preconception counseling, or early prenatal period, about the availability of genetic carrier screening and its potential to provide actionable information in a timely manner. The ultimate objective of genetic carrier screening is to enable individuals to make an informed decision regarding their reproductive choices based on their personal values. In a study by Larsen and colleagues, the uptake of genetic carrier screening was significantly higher when offered in the preconception period (68.7%), compared with during pregnancy (35.1%), which highlights the significance of early counseling.¹  

Based on the Centers for Disease Control and Prevention's Birth/Infant Death Data set, birth defects affect 1 in every 33 (about 3%) of all babies born in the United States each year and account for 20% of infant mortality.² About 20% of birth defects are caused by single-gene (monogenic) disorders, and although some of these are due to dominant conditions or de novo mutations, a significant proportion are due to autosomal recessive, or X-chromosome linked conditions that are commonly assessed by genetic carrier screening.  

ACOG published a committee opinion on "Carrier Screening in the Age of Genomic Medicine" in March 2017, which was reaffirmed in 2019.³  

Residual risk. Several points discussed in this document are of paramount importance, including the need for pretest and posttest counseling and consent, as well as a discussion of "residual risk." Newer platforms employ sequencing techniques that potentially can detect most, if not all, of the disease-causing variants in the tested genes, such as the gene for cystic fibrosis and, therefore, have a higher detection rate compared with the older PCR-based techniques for a limited number of specific mutations included in the panel. Due to a variety of technical and biological limitations, however, such as allelic dropouts and the occurrence of de novo mutations, the detection rate is not 100%; there is always a residual risk that needs to be estimated and provided to individuals based on the existing knowledge on frequency of gene, penetrance of phenotype, and prevalence of condition in the general and specific ethnic populations.  

Continue to: Expanded vs panethnic screening...

Expanded vs panethnic screening. Furthermore, although sequencing technology has made "expanded carrier screening" for several hundred conditions, simultaneous to and independent of ethnicity and family history, more easily available and affordable, ethnic-specific and panethnic screening for a more limited number of conditions are still acceptable approaches. Having said this, when the first partner screened is identified to be a carrier, his/her reproductive partners must be offered next-generation sequencing to identify less common disease-causing variants.⁴  

A cautionary point to consider when expanded carrier screening panels are requested is the significant variability among commercial laboratories with regard to the conditions included in their panels. In addition, consider the absence of a well-defined or predictable phenotype for some of the included conditions.  

Perhaps the most important matter when it comes to genetic carrier screening is to have a standard counseling approach that is persistently followed and offers the opportunity for individuals to know about their genetic testing options and available reproductive choices, including the use of donor gametes, preimplantation genetic testing for monogenic disease (PGT-M, formerly known as preimplantation genetic diagnosis, or PGD), prenatal testing, and pregnancy management options. For couples and/or individuals who decide to proceed with an affected pregnancy, earlier diagnosis can assist with postnatal management.  

Medicolegal responsibility. Genetic carrier screening also is of specific relevance to the field of fertility medicine and assisted reproductive technology (ART) as a potential liability issue. Couples and individuals who are undergoing fertility treatment with in vitro fertilization (IVF) for a variety of medical or personal reasons are a specific group that certainly should be offered genetic carrier screening, as they have the option of "adding on" PGT-M (PGD) to their existing treatment plan at a fraction of the cost and treatment burden that would have otherwise been needed if they were not undergoing IVF. After counseling, some individuals and couples may ultimately opt out of genetic carrier screening. The counseling discussion needs to be clearly documented in the medical chart.

Continue to: Artificial intelligence and embryo selection...

Artificial intelligence and embryo selection  

With continued improvements in embryo culture conditions and cryopreservation technology, there has been a tremendous amount of interest in developing better methods for embryo selection. These efforts are aimed at encouraging elective single embryo transfer (eSET) for women of all ages, thereby lowering the risk of multiple pregnancy and its associated adverse neonatal and obstetric outcomes—without compromising the pregnancy rates per transfer or lengthening the time to pregnancy.  

One of the most extensively studied methods for this purpose is preimplantation genetic testing for aneuploidy (PGT-A, formerly known as PGS), but emerging data from large multicenter randomized clinical trials (RCTs) have again cast significant doubt on PGT-A's efficacy and utility.⁵ Meanwhile, alternative methods for embryo selection are currently under investigation, including noninvasive PGT-A and morphokinetic assessment of embryo development via analysis of images obtained by time-lapse imaging.  

The potential of time-lapse imaging 

Despite the initial promising results from time-lapse imaging, subsequent RCTs have not shown a significant clinical benefit.⁶ However, these early methods of morphokinetic assessment are mainly dependent on the embryologists' subjective assessment of individual static frames and "annotation" of observed spatial and temporal features of embryo development. In addition to being a very time-consuming task, this process is subject to significant interobserver and intraobserver variability.  

Considering these limitations, even machine-based algorithms that incorporate these annotations along with such other clinical variables as parental age and prior obstetric history, have a low predictive power for the outcome of embryo transfer, with an area under the curve (AUC) of the ROC curve of 0.65 to 0.74. (An AUC of 0.5 represents completely random prediction and an AUC of 1.0 suggests perfect prediction.)⁷ 

A recent study by Tran and colleagues has employed a deep learning (neural network) model to analyze the entire raw time-lapse videos in an automated manner without prior annotation by embryologists. After analysis of 10,638 embryos from 8 different IVF clinics in 4 different countries, they have reported an AUC of 0.93 (95% confidence interval, 0.92-0.94) for prediction of fetal heart rate activity detected at 7 weeks of gestation or beyond. Although these data are very preliminary and have not yet been validated prospectively in larger datasets for live birth, it may herald the beginning of a new era for the automation and standardization of embryo assessment with artificial intelligence—similar to the rapidly increasing role of facial recognition technology for various applications.

Continue to: Environmental toxicants: The hidden danger...

Environmental toxicants: The hidden danger 

Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112:613-621. 

We receive news daily about the existential risk to humans of climate change. However, a risk that is likely as serious goes almost unseen by the public and most health care providers. That risk is environmental toxicants.⁸ 

More than 80,000 chemicals are registered in the United States, most in the last 75 years. These chemicals are ubiquitous. All of us are continuously exposed to and suffused with these toxicants and their metabolites. Air pollution adds insult to injury. Since this exposure has especially significant implications for fertility, infertility, pregnancy, perinatal health, childhood development, adult diseases, and later generational reproduction, it is imperative that reproductive health professionals take responsibility for helping mitigate this environmental crisis. 

The problem is exceptionally complicated  

The risks posed by environmental toxicants are much less visible than those for climate change, so the public, policymakers, and providers are largely unaware or may even seem uncaring. Few health professionals have sufficient knowledge to deliver care in this area, know which questions to ask, or have adequate information/medical record tools to assist them in care—and what are the possible interventions? 

Addressing risk posed by individual toxicants 

Addressing the problem clinically requires asking patients questions about exposure and recommending interventions. Toxicant chemicals include the neurotoxin mercury, which can be addressed by limiting intake of fish, especially certain types. 

Lead was used before 1978 in paint, it also was used in gas and in water pipes. People living in older homes may be exposed, as well as those in occupations exposed to lead. Others with lead exposure risk include immigrants from areas without lead regulations and people using pica- or lead-glazed pottery. Lead exposure has been associated with multiple pregnancy complications and permanently impaired intellectual development in children. If lead testing reveals high levels, chelation therapy can help. 

Cadmium is a heavy metal used in rechargeable batteries, paint pigment, and plastic production. Exposure results from food intake, smoking, and second-hand smoke. Cadmium accumulates in the liver, kidneys, testes, ovaries, and placenta. Exposure causes itai-itai disease, which is characterized by osteomalacia and renal tubular dysfunction as well as epigenetic changes in placental DNA and damage to the reproductive system. Eating organic food and reducing industrial exposure to cadmium are preventive strategies. 

Pesticides are ubiquitous, with 90% of the US population having detectable levels. Exposure during the preconception period can lead to intrauterine growth restriction, low birth weight, subsequent cancers, and other problems. Eating organic food can reduce risk, as can frequent hand washing when exposed to pesticides, using protective gear, and removing shoes in the home. 

Endocrine-disrupting chemicals (EDCs) are chemicals that can mimic or block endogenous hormones, which leads to adverse health outcomes. In addition to heavy metals, 3 important EDCs are bisphenol A (BPA), phthalates, and polybrominated diethyl ethers (PBDEs). Exposure is ubiquitous from industrial food processing, personal care products, cosmetics, and dust. Phthalates and BPA have short half-lives of hours to days, while PBDEs can persist in adipose tissue for months. Abnormal urogenital and neurologic development and thyroid disruption can result. Eating organic food, eating at home, and decreasing processed food intake can reduce exposure. 

BPA is used in plastics, canned food liners, cash register receipts, and epoxy resins. Exposure is through inhalation, ingestion, and dermal absorption and affects semen quality, fertilization, placentation, and early reproduction. Limiting the use of plastic containers, not microwaving food in plastic, and avoiding thermal paper cash register receipts can reduce exposure. 

Phthalates are synthetically derived and used as plasticizers in personal and medical products. The major source of phthalate exposure is food; exposure causes sperm, egg, and DNA damage. Phthalate avoidance involves replacing plastic bottles with glass or stainless steel, avoiding reheating food in plastic containers, and choosing "fragrance free" products. 

PBDEs are used in flame retardants on upholstery, textiles, carpeting, and some electronics. Most PBDEs have been replaced by alternatives; however, their half-life is up to 12 years. Complications caused by PBDEs include thyroid disruption, resulting in abnormal fetal brain development. Avoiding dust and furniture that contain PBDEs, as well as hand washing, reduces exposure risk. 

Air pollutants are associated with adverse obstetric outcomes and lower cognitive function in children. Avoiding areas with heavy traffic, staying indoors when air is heavily polluted, and using a HEPA filter in the home can reduce chemicals from air pollution. 

Recommendations 

The magnitude of the problem that environmental toxicant exposure creates requires health care providers to take action. The table in the publication by Segal and Giudice can be used as a tool that patients can answer first themselves before review by their provider.² It can be added to your electronic health record and/or patient portal. Even making general comments to raise awareness, asking questions regarding exposure, and making recommendations can be helpful (TABLES 1 and 2). When possible, we also should advocate for public awareness and policy changes that address this significant health issue. 

Although we are not able to cover all of the important developments in fertility medicine over the past year, there were 3 important articles published in the past 12 months that we highlight here. First, we discuss an American College of Obstetricians and Gynecologists (ACOG) committee opinion on genetic carrier screening that was reaffirmed in 2019. Second, we explore an interesting retrospective analysis of time-lapse videos and clinical outcomes of more than 10,000 embryos from 8 IVF clinics, across 4 countries. The authors assessed whether a deep learning model could predict the probability of pregnancy with fetal heart from time-lapse videos in the hopes that their research can improve prioritization of the most viable embryo for single embryo transfer. Last, we consider a review of the data on obstetric and reproductive health effects of preconception and prenatal exposure to several environmental toxicants, including heavy metals, endocrine-disrupting chemicals, pesticides, and air pollution.

Preconception genetic carrier screening: Standardize your counseling approach 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129:e35-e40. 

With the rapid development of advanced and high throughput platforms for DNA sequencing in the past several years, the cost of genetic testing has decreased dramatically. Women's health care providers in general, and fertility specialists in particular, are uniquely positioned to take advantage of these novel and yet affordable technologies by counseling prospective parents during the preconception counseling, or early prenatal period, about the availability of genetic carrier screening and its potential to provide actionable information in a timely manner. The ultimate objective of genetic carrier screening is to enable individuals to make an informed decision regarding their reproductive choices based on their personal values. In a study by Larsen and colleagues, the uptake of genetic carrier screening was significantly higher when offered in the preconception period (68.7%), compared with during pregnancy (35.1%), which highlights the significance of early counseling.¹  

Based on the Centers for Disease Control and Prevention's Birth/Infant Death Data set, birth defects affect 1 in every 33 (about 3%) of all babies born in the United States each year and account for 20% of infant mortality.² About 20% of birth defects are caused by single-gene (monogenic) disorders, and although some of these are due to dominant conditions or de novo mutations, a significant proportion are due to autosomal recessive, or X-chromosome linked conditions that are commonly assessed by genetic carrier screening.  

ACOG published a committee opinion on "Carrier Screening in the Age of Genomic Medicine" in March 2017, which was reaffirmed in 2019.³  

Residual risk. Several points discussed in this document are of paramount importance, including the need for pretest and posttest counseling and consent, as well as a discussion of "residual risk." Newer platforms employ sequencing techniques that potentially can detect most, if not all, of the disease-causing variants in the tested genes, such as the gene for cystic fibrosis and, therefore, have a higher detection rate compared with the older PCR-based techniques for a limited number of specific mutations included in the panel. Due to a variety of technical and biological limitations, however, such as allelic dropouts and the occurrence of de novo mutations, the detection rate is not 100%; there is always a residual risk that needs to be estimated and provided to individuals based on the existing knowledge on frequency of gene, penetrance of phenotype, and prevalence of condition in the general and specific ethnic populations.  

Continue to: Expanded vs panethnic screening...

Expanded vs panethnic screening. Furthermore, although sequencing technology has made "expanded carrier screening" for several hundred conditions, simultaneous to and independent of ethnicity and family history, more easily available and affordable, ethnic-specific and panethnic screening for a more limited number of conditions are still acceptable approaches. Having said this, when the first partner screened is identified to be a carrier, his/her reproductive partners must be offered next-generation sequencing to identify less common disease-causing variants.⁴  

A cautionary point to consider when expanded carrier screening panels are requested is the significant variability among commercial laboratories with regard to the conditions included in their panels. In addition, consider the absence of a well-defined or predictable phenotype for some of the included conditions.  

Perhaps the most important matter when it comes to genetic carrier screening is to have a standard counseling approach that is persistently followed and offers the opportunity for individuals to know about their genetic testing options and available reproductive choices, including the use of donor gametes, preimplantation genetic testing for monogenic disease (PGT-M, formerly known as preimplantation genetic diagnosis, or PGD), prenatal testing, and pregnancy management options. For couples and/or individuals who decide to proceed with an affected pregnancy, earlier diagnosis can assist with postnatal management.  

Medicolegal responsibility. Genetic carrier screening also is of specific relevance to the field of fertility medicine and assisted reproductive technology (ART) as a potential liability issue. Couples and individuals who are undergoing fertility treatment with in vitro fertilization (IVF) for a variety of medical or personal reasons are a specific group that certainly should be offered genetic carrier screening, as they have the option of "adding on" PGT-M (PGD) to their existing treatment plan at a fraction of the cost and treatment burden that would have otherwise been needed if they were not undergoing IVF. After counseling, some individuals and couples may ultimately opt out of genetic carrier screening. The counseling discussion needs to be clearly documented in the medical chart.

Continue to: Artificial intelligence and embryo selection...

Artificial intelligence and embryo selection  

With continued improvements in embryo culture conditions and cryopreservation technology, there has been a tremendous amount of interest in developing better methods for embryo selection. These efforts are aimed at encouraging elective single embryo transfer (eSET) for women of all ages, thereby lowering the risk of multiple pregnancy and its associated adverse neonatal and obstetric outcomes—without compromising the pregnancy rates per transfer or lengthening the time to pregnancy.  

One of the most extensively studied methods for this purpose is preimplantation genetic testing for aneuploidy (PGT-A, formerly known as PGS), but emerging data from large multicenter randomized clinical trials (RCTs) have again cast significant doubt on PGT-A's efficacy and utility.⁵ Meanwhile, alternative methods for embryo selection are currently under investigation, including noninvasive PGT-A and morphokinetic assessment of embryo development via analysis of images obtained by time-lapse imaging.  

The potential of time-lapse imaging 

Despite the initial promising results from time-lapse imaging, subsequent RCTs have not shown a significant clinical benefit.⁶ However, these early methods of morphokinetic assessment are mainly dependent on the embryologists' subjective assessment of individual static frames and "annotation" of observed spatial and temporal features of embryo development. In addition to being a very time-consuming task, this process is subject to significant interobserver and intraobserver variability.  

Considering these limitations, even machine-based algorithms that incorporate these annotations along with such other clinical variables as parental age and prior obstetric history, have a low predictive power for the outcome of embryo transfer, with an area under the curve (AUC) of the ROC curve of 0.65 to 0.74. (An AUC of 0.5 represents completely random prediction and an AUC of 1.0 suggests perfect prediction.)⁷ 

A recent study by Tran and colleagues has employed a deep learning (neural network) model to analyze the entire raw time-lapse videos in an automated manner without prior annotation by embryologists. After analysis of 10,638 embryos from 8 different IVF clinics in 4 different countries, they have reported an AUC of 0.93 (95% confidence interval, 0.92-0.94) for prediction of fetal heart rate activity detected at 7 weeks of gestation or beyond. Although these data are very preliminary and have not yet been validated prospectively in larger datasets for live birth, it may herald the beginning of a new era for the automation and standardization of embryo assessment with artificial intelligence—similar to the rapidly increasing role of facial recognition technology for various applications.

Continue to: Environmental toxicants: The hidden danger...

Environmental toxicants: The hidden danger 

Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112:613-621. 

We receive news daily about the existential risk to humans of climate change. However, a risk that is likely as serious goes almost unseen by the public and most health care providers. That risk is environmental toxicants.⁸ 

More than 80,000 chemicals are registered in the United States, most in the last 75 years. These chemicals are ubiquitous. All of us are continuously exposed to and suffused with these toxicants and their metabolites. Air pollution adds insult to injury. Since this exposure has especially significant implications for fertility, infertility, pregnancy, perinatal health, childhood development, adult diseases, and later generational reproduction, it is imperative that reproductive health professionals take responsibility for helping mitigate this environmental crisis. 

The problem is exceptionally complicated  

The risks posed by environmental toxicants are much less visible than those for climate change, so the public, policymakers, and providers are largely unaware or may even seem uncaring. Few health professionals have sufficient knowledge to deliver care in this area, know which questions to ask, or have adequate information/medical record tools to assist them in care—and what are the possible interventions? 

Addressing risk posed by individual toxicants 

Addressing the problem clinically requires asking patients questions about exposure and recommending interventions. Toxicant chemicals include the neurotoxin mercury, which can be addressed by limiting intake of fish, especially certain types. 

Lead was used before 1978 in paint, it also was used in gas and in water pipes. People living in older homes may be exposed, as well as those in occupations exposed to lead. Others with lead exposure risk include immigrants from areas without lead regulations and people using pica- or lead-glazed pottery. Lead exposure has been associated with multiple pregnancy complications and permanently impaired intellectual development in children. If lead testing reveals high levels, chelation therapy can help. 

Cadmium is a heavy metal used in rechargeable batteries, paint pigment, and plastic production. Exposure results from food intake, smoking, and second-hand smoke. Cadmium accumulates in the liver, kidneys, testes, ovaries, and placenta. Exposure causes itai-itai disease, which is characterized by osteomalacia and renal tubular dysfunction as well as epigenetic changes in placental DNA and damage to the reproductive system. Eating organic food and reducing industrial exposure to cadmium are preventive strategies. 

Pesticides are ubiquitous, with 90% of the US population having detectable levels. Exposure during the preconception period can lead to intrauterine growth restriction, low birth weight, subsequent cancers, and other problems. Eating organic food can reduce risk, as can frequent hand washing when exposed to pesticides, using protective gear, and removing shoes in the home. 

Endocrine-disrupting chemicals (EDCs) are chemicals that can mimic or block endogenous hormones, which leads to adverse health outcomes. In addition to heavy metals, 3 important EDCs are bisphenol A (BPA), phthalates, and polybrominated diethyl ethers (PBDEs). Exposure is ubiquitous from industrial food processing, personal care products, cosmetics, and dust. Phthalates and BPA have short half-lives of hours to days, while PBDEs can persist in adipose tissue for months. Abnormal urogenital and neurologic development and thyroid disruption can result. Eating organic food, eating at home, and decreasing processed food intake can reduce exposure. 

BPA is used in plastics, canned food liners, cash register receipts, and epoxy resins. Exposure is through inhalation, ingestion, and dermal absorption and affects semen quality, fertilization, placentation, and early reproduction. Limiting the use of plastic containers, not microwaving food in plastic, and avoiding thermal paper cash register receipts can reduce exposure. 

Phthalates are synthetically derived and used as plasticizers in personal and medical products. The major source of phthalate exposure is food; exposure causes sperm, egg, and DNA damage. Phthalate avoidance involves replacing plastic bottles with glass or stainless steel, avoiding reheating food in plastic containers, and choosing "fragrance free" products. 

PBDEs are used in flame retardants on upholstery, textiles, carpeting, and some electronics. Most PBDEs have been replaced by alternatives; however, their half-life is up to 12 years. Complications caused by PBDEs include thyroid disruption, resulting in abnormal fetal brain development. Avoiding dust and furniture that contain PBDEs, as well as hand washing, reduces exposure risk. 

Air pollutants are associated with adverse obstetric outcomes and lower cognitive function in children. Avoiding areas with heavy traffic, staying indoors when air is heavily polluted, and using a HEPA filter in the home can reduce chemicals from air pollution. 

Recommendations 

The magnitude of the problem that environmental toxicant exposure creates requires health care providers to take action. The table in the publication by Segal and Giudice can be used as a tool that patients can answer first themselves before review by their provider.² It can be added to your electronic health record and/or patient portal. Even making general comments to raise awareness, asking questions regarding exposure, and making recommendations can be helpful (TABLES 1 and 2). When possible, we also should advocate for public awareness and policy changes that address this significant health issue. 

Although we are not able to cover all of the important developments in fertility medicine over the past year, there were 3 important articles published in the past 12 months that we highlight here. First, we discuss an American College of Obstetricians and Gynecologists (ACOG) committee opinion on genetic carrier screening that was reaffirmed in 2019. Second, we explore an interesting retrospective analysis of time-lapse videos and clinical outcomes of more than 10,000 embryos from 8 IVF clinics, across 4 countries. The authors assessed whether a deep learning model could predict the probability of pregnancy with fetal heart from time-lapse videos in the hopes that their research can improve prioritization of the most viable embryo for single embryo transfer. Last, we consider a review of the data on obstetric and reproductive health effects of preconception and prenatal exposure to several environmental toxicants, including heavy metals, endocrine-disrupting chemicals, pesticides, and air pollution.

Preconception genetic carrier screening: Standardize your counseling approach 

American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 690: carrier screening in the age of genomic medicine. Obstet Gynecol. 2017;129:e35-e40. 

With the rapid development of advanced and high throughput platforms for DNA sequencing in the past several years, the cost of genetic testing has decreased dramatically. Women's health care providers in general, and fertility specialists in particular, are uniquely positioned to take advantage of these novel and yet affordable technologies by counseling prospective parents during the preconception counseling, or early prenatal period, about the availability of genetic carrier screening and its potential to provide actionable information in a timely manner. The ultimate objective of genetic carrier screening is to enable individuals to make an informed decision regarding their reproductive choices based on their personal values. In a study by Larsen and colleagues, the uptake of genetic carrier screening was significantly higher when offered in the preconception period (68.7%), compared with during pregnancy (35.1%), which highlights the significance of early counseling.¹  

Based on the Centers for Disease Control and Prevention's Birth/Infant Death Data set, birth defects affect 1 in every 33 (about 3%) of all babies born in the United States each year and account for 20% of infant mortality.² About 20% of birth defects are caused by single-gene (monogenic) disorders, and although some of these are due to dominant conditions or de novo mutations, a significant proportion are due to autosomal recessive, or X-chromosome linked conditions that are commonly assessed by genetic carrier screening.  

ACOG published a committee opinion on "Carrier Screening in the Age of Genomic Medicine" in March 2017, which was reaffirmed in 2019.³  

Residual risk. Several points discussed in this document are of paramount importance, including the need for pretest and posttest counseling and consent, as well as a discussion of "residual risk." Newer platforms employ sequencing techniques that potentially can detect most, if not all, of the disease-causing variants in the tested genes, such as the gene for cystic fibrosis and, therefore, have a higher detection rate compared with the older PCR-based techniques for a limited number of specific mutations included in the panel. Due to a variety of technical and biological limitations, however, such as allelic dropouts and the occurrence of de novo mutations, the detection rate is not 100%; there is always a residual risk that needs to be estimated and provided to individuals based on the existing knowledge on frequency of gene, penetrance of phenotype, and prevalence of condition in the general and specific ethnic populations.  

Continue to: Expanded vs panethnic screening...

Expanded vs panethnic screening. Furthermore, although sequencing technology has made "expanded carrier screening" for several hundred conditions, simultaneous to and independent of ethnicity and family history, more easily available and affordable, ethnic-specific and panethnic screening for a more limited number of conditions are still acceptable approaches. Having said this, when the first partner screened is identified to be a carrier, his/her reproductive partners must be offered next-generation sequencing to identify less common disease-causing variants.⁴  

A cautionary point to consider when expanded carrier screening panels are requested is the significant variability among commercial laboratories with regard to the conditions included in their panels. In addition, consider the absence of a well-defined or predictable phenotype for some of the included conditions.  

Perhaps the most important matter when it comes to genetic carrier screening is to have a standard counseling approach that is persistently followed and offers the opportunity for individuals to know about their genetic testing options and available reproductive choices, including the use of donor gametes, preimplantation genetic testing for monogenic disease (PGT-M, formerly known as preimplantation genetic diagnosis, or PGD), prenatal testing, and pregnancy management options. For couples and/or individuals who decide to proceed with an affected pregnancy, earlier diagnosis can assist with postnatal management.  

Medicolegal responsibility. Genetic carrier screening also is of specific relevance to the field of fertility medicine and assisted reproductive technology (ART) as a potential liability issue. Couples and individuals who are undergoing fertility treatment with in vitro fertilization (IVF) for a variety of medical or personal reasons are a specific group that certainly should be offered genetic carrier screening, as they have the option of "adding on" PGT-M (PGD) to their existing treatment plan at a fraction of the cost and treatment burden that would have otherwise been needed if they were not undergoing IVF. After counseling, some individuals and couples may ultimately opt out of genetic carrier screening. The counseling discussion needs to be clearly documented in the medical chart.

Continue to: Artificial intelligence and embryo selection...

Artificial intelligence and embryo selection  

With continued improvements in embryo culture conditions and cryopreservation technology, there has been a tremendous amount of interest in developing better methods for embryo selection. These efforts are aimed at encouraging elective single embryo transfer (eSET) for women of all ages, thereby lowering the risk of multiple pregnancy and its associated adverse neonatal and obstetric outcomes—without compromising the pregnancy rates per transfer or lengthening the time to pregnancy.  

One of the most extensively studied methods for this purpose is preimplantation genetic testing for aneuploidy (PGT-A, formerly known as PGS), but emerging data from large multicenter randomized clinical trials (RCTs) have again cast significant doubt on PGT-A's efficacy and utility.⁵ Meanwhile, alternative methods for embryo selection are currently under investigation, including noninvasive PGT-A and morphokinetic assessment of embryo development via analysis of images obtained by time-lapse imaging.  

The potential of time-lapse imaging 

Despite the initial promising results from time-lapse imaging, subsequent RCTs have not shown a significant clinical benefit.⁶ However, these early methods of morphokinetic assessment are mainly dependent on the embryologists' subjective assessment of individual static frames and "annotation" of observed spatial and temporal features of embryo development. In addition to being a very time-consuming task, this process is subject to significant interobserver and intraobserver variability.  

Considering these limitations, even machine-based algorithms that incorporate these annotations along with such other clinical variables as parental age and prior obstetric history, have a low predictive power for the outcome of embryo transfer, with an area under the curve (AUC) of the ROC curve of 0.65 to 0.74. (An AUC of 0.5 represents completely random prediction and an AUC of 1.0 suggests perfect prediction.)⁷ 

A recent study by Tran and colleagues has employed a deep learning (neural network) model to analyze the entire raw time-lapse videos in an automated manner without prior annotation by embryologists. After analysis of 10,638 embryos from 8 different IVF clinics in 4 different countries, they have reported an AUC of 0.93 (95% confidence interval, 0.92-0.94) for prediction of fetal heart rate activity detected at 7 weeks of gestation or beyond. Although these data are very preliminary and have not yet been validated prospectively in larger datasets for live birth, it may herald the beginning of a new era for the automation and standardization of embryo assessment with artificial intelligence—similar to the rapidly increasing role of facial recognition technology for various applications.

Continue to: Environmental toxicants: The hidden danger...

Environmental toxicants: The hidden danger 

Segal TR, Giudice LC. Before the beginning: environmental exposures and reproductive and obstetrical outcomes. Fertil Steril. 2019;112:613-621. 

We receive news daily about the existential risk to humans of climate change. However, a risk that is likely as serious goes almost unseen by the public and most health care providers. That risk is environmental toxicants.⁸ 

More than 80,000 chemicals are registered in the United States, most in the last 75 years. These chemicals are ubiquitous. All of us are continuously exposed to and suffused with these toxicants and their metabolites. Air pollution adds insult to injury. Since this exposure has especially significant implications for fertility, infertility, pregnancy, perinatal health, childhood development, adult diseases, and later generational reproduction, it is imperative that reproductive health professionals take responsibility for helping mitigate this environmental crisis. 

The problem is exceptionally complicated  

The risks posed by environmental toxicants are much less visible than those for climate change, so the public, policymakers, and providers are largely unaware or may even seem uncaring. Few health professionals have sufficient knowledge to deliver care in this area, know which questions to ask, or have adequate information/medical record tools to assist them in care—and what are the possible interventions? 

Addressing risk posed by individual toxicants 

Addressing the problem clinically requires asking patients questions about exposure and recommending interventions. Toxicant chemicals include the neurotoxin mercury, which can be addressed by limiting intake of fish, especially certain types. 

Lead was used before 1978 in paint, it also was used in gas and in water pipes. People living in older homes may be exposed, as well as those in occupations exposed to lead. Others with lead exposure risk include immigrants from areas without lead regulations and people using pica- or lead-glazed pottery. Lead exposure has been associated with multiple pregnancy complications and permanently impaired intellectual development in children. If lead testing reveals high levels, chelation therapy can help. 

Cadmium is a heavy metal used in rechargeable batteries, paint pigment, and plastic production. Exposure results from food intake, smoking, and second-hand smoke. Cadmium accumulates in the liver, kidneys, testes, ovaries, and placenta. Exposure causes itai-itai disease, which is characterized by osteomalacia and renal tubular dysfunction as well as epigenetic changes in placental DNA and damage to the reproductive system. Eating organic food and reducing industrial exposure to cadmium are preventive strategies. 

Pesticides are ubiquitous, with 90% of the US population having detectable levels. Exposure during the preconception period can lead to intrauterine growth restriction, low birth weight, subsequent cancers, and other problems. Eating organic food can reduce risk, as can frequent hand washing when exposed to pesticides, using protective gear, and removing shoes in the home. 

Endocrine-disrupting chemicals (EDCs) are chemicals that can mimic or block endogenous hormones, which leads to adverse health outcomes. In addition to heavy metals, 3 important EDCs are bisphenol A (BPA), phthalates, and polybrominated diethyl ethers (PBDEs). Exposure is ubiquitous from industrial food processing, personal care products, cosmetics, and dust. Phthalates and BPA have short half-lives of hours to days, while PBDEs can persist in adipose tissue for months. Abnormal urogenital and neurologic development and thyroid disruption can result. Eating organic food, eating at home, and decreasing processed food intake can reduce exposure. 

BPA is used in plastics, canned food liners, cash register receipts, and epoxy resins. Exposure is through inhalation, ingestion, and dermal absorption and affects semen quality, fertilization, placentation, and early reproduction. Limiting the use of plastic containers, not microwaving food in plastic, and avoiding thermal paper cash register receipts can reduce exposure. 

Phthalates are synthetically derived and used as plasticizers in personal and medical products. The major source of phthalate exposure is food; exposure causes sperm, egg, and DNA damage. Phthalate avoidance involves replacing plastic bottles with glass or stainless steel, avoiding reheating food in plastic containers, and choosing "fragrance free" products. 

PBDEs are used in flame retardants on upholstery, textiles, carpeting, and some electronics. Most PBDEs have been replaced by alternatives; however, their half-life is up to 12 years. Complications caused by PBDEs include thyroid disruption, resulting in abnormal fetal brain development. Avoiding dust and furniture that contain PBDEs, as well as hand washing, reduces exposure risk. 

Air pollutants are associated with adverse obstetric outcomes and lower cognitive function in children. Avoiding areas with heavy traffic, staying indoors when air is heavily polluted, and using a HEPA filter in the home can reduce chemicals from air pollution. 

Recommendations 

The magnitude of the problem that environmental toxicant exposure creates requires health care providers to take action. The table in the publication by Segal and Giudice can be used as a tool that patients can answer first themselves before review by their provider.² It can be added to your electronic health record and/or patient portal. Even making general comments to raise awareness, asking questions regarding exposure, and making recommendations can be helpful (TABLES 1 and 2). When possible, we also should advocate for public awareness and policy changes that address this significant health issue. 

Professional societies, global organizations, and advocacy groups are continually working toward the goal of having the costs of infertility care covered by insurance carriers. Paramount to that effort is obtaining recognition of infertility as a burdensome disease. In this Update, we summarize national and international initiatives and societal trends that are helping to move us closer to that goal, and we encourage ObGyns to lead advocacy efforts. 

Next, we detail several notable new features available in the annual report of the Society for Assisted Reproductive Technology (SART), an online interactive document that can be used to assist clinicians and patients in treatment decisions. 

We also tackle the complexities of embryo selection for in vitro fertilization (IVF) and describe a potentially promising aneuploidy screening test, and explore its limitations. 

Advances in recognizing infertility as a disease that merits insurance coverage 

Major reproductive medicine organizations globally have endorsed the definition of infertility as a disease that "generates disability as an impairment of function" (TABLE 1).² Fortunately, medical, societal, and judicial changes have resulted in progress for the 6.1 million women (and equivalent number of men) affected by infertility in the United States.³  

Professional group advocacy efforts, and judicial rulings 

The World Health Organization (WHO) has addressed infertility over the past several decades, with the organization's standards on semen analysis being the most recognized outcome. Progress has been limited, however, regarding global or national policy that recognizes the importance of infertility as a medical and public health problem. 

In 2009, the glossary published by the WHO with the International Committee for Monitoring Assisted Reproductive Technology (ICMART) defined infertility as a disease.⁴ This recognition is important because it aids policy making, insurance coverage, and/or other payments for services. 

The WHO also has begun the process of developing new infertility guidelines. Recently, the WHO held a summit on safety and access to fertility care, which was attended by many representatives of nation-state governments and international experts. It is hoped that a document from those proceedings will reinforce the public health importance of infertility and support the need to promote equality in access to safe fertility care. WHO initiatives matter because they apply to nation-states. 

In the United States, the American Society for Reproductive Medicine (ASRM) for many years has recognized infertility as a disease. Only in 2017, however, did delegates at the American Medical Association's annual meeting vote to support the WHO's designation of infertility as a disease.

Continue to: Judicial views 

Judicial views. In 1998, the US Supreme Court held that infertility is a disability under the Americans with Disabilities Act (ADA). The Court subsequently held, however, that a person is not considered disabled under the act if the disability can be overcome by mitigating or corrective measures. In 2000, a lower court held that, while infertility is a disability, an employer's health plan that excludes treatment for it is not discriminatory under the ADA if it applies to all employees. 

Societal recognition. Interestingly, improved technology for oocyte cryopreservation has resulted in greater recognition of reproductive issues and the disparity in reproductive health societal norms and rights between men and women. 

Media stories and gender issues in employment, especially in such high-profile industries as technology and finance, have highlighted long-standing inequities, many of which concern reproductive issues. These issues have been further disseminated by the #metoo movement. Some employers are beginning to respond by recognizing their employees' reproductive needs and providing improved benefits for reproductive care. 

ObGyns must continue to lead advocacy 

Not all has been progress. Personhood bills in several states threaten basic reproductive rights of women and men. The ASRM and Resolve (the National Infertility Association) have taken leading roles in opposing these legislative initiatives and supporting reproductive rights.⁵ 

Advocacy efforts through events and trends have resulted in gradually improving the recognition of the burden of infertility, inadequate insurance coverage, and continuing gender inequalities in reproduction. Today, patients, professionals, and national and international organizations are coalescing around demands for recognition, access to care, and gender and diversity equality. While much remains to be done, progress is being made in society, government, the workplace, and the health care system. 

ObGyns and other women's health care providers can help continue the progress toward equality in reproductive rights, including access to infertility care, by discussing insurance inequities with patients, informing insurance companies that infertility is a disease, and encouraging patients to challenge inadequate and unequal insurance coverage of needed reproductive health care.

Latest SART report offers new features to aid in treatment decision making 

Knowledge of the prognosis and its various treatment options is an important aspect of infertility treatment. The SART recently updated its annual Clinic Summary Report (CSR), which includes valuable new features for patients and physicians considering assisted reproductive technology (ART) treatment.⁶ 

SART compiles complex data and reports outcomes 

The SART has been reporting IVF outcomes and other ART outcomes since 1988. The society's annual report is widely read by consumers, patients, physicians, and policy makers, and it has many important uses. However, the report is complicated and difficult to interpret for many reasons. For example, treatments are complex and varied (especially with application of new cryopreservation technology), and there are variations among clinics with respect to patient selection, protocols used, philosophy of practice, and numerous other variables.

Continue to: Because of this...

Because of this, the SART states, "The SART Clinic Summary Report (CSR) allows patients to view national and individual clinic IVF success rates. The data presented in this report should not be used for comparing clinics. Clinics may have differences in patient selection and treatment approaches which may artificially inflate or lower pregnancy rates relative to another clinic. Please discuss this with your doctor."⁶ 

Nevertheless, the CSR is extremely useful because it reports outcomes, which can lead to more informed patients and physicians and thus better access to safe and effective use of ART. The SART has redesigned the CSR to make it more useful. 

Redesigned CSR focuses on outcomes important to patients 

In recent years, new technologies have increased dramatically the use of embryo cryopreservation, genetic testing, and single embryo transfer (SET). The new CSR format is more patient focused and identifies more directly the treatment burden: ovarian stimulation, egg retrieval, intracytoplasmic sperm injection, preimplantation genetic testing (PGT), cryopreservation, frozen embryo transfer, and multiple cycles. It also focuses on the important patient outcomes, including live birth of a healthy child, multiple pregnancy, number of cycles, and chances of success per patient over time (including both fresh and frozen embryo transfers). 

Notable changes 

A major change in the CSR is that there is a preliminary report for a given year and then a final report the following year. This helps to more accurately report cycles that have been "delayed" because of egg retrieval and embryo freezing performed in the reported year but then transferred in the following reporting year. 

Cycle counting. A cycle is counted when a woman has started medications for an ART procedure or, in a "natural" cycle when no medications are used, the first day of menses of the ART cycle. If several cycles are performed to bank eggs or embryos, each will be counted in the denominator when calculating the pregnancy rate. This more accurately reflects the patient treatment burden and costs. A cycle cancelled before egg retrieval is still counted as a cycle. 

Defining success. Success is characterized as delivery of a child, since this is the outcome patients desire. Singleton deliveries are emphasized, since twin and higher-order multiple pregnancies have a higher risk of prematurity, morbidity, mortality, and cost. The percentages of triplet, twin, and singleton births contributing to the live birth rate are provided for each cycle group, as is prematurity (TABLE 2).⁶ 

The end point of a treatment cycle can vary. The new CSR captures the success rate following one or more egg retrievals and the first embryo transfer (primary outcome), the success of subsequent cycles using frozen eggs or embryos not transferred in the first embryo transfer, and the combined contribution of the primary and subsequent cycles to the cumulative live birth rate for a patient both in the preliminary report and the final report for any given year. The live birth rate per patient also is reported and includes the outcomes for patients who are new to an infertility center and starting their first cycle for retrieval of their own eggs during the reporting year. 

Continue to: Outcomes and prognostic factors...

Outcomes and prognostic factors. Outcomes are reported by multiple factors, including patient age and source of the eggs. These are important prognostic factors; separating the data allows you to obtain a better idea of both national and individual clinic experience by these factors. 

The CSR also contains filters for infertility diagnosis, stimulation type, and other treatment details (FIGURE).⁶ The filter is a useful feature because multiple types of treatment can be included or excluded. The outcome of different treatment interventions can then be estimated based on outcomes from the entire sample of US patients with similar characteristics and interventions. This powerful tool can help patients and physicians choose the best treatment based on prognosis. 

Personalized prognosis. An important new feature is the SART Patient Predictor (https://www.sartcorsonline.com/predictor/patient), a model that permits an individual patient to obtain a more personalized prognosis. While the SART predictor uses only basic patient information, such as age, body mass index, and diagnosis, its estimate is based on the entire US sample of reported ART experience and therefore can help patients in decision making. Furthermore, the predictor calculates percentages for the outcome of one transfer of 2 embryos, and 2 transfers of a single embryo, to demonstrate the advantages of SET that result in a higher live birth rate but a significantly lower multiple pregnancy rate. 

Summing up 

The SART's new CSR is extremely useful to patients and to any physician who cares for infertility patients. It can help users both understand the expected results from different ART treatments and enable better physician-patient communication and decision making. 
 

Embryo selection techniques refined with use of newer technologies 

Since the introduction of IVF in 1978, the final cumulative live birth rates per cycle initiated  for oocyte retrieval after all resulting embryos have been trasferred continue to rise, currently standing at 54% for women younger than age 35 in the United States.⁷ A number of achievements have contributed to this remarkable success, namely, improvements in IVF laboratory and embryo culture systems, advances in cryopreservation technology, availability of highly effective gonadotropins and gonadotropin-releasing hormone analogues, improved ultrasound technology, and the introduction of soft catheters for atraumatic embryo transfers. 

Treatment now focuses on improved embryo selection 

Now that excellent success rates have been attained, the focus of optimizing efforts in fertility treatment has shifted to improving safety by reducing the rates of multiple pregnancy through elective single embryo transfer (eSET), reducing the rates of miscarriage, and shortening the time to live birth. Methods to improve embryo selection lie at the forefront of these initiatives. These vary and include extended culture to blastocyst stage, standard morphologic evaluation as well as morphokinetic assessment of embryonic development via time-lapse imaging, and more recently the reintroduction of preimplantation genetic testing for aneuploidy (PGT-A), formerly known as preimplantation genetic screening (PGS). 

Chromosomal abnormalities of the embryo, or embryo aneuploidies, are the most common cause of treatment failure following embryo transfer in IVF. The proportion of embryos affected with aneuploidies significantly increases with advancing maternal age: 40% to 50% of blastocysts in women younger than age 35 and about 90% of blastocysts in women older than age 42.⁸ The premise with PGT-A is to identify these aneuploid embryos and increase the chances of success per embryo transfer by transferring euploid embryos. 

Continue to: That concept was initially applied...

That concept was initially applied to cleavage-stage embryos through the use of fluorescence in situ hybridization (FISH) technology to interrogate a maximum of 5 to 9 chromosomes in a single cell (single blastomere); however, although initial results from observational studies were encouraging, subsequent randomized controlled studies unexpectedly showed a reduction in pregnancy rates.⁹ This was attributed to several factors, including biopsy-related damage to the cleavage-stage embryo, inability of FISH technology to assess aneuploidies of more than 5 to 9 chromosomes, mosaicism, and technical limitations associated with single-cell analysis. 

Second-generation PGT-A testing has promise, and limitations 

The newer PGT-A tests the embryos at the blastocyst stage by using biopsy samples from the trophectoderm (which will form the future placenta); this is expected to spare the inner cell mass ([ICM] which will give rise to the embryo proper) from biopsy-related injury. 

On the genetics side, newer technologies, such as array comparative genomic hybridization, single nucleotide polymorphism arrays, quantitative polymerase chain reaction, and next-generation sequencing, offer the opportunity to assess all 24 chromosomes in a single biopsy specimen. Although a detailed discussion of these testing platforms is beyond the scope of this Update, certain points are worth mentioning. All these technologies require some form of genetic material amplification (most commonly whole genome amplification or multiplex polymerase chain reaction) to increase the relatively scant amount of DNA obtained from a sample of 4 to 6 cells. These amplification techniques have limitations that can subsequently impact the validity of the test results. 

Furthermore, there is no consistency in depth of coverage for various parts of the genome, and subchromosomal (segmental) copy number variations below 3 to 5 Mb may not be detected. The threshold used in bioinformatics algorithms employed to interpret the raw data is subject to several biases and is not consistent among laboratories. As a result, the same sample assessed in different laboratories can potentially yield different results. 

In addition to these technical limitations, mosaicism can pose another biologic limitation, as the biopsied trophectoderm cells may not accurately represent the chromosomal makeup of the ICM. Also, an embryo may be able to undergo self-correction during subsequent stages of development, and therefore even a documented trophectoderm abnormality at the blastocyst stage may not necessarily preclude that embryo from developing into a healthy baby. 

Standardization is needed. Despite widespread promotion of PGT-A, well-designed randomized clinical trials (RCTs) have not yet consistently shown its benefits in improving pregnancy rates or reducing miscarriage rates. Although the initial small RCTs in a selected group of good prognosis patients suggested a beneficial effect in ongoing pregnancy rates per transfer, the largest multicenter RCT to date did not show any improvement in pregnancy rates or reduction in miscarriage rates.¹⁰ In that study, a post hoc subgroup analysis suggested a possible beneficial effect in women aged 35 to 40. However, those results must be validated and reproduced with randomization at the start of stimulation, with the primary outcome being the live birth rate per initiated cycle, instead of per transfer, before PGT-A can be adopted universally in clinical practice. 

Continue to: With all the above considerations...

With all the above considerations, the ASRM has appropriately concluded that "the value of preimplantation genetic testing for aneuploidy (PGT-A) as a screening test for IVF patients has yet to be determined."¹¹ 

Professional societies, global organizations, and advocacy groups are continually working toward the goal of having the costs of infertility care covered by insurance carriers. Paramount to that effort is obtaining recognition of infertility as a burdensome disease. In this Update, we summarize national and international initiatives and societal trends that are helping to move us closer to that goal, and we encourage ObGyns to lead advocacy efforts. 

Next, we detail several notable new features available in the annual report of the Society for Assisted Reproductive Technology (SART), an online interactive document that can be used to assist clinicians and patients in treatment decisions. 

We also tackle the complexities of embryo selection for in vitro fertilization (IVF) and describe a potentially promising aneuploidy screening test, and explore its limitations. 

Advances in recognizing infertility as a disease that merits insurance coverage 

Major reproductive medicine organizations globally have endorsed the definition of infertility as a disease that "generates disability as an impairment of function" (TABLE 1).² Fortunately, medical, societal, and judicial changes have resulted in progress for the 6.1 million women (and equivalent number of men) affected by infertility in the United States.³  

Professional group advocacy efforts, and judicial rulings 

The World Health Organization (WHO) has addressed infertility over the past several decades, with the organization's standards on semen analysis being the most recognized outcome. Progress has been limited, however, regarding global or national policy that recognizes the importance of infertility as a medical and public health problem. 

In 2009, the glossary published by the WHO with the International Committee for Monitoring Assisted Reproductive Technology (ICMART) defined infertility as a disease.⁴ This recognition is important because it aids policy making, insurance coverage, and/or other payments for services. 

The WHO also has begun the process of developing new infertility guidelines. Recently, the WHO held a summit on safety and access to fertility care, which was attended by many representatives of nation-state governments and international experts. It is hoped that a document from those proceedings will reinforce the public health importance of infertility and support the need to promote equality in access to safe fertility care. WHO initiatives matter because they apply to nation-states. 

In the United States, the American Society for Reproductive Medicine (ASRM) for many years has recognized infertility as a disease. Only in 2017, however, did delegates at the American Medical Association's annual meeting vote to support the WHO's designation of infertility as a disease.

Continue to: Judicial views 

Judicial views. In 1998, the US Supreme Court held that infertility is a disability under the Americans with Disabilities Act (ADA). The Court subsequently held, however, that a person is not considered disabled under the act if the disability can be overcome by mitigating or corrective measures. In 2000, a lower court held that, while infertility is a disability, an employer's health plan that excludes treatment for it is not discriminatory under the ADA if it applies to all employees. 

Societal recognition. Interestingly, improved technology for oocyte cryopreservation has resulted in greater recognition of reproductive issues and the disparity in reproductive health societal norms and rights between men and women. 

Media stories and gender issues in employment, especially in such high-profile industries as technology and finance, have highlighted long-standing inequities, many of which concern reproductive issues. These issues have been further disseminated by the #metoo movement. Some employers are beginning to respond by recognizing their employees' reproductive needs and providing improved benefits for reproductive care. 

ObGyns must continue to lead advocacy 

Not all has been progress. Personhood bills in several states threaten basic reproductive rights of women and men. The ASRM and Resolve (the National Infertility Association) have taken leading roles in opposing these legislative initiatives and supporting reproductive rights.⁵ 

Advocacy efforts through events and trends have resulted in gradually improving the recognition of the burden of infertility, inadequate insurance coverage, and continuing gender inequalities in reproduction. Today, patients, professionals, and national and international organizations are coalescing around demands for recognition, access to care, and gender and diversity equality. While much remains to be done, progress is being made in society, government, the workplace, and the health care system. 

ObGyns and other women's health care providers can help continue the progress toward equality in reproductive rights, including access to infertility care, by discussing insurance inequities with patients, informing insurance companies that infertility is a disease, and encouraging patients to challenge inadequate and unequal insurance coverage of needed reproductive health care.

Latest SART report offers new features to aid in treatment decision making 

Knowledge of the prognosis and its various treatment options is an important aspect of infertility treatment. The SART recently updated its annual Clinic Summary Report (CSR), which includes valuable new features for patients and physicians considering assisted reproductive technology (ART) treatment.⁶ 

SART compiles complex data and reports outcomes 

The SART has been reporting IVF outcomes and other ART outcomes since 1988. The society's annual report is widely read by consumers, patients, physicians, and policy makers, and it has many important uses. However, the report is complicated and difficult to interpret for many reasons. For example, treatments are complex and varied (especially with application of new cryopreservation technology), and there are variations among clinics with respect to patient selection, protocols used, philosophy of practice, and numerous other variables.

Continue to: Because of this...

Because of this, the SART states, "The SART Clinic Summary Report (CSR) allows patients to view national and individual clinic IVF success rates. The data presented in this report should not be used for comparing clinics. Clinics may have differences in patient selection and treatment approaches which may artificially inflate or lower pregnancy rates relative to another clinic. Please discuss this with your doctor."⁶ 

Nevertheless, the CSR is extremely useful because it reports outcomes, which can lead to more informed patients and physicians and thus better access to safe and effective use of ART. The SART has redesigned the CSR to make it more useful. 

Redesigned CSR focuses on outcomes important to patients 

In recent years, new technologies have increased dramatically the use of embryo cryopreservation, genetic testing, and single embryo transfer (SET). The new CSR format is more patient focused and identifies more directly the treatment burden: ovarian stimulation, egg retrieval, intracytoplasmic sperm injection, preimplantation genetic testing (PGT), cryopreservation, frozen embryo transfer, and multiple cycles. It also focuses on the important patient outcomes, including live birth of a healthy child, multiple pregnancy, number of cycles, and chances of success per patient over time (including both fresh and frozen embryo transfers). 

Notable changes 

A major change in the CSR is that there is a preliminary report for a given year and then a final report the following year. This helps to more accurately report cycles that have been "delayed" because of egg retrieval and embryo freezing performed in the reported year but then transferred in the following reporting year. 

Cycle counting. A cycle is counted when a woman has started medications for an ART procedure or, in a "natural" cycle when no medications are used, the first day of menses of the ART cycle. If several cycles are performed to bank eggs or embryos, each will be counted in the denominator when calculating the pregnancy rate. This more accurately reflects the patient treatment burden and costs. A cycle cancelled before egg retrieval is still counted as a cycle. 

Defining success. Success is characterized as delivery of a child, since this is the outcome patients desire. Singleton deliveries are emphasized, since twin and higher-order multiple pregnancies have a higher risk of prematurity, morbidity, mortality, and cost. The percentages of triplet, twin, and singleton births contributing to the live birth rate are provided for each cycle group, as is prematurity (TABLE 2).⁶ 

The end point of a treatment cycle can vary. The new CSR captures the success rate following one or more egg retrievals and the first embryo transfer (primary outcome), the success of subsequent cycles using frozen eggs or embryos not transferred in the first embryo transfer, and the combined contribution of the primary and subsequent cycles to the cumulative live birth rate for a patient both in the preliminary report and the final report for any given year. The live birth rate per patient also is reported and includes the outcomes for patients who are new to an infertility center and starting their first cycle for retrieval of their own eggs during the reporting year. 

Continue to: Outcomes and prognostic factors...

Outcomes and prognostic factors. Outcomes are reported by multiple factors, including patient age and source of the eggs. These are important prognostic factors; separating the data allows you to obtain a better idea of both national and individual clinic experience by these factors. 

The CSR also contains filters for infertility diagnosis, stimulation type, and other treatment details (FIGURE).⁶ The filter is a useful feature because multiple types of treatment can be included or excluded. The outcome of different treatment interventions can then be estimated based on outcomes from the entire sample of US patients with similar characteristics and interventions. This powerful tool can help patients and physicians choose the best treatment based on prognosis. 

Personalized prognosis. An important new feature is the SART Patient Predictor (https://www.sartcorsonline.com/predictor/patient), a model that permits an individual patient to obtain a more personalized prognosis. While the SART predictor uses only basic patient information, such as age, body mass index, and diagnosis, its estimate is based on the entire US sample of reported ART experience and therefore can help patients in decision making. Furthermore, the predictor calculates percentages for the outcome of one transfer of 2 embryos, and 2 transfers of a single embryo, to demonstrate the advantages of SET that result in a higher live birth rate but a significantly lower multiple pregnancy rate. 

Summing up 

The SART's new CSR is extremely useful to patients and to any physician who cares for infertility patients. It can help users both understand the expected results from different ART treatments and enable better physician-patient communication and decision making. 
 

Embryo selection techniques refined with use of newer technologies 

Since the introduction of IVF in 1978, the final cumulative live birth rates per cycle initiated  for oocyte retrieval after all resulting embryos have been trasferred continue to rise, currently standing at 54% for women younger than age 35 in the United States.⁷ A number of achievements have contributed to this remarkable success, namely, improvements in IVF laboratory and embryo culture systems, advances in cryopreservation technology, availability of highly effective gonadotropins and gonadotropin-releasing hormone analogues, improved ultrasound technology, and the introduction of soft catheters for atraumatic embryo transfers. 

Treatment now focuses on improved embryo selection 

Now that excellent success rates have been attained, the focus of optimizing efforts in fertility treatment has shifted to improving safety by reducing the rates of multiple pregnancy through elective single embryo transfer (eSET), reducing the rates of miscarriage, and shortening the time to live birth. Methods to improve embryo selection lie at the forefront of these initiatives. These vary and include extended culture to blastocyst stage, standard morphologic evaluation as well as morphokinetic assessment of embryonic development via time-lapse imaging, and more recently the reintroduction of preimplantation genetic testing for aneuploidy (PGT-A), formerly known as preimplantation genetic screening (PGS). 

Chromosomal abnormalities of the embryo, or embryo aneuploidies, are the most common cause of treatment failure following embryo transfer in IVF. The proportion of embryos affected with aneuploidies significantly increases with advancing maternal age: 40% to 50% of blastocysts in women younger than age 35 and about 90% of blastocysts in women older than age 42.⁸ The premise with PGT-A is to identify these aneuploid embryos and increase the chances of success per embryo transfer by transferring euploid embryos. 

Continue to: That concept was initially applied...

That concept was initially applied to cleavage-stage embryos through the use of fluorescence in situ hybridization (FISH) technology to interrogate a maximum of 5 to 9 chromosomes in a single cell (single blastomere); however, although initial results from observational studies were encouraging, subsequent randomized controlled studies unexpectedly showed a reduction in pregnancy rates.⁹ This was attributed to several factors, including biopsy-related damage to the cleavage-stage embryo, inability of FISH technology to assess aneuploidies of more than 5 to 9 chromosomes, mosaicism, and technical limitations associated with single-cell analysis. 

Second-generation PGT-A testing has promise, and limitations 

The newer PGT-A tests the embryos at the blastocyst stage by using biopsy samples from the trophectoderm (which will form the future placenta); this is expected to spare the inner cell mass ([ICM] which will give rise to the embryo proper) from biopsy-related injury. 

On the genetics side, newer technologies, such as array comparative genomic hybridization, single nucleotide polymorphism arrays, quantitative polymerase chain reaction, and next-generation sequencing, offer the opportunity to assess all 24 chromosomes in a single biopsy specimen. Although a detailed discussion of these testing platforms is beyond the scope of this Update, certain points are worth mentioning. All these technologies require some form of genetic material amplification (most commonly whole genome amplification or multiplex polymerase chain reaction) to increase the relatively scant amount of DNA obtained from a sample of 4 to 6 cells. These amplification techniques have limitations that can subsequently impact the validity of the test results. 

Furthermore, there is no consistency in depth of coverage for various parts of the genome, and subchromosomal (segmental) copy number variations below 3 to 5 Mb may not be detected. The threshold used in bioinformatics algorithms employed to interpret the raw data is subject to several biases and is not consistent among laboratories. As a result, the same sample assessed in different laboratories can potentially yield different results. 

In addition to these technical limitations, mosaicism can pose another biologic limitation, as the biopsied trophectoderm cells may not accurately represent the chromosomal makeup of the ICM. Also, an embryo may be able to undergo self-correction during subsequent stages of development, and therefore even a documented trophectoderm abnormality at the blastocyst stage may not necessarily preclude that embryo from developing into a healthy baby. 

Standardization is needed. Despite widespread promotion of PGT-A, well-designed randomized clinical trials (RCTs) have not yet consistently shown its benefits in improving pregnancy rates or reducing miscarriage rates. Although the initial small RCTs in a selected group of good prognosis patients suggested a beneficial effect in ongoing pregnancy rates per transfer, the largest multicenter RCT to date did not show any improvement in pregnancy rates or reduction in miscarriage rates.¹⁰ In that study, a post hoc subgroup analysis suggested a possible beneficial effect in women aged 35 to 40. However, those results must be validated and reproduced with randomization at the start of stimulation, with the primary outcome being the live birth rate per initiated cycle, instead of per transfer, before PGT-A can be adopted universally in clinical practice. 

Continue to: With all the above considerations...

With all the above considerations, the ASRM has appropriately concluded that "the value of preimplantation genetic testing for aneuploidy (PGT-A) as a screening test for IVF patients has yet to be determined."¹¹ 

Professional societies, global organizations, and advocacy groups are continually working toward the goal of having the costs of infertility care covered by insurance carriers. Paramount to that effort is obtaining recognition of infertility as a burdensome disease. In this Update, we summarize national and international initiatives and societal trends that are helping to move us closer to that goal, and we encourage ObGyns to lead advocacy efforts. 

Next, we detail several notable new features available in the annual report of the Society for Assisted Reproductive Technology (SART), an online interactive document that can be used to assist clinicians and patients in treatment decisions. 

We also tackle the complexities of embryo selection for in vitro fertilization (IVF) and describe a potentially promising aneuploidy screening test, and explore its limitations. 

Advances in recognizing infertility as a disease that merits insurance coverage 

Major reproductive medicine organizations globally have endorsed the definition of infertility as a disease that "generates disability as an impairment of function" (TABLE 1).² Fortunately, medical, societal, and judicial changes have resulted in progress for the 6.1 million women (and equivalent number of men) affected by infertility in the United States.³  

Professional group advocacy efforts, and judicial rulings 

The World Health Organization (WHO) has addressed infertility over the past several decades, with the organization's standards on semen analysis being the most recognized outcome. Progress has been limited, however, regarding global or national policy that recognizes the importance of infertility as a medical and public health problem. 

In 2009, the glossary published by the WHO with the International Committee for Monitoring Assisted Reproductive Technology (ICMART) defined infertility as a disease.⁴ This recognition is important because it aids policy making, insurance coverage, and/or other payments for services. 

The WHO also has begun the process of developing new infertility guidelines. Recently, the WHO held a summit on safety and access to fertility care, which was attended by many representatives of nation-state governments and international experts. It is hoped that a document from those proceedings will reinforce the public health importance of infertility and support the need to promote equality in access to safe fertility care. WHO initiatives matter because they apply to nation-states. 

In the United States, the American Society for Reproductive Medicine (ASRM) for many years has recognized infertility as a disease. Only in 2017, however, did delegates at the American Medical Association's annual meeting vote to support the WHO's designation of infertility as a disease.

Continue to: Judicial views 

Judicial views. In 1998, the US Supreme Court held that infertility is a disability under the Americans with Disabilities Act (ADA). The Court subsequently held, however, that a person is not considered disabled under the act if the disability can be overcome by mitigating or corrective measures. In 2000, a lower court held that, while infertility is a disability, an employer's health plan that excludes treatment for it is not discriminatory under the ADA if it applies to all employees. 

Societal recognition. Interestingly, improved technology for oocyte cryopreservation has resulted in greater recognition of reproductive issues and the disparity in reproductive health societal norms and rights between men and women. 

Media stories and gender issues in employment, especially in such high-profile industries as technology and finance, have highlighted long-standing inequities, many of which concern reproductive issues. These issues have been further disseminated by the #metoo movement. Some employers are beginning to respond by recognizing their employees' reproductive needs and providing improved benefits for reproductive care. 

ObGyns must continue to lead advocacy 

Not all has been progress. Personhood bills in several states threaten basic reproductive rights of women and men. The ASRM and Resolve (the National Infertility Association) have taken leading roles in opposing these legislative initiatives and supporting reproductive rights.⁵ 

Advocacy efforts through events and trends have resulted in gradually improving the recognition of the burden of infertility, inadequate insurance coverage, and continuing gender inequalities in reproduction. Today, patients, professionals, and national and international organizations are coalescing around demands for recognition, access to care, and gender and diversity equality. While much remains to be done, progress is being made in society, government, the workplace, and the health care system. 

ObGyns and other women's health care providers can help continue the progress toward equality in reproductive rights, including access to infertility care, by discussing insurance inequities with patients, informing insurance companies that infertility is a disease, and encouraging patients to challenge inadequate and unequal insurance coverage of needed reproductive health care.

Latest SART report offers new features to aid in treatment decision making 

Knowledge of the prognosis and its various treatment options is an important aspect of infertility treatment. The SART recently updated its annual Clinic Summary Report (CSR), which includes valuable new features for patients and physicians considering assisted reproductive technology (ART) treatment.⁶ 

SART compiles complex data and reports outcomes 

The SART has been reporting IVF outcomes and other ART outcomes since 1988. The society's annual report is widely read by consumers, patients, physicians, and policy makers, and it has many important uses. However, the report is complicated and difficult to interpret for many reasons. For example, treatments are complex and varied (especially with application of new cryopreservation technology), and there are variations among clinics with respect to patient selection, protocols used, philosophy of practice, and numerous other variables.

Continue to: Because of this...

Because of this, the SART states, "The SART Clinic Summary Report (CSR) allows patients to view national and individual clinic IVF success rates. The data presented in this report should not be used for comparing clinics. Clinics may have differences in patient selection and treatment approaches which may artificially inflate or lower pregnancy rates relative to another clinic. Please discuss this with your doctor."⁶ 

Nevertheless, the CSR is extremely useful because it reports outcomes, which can lead to more informed patients and physicians and thus better access to safe and effective use of ART. The SART has redesigned the CSR to make it more useful. 

Redesigned CSR focuses on outcomes important to patients 

In recent years, new technologies have increased dramatically the use of embryo cryopreservation, genetic testing, and single embryo transfer (SET). The new CSR format is more patient focused and identifies more directly the treatment burden: ovarian stimulation, egg retrieval, intracytoplasmic sperm injection, preimplantation genetic testing (PGT), cryopreservation, frozen embryo transfer, and multiple cycles. It also focuses on the important patient outcomes, including live birth of a healthy child, multiple pregnancy, number of cycles, and chances of success per patient over time (including both fresh and frozen embryo transfers). 

Notable changes 

A major change in the CSR is that there is a preliminary report for a given year and then a final report the following year. This helps to more accurately report cycles that have been "delayed" because of egg retrieval and embryo freezing performed in the reported year but then transferred in the following reporting year. 

Cycle counting. A cycle is counted when a woman has started medications for an ART procedure or, in a "natural" cycle when no medications are used, the first day of menses of the ART cycle. If several cycles are performed to bank eggs or embryos, each will be counted in the denominator when calculating the pregnancy rate. This more accurately reflects the patient treatment burden and costs. A cycle cancelled before egg retrieval is still counted as a cycle. 

Defining success. Success is characterized as delivery of a child, since this is the outcome patients desire. Singleton deliveries are emphasized, since twin and higher-order multiple pregnancies have a higher risk of prematurity, morbidity, mortality, and cost. The percentages of triplet, twin, and singleton births contributing to the live birth rate are provided for each cycle group, as is prematurity (TABLE 2).⁶ 

The end point of a treatment cycle can vary. The new CSR captures the success rate following one or more egg retrievals and the first embryo transfer (primary outcome), the success of subsequent cycles using frozen eggs or embryos not transferred in the first embryo transfer, and the combined contribution of the primary and subsequent cycles to the cumulative live birth rate for a patient both in the preliminary report and the final report for any given year. The live birth rate per patient also is reported and includes the outcomes for patients who are new to an infertility center and starting their first cycle for retrieval of their own eggs during the reporting year. 

Continue to: Outcomes and prognostic factors...

Outcomes and prognostic factors. Outcomes are reported by multiple factors, including patient age and source of the eggs. These are important prognostic factors; separating the data allows you to obtain a better idea of both national and individual clinic experience by these factors. 

The CSR also contains filters for infertility diagnosis, stimulation type, and other treatment details (FIGURE).⁶ The filter is a useful feature because multiple types of treatment can be included or excluded. The outcome of different treatment interventions can then be estimated based on outcomes from the entire sample of US patients with similar characteristics and interventions. This powerful tool can help patients and physicians choose the best treatment based on prognosis. 

Personalized prognosis. An important new feature is the SART Patient Predictor (https://www.sartcorsonline.com/predictor/patient), a model that permits an individual patient to obtain a more personalized prognosis. While the SART predictor uses only basic patient information, such as age, body mass index, and diagnosis, its estimate is based on the entire US sample of reported ART experience and therefore can help patients in decision making. Furthermore, the predictor calculates percentages for the outcome of one transfer of 2 embryos, and 2 transfers of a single embryo, to demonstrate the advantages of SET that result in a higher live birth rate but a significantly lower multiple pregnancy rate. 

Summing up 

The SART's new CSR is extremely useful to patients and to any physician who cares for infertility patients. It can help users both understand the expected results from different ART treatments and enable better physician-patient communication and decision making. 
 

Embryo selection techniques refined with use of newer technologies 

Since the introduction of IVF in 1978, the final cumulative live birth rates per cycle initiated  for oocyte retrieval after all resulting embryos have been trasferred continue to rise, currently standing at 54% for women younger than age 35 in the United States.⁷ A number of achievements have contributed to this remarkable success, namely, improvements in IVF laboratory and embryo culture systems, advances in cryopreservation technology, availability of highly effective gonadotropins and gonadotropin-releasing hormone analogues, improved ultrasound technology, and the introduction of soft catheters for atraumatic embryo transfers. 

Treatment now focuses on improved embryo selection 

Now that excellent success rates have been attained, the focus of optimizing efforts in fertility treatment has shifted to improving safety by reducing the rates of multiple pregnancy through elective single embryo transfer (eSET), reducing the rates of miscarriage, and shortening the time to live birth. Methods to improve embryo selection lie at the forefront of these initiatives. These vary and include extended culture to blastocyst stage, standard morphologic evaluation as well as morphokinetic assessment of embryonic development via time-lapse imaging, and more recently the reintroduction of preimplantation genetic testing for aneuploidy (PGT-A), formerly known as preimplantation genetic screening (PGS). 

Chromosomal abnormalities of the embryo, or embryo aneuploidies, are the most common cause of treatment failure following embryo transfer in IVF. The proportion of embryos affected with aneuploidies significantly increases with advancing maternal age: 40% to 50% of blastocysts in women younger than age 35 and about 90% of blastocysts in women older than age 42.⁸ The premise with PGT-A is to identify these aneuploid embryos and increase the chances of success per embryo transfer by transferring euploid embryos. 

Continue to: That concept was initially applied...

That concept was initially applied to cleavage-stage embryos through the use of fluorescence in situ hybridization (FISH) technology to interrogate a maximum of 5 to 9 chromosomes in a single cell (single blastomere); however, although initial results from observational studies were encouraging, subsequent randomized controlled studies unexpectedly showed a reduction in pregnancy rates.⁹ This was attributed to several factors, including biopsy-related damage to the cleavage-stage embryo, inability of FISH technology to assess aneuploidies of more than 5 to 9 chromosomes, mosaicism, and technical limitations associated with single-cell analysis. 

Second-generation PGT-A testing has promise, and limitations 

The newer PGT-A tests the embryos at the blastocyst stage by using biopsy samples from the trophectoderm (which will form the future placenta); this is expected to spare the inner cell mass ([ICM] which will give rise to the embryo proper) from biopsy-related injury. 

On the genetics side, newer technologies, such as array comparative genomic hybridization, single nucleotide polymorphism arrays, quantitative polymerase chain reaction, and next-generation sequencing, offer the opportunity to assess all 24 chromosomes in a single biopsy specimen. Although a detailed discussion of these testing platforms is beyond the scope of this Update, certain points are worth mentioning. All these technologies require some form of genetic material amplification (most commonly whole genome amplification or multiplex polymerase chain reaction) to increase the relatively scant amount of DNA obtained from a sample of 4 to 6 cells. These amplification techniques have limitations that can subsequently impact the validity of the test results. 

Furthermore, there is no consistency in depth of coverage for various parts of the genome, and subchromosomal (segmental) copy number variations below 3 to 5 Mb may not be detected. The threshold used in bioinformatics algorithms employed to interpret the raw data is subject to several biases and is not consistent among laboratories. As a result, the same sample assessed in different laboratories can potentially yield different results. 

In addition to these technical limitations, mosaicism can pose another biologic limitation, as the biopsied trophectoderm cells may not accurately represent the chromosomal makeup of the ICM. Also, an embryo may be able to undergo self-correction during subsequent stages of development, and therefore even a documented trophectoderm abnormality at the blastocyst stage may not necessarily preclude that embryo from developing into a healthy baby. 

Standardization is needed. Despite widespread promotion of PGT-A, well-designed randomized clinical trials (RCTs) have not yet consistently shown its benefits in improving pregnancy rates or reducing miscarriage rates. Although the initial small RCTs in a selected group of good prognosis patients suggested a beneficial effect in ongoing pregnancy rates per transfer, the largest multicenter RCT to date did not show any improvement in pregnancy rates or reduction in miscarriage rates.¹⁰ In that study, a post hoc subgroup analysis suggested a possible beneficial effect in women aged 35 to 40. However, those results must be validated and reproduced with randomization at the start of stimulation, with the primary outcome being the live birth rate per initiated cycle, instead of per transfer, before PGT-A can be adopted universally in clinical practice. 

Continue to: With all the above considerations...

With all the above considerations, the ASRM has appropriately concluded that "the value of preimplantation genetic testing for aneuploidy (PGT-A) as a screening test for IVF patients has yet to be determined."¹¹ 

Clinicians always should consider endometriosis in the diagnostic work-up of an infertility patient. But the diagnosis of endometriosis is often difficult, and management is complex. In this Update, we summarize international consensus documents on endometriosis with the aim of enhancing clinicians’ ability to make evidence-based decisions. In addition, we explore the interesting results of a large hysterosalpingography trial in which 2 different contrast mediums were used. Finally, we urge all clinicians to adapt the new standardized lexicon of infertility and fertility care terms that comprise the recently revised international glossary.

Endometriosis and infertility: The knowns and unknowns

Johnson NP, Hummelshoj L, Adamson GD, et al; World Endometriosis Society Sao Paulo Consortium. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32(2):315-324.

Johnson NP, Hummelshoj L; World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552-1568.

Rogers PA, Adamson GD, Al-Jefout M, et al; WES/WERF Consortium for Research Priorities in Endometriosis. Research priorities for endometriosis. Reprod Sci. 2017;24(2):202-226.

Endometriosis is defined as "a disease characterized by the presence of endometrium-like epithelium and stroma outside the endometrium and myometrium. Intrapelvic endometriosis can be located superficially on the peritoneum (peritoneal endometriosis), can extend 5 mm or more beneath the peritoneum (deep endometriosis) or can be present as an ovarian endometriotic cyst (endometrioma)."¹ Always consider endometriosis in the infertile patient.

Although many professional societies and numerous Cochrane Database Systematic Reviews have provided guidelines on endometriosis, controversy and uncertainty remain. The World Endometriosis Society (WES) and the World Endometriosis Research Foundation (WERF), however, have now published several consensus documents that assess the global literature and professional organization guidelines in a structured, consensus-driven process.^2-4 These WES and WERF documents consolidate known information and can be used to inform the clinician in making evidence-linked diagnostic and treatment decisions. Recommendations offered in this discussion are based on those documents.

Establishing the diagnosis can be difficult

Diagnosis of endometriosis is often difficult and is delayed an average of 7 years from onset of symptoms. These include severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms (bowel or bladder associated) with or without abnormal bleeding, chronic fatigue, and infertility. A major difficulty is that the predictive value of any one symptom or set of symptoms remains uncertain, as each of these symptoms can have other causes, and a significant proportion of affected women are asymptomatic.

For a definitive diagnosis of endometriosis, visual inspection of the pelvis at laparoscopy is the gold standard investigation, unless disease is visible in the vagina or elsewhere. Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is present is controversial: visual inspection usually is adequate, but histologic confirmation of at least one lesion is ideal. In cases of ovarian endometrioma (>4 cm in diameter) and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy.

Compared with laparoscopy, transvaginal ultrasonography (TVUS) has no value in diagnosing peritoneal endometriosis, but it is a useful tool for both making and excluding the diagnosis of an ovarian endometrioma. TVUS may have a role in the diagnosis of disease involving the bladder or rectum.

At present, evidence is insufficient to indicate that magnetic resonance imaging (MRI) is useful for diagnosing or excluding endometriosis compared with laparoscopy. MRI should be reserved for when ultrasound results are equivocal in cases of rectovaginal or bladder endometriosis.

Serum cancer antigen 125 (CA 125) levels may be elevated in endometriosis. However, measuring serum CA 125 levels has no value as a diagnostic tool.

No fertility benefit with ovarian suppression

More than 2 dozen randomized controlled trials (RCTs) provide strong evidence that there is no fertility benefit from ovarian suppression. The drug costs and delayed time to pregnancy mean that ovarian suppression with oral contraceptives, other progestational agents, or gonadotropin-releasing hormone (GnRH) agonists before fertility treatment is not indicated, with the possible exception of using it prior to in vitro fertilization (IVF).

Ovarian suppression also has been suggested as beneficial in conjunction with surgery. However, at least 16 RCTs have failed to show fertility improvement when ovarian suppression is given either preoperatively or postoperatively. Again, the delay in attempting pregnancy, drug costs, and adverse effects render ovarian suppression not appropriate.

While ovarian suppression has not been shown to increase pregnancy rates, ovarian stimulation (OS) likely does, especially when combined with intrauterine insemination (IUI).⁵

Laparoscopy: Appropriate for selected patients

A major decision for clinicians and patients dealing with infertility is whether to perform a laparoscopy, both for diagnostic and for treatment reasons. Currently, data are insufficient to recommend laparoscopic surgery prior to OS/IUI unless there is a history of evidence of anatomic disease and/or the patient has sufficient pain to justify the physical, emotional, financial, and time costs of laparoscopy. Laparoscopy therefore can be considered as possibly appropriate in younger women (<37 years of age) with short duration of infertility (<4 years), normal male factor, normal or treatable uterus, normal or treatable ovulation disorder, and limited prior treatment.

It is important to consider what disease might be found and how much of an increase in fertility can be obtained by treatment, so that the number needed to treat (NNT) can be used as an estimate of the potential value of laparoscopy in a given patient. A patient also should have no contraindications to laparoscopy and accept 9 to 15 months of attempting pregnancy before undergoing IVF treatment.

When laparoscopy is performed for minimal to mild disease, the odds ratio for pregnancy is 1.66 with treatment. It is important to remove all visible disease without injuring healthy tissue. When disease is moderate to severe, there is often severe anatomic distortion and a very low background pregnancy rate. Numerous uncontrolled trials show benefit of operative laparoscopy, especially for invasive, adhesive, and cystic endometriosis. However, repeat surgery is rarely indicated. After surgery, the Endometriosis Fertility Index (EFI) can be used to determine prognosis and plan management (FIGURE  1).⁶ An easy-to-use electronic EFI calculator is available online at www.endometriosisefi.com.

Management of endometriomas

Endometriomas are often operated on because of pain. Initial pain relief occurs in 60% to 100% of patients, but cysts recur following stripping about 10% of the time, and drainage without stripping, about 20%. With recurrence, pain is present about 75% of the time.

Pregnancy rates following endometrioma treatment depend on patient age and the status of the pelvis following operative intervention. This can be determined from the EFI. Often, the dilemma with endometriomas is how aggressive to be in removing them. The principles involved are to remove all the cyst wall if possible, but absolutely to minimize ovarian tissue damage, because reduced ovarian reserve is a possible major negative consequence of ovarian surgery. 

Recommendations

While endometriosis is often a cause of infertility, often infertile patients do not have endometriosis. A careful history, physical examination, and ultrasonography, and possibly other imaging studies, are prerequisites to careful clinical judgment in diagnosing and treating infertile patients who might or do have endometriosis.

When pelvic pain is present, initially nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives (OCs), progestational agents, or an intrauterine device can be helpful. These ovarian suppression medications do not increase fertility, however, and should be stopped in any patient who desires to get pregnant.

When pelvic and male fertility factors appear reasonably normal (even if minimal or mild endometriosis is suspected), treatment with clomiphene 100 mg on cycle days 3 through 7 and IUI for 3 to 6 cycles is an effective first step. However, if the patient has persistent pain and/or infertility without other significant infertility factors, then diagnostic laparoscopy with intraoperative treatment of disease is indicated.

Surgery well performed is effective treatment for all stages of endometriosis and endometriomas, both for infertility and for pain. Repeat surgery, however, is rarely indicated because of limited results, so it is important to obtain the best possible result on the first surgery. Surgery is indicated for large endometriomas (>4 cm). Endometriosis has almost no effect on the IVF live birth rate unless ovarian reserve has been reduced by endometriomas or surgery, so endometriosis surgery should be performed by skilled and experienced surgeons.

Read about why oil-based contrast may be better than water-based contrast with HSG.

Oil-based contrast medium use in hysterosalpingography is associated with higher pregnancy rates compared with water-based contrast

Dreyer K, van Rijswijk J, Mijatovic V, et al. Oil-based or water-based contrast for hysterosalpingography in infertile women. N Engl J Med. 2017;376(21):2043-2052.

Hysterosalpingography (HSG) to assess tubal patency has been a mainstay of infertility diagnosis for decades. Some, but not all, studies also have suggested that pregnancy rates are higher after this tubal flushing procedure, especially if performed with oil contrast.^7,8 A recent multicenter, randomized, controlled trial by Dreyer and colleagues that compared ongoing pregnancy rates and other outcomes among women who had HSG with oil contrast versus with water contrast provides additional valuable information.⁹

Trial details

In this study, 1,294 infertile women in 27 academic, teaching and nonteaching hospitals were screened for trial eligibility; 1,119 women provided written informed consent. Of these, 557 women were randomly assigned to HSG with oil contrast and 562 to water contrast. The women had spontaneous menstrual cycles, had been attempting pregnancy for at least 1 year, and had indications for HSG.

Exclusion criteria were known endocrine disorders, fewer than 8 menstrual cycles per year, a high risk of tubal disease, iodine allergy, and a total motile sperm count after sperm wash of less than 3 million/mL in the male partner (or a total motile sperm count of less than 1 million/mL when an analysis after sperm wash was not performed).

Just prior to undergoing HSG, the women were randomly assigned to receive either oil contrast or water contrast medium. (The trial was not blinded to participants or caregivers.) HSG was performed according to local protocols using cervical vacuum cup, metal cannula (hysterophore), or balloon catheter and approximately 5 to 10 mL of contrast medium.

After HSG, couples received expectant management when the predicted likelihood of pregnancy within 12 months, based on the prognostic model of Hunault, was 30% or greater.¹⁰ IUI was offered for pregnancy likelihood less than 30%, mild male infertility, or failure after a period of expectant management. IUI with or without mild ovarian stimulation (2-3 follicles) with clomiphene or gonadotropins was initiated after a minimum of 2 months of expectant management after HSG.

The primary outcome measure was ongoing pregnancy, defined as a positive fetal heartbeat on ultrasonographic examination after 12 weeks of gestation, with the first day of the last menstrual cycle for the pregnancy within 6 months after randomization. Secondary outcome measures were clinical pregnancy, live birth, miscarriage, ectopic pregnancy, time to pregnancy, and pain scores after HSG. All data were analyzed according to intention-to-treat.

Pregnancy rates increased with oil-contrast HSG

The baseline characteristics of the 2 groups were similar. HSG showed bilateral tubal patency in 477 of 554 women (86.1%) in the oil contrast group and in 491 of 554 women (88.6%) who received the water contrast (rate ratio, 0.97; 95% confidence interval [CI], 0.93-1.02). Bilateral tubal occlusion occurred in 9 women in the oil group (1.6%) and in 13 in the water group (2.3%) (relative risk, 0.69; 95% CI, 0.30-1.61).

A total of 58.3% of the women assigned to oil contrast and 57.2% of those assigned to water contrast received expectant management. Similar percentages of women in the oil group and in the water group underwent IUI (39.7% and 41.0%, respectively), IVF or intracytoplasmic sperm injection (ICSI) (2.3% and 2.2%), laparoscopy (6.2% in each group), and hysteroscopy (4.4% and 4.2%).

Ongoing pregnancy occurred in 220 of 554 women (39.7%) in the oil contrast group and in 161 of 554 women (29.1%) in the water contrast group (rate ratio, 1.37; 95% CI, 1.16-1.61; P<.001). The median time to the onset of pregnancy in the oil group was 2.7 months (interquartile range, 1.5-4.7) (FIGURE 2), while in the water group it was 3.1 months (interquartile range, 1.6-4.8) (P = .44).

While the proportion of women getting pregnant with or without the different interventions was similar in both groups, the live birth rate was 38.8% in the oil group versus 28.1% in the water group (rate ratio, 1.38; 95% CI, 1.17-1.64; P<.001). Three of 554 women (0.5%) assigned to oil contrast and 4 of  554 women (0.7%) in the water contrast group had an adverse event during the trial period. Three women (1.4%), all in the oil group, delivered a child with a congenital anomaly.

Why this study is important

This is the largest and best methodologic study on this clinical issue. It showed higher pregnancy and live birth rates within 6 months of HSG performed with oil compared with water. Although the study was not blinded, the group similarities and objective outcomes support minimal bias. Importantly, these results can be generalized only to women with similar inclusion characteristics. 

It is unclear why oil HSG might enhance fertility. Suggested mechanisms include flushing of debris and/or mucous plugs or an effect on peritoneal macrophages or endometrial receptivity. Since HSG is minimally invasive and inexpensive, and the 10% increase in pregnancy rates corresponds to an NNT of 10, it is reasonable to consider, although formal cost-effectiveness data are lacking.

Concerns include the rare theoretical risk of intravasation with subsequent allergic  reaction or fat embolism. Three infants in the oil group and none in the water group had congenital anomalies. This is likely due to chance, since this rate is not higher than that in the general population and no other data suggest an increased risk. Comparison of these results with other new techniques, such as sonohysterography (saline infusion sonogram), awaits further studies.

Recommendation

HSG with oil contrast should be considered a potential therapeutic as well as diagnostic intervention in selected patients.

Read about new definitions of infertility terminology you should know.

Infertility glossary is newly updated

Zegers-Hochchild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393-406.

Terms and definitions used in infertility and fertility care frequently have had different meanings for different stakeholders, especially on a global basis. This can result in misunderstandings and inappropriate interpretation and comparison of published information and research. To help address these issues, international fertility organizations recently developed an updated glossary on infertilityterminology.

The consensus process for updating the glossary

The International Glossary on Infertility and Fertility Care, 2017, was recently published simultaneously in Fertility and Sterility and Human Reproduction. This is the second revision; the first glossary was published in 2006 and revised in 2009. This revision's 25 lead experts began work in 2014. Their teams of professionals interacted by electronic mail, at international and regional society meetings, and at 2 consultations held in Geneva, Switzerland. This glossary represents consensus agreement reached on 283 evidence-driven terms and definitions.

The work was led by the International Committee for Monitoring Assisted Reproductive Technologies in partnership with the American Society for Reproductive Medicine, European Society of Human Reproduction and Embryology, International Federation of Fertility Societies, March of Dimes, African Fertility Society, Groupe Inter-africain d'Etude de Recherche et d'Application sur la Fertilité, Asian Pacific Initiative on Reproduction, Middle East Fertility Society, Red Latinoamericana de Reproducción Asistida, and the International Federation of Gynecology and Obstetrics.

All together, 108 international professional experts (clinicians, basic scientists, epidemiologists, and social scientists), along with national and regional representatives of infertile persons, participated in the development of this evidence-base driven glossary. As such, these definitions now set the standard for international communication among clinicians, scientists, and policymakers.

Definition of infertility is broadened

The definitions take account of ethics, human rights, cultural sensitivities, ethnic minorities, and gender equality. For example, the first modification included broadening the concept of infertility to be an "impairment of individuals" in their capacity to reproduce, irrespective of whether the individual has a partner. (See “Broadened definition of infertility” below). Reproductive rights are individual human rights and do not depend on a relationship with another individual. The revised definition also reinforces the concept of infertility as a disease that can generate an impairment of function. 

New--and changed--definitions

Certain terms need to be consistent with those used currently internationally, for example, at which gestational age a miscarriage/abortion becomes a stillbirth.

Some terms are confusing, such as subfertility, which does not define a different or less severe fertility status than infertility, does not exist before infertility is diagnosed, and should not be confused with sterility, which is a permanent state of infertility. The term subfertility therefore is redundant and has been removed and replaced by infertility (See “Some terms with an important new definition” below).

In a different context, the term conception, and its derivatives such as conceiving or conceived, was removed because it cannot be described biologically during the process of reproduction. Instead, terms such as fertilization, implantation, pregnancy, and live birth should be used.

Important male terms also changed: oligospermia is a term for low semen volume that is now replaced by hypospermia to avoid confusion with oligozoospermia, which is low concentration of spermatozoa in the ejaculate below the lower reference limit. When reporting results, the reference criteria should be specified.

Lastly, owing to the lack of standardization in determining the burden of infertility, and to better ensure comparability of prevalence data published globally, this glossary includes definitions for terms frequently used in epidemiology and public health. Examples include voluntary and involuntary childlessness, primary and secondary infertility, fertility care, fecundity, and fecundability, among others. 

Getting the word out

The glossary has been approved by all of the participating organizations who are assisting in its distribution. It is being presented at national and international meetings and is used in The FIGO Fertility Toolbox (www.fertilitytool.com). It is hoped that all professionals and other stakeholders will begin to use its terminology globally to provide quality care and ensure consistency in registering specific fertility care interventions and more accurate reporting of their outcomes.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Clinicians always should consider endometriosis in the diagnostic work-up of an infertility patient. But the diagnosis of endometriosis is often difficult, and management is complex. In this Update, we summarize international consensus documents on endometriosis with the aim of enhancing clinicians’ ability to make evidence-based decisions. In addition, we explore the interesting results of a large hysterosalpingography trial in which 2 different contrast mediums were used. Finally, we urge all clinicians to adapt the new standardized lexicon of infertility and fertility care terms that comprise the recently revised international glossary.

Endometriosis and infertility: The knowns and unknowns

Johnson NP, Hummelshoj L, Adamson GD, et al; World Endometriosis Society Sao Paulo Consortium. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32(2):315-324.

Johnson NP, Hummelshoj L; World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552-1568.

Rogers PA, Adamson GD, Al-Jefout M, et al; WES/WERF Consortium for Research Priorities in Endometriosis. Research priorities for endometriosis. Reprod Sci. 2017;24(2):202-226.

Endometriosis is defined as "a disease characterized by the presence of endometrium-like epithelium and stroma outside the endometrium and myometrium. Intrapelvic endometriosis can be located superficially on the peritoneum (peritoneal endometriosis), can extend 5 mm or more beneath the peritoneum (deep endometriosis) or can be present as an ovarian endometriotic cyst (endometrioma)."¹ Always consider endometriosis in the infertile patient.

Although many professional societies and numerous Cochrane Database Systematic Reviews have provided guidelines on endometriosis, controversy and uncertainty remain. The World Endometriosis Society (WES) and the World Endometriosis Research Foundation (WERF), however, have now published several consensus documents that assess the global literature and professional organization guidelines in a structured, consensus-driven process.^2-4 These WES and WERF documents consolidate known information and can be used to inform the clinician in making evidence-linked diagnostic and treatment decisions. Recommendations offered in this discussion are based on those documents.

Establishing the diagnosis can be difficult

Diagnosis of endometriosis is often difficult and is delayed an average of 7 years from onset of symptoms. These include severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms (bowel or bladder associated) with or without abnormal bleeding, chronic fatigue, and infertility. A major difficulty is that the predictive value of any one symptom or set of symptoms remains uncertain, as each of these symptoms can have other causes, and a significant proportion of affected women are asymptomatic.

For a definitive diagnosis of endometriosis, visual inspection of the pelvis at laparoscopy is the gold standard investigation, unless disease is visible in the vagina or elsewhere. Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is present is controversial: visual inspection usually is adequate, but histologic confirmation of at least one lesion is ideal. In cases of ovarian endometrioma (>4 cm in diameter) and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy.

Compared with laparoscopy, transvaginal ultrasonography (TVUS) has no value in diagnosing peritoneal endometriosis, but it is a useful tool for both making and excluding the diagnosis of an ovarian endometrioma. TVUS may have a role in the diagnosis of disease involving the bladder or rectum.

At present, evidence is insufficient to indicate that magnetic resonance imaging (MRI) is useful for diagnosing or excluding endometriosis compared with laparoscopy. MRI should be reserved for when ultrasound results are equivocal in cases of rectovaginal or bladder endometriosis.

Serum cancer antigen 125 (CA 125) levels may be elevated in endometriosis. However, measuring serum CA 125 levels has no value as a diagnostic tool.

No fertility benefit with ovarian suppression

More than 2 dozen randomized controlled trials (RCTs) provide strong evidence that there is no fertility benefit from ovarian suppression. The drug costs and delayed time to pregnancy mean that ovarian suppression with oral contraceptives, other progestational agents, or gonadotropin-releasing hormone (GnRH) agonists before fertility treatment is not indicated, with the possible exception of using it prior to in vitro fertilization (IVF).

Ovarian suppression also has been suggested as beneficial in conjunction with surgery. However, at least 16 RCTs have failed to show fertility improvement when ovarian suppression is given either preoperatively or postoperatively. Again, the delay in attempting pregnancy, drug costs, and adverse effects render ovarian suppression not appropriate.

While ovarian suppression has not been shown to increase pregnancy rates, ovarian stimulation (OS) likely does, especially when combined with intrauterine insemination (IUI).⁵

Laparoscopy: Appropriate for selected patients

A major decision for clinicians and patients dealing with infertility is whether to perform a laparoscopy, both for diagnostic and for treatment reasons. Currently, data are insufficient to recommend laparoscopic surgery prior to OS/IUI unless there is a history of evidence of anatomic disease and/or the patient has sufficient pain to justify the physical, emotional, financial, and time costs of laparoscopy. Laparoscopy therefore can be considered as possibly appropriate in younger women (<37 years of age) with short duration of infertility (<4 years), normal male factor, normal or treatable uterus, normal or treatable ovulation disorder, and limited prior treatment.

It is important to consider what disease might be found and how much of an increase in fertility can be obtained by treatment, so that the number needed to treat (NNT) can be used as an estimate of the potential value of laparoscopy in a given patient. A patient also should have no contraindications to laparoscopy and accept 9 to 15 months of attempting pregnancy before undergoing IVF treatment.

When laparoscopy is performed for minimal to mild disease, the odds ratio for pregnancy is 1.66 with treatment. It is important to remove all visible disease without injuring healthy tissue. When disease is moderate to severe, there is often severe anatomic distortion and a very low background pregnancy rate. Numerous uncontrolled trials show benefit of operative laparoscopy, especially for invasive, adhesive, and cystic endometriosis. However, repeat surgery is rarely indicated. After surgery, the Endometriosis Fertility Index (EFI) can be used to determine prognosis and plan management (FIGURE  1).⁶ An easy-to-use electronic EFI calculator is available online at www.endometriosisefi.com.

Management of endometriomas

Endometriomas are often operated on because of pain. Initial pain relief occurs in 60% to 100% of patients, but cysts recur following stripping about 10% of the time, and drainage without stripping, about 20%. With recurrence, pain is present about 75% of the time.

Pregnancy rates following endometrioma treatment depend on patient age and the status of the pelvis following operative intervention. This can be determined from the EFI. Often, the dilemma with endometriomas is how aggressive to be in removing them. The principles involved are to remove all the cyst wall if possible, but absolutely to minimize ovarian tissue damage, because reduced ovarian reserve is a possible major negative consequence of ovarian surgery. 

Recommendations

While endometriosis is often a cause of infertility, often infertile patients do not have endometriosis. A careful history, physical examination, and ultrasonography, and possibly other imaging studies, are prerequisites to careful clinical judgment in diagnosing and treating infertile patients who might or do have endometriosis.

When pelvic pain is present, initially nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives (OCs), progestational agents, or an intrauterine device can be helpful. These ovarian suppression medications do not increase fertility, however, and should be stopped in any patient who desires to get pregnant.

When pelvic and male fertility factors appear reasonably normal (even if minimal or mild endometriosis is suspected), treatment with clomiphene 100 mg on cycle days 3 through 7 and IUI for 3 to 6 cycles is an effective first step. However, if the patient has persistent pain and/or infertility without other significant infertility factors, then diagnostic laparoscopy with intraoperative treatment of disease is indicated.

Surgery well performed is effective treatment for all stages of endometriosis and endometriomas, both for infertility and for pain. Repeat surgery, however, is rarely indicated because of limited results, so it is important to obtain the best possible result on the first surgery. Surgery is indicated for large endometriomas (>4 cm). Endometriosis has almost no effect on the IVF live birth rate unless ovarian reserve has been reduced by endometriomas or surgery, so endometriosis surgery should be performed by skilled and experienced surgeons.

Read about why oil-based contrast may be better than water-based contrast with HSG.

Oil-based contrast medium use in hysterosalpingography is associated with higher pregnancy rates compared with water-based contrast

Dreyer K, van Rijswijk J, Mijatovic V, et al. Oil-based or water-based contrast for hysterosalpingography in infertile women. N Engl J Med. 2017;376(21):2043-2052.

Hysterosalpingography (HSG) to assess tubal patency has been a mainstay of infertility diagnosis for decades. Some, but not all, studies also have suggested that pregnancy rates are higher after this tubal flushing procedure, especially if performed with oil contrast.^7,8 A recent multicenter, randomized, controlled trial by Dreyer and colleagues that compared ongoing pregnancy rates and other outcomes among women who had HSG with oil contrast versus with water contrast provides additional valuable information.⁹

Trial details

In this study, 1,294 infertile women in 27 academic, teaching and nonteaching hospitals were screened for trial eligibility; 1,119 women provided written informed consent. Of these, 557 women were randomly assigned to HSG with oil contrast and 562 to water contrast. The women had spontaneous menstrual cycles, had been attempting pregnancy for at least 1 year, and had indications for HSG.

Exclusion criteria were known endocrine disorders, fewer than 8 menstrual cycles per year, a high risk of tubal disease, iodine allergy, and a total motile sperm count after sperm wash of less than 3 million/mL in the male partner (or a total motile sperm count of less than 1 million/mL when an analysis after sperm wash was not performed).

Just prior to undergoing HSG, the women were randomly assigned to receive either oil contrast or water contrast medium. (The trial was not blinded to participants or caregivers.) HSG was performed according to local protocols using cervical vacuum cup, metal cannula (hysterophore), or balloon catheter and approximately 5 to 10 mL of contrast medium.

After HSG, couples received expectant management when the predicted likelihood of pregnancy within 12 months, based on the prognostic model of Hunault, was 30% or greater.¹⁰ IUI was offered for pregnancy likelihood less than 30%, mild male infertility, or failure after a period of expectant management. IUI with or without mild ovarian stimulation (2-3 follicles) with clomiphene or gonadotropins was initiated after a minimum of 2 months of expectant management after HSG.

The primary outcome measure was ongoing pregnancy, defined as a positive fetal heartbeat on ultrasonographic examination after 12 weeks of gestation, with the first day of the last menstrual cycle for the pregnancy within 6 months after randomization. Secondary outcome measures were clinical pregnancy, live birth, miscarriage, ectopic pregnancy, time to pregnancy, and pain scores after HSG. All data were analyzed according to intention-to-treat.

Pregnancy rates increased with oil-contrast HSG

The baseline characteristics of the 2 groups were similar. HSG showed bilateral tubal patency in 477 of 554 women (86.1%) in the oil contrast group and in 491 of 554 women (88.6%) who received the water contrast (rate ratio, 0.97; 95% confidence interval [CI], 0.93-1.02). Bilateral tubal occlusion occurred in 9 women in the oil group (1.6%) and in 13 in the water group (2.3%) (relative risk, 0.69; 95% CI, 0.30-1.61).

A total of 58.3% of the women assigned to oil contrast and 57.2% of those assigned to water contrast received expectant management. Similar percentages of women in the oil group and in the water group underwent IUI (39.7% and 41.0%, respectively), IVF or intracytoplasmic sperm injection (ICSI) (2.3% and 2.2%), laparoscopy (6.2% in each group), and hysteroscopy (4.4% and 4.2%).

Ongoing pregnancy occurred in 220 of 554 women (39.7%) in the oil contrast group and in 161 of 554 women (29.1%) in the water contrast group (rate ratio, 1.37; 95% CI, 1.16-1.61; P<.001). The median time to the onset of pregnancy in the oil group was 2.7 months (interquartile range, 1.5-4.7) (FIGURE 2), while in the water group it was 3.1 months (interquartile range, 1.6-4.8) (P = .44).

While the proportion of women getting pregnant with or without the different interventions was similar in both groups, the live birth rate was 38.8% in the oil group versus 28.1% in the water group (rate ratio, 1.38; 95% CI, 1.17-1.64; P<.001). Three of 554 women (0.5%) assigned to oil contrast and 4 of  554 women (0.7%) in the water contrast group had an adverse event during the trial period. Three women (1.4%), all in the oil group, delivered a child with a congenital anomaly.

Why this study is important

This is the largest and best methodologic study on this clinical issue. It showed higher pregnancy and live birth rates within 6 months of HSG performed with oil compared with water. Although the study was not blinded, the group similarities and objective outcomes support minimal bias. Importantly, these results can be generalized only to women with similar inclusion characteristics. 

It is unclear why oil HSG might enhance fertility. Suggested mechanisms include flushing of debris and/or mucous plugs or an effect on peritoneal macrophages or endometrial receptivity. Since HSG is minimally invasive and inexpensive, and the 10% increase in pregnancy rates corresponds to an NNT of 10, it is reasonable to consider, although formal cost-effectiveness data are lacking.

Concerns include the rare theoretical risk of intravasation with subsequent allergic  reaction or fat embolism. Three infants in the oil group and none in the water group had congenital anomalies. This is likely due to chance, since this rate is not higher than that in the general population and no other data suggest an increased risk. Comparison of these results with other new techniques, such as sonohysterography (saline infusion sonogram), awaits further studies.

Recommendation

HSG with oil contrast should be considered a potential therapeutic as well as diagnostic intervention in selected patients.

Read about new definitions of infertility terminology you should know.

Infertility glossary is newly updated

Zegers-Hochchild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393-406.

Terms and definitions used in infertility and fertility care frequently have had different meanings for different stakeholders, especially on a global basis. This can result in misunderstandings and inappropriate interpretation and comparison of published information and research. To help address these issues, international fertility organizations recently developed an updated glossary on infertilityterminology.

The consensus process for updating the glossary

The International Glossary on Infertility and Fertility Care, 2017, was recently published simultaneously in Fertility and Sterility and Human Reproduction. This is the second revision; the first glossary was published in 2006 and revised in 2009. This revision's 25 lead experts began work in 2014. Their teams of professionals interacted by electronic mail, at international and regional society meetings, and at 2 consultations held in Geneva, Switzerland. This glossary represents consensus agreement reached on 283 evidence-driven terms and definitions.

The work was led by the International Committee for Monitoring Assisted Reproductive Technologies in partnership with the American Society for Reproductive Medicine, European Society of Human Reproduction and Embryology, International Federation of Fertility Societies, March of Dimes, African Fertility Society, Groupe Inter-africain d'Etude de Recherche et d'Application sur la Fertilité, Asian Pacific Initiative on Reproduction, Middle East Fertility Society, Red Latinoamericana de Reproducción Asistida, and the International Federation of Gynecology and Obstetrics.

All together, 108 international professional experts (clinicians, basic scientists, epidemiologists, and social scientists), along with national and regional representatives of infertile persons, participated in the development of this evidence-base driven glossary. As such, these definitions now set the standard for international communication among clinicians, scientists, and policymakers.

Definition of infertility is broadened

The definitions take account of ethics, human rights, cultural sensitivities, ethnic minorities, and gender equality. For example, the first modification included broadening the concept of infertility to be an "impairment of individuals" in their capacity to reproduce, irrespective of whether the individual has a partner. (See “Broadened definition of infertility” below). Reproductive rights are individual human rights and do not depend on a relationship with another individual. The revised definition also reinforces the concept of infertility as a disease that can generate an impairment of function. 

New--and changed--definitions

Certain terms need to be consistent with those used currently internationally, for example, at which gestational age a miscarriage/abortion becomes a stillbirth.

Some terms are confusing, such as subfertility, which does not define a different or less severe fertility status than infertility, does not exist before infertility is diagnosed, and should not be confused with sterility, which is a permanent state of infertility. The term subfertility therefore is redundant and has been removed and replaced by infertility (See “Some terms with an important new definition” below).

In a different context, the term conception, and its derivatives such as conceiving or conceived, was removed because it cannot be described biologically during the process of reproduction. Instead, terms such as fertilization, implantation, pregnancy, and live birth should be used.

Important male terms also changed: oligospermia is a term for low semen volume that is now replaced by hypospermia to avoid confusion with oligozoospermia, which is low concentration of spermatozoa in the ejaculate below the lower reference limit. When reporting results, the reference criteria should be specified.

Lastly, owing to the lack of standardization in determining the burden of infertility, and to better ensure comparability of prevalence data published globally, this glossary includes definitions for terms frequently used in epidemiology and public health. Examples include voluntary and involuntary childlessness, primary and secondary infertility, fertility care, fecundity, and fecundability, among others. 

Getting the word out

The glossary has been approved by all of the participating organizations who are assisting in its distribution. It is being presented at national and international meetings and is used in The FIGO Fertility Toolbox (www.fertilitytool.com). It is hoped that all professionals and other stakeholders will begin to use its terminology globally to provide quality care and ensure consistency in registering specific fertility care interventions and more accurate reporting of their outcomes.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Clinicians always should consider endometriosis in the diagnostic work-up of an infertility patient. But the diagnosis of endometriosis is often difficult, and management is complex. In this Update, we summarize international consensus documents on endometriosis with the aim of enhancing clinicians’ ability to make evidence-based decisions. In addition, we explore the interesting results of a large hysterosalpingography trial in which 2 different contrast mediums were used. Finally, we urge all clinicians to adapt the new standardized lexicon of infertility and fertility care terms that comprise the recently revised international glossary.

Endometriosis and infertility: The knowns and unknowns

Johnson NP, Hummelshoj L, Adamson GD, et al; World Endometriosis Society Sao Paulo Consortium. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32(2):315-324.

Johnson NP, Hummelshoj L; World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod. 2013;28(6):1552-1568.

Rogers PA, Adamson GD, Al-Jefout M, et al; WES/WERF Consortium for Research Priorities in Endometriosis. Research priorities for endometriosis. Reprod Sci. 2017;24(2):202-226.

Endometriosis is defined as "a disease characterized by the presence of endometrium-like epithelium and stroma outside the endometrium and myometrium. Intrapelvic endometriosis can be located superficially on the peritoneum (peritoneal endometriosis), can extend 5 mm or more beneath the peritoneum (deep endometriosis) or can be present as an ovarian endometriotic cyst (endometrioma)."¹ Always consider endometriosis in the infertile patient.

Although many professional societies and numerous Cochrane Database Systematic Reviews have provided guidelines on endometriosis, controversy and uncertainty remain. The World Endometriosis Society (WES) and the World Endometriosis Research Foundation (WERF), however, have now published several consensus documents that assess the global literature and professional organization guidelines in a structured, consensus-driven process.^2-4 These WES and WERF documents consolidate known information and can be used to inform the clinician in making evidence-linked diagnostic and treatment decisions. Recommendations offered in this discussion are based on those documents.

Establishing the diagnosis can be difficult

Diagnosis of endometriosis is often difficult and is delayed an average of 7 years from onset of symptoms. These include severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms (bowel or bladder associated) with or without abnormal bleeding, chronic fatigue, and infertility. A major difficulty is that the predictive value of any one symptom or set of symptoms remains uncertain, as each of these symptoms can have other causes, and a significant proportion of affected women are asymptomatic.

For a definitive diagnosis of endometriosis, visual inspection of the pelvis at laparoscopy is the gold standard investigation, unless disease is visible in the vagina or elsewhere. Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is present is controversial: visual inspection usually is adequate, but histologic confirmation of at least one lesion is ideal. In cases of ovarian endometrioma (>4 cm in diameter) and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy.

Compared with laparoscopy, transvaginal ultrasonography (TVUS) has no value in diagnosing peritoneal endometriosis, but it is a useful tool for both making and excluding the diagnosis of an ovarian endometrioma. TVUS may have a role in the diagnosis of disease involving the bladder or rectum.

At present, evidence is insufficient to indicate that magnetic resonance imaging (MRI) is useful for diagnosing or excluding endometriosis compared with laparoscopy. MRI should be reserved for when ultrasound results are equivocal in cases of rectovaginal or bladder endometriosis.

Serum cancer antigen 125 (CA 125) levels may be elevated in endometriosis. However, measuring serum CA 125 levels has no value as a diagnostic tool.

No fertility benefit with ovarian suppression

More than 2 dozen randomized controlled trials (RCTs) provide strong evidence that there is no fertility benefit from ovarian suppression. The drug costs and delayed time to pregnancy mean that ovarian suppression with oral contraceptives, other progestational agents, or gonadotropin-releasing hormone (GnRH) agonists before fertility treatment is not indicated, with the possible exception of using it prior to in vitro fertilization (IVF).

Ovarian suppression also has been suggested as beneficial in conjunction with surgery. However, at least 16 RCTs have failed to show fertility improvement when ovarian suppression is given either preoperatively or postoperatively. Again, the delay in attempting pregnancy, drug costs, and adverse effects render ovarian suppression not appropriate.

While ovarian suppression has not been shown to increase pregnancy rates, ovarian stimulation (OS) likely does, especially when combined with intrauterine insemination (IUI).⁵

Laparoscopy: Appropriate for selected patients

A major decision for clinicians and patients dealing with infertility is whether to perform a laparoscopy, both for diagnostic and for treatment reasons. Currently, data are insufficient to recommend laparoscopic surgery prior to OS/IUI unless there is a history of evidence of anatomic disease and/or the patient has sufficient pain to justify the physical, emotional, financial, and time costs of laparoscopy. Laparoscopy therefore can be considered as possibly appropriate in younger women (<37 years of age) with short duration of infertility (<4 years), normal male factor, normal or treatable uterus, normal or treatable ovulation disorder, and limited prior treatment.

It is important to consider what disease might be found and how much of an increase in fertility can be obtained by treatment, so that the number needed to treat (NNT) can be used as an estimate of the potential value of laparoscopy in a given patient. A patient also should have no contraindications to laparoscopy and accept 9 to 15 months of attempting pregnancy before undergoing IVF treatment.

When laparoscopy is performed for minimal to mild disease, the odds ratio for pregnancy is 1.66 with treatment. It is important to remove all visible disease without injuring healthy tissue. When disease is moderate to severe, there is often severe anatomic distortion and a very low background pregnancy rate. Numerous uncontrolled trials show benefit of operative laparoscopy, especially for invasive, adhesive, and cystic endometriosis. However, repeat surgery is rarely indicated. After surgery, the Endometriosis Fertility Index (EFI) can be used to determine prognosis and plan management (FIGURE  1).⁶ An easy-to-use electronic EFI calculator is available online at www.endometriosisefi.com.

Management of endometriomas

Endometriomas are often operated on because of pain. Initial pain relief occurs in 60% to 100% of patients, but cysts recur following stripping about 10% of the time, and drainage without stripping, about 20%. With recurrence, pain is present about 75% of the time.

Pregnancy rates following endometrioma treatment depend on patient age and the status of the pelvis following operative intervention. This can be determined from the EFI. Often, the dilemma with endometriomas is how aggressive to be in removing them. The principles involved are to remove all the cyst wall if possible, but absolutely to minimize ovarian tissue damage, because reduced ovarian reserve is a possible major negative consequence of ovarian surgery. 

Recommendations

While endometriosis is often a cause of infertility, often infertile patients do not have endometriosis. A careful history, physical examination, and ultrasonography, and possibly other imaging studies, are prerequisites to careful clinical judgment in diagnosing and treating infertile patients who might or do have endometriosis.

When pelvic pain is present, initially nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives (OCs), progestational agents, or an intrauterine device can be helpful. These ovarian suppression medications do not increase fertility, however, and should be stopped in any patient who desires to get pregnant.

When pelvic and male fertility factors appear reasonably normal (even if minimal or mild endometriosis is suspected), treatment with clomiphene 100 mg on cycle days 3 through 7 and IUI for 3 to 6 cycles is an effective first step. However, if the patient has persistent pain and/or infertility without other significant infertility factors, then diagnostic laparoscopy with intraoperative treatment of disease is indicated.

Surgery well performed is effective treatment for all stages of endometriosis and endometriomas, both for infertility and for pain. Repeat surgery, however, is rarely indicated because of limited results, so it is important to obtain the best possible result on the first surgery. Surgery is indicated for large endometriomas (>4 cm). Endometriosis has almost no effect on the IVF live birth rate unless ovarian reserve has been reduced by endometriomas or surgery, so endometriosis surgery should be performed by skilled and experienced surgeons.

Read about why oil-based contrast may be better than water-based contrast with HSG.

Oil-based contrast medium use in hysterosalpingography is associated with higher pregnancy rates compared with water-based contrast

Dreyer K, van Rijswijk J, Mijatovic V, et al. Oil-based or water-based contrast for hysterosalpingography in infertile women. N Engl J Med. 2017;376(21):2043-2052.

Hysterosalpingography (HSG) to assess tubal patency has been a mainstay of infertility diagnosis for decades. Some, but not all, studies also have suggested that pregnancy rates are higher after this tubal flushing procedure, especially if performed with oil contrast.^7,8 A recent multicenter, randomized, controlled trial by Dreyer and colleagues that compared ongoing pregnancy rates and other outcomes among women who had HSG with oil contrast versus with water contrast provides additional valuable information.⁹

Trial details

In this study, 1,294 infertile women in 27 academic, teaching and nonteaching hospitals were screened for trial eligibility; 1,119 women provided written informed consent. Of these, 557 women were randomly assigned to HSG with oil contrast and 562 to water contrast. The women had spontaneous menstrual cycles, had been attempting pregnancy for at least 1 year, and had indications for HSG.

Exclusion criteria were known endocrine disorders, fewer than 8 menstrual cycles per year, a high risk of tubal disease, iodine allergy, and a total motile sperm count after sperm wash of less than 3 million/mL in the male partner (or a total motile sperm count of less than 1 million/mL when an analysis after sperm wash was not performed).

Just prior to undergoing HSG, the women were randomly assigned to receive either oil contrast or water contrast medium. (The trial was not blinded to participants or caregivers.) HSG was performed according to local protocols using cervical vacuum cup, metal cannula (hysterophore), or balloon catheter and approximately 5 to 10 mL of contrast medium.

After HSG, couples received expectant management when the predicted likelihood of pregnancy within 12 months, based on the prognostic model of Hunault, was 30% or greater.¹⁰ IUI was offered for pregnancy likelihood less than 30%, mild male infertility, or failure after a period of expectant management. IUI with or without mild ovarian stimulation (2-3 follicles) with clomiphene or gonadotropins was initiated after a minimum of 2 months of expectant management after HSG.

The primary outcome measure was ongoing pregnancy, defined as a positive fetal heartbeat on ultrasonographic examination after 12 weeks of gestation, with the first day of the last menstrual cycle for the pregnancy within 6 months after randomization. Secondary outcome measures were clinical pregnancy, live birth, miscarriage, ectopic pregnancy, time to pregnancy, and pain scores after HSG. All data were analyzed according to intention-to-treat.

Pregnancy rates increased with oil-contrast HSG

The baseline characteristics of the 2 groups were similar. HSG showed bilateral tubal patency in 477 of 554 women (86.1%) in the oil contrast group and in 491 of 554 women (88.6%) who received the water contrast (rate ratio, 0.97; 95% confidence interval [CI], 0.93-1.02). Bilateral tubal occlusion occurred in 9 women in the oil group (1.6%) and in 13 in the water group (2.3%) (relative risk, 0.69; 95% CI, 0.30-1.61).

A total of 58.3% of the women assigned to oil contrast and 57.2% of those assigned to water contrast received expectant management. Similar percentages of women in the oil group and in the water group underwent IUI (39.7% and 41.0%, respectively), IVF or intracytoplasmic sperm injection (ICSI) (2.3% and 2.2%), laparoscopy (6.2% in each group), and hysteroscopy (4.4% and 4.2%).

Ongoing pregnancy occurred in 220 of 554 women (39.7%) in the oil contrast group and in 161 of 554 women (29.1%) in the water contrast group (rate ratio, 1.37; 95% CI, 1.16-1.61; P<.001). The median time to the onset of pregnancy in the oil group was 2.7 months (interquartile range, 1.5-4.7) (FIGURE 2), while in the water group it was 3.1 months (interquartile range, 1.6-4.8) (P = .44).

While the proportion of women getting pregnant with or without the different interventions was similar in both groups, the live birth rate was 38.8% in the oil group versus 28.1% in the water group (rate ratio, 1.38; 95% CI, 1.17-1.64; P<.001). Three of 554 women (0.5%) assigned to oil contrast and 4 of  554 women (0.7%) in the water contrast group had an adverse event during the trial period. Three women (1.4%), all in the oil group, delivered a child with a congenital anomaly.

Why this study is important

This is the largest and best methodologic study on this clinical issue. It showed higher pregnancy and live birth rates within 6 months of HSG performed with oil compared with water. Although the study was not blinded, the group similarities and objective outcomes support minimal bias. Importantly, these results can be generalized only to women with similar inclusion characteristics. 

It is unclear why oil HSG might enhance fertility. Suggested mechanisms include flushing of debris and/or mucous plugs or an effect on peritoneal macrophages or endometrial receptivity. Since HSG is minimally invasive and inexpensive, and the 10% increase in pregnancy rates corresponds to an NNT of 10, it is reasonable to consider, although formal cost-effectiveness data are lacking.

Concerns include the rare theoretical risk of intravasation with subsequent allergic  reaction or fat embolism. Three infants in the oil group and none in the water group had congenital anomalies. This is likely due to chance, since this rate is not higher than that in the general population and no other data suggest an increased risk. Comparison of these results with other new techniques, such as sonohysterography (saline infusion sonogram), awaits further studies.

Recommendation

HSG with oil contrast should be considered a potential therapeutic as well as diagnostic intervention in selected patients.

Read about new definitions of infertility terminology you should know.

Infertility glossary is newly updated

Zegers-Hochchild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017;108(3):393-406.

Terms and definitions used in infertility and fertility care frequently have had different meanings for different stakeholders, especially on a global basis. This can result in misunderstandings and inappropriate interpretation and comparison of published information and research. To help address these issues, international fertility organizations recently developed an updated glossary on infertilityterminology.

The consensus process for updating the glossary

The International Glossary on Infertility and Fertility Care, 2017, was recently published simultaneously in Fertility and Sterility and Human Reproduction. This is the second revision; the first glossary was published in 2006 and revised in 2009. This revision's 25 lead experts began work in 2014. Their teams of professionals interacted by electronic mail, at international and regional society meetings, and at 2 consultations held in Geneva, Switzerland. This glossary represents consensus agreement reached on 283 evidence-driven terms and definitions.

The work was led by the International Committee for Monitoring Assisted Reproductive Technologies in partnership with the American Society for Reproductive Medicine, European Society of Human Reproduction and Embryology, International Federation of Fertility Societies, March of Dimes, African Fertility Society, Groupe Inter-africain d'Etude de Recherche et d'Application sur la Fertilité, Asian Pacific Initiative on Reproduction, Middle East Fertility Society, Red Latinoamericana de Reproducción Asistida, and the International Federation of Gynecology and Obstetrics.

All together, 108 international professional experts (clinicians, basic scientists, epidemiologists, and social scientists), along with national and regional representatives of infertile persons, participated in the development of this evidence-base driven glossary. As such, these definitions now set the standard for international communication among clinicians, scientists, and policymakers.

Definition of infertility is broadened

The definitions take account of ethics, human rights, cultural sensitivities, ethnic minorities, and gender equality. For example, the first modification included broadening the concept of infertility to be an "impairment of individuals" in their capacity to reproduce, irrespective of whether the individual has a partner. (See “Broadened definition of infertility” below). Reproductive rights are individual human rights and do not depend on a relationship with another individual. The revised definition also reinforces the concept of infertility as a disease that can generate an impairment of function. 

New--and changed--definitions

Certain terms need to be consistent with those used currently internationally, for example, at which gestational age a miscarriage/abortion becomes a stillbirth.

Some terms are confusing, such as subfertility, which does not define a different or less severe fertility status than infertility, does not exist before infertility is diagnosed, and should not be confused with sterility, which is a permanent state of infertility. The term subfertility therefore is redundant and has been removed and replaced by infertility (See “Some terms with an important new definition” below).

In a different context, the term conception, and its derivatives such as conceiving or conceived, was removed because it cannot be described biologically during the process of reproduction. Instead, terms such as fertilization, implantation, pregnancy, and live birth should be used.

Important male terms also changed: oligospermia is a term for low semen volume that is now replaced by hypospermia to avoid confusion with oligozoospermia, which is low concentration of spermatozoa in the ejaculate below the lower reference limit. When reporting results, the reference criteria should be specified.

Lastly, owing to the lack of standardization in determining the burden of infertility, and to better ensure comparability of prevalence data published globally, this glossary includes definitions for terms frequently used in epidemiology and public health. Examples include voluntary and involuntary childlessness, primary and secondary infertility, fertility care, fecundity, and fecundability, among others. 

Getting the word out

The glossary has been approved by all of the participating organizations who are assisting in its distribution. It is being presented at national and international meetings and is used in The FIGO Fertility Toolbox (www.fertilitytool.com). It is hoped that all professionals and other stakeholders will begin to use its terminology globally to provide quality care and ensure consistency in registering specific fertility care interventions and more accurate reporting of their outcomes.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Zika virus is a serious problem. Education and infection prevention are critical to effective management, and why we chose to include Zika virus as a topic for this year’s Update. We also discuss obesity’s effects on reproduction—a very relevant concern for all ObGyns and patients alike as about half of reproductive-age women are obese. Finally, subclinical hypothyroidism can present unique management challenges, such as determining when it is present and when treatment is indicated.

Read about counseling patients about Zika virus

Managing attempted pregnancy in the era of Zika virus

Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure--United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65(29):739-744.

Petersen EE, Meaney-Delman D, Neblett-Fanfair R, et al. Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for persons with possible Zika virus exposure--United States, September 2016. MMWR Morb Mortal Wkly Rep. 2016;65(39):1077-1081.

US Food and Drug Administration. Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM488582.pdf. Published March 2016. Accessed January 12, 2017.

National Institutes of Health. Zika: Overview. https://www.nichd.nih.gov/health/topics/zika/Pages/default.aspx. Accessed January 12, 2017.

World Health Organization. Prevention of sexual transmission of Zika virus interim guidance. WHO reference number: WHO/ZIKV/MOC/16. 1 Rev. 3, September 6, 2016. 

Zika Virus Guidance Task Force of the American Society for Reproductive Medicine. Rev. 13, September 2016.  

Zika virus presents unique challenges to physicians managing the care of patients attempting pregnancy, with or without fertility treatment. Neonatal Zika virus infection sequelae only recently have been appreciated; microcephaly was associated with Zika virus in October 2015, followed by other neurologic conditions including brain abnormalities, neural tube defects, and eye abnormalities. Results of recent studies involving the US Zika Pregnancy Registry show that 6% of women with Zika at any time in pregnancy had affected babies, but 11% of those who contracted the disease in the first trimester were affected. 

Diagnosis is difficult because symptoms are generally mild, with 80% of affected patients asymptomatic. Possible Zika virus exposure is defined as travel to or residence in an area of active Zika virus transmission, or sex without a condom with a partner who traveled to or lived in an area of active transmission. Much is unknown about the interval from exposure to symptoms. Testing availability is limited and variable, and much is unknown about sensitivity and specificity of direct viral RNA testing, appearance and disappearance of detectable immunoglobulin (Ig) M and IgG antibodies that affect false positive and false negative test results, duration of infectious phase, risk of transmission, and numerous other factors.

Positive serum viral testing likely indicates virus in semen or other bodily fluids, but a negative serum viral test cannot definitively preclude virus in other bodily fluids. Zika virus likely can be passed from any combination of semen and vaginal and cervical fluids, but validating tests for these fluids are not yet available. It is not known if sperm preparation and assisted reproductive technology (ART) procedures that minimize risk of HIV transmission are effective against Zika virus or whether or not cryopreservation can destroy the virus. 

Pregnancy timing

The Centers for Disease Control and Prevention now recommends that all men with possible Zika virus exposure who are considering attempting pregnancy with their partner wait to get pregnant until at least 6 months after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). Women with possible Zika virus exposure are recommended to wait to get pregnant until at least 8 weeks after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic).

Women and men with possible exposure to Zika virus but without clinical symptoms of illness should consider testing for Zika viral RNA within 2 weeks of suspected exposure and wait at least 8 weeks after the last date of exposure before being re-tested. If direct viral testing (using rRT-PCR) results initially are negative, ideally, antibody testing would be obtained, if available, at 8 weeks. However, no testing paradigm will absolutely guarantee lack of Zika virus infectivity.

Virus management problems are dramatically compounded in areas endemic for Zika. Women and men who have had Zika virus disease should wait at least 6 months after illness onset to attempt reproduction. The temporal relationship between the presence of viral RNA and infectivity is not known definitively, and so the absolute duration of time to wait before attempting pregnancy is unknown. Male and female partners who become infected should avoid all forms of intimate sexual conduct or use condoms for the same 6 months. There is no evidence Zika will cause congenital infection in pregnancies initiated after resolution of maternal Zika viremia. However, any testing performed at a time other than the time of treatment might not reflect true viral status, particularly in areas of active Zika virus transmission.

Prevention

Women and men, especially those residing in areas of active Zika virus transmission, should talk with their physicians regarding pregnancy plans and avoid mosquito bites using the usual precautions: avoid mosquito areas, drain standing water, use mosquito repellent containing DEET, and use mosquito netting. Some people have gone so far as to relocate to nonendemic areas.

Those contemplating pregnancy should be advised to consider what they would do if they become exposed to or have suspected or confirmed Zika virus during pregnancy. Additional considerations are gamete or embryo cryopreservation and quarantine until a subsequent rRT-PCR test result is negative in both the male and female and at least 8 weeks have passed from gamete collection.

Patient counseling essentials

Counsel patients considering reproduction  about:  

• Zika virus as a new reproductive hazard  
• the significance of the hazard to the fetus if infected
• the areas of active transmission, and that they are constantly changing
• avoidance of Zika areas if possible
• methods of transmission through mosquito bites or sex
• avoidance of mosquito bites
• symptoms of Zika infection
• safe sex practices
• testing limitations and knowledge deficiency about Zika.

Not uncommonly, clinical situations require complex individualized management decisions regarding trade-offs of risks, especially in older patients with decreased ovarian reserve. Consultation with infectious disease and reproductive specialists should be obtained when complicated and consequential decisions have to be made.

All practitioners should inform their patients, especially those undergoing fertility treatments, about Zika, and develop language in their informed consent that conveys the gap in knowledge to these patients.

Read how obesity specifically affects reproduction in an adverse way

Obesity adversely affects reproduction, but how specifically?

Practice Committee of the American Society for Reproductive Medicine. Obesity and Reproduction: A committee opinion. Fertil Steril. 2015;104(5):1116-1126.

The prevalence of obesity has increased substantially over the past 2 decades. Almost two-thirds of women and three-fourths of men in the United States are overweight or obese (defined as a body mass index [BMI] ≥25 kg/m² and BMI ≥30 kg/m², respectively; TABLE). Nearly 50% of reproductive-age women are obese.

A disease of excess body fat and insulin resistance, obesity increases the risks of hypertension, diabetes, dyslipidemia, cardiovascular disease, sleep apnea, respiratory problems, and cancer as well as other serious health problems. While not all individuals with obesity will have infertility, obesity is associated with impaired reproduction in both women and men, adverse obstetric outcomes, and health problems in offspring. The American Society for Reproductive Medicine (ASRM) reviewed this important issue in a recent practice committee opinion.  

Menstrual cycle and ovulatory dysfunction

Menstrual cycle abnormalities are more common in women with obesity. Elevated levels of insulin in obese women suppress sex hormone−binding globulin (SHBG) which in turn reduces gonadotropin secretion due to increased production of estrogen from conversion of androgens by adipose aromatase.¹ Adipose tissue produces adipokines, which directly can suppress ovarian function.²

Ovulatory dysfunction is common among obese women; the relative risk of such dysfunction is 3.1 (95% confidence interval [CI], 2.2−4.4) among women with BMI levels >27 kg/m² versus BMI levels 20.0 to 24.9 kg/m².^3,4  Obesity decreases fecundity even in women with normal menstrual cycles.⁵ This may in part be due to altered ovulatory dynamics with reduced early follicular luteinizing hormone pulse amplitude accompanied by prolonged folliculogenesis and reduced luteal progesterone levels.⁶

Compared with normal-weight women, obese women have a lower chance of conception within 1 year of stopping contraception; about 66% of obese women conceive within 1 year of stopping contraception, compared with about 81% of women with normal weight.⁷ Results of a Dutch study of 3,029 women with regular ovulation, at least one patent tube, and a partner with a normal semen analysis indicated a direct correlation between obesity and delayed conception, with a 4% lower spontaneous pregnancy rate per kg/m2 increase in women with a BMI >29 kg/m² versus a BMI of 21 to 29 kg/m² (hazard ratio, 0.96; 95% CI, 0.91−0.99).⁸  

Assisted reproduction

Assisted reproduction in women with obesity is associated with lower success rates than in women with normal weight. A systematic review of 27 in vitro fertilization (IVF) studies (23 of which were retrospective) reveals  10% lower live-birth rate in overweight (BMI >25 kg/m²) versus normal-weight women (BMI <25 kg/m²) undergoing IVF (odds ratio [OR], 0.90; 95% CI, 0.82−1.0).⁹ Data from a meta-analysis of 33 IVF studies, including 47,967 cycles, show that, compared with women with a BMI <25 kg/m², overweight or obese women have significantly reduced rates of clinical pregnancy (relative risk [RR], 0.90; P<.0001) and live birth (RR, 0.84; P = .0002).¹⁰

Results of a retrospective study of 4,609 women undergoing first IVF or IVF/intracytoplasmic sperm injection cycles revealed impaired embryo implantation (controlling for embryo quality and transfer day), reducing the age-adjusted odds of live birth in a BMI-dependent manner by 37% (BMI, 30.0−34.9 kg/m²), 61% (BMI, 35.0−39.9 kg/m2), and 68% (BMI, >40 kg/m²) compared with women with a BMI of 18.5 to 24.9 kg/m².¹¹ In a study of 12,566 Danish couples undergoing assisted reproduction, overweight and obese ovulatory women had a 12% (95% CI, 0.79−0.99) and 25% (95% CI, 0.63−0.90) reduction in IVF-related live birth rate, respectively (referent BMI, 18.5−24.9 kg/m²), with a 2% (95% CI, 0.97−0.99) decrease in live-birth rate for every one-unit increase in BMI.¹² Putative mechanisms for these findings include altered oocyte morphology and reduced fertilization in eggs from obese women,¹³ and impaired embryo quality in women less than age 35.¹⁴ Oocytes from women with a BMI >25 kg/m² are smaller and less likely to complete development postfertilization, with embryos arrested prior to blastulation containing more triglyceride than those forming blastocysts.¹⁵

Blastocysts developed from oocytes of high-BMI women are smaller, contain fewer cells and have a higher content of triglycerides, lower glucose consumption, and altered amino acid metabolism compared with embryos of normal-weight women (BMI <24.9 kg/m2).¹⁵ Obesity may alter endometrial receptivity during IVF given the finding that third-party surrogate women with a BMI >35 kg/m² have a lower live-birth rate (25%) compared with women with a BMI <35 kg/m² (49%; P<.05).¹⁶

Pregnancy outcomes

Obesity is linked to an increased risk of miscarriage. Results of a meta-analysis of 33 IVF studies including 47,967 cycles indicated that overweight or obese women have a higher rate of miscarriage (RR, 1.31; P<.0001) than normal-weight women (BMI <25 kg/m2).¹⁷ Maternal and perinatal morbid obesity are strongly associated with obstetric and perinatal complications, including gestational diabetes, hypertension, preeclampsia, preterm delivery, shoulder dystocia, fetal distress, early neonatal death, and small- as well as large-for-gestational age infants.

Obese women who conceive by IVF are at increased risk for preeclampsia, gestational diabetes, preterm delivery, and cesarean delivery.¹³ Authors of a meta-analysis of 18 observational studies concluded that obese mothers were at increased odds of pregnancies affected by such birth defects as neural tube defects, cardiovascular anomalies, and cleft lip and palate, among others.¹⁸

In addition to being the cause of these fetal abnormalities, maternal metabolic dysfunction is linked to promoting obesity in offspring, thereby perpetuating a cycle of obesity and adverse health outcomes that include an increased risk of premature death in adult offspring in subsequent generations.¹³

Treatment for obesity

Lifestyle modification is the first-line treatment for obesity.  
Pre-fertility therapy and pregnancy goals. Targets for pregnancy should include:  

• preconception weight loss to a BMI of 35 kg/m2
• prevention of excess weight gain in pregnancy
• long-term reduction in weight.

For all obese individuals, lifestyle modifications should include a weight loss of 7% of body weight and increased physical activity to at least 150 minutes of moderate activity, such as walking, per week. Calorie restriction should be emphasized. A 500 to 1,000 kcal/day decrease from usual dietary intake is expected to result in a 1- to 2-lb weight loss per week. A low-calorie diet of 1,000 to 1,200 kcal/day can lead to an average 10% decrease in total body weight over 6 months.

Adjunct supervised medical therapy or bariatric surgery can play an important role in successful weight loss prepregnancy but are not appropriate for women actively attempting conception. Importantly, pregnancy should be deferred for a minimum of 1 year after bariatric surgery. The decision to postpone pregnancy to achieve weight loss must be balanced against the risk of declining fertility with advancing age of the woman. 

Read about when to treat subclinical hypothyroidism

Optimal management of subclinical hypothyroidism in women with infertility

Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(3):545-553.

Thyroid disorders long have been associated with the potential for adverse reproductive outcomes. While overt hypothyroidism has been linked to infertility, increased miscarriage risk, and poor maternal and fetal outcomes, controversy has existed regarding the association between subclinical hypothyroidism (SCH) and reproductive problems. The ASRM recently published a guideline on the role of SCH in the infertile female population.  

How is subclinical hypothyroidism defined?

SCH is classically defined as a thyrotropin (TSH) level above the upper limit of normal range (4.5−5.0 mIU/L) with normal free thyroxine (FT4) levels. The National Health and Nutrition Examination Survey (NHANES III) population has been used to establish normative data for TSH for a disease-free population. These include a median serum level for TSH of 1.5 mIU/L, with the corresponding 2.5 and 97.5 percentiles of 0.41 and 6.10, respectively.¹⁹ Data from the National Academy of Clinical Biochemistry, however, reveal that 95% of individuals without evidence of thyroid disease have a TSH level <2.5 mIU/L, and that the normal reference range is skewed to the right.20 Adjusting the upper limit of the normal range to 2.5 mIU/L would result in an additional 11.8% to 14.2% of the United States population (22 to 28 million individuals) being diagnosed with hypothyroidism.

This information raises several important questions.

1. Should nonpregnant women be treated for SCH?

No. There is no benefit from the standpoint of lipid profile or alteration of cardiovascular risk in the treatment of TSH levels between 5 and 10 mIU/L and, therefore, treatment of individuals with TSH <5 mIU/L is questionable. Furthermore, the risk of overtreatment resulting in bone loss is a concern. The Endocrine Society does not recommend changing the current normal TSH range for nonpregnant women.

2. What are normal TSH levels in pregnant women?

Because human chorionic gonadotropin (hCG) can bind to and affect the TSH receptor, thereby influencing TSH values, the normal range for TSH is modified in pregnancy. The Endocrine Society recommends the following pregnancy trimester guidelines for TSH levels: 2.5 mIU/L is the recommended upper limit of normal in the first trimester, 3.0 mIU/L in the second trimester, and 3.5 mIU/L in the third trimester.

3. Is untreated SCH associated with miscarriage?

There is fair evidence that SCH, defined as a TSH level >4 mIU/L during pregnancy, is associated with miscarriage, but there is insufficient evidence that TSH levels between 2.5 and 4 mIU/L are associated with miscarriage.

4. Is untreated SCH associated with infertility?

Limited data are available to assess the effect of SCH on infertility. While a few studies show an association between SCH on unexplained infertility and ovulatory disorders, SCH does not appear to be increased in other causes of infertility.

5. Is SCH associated with adverse obstetric outcomes?

Available data reveal that SCH with TSH levels outside the normal pregnancy range are associated with an increased risk of such obstetric complications as placental abruption, preterm birth, fetal death, and preterm premature rupture of membranes (PPROM). However, it is unclear if prepregnancy TSH levels between 2.5 and 4 mIU/L are associated with adverse obstetric outcomes.

6. Does untreated SCH affect developmental outcomes in children?

The fetus is solely dependent on maternal thyroid hormone in early pregnancy because the fetal thyroid does not produce thyroid hormone before 10 to 13 weeks of gestation. Significant evidence has associated untreated maternal hypothyroidism with delayed fetal neurologic development, impaired school performance, and lower intelligence quotient (IQ) among offspring.21 There is fair evidence that SCH diagnosed in pregnancy is associated with adverse neurologic development. There is no evidence that SCH prior to pregnancy is associated with adverse neurodevelopmental outcomes. It should be noted that only one study has examined whether treatment of SCH improves developmental outcomes (measured by IQ scored at age 3 years) and no significant differences were observed in women with SCH who were treated with levothyroxine versus those who were not.²²

7. Does treatment of SCH improve miscarriage rates, live-birth rates, and/or clinical pregnancy rates?

Small randomized controlled studies of women undergoing infertility treatment and a few observational studies in the general population yield good evidence that levothyroxine treatment in women with SCH defined as TSH >4.0 mIU/L is associated with improvement in pregnancy, live birth, and miscarriage rates. There are no randomized trials assessing whether levothyroxine treatment in women with TSH levels between 2.5 and 4 mIU/L would yield similar benefits to those observed in women with TSH levels above 4 mIU/L.

8. Are thyroid antibodies associated with infertility or adverse reproductive outcomes?

There is good evidence that the thyroid autoimmunity, or the presence of TPO-Ab, is associated with miscarriage and fair evidence that it is associated with infertility. Treatment with levothyroxine may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L.

9. Should there be universal screening for hypothyroidism in the first trimester of pregnancy?

Current evidence does not reveal a benefit of universal screening at this time. The American College of Obstetricians and Gynecologists does not recommend routine screening for hypothyroidism in pregnancy unless women have risk factors for thyroid disease, including a personal or family history of thyroid disease, physical findings or symptoms of goiter or hypothyroidism, type 1 diabetes mellitus, infertility, history of miscarriage or preterm delivery, and/or personal or family history of autoimmune disease.

The bottom line

SCH, defined as a TSH level greater than the upper limit of normal range (4.5&#8722;5.0 mIU/L)with normal FT4 levels, is associated with adverse reproductive outcomes including miscarriage, pregnancy complications, and delayed fetal neurodevelopment. Thyroid supplementation is beneficial; however, treatment has not been shown to improve long-term neurologic developmental outcomes in offspring. Data are limited on whether TSH values between 2.5 mIU/L and the upper range of normal are associated with adverse pregnancy outcomes and therefore treatment in this group remains controversial. Although available evidence is weak, there may be a benefit in some subgroups, and because risk is minimal, it may be reasonable to treat or to monitor levels and treat above nonpregnant and pregnancy ranges. There is fair evidence that thyroid autoimmunity (positive thyroid antibody) is associated with miscarriage and infertility. Levothyroxine therapy may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L. While universal screening of thyroid function in pregnancy is not recommended, women at high risk for thyroid disease should be screened.23

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Zika virus is a serious problem. Education and infection prevention are critical to effective management, and why we chose to include Zika virus as a topic for this year’s Update. We also discuss obesity’s effects on reproduction—a very relevant concern for all ObGyns and patients alike as about half of reproductive-age women are obese. Finally, subclinical hypothyroidism can present unique management challenges, such as determining when it is present and when treatment is indicated.

Read about counseling patients about Zika virus

Managing attempted pregnancy in the era of Zika virus

Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure--United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65(29):739-744.

Petersen EE, Meaney-Delman D, Neblett-Fanfair R, et al. Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for persons with possible Zika virus exposure--United States, September 2016. MMWR Morb Mortal Wkly Rep. 2016;65(39):1077-1081.

US Food and Drug Administration. Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM488582.pdf. Published March 2016. Accessed January 12, 2017.

National Institutes of Health. Zika: Overview. https://www.nichd.nih.gov/health/topics/zika/Pages/default.aspx. Accessed January 12, 2017.

World Health Organization. Prevention of sexual transmission of Zika virus interim guidance. WHO reference number: WHO/ZIKV/MOC/16. 1 Rev. 3, September 6, 2016. 

Zika Virus Guidance Task Force of the American Society for Reproductive Medicine. Rev. 13, September 2016.  

Zika virus presents unique challenges to physicians managing the care of patients attempting pregnancy, with or without fertility treatment. Neonatal Zika virus infection sequelae only recently have been appreciated; microcephaly was associated with Zika virus in October 2015, followed by other neurologic conditions including brain abnormalities, neural tube defects, and eye abnormalities. Results of recent studies involving the US Zika Pregnancy Registry show that 6% of women with Zika at any time in pregnancy had affected babies, but 11% of those who contracted the disease in the first trimester were affected. 

Diagnosis is difficult because symptoms are generally mild, with 80% of affected patients asymptomatic. Possible Zika virus exposure is defined as travel to or residence in an area of active Zika virus transmission, or sex without a condom with a partner who traveled to or lived in an area of active transmission. Much is unknown about the interval from exposure to symptoms. Testing availability is limited and variable, and much is unknown about sensitivity and specificity of direct viral RNA testing, appearance and disappearance of detectable immunoglobulin (Ig) M and IgG antibodies that affect false positive and false negative test results, duration of infectious phase, risk of transmission, and numerous other factors.

Positive serum viral testing likely indicates virus in semen or other bodily fluids, but a negative serum viral test cannot definitively preclude virus in other bodily fluids. Zika virus likely can be passed from any combination of semen and vaginal and cervical fluids, but validating tests for these fluids are not yet available. It is not known if sperm preparation and assisted reproductive technology (ART) procedures that minimize risk of HIV transmission are effective against Zika virus or whether or not cryopreservation can destroy the virus. 

Pregnancy timing

The Centers for Disease Control and Prevention now recommends that all men with possible Zika virus exposure who are considering attempting pregnancy with their partner wait to get pregnant until at least 6 months after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). Women with possible Zika virus exposure are recommended to wait to get pregnant until at least 8 weeks after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic).

Women and men with possible exposure to Zika virus but without clinical symptoms of illness should consider testing for Zika viral RNA within 2 weeks of suspected exposure and wait at least 8 weeks after the last date of exposure before being re-tested. If direct viral testing (using rRT-PCR) results initially are negative, ideally, antibody testing would be obtained, if available, at 8 weeks. However, no testing paradigm will absolutely guarantee lack of Zika virus infectivity.

Virus management problems are dramatically compounded in areas endemic for Zika. Women and men who have had Zika virus disease should wait at least 6 months after illness onset to attempt reproduction. The temporal relationship between the presence of viral RNA and infectivity is not known definitively, and so the absolute duration of time to wait before attempting pregnancy is unknown. Male and female partners who become infected should avoid all forms of intimate sexual conduct or use condoms for the same 6 months. There is no evidence Zika will cause congenital infection in pregnancies initiated after resolution of maternal Zika viremia. However, any testing performed at a time other than the time of treatment might not reflect true viral status, particularly in areas of active Zika virus transmission.

Prevention

Women and men, especially those residing in areas of active Zika virus transmission, should talk with their physicians regarding pregnancy plans and avoid mosquito bites using the usual precautions: avoid mosquito areas, drain standing water, use mosquito repellent containing DEET, and use mosquito netting. Some people have gone so far as to relocate to nonendemic areas.

Those contemplating pregnancy should be advised to consider what they would do if they become exposed to or have suspected or confirmed Zika virus during pregnancy. Additional considerations are gamete or embryo cryopreservation and quarantine until a subsequent rRT-PCR test result is negative in both the male and female and at least 8 weeks have passed from gamete collection.

Patient counseling essentials

Counsel patients considering reproduction  about:  

• Zika virus as a new reproductive hazard  
• the significance of the hazard to the fetus if infected
• the areas of active transmission, and that they are constantly changing
• avoidance of Zika areas if possible
• methods of transmission through mosquito bites or sex
• avoidance of mosquito bites
• symptoms of Zika infection
• safe sex practices
• testing limitations and knowledge deficiency about Zika.

Not uncommonly, clinical situations require complex individualized management decisions regarding trade-offs of risks, especially in older patients with decreased ovarian reserve. Consultation with infectious disease and reproductive specialists should be obtained when complicated and consequential decisions have to be made.

All practitioners should inform their patients, especially those undergoing fertility treatments, about Zika, and develop language in their informed consent that conveys the gap in knowledge to these patients.

Read how obesity specifically affects reproduction in an adverse way

Obesity adversely affects reproduction, but how specifically?

Practice Committee of the American Society for Reproductive Medicine. Obesity and Reproduction: A committee opinion. Fertil Steril. 2015;104(5):1116-1126.

The prevalence of obesity has increased substantially over the past 2 decades. Almost two-thirds of women and three-fourths of men in the United States are overweight or obese (defined as a body mass index [BMI] ≥25 kg/m² and BMI ≥30 kg/m², respectively; TABLE). Nearly 50% of reproductive-age women are obese.

A disease of excess body fat and insulin resistance, obesity increases the risks of hypertension, diabetes, dyslipidemia, cardiovascular disease, sleep apnea, respiratory problems, and cancer as well as other serious health problems. While not all individuals with obesity will have infertility, obesity is associated with impaired reproduction in both women and men, adverse obstetric outcomes, and health problems in offspring. The American Society for Reproductive Medicine (ASRM) reviewed this important issue in a recent practice committee opinion.  

Menstrual cycle and ovulatory dysfunction

Menstrual cycle abnormalities are more common in women with obesity. Elevated levels of insulin in obese women suppress sex hormone−binding globulin (SHBG) which in turn reduces gonadotropin secretion due to increased production of estrogen from conversion of androgens by adipose aromatase.¹ Adipose tissue produces adipokines, which directly can suppress ovarian function.²

Ovulatory dysfunction is common among obese women; the relative risk of such dysfunction is 3.1 (95% confidence interval [CI], 2.2−4.4) among women with BMI levels >27 kg/m² versus BMI levels 20.0 to 24.9 kg/m².^3,4  Obesity decreases fecundity even in women with normal menstrual cycles.⁵ This may in part be due to altered ovulatory dynamics with reduced early follicular luteinizing hormone pulse amplitude accompanied by prolonged folliculogenesis and reduced luteal progesterone levels.⁶

Compared with normal-weight women, obese women have a lower chance of conception within 1 year of stopping contraception; about 66% of obese women conceive within 1 year of stopping contraception, compared with about 81% of women with normal weight.⁷ Results of a Dutch study of 3,029 women with regular ovulation, at least one patent tube, and a partner with a normal semen analysis indicated a direct correlation between obesity and delayed conception, with a 4% lower spontaneous pregnancy rate per kg/m2 increase in women with a BMI >29 kg/m² versus a BMI of 21 to 29 kg/m² (hazard ratio, 0.96; 95% CI, 0.91−0.99).⁸  

Assisted reproduction

Assisted reproduction in women with obesity is associated with lower success rates than in women with normal weight. A systematic review of 27 in vitro fertilization (IVF) studies (23 of which were retrospective) reveals  10% lower live-birth rate in overweight (BMI >25 kg/m²) versus normal-weight women (BMI <25 kg/m²) undergoing IVF (odds ratio [OR], 0.90; 95% CI, 0.82−1.0).⁹ Data from a meta-analysis of 33 IVF studies, including 47,967 cycles, show that, compared with women with a BMI <25 kg/m², overweight or obese women have significantly reduced rates of clinical pregnancy (relative risk [RR], 0.90; P<.0001) and live birth (RR, 0.84; P = .0002).¹⁰

Results of a retrospective study of 4,609 women undergoing first IVF or IVF/intracytoplasmic sperm injection cycles revealed impaired embryo implantation (controlling for embryo quality and transfer day), reducing the age-adjusted odds of live birth in a BMI-dependent manner by 37% (BMI, 30.0−34.9 kg/m²), 61% (BMI, 35.0−39.9 kg/m2), and 68% (BMI, >40 kg/m²) compared with women with a BMI of 18.5 to 24.9 kg/m².¹¹ In a study of 12,566 Danish couples undergoing assisted reproduction, overweight and obese ovulatory women had a 12% (95% CI, 0.79−0.99) and 25% (95% CI, 0.63−0.90) reduction in IVF-related live birth rate, respectively (referent BMI, 18.5−24.9 kg/m²), with a 2% (95% CI, 0.97−0.99) decrease in live-birth rate for every one-unit increase in BMI.¹² Putative mechanisms for these findings include altered oocyte morphology and reduced fertilization in eggs from obese women,¹³ and impaired embryo quality in women less than age 35.¹⁴ Oocytes from women with a BMI >25 kg/m² are smaller and less likely to complete development postfertilization, with embryos arrested prior to blastulation containing more triglyceride than those forming blastocysts.¹⁵

Blastocysts developed from oocytes of high-BMI women are smaller, contain fewer cells and have a higher content of triglycerides, lower glucose consumption, and altered amino acid metabolism compared with embryos of normal-weight women (BMI <24.9 kg/m2).¹⁵ Obesity may alter endometrial receptivity during IVF given the finding that third-party surrogate women with a BMI >35 kg/m² have a lower live-birth rate (25%) compared with women with a BMI <35 kg/m² (49%; P<.05).¹⁶

Pregnancy outcomes

Obesity is linked to an increased risk of miscarriage. Results of a meta-analysis of 33 IVF studies including 47,967 cycles indicated that overweight or obese women have a higher rate of miscarriage (RR, 1.31; P<.0001) than normal-weight women (BMI <25 kg/m2).¹⁷ Maternal and perinatal morbid obesity are strongly associated with obstetric and perinatal complications, including gestational diabetes, hypertension, preeclampsia, preterm delivery, shoulder dystocia, fetal distress, early neonatal death, and small- as well as large-for-gestational age infants.

Obese women who conceive by IVF are at increased risk for preeclampsia, gestational diabetes, preterm delivery, and cesarean delivery.¹³ Authors of a meta-analysis of 18 observational studies concluded that obese mothers were at increased odds of pregnancies affected by such birth defects as neural tube defects, cardiovascular anomalies, and cleft lip and palate, among others.¹⁸

In addition to being the cause of these fetal abnormalities, maternal metabolic dysfunction is linked to promoting obesity in offspring, thereby perpetuating a cycle of obesity and adverse health outcomes that include an increased risk of premature death in adult offspring in subsequent generations.¹³

Treatment for obesity

Lifestyle modification is the first-line treatment for obesity.  
Pre-fertility therapy and pregnancy goals. Targets for pregnancy should include:  

• preconception weight loss to a BMI of 35 kg/m2
• prevention of excess weight gain in pregnancy
• long-term reduction in weight.

For all obese individuals, lifestyle modifications should include a weight loss of 7% of body weight and increased physical activity to at least 150 minutes of moderate activity, such as walking, per week. Calorie restriction should be emphasized. A 500 to 1,000 kcal/day decrease from usual dietary intake is expected to result in a 1- to 2-lb weight loss per week. A low-calorie diet of 1,000 to 1,200 kcal/day can lead to an average 10% decrease in total body weight over 6 months.

Adjunct supervised medical therapy or bariatric surgery can play an important role in successful weight loss prepregnancy but are not appropriate for women actively attempting conception. Importantly, pregnancy should be deferred for a minimum of 1 year after bariatric surgery. The decision to postpone pregnancy to achieve weight loss must be balanced against the risk of declining fertility with advancing age of the woman. 

Read about when to treat subclinical hypothyroidism

Optimal management of subclinical hypothyroidism in women with infertility

Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(3):545-553.

Thyroid disorders long have been associated with the potential for adverse reproductive outcomes. While overt hypothyroidism has been linked to infertility, increased miscarriage risk, and poor maternal and fetal outcomes, controversy has existed regarding the association between subclinical hypothyroidism (SCH) and reproductive problems. The ASRM recently published a guideline on the role of SCH in the infertile female population.  

How is subclinical hypothyroidism defined?

SCH is classically defined as a thyrotropin (TSH) level above the upper limit of normal range (4.5−5.0 mIU/L) with normal free thyroxine (FT4) levels. The National Health and Nutrition Examination Survey (NHANES III) population has been used to establish normative data for TSH for a disease-free population. These include a median serum level for TSH of 1.5 mIU/L, with the corresponding 2.5 and 97.5 percentiles of 0.41 and 6.10, respectively.¹⁹ Data from the National Academy of Clinical Biochemistry, however, reveal that 95% of individuals without evidence of thyroid disease have a TSH level <2.5 mIU/L, and that the normal reference range is skewed to the right.20 Adjusting the upper limit of the normal range to 2.5 mIU/L would result in an additional 11.8% to 14.2% of the United States population (22 to 28 million individuals) being diagnosed with hypothyroidism.

This information raises several important questions.

1. Should nonpregnant women be treated for SCH?

No. There is no benefit from the standpoint of lipid profile or alteration of cardiovascular risk in the treatment of TSH levels between 5 and 10 mIU/L and, therefore, treatment of individuals with TSH <5 mIU/L is questionable. Furthermore, the risk of overtreatment resulting in bone loss is a concern. The Endocrine Society does not recommend changing the current normal TSH range for nonpregnant women.

2. What are normal TSH levels in pregnant women?

Because human chorionic gonadotropin (hCG) can bind to and affect the TSH receptor, thereby influencing TSH values, the normal range for TSH is modified in pregnancy. The Endocrine Society recommends the following pregnancy trimester guidelines for TSH levels: 2.5 mIU/L is the recommended upper limit of normal in the first trimester, 3.0 mIU/L in the second trimester, and 3.5 mIU/L in the third trimester.

3. Is untreated SCH associated with miscarriage?

There is fair evidence that SCH, defined as a TSH level >4 mIU/L during pregnancy, is associated with miscarriage, but there is insufficient evidence that TSH levels between 2.5 and 4 mIU/L are associated with miscarriage.

4. Is untreated SCH associated with infertility?

Limited data are available to assess the effect of SCH on infertility. While a few studies show an association between SCH on unexplained infertility and ovulatory disorders, SCH does not appear to be increased in other causes of infertility.

5. Is SCH associated with adverse obstetric outcomes?

Available data reveal that SCH with TSH levels outside the normal pregnancy range are associated with an increased risk of such obstetric complications as placental abruption, preterm birth, fetal death, and preterm premature rupture of membranes (PPROM). However, it is unclear if prepregnancy TSH levels between 2.5 and 4 mIU/L are associated with adverse obstetric outcomes.

6. Does untreated SCH affect developmental outcomes in children?

The fetus is solely dependent on maternal thyroid hormone in early pregnancy because the fetal thyroid does not produce thyroid hormone before 10 to 13 weeks of gestation. Significant evidence has associated untreated maternal hypothyroidism with delayed fetal neurologic development, impaired school performance, and lower intelligence quotient (IQ) among offspring.21 There is fair evidence that SCH diagnosed in pregnancy is associated with adverse neurologic development. There is no evidence that SCH prior to pregnancy is associated with adverse neurodevelopmental outcomes. It should be noted that only one study has examined whether treatment of SCH improves developmental outcomes (measured by IQ scored at age 3 years) and no significant differences were observed in women with SCH who were treated with levothyroxine versus those who were not.²²

7. Does treatment of SCH improve miscarriage rates, live-birth rates, and/or clinical pregnancy rates?

Small randomized controlled studies of women undergoing infertility treatment and a few observational studies in the general population yield good evidence that levothyroxine treatment in women with SCH defined as TSH >4.0 mIU/L is associated with improvement in pregnancy, live birth, and miscarriage rates. There are no randomized trials assessing whether levothyroxine treatment in women with TSH levels between 2.5 and 4 mIU/L would yield similar benefits to those observed in women with TSH levels above 4 mIU/L.

8. Are thyroid antibodies associated with infertility or adverse reproductive outcomes?

There is good evidence that the thyroid autoimmunity, or the presence of TPO-Ab, is associated with miscarriage and fair evidence that it is associated with infertility. Treatment with levothyroxine may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L.

9. Should there be universal screening for hypothyroidism in the first trimester of pregnancy?

Current evidence does not reveal a benefit of universal screening at this time. The American College of Obstetricians and Gynecologists does not recommend routine screening for hypothyroidism in pregnancy unless women have risk factors for thyroid disease, including a personal or family history of thyroid disease, physical findings or symptoms of goiter or hypothyroidism, type 1 diabetes mellitus, infertility, history of miscarriage or preterm delivery, and/or personal or family history of autoimmune disease.

The bottom line

SCH, defined as a TSH level greater than the upper limit of normal range (4.5&#8722;5.0 mIU/L)with normal FT4 levels, is associated with adverse reproductive outcomes including miscarriage, pregnancy complications, and delayed fetal neurodevelopment. Thyroid supplementation is beneficial; however, treatment has not been shown to improve long-term neurologic developmental outcomes in offspring. Data are limited on whether TSH values between 2.5 mIU/L and the upper range of normal are associated with adverse pregnancy outcomes and therefore treatment in this group remains controversial. Although available evidence is weak, there may be a benefit in some subgroups, and because risk is minimal, it may be reasonable to treat or to monitor levels and treat above nonpregnant and pregnancy ranges. There is fair evidence that thyroid autoimmunity (positive thyroid antibody) is associated with miscarriage and infertility. Levothyroxine therapy may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L. While universal screening of thyroid function in pregnancy is not recommended, women at high risk for thyroid disease should be screened.23

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Zika virus is a serious problem. Education and infection prevention are critical to effective management, and why we chose to include Zika virus as a topic for this year’s Update. We also discuss obesity’s effects on reproduction—a very relevant concern for all ObGyns and patients alike as about half of reproductive-age women are obese. Finally, subclinical hypothyroidism can present unique management challenges, such as determining when it is present and when treatment is indicated.

Read about counseling patients about Zika virus

Managing attempted pregnancy in the era of Zika virus

Oduyebo T, Igbinosa I, Petersen EE, et al. Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure--United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65(29):739-744.

Petersen EE, Meaney-Delman D, Neblett-Fanfair R, et al. Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for persons with possible Zika virus exposure--United States, September 2016. MMWR Morb Mortal Wkly Rep. 2016;65(39):1077-1081.

US Food and Drug Administration. Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products. http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM488582.pdf. Published March 2016. Accessed January 12, 2017.

National Institutes of Health. Zika: Overview. https://www.nichd.nih.gov/health/topics/zika/Pages/default.aspx. Accessed January 12, 2017.

World Health Organization. Prevention of sexual transmission of Zika virus interim guidance. WHO reference number: WHO/ZIKV/MOC/16. 1 Rev. 3, September 6, 2016. 

Zika Virus Guidance Task Force of the American Society for Reproductive Medicine. Rev. 13, September 2016.  

Zika virus presents unique challenges to physicians managing the care of patients attempting pregnancy, with or without fertility treatment. Neonatal Zika virus infection sequelae only recently have been appreciated; microcephaly was associated with Zika virus in October 2015, followed by other neurologic conditions including brain abnormalities, neural tube defects, and eye abnormalities. Results of recent studies involving the US Zika Pregnancy Registry show that 6% of women with Zika at any time in pregnancy had affected babies, but 11% of those who contracted the disease in the first trimester were affected. 

Diagnosis is difficult because symptoms are generally mild, with 80% of affected patients asymptomatic. Possible Zika virus exposure is defined as travel to or residence in an area of active Zika virus transmission, or sex without a condom with a partner who traveled to or lived in an area of active transmission. Much is unknown about the interval from exposure to symptoms. Testing availability is limited and variable, and much is unknown about sensitivity and specificity of direct viral RNA testing, appearance and disappearance of detectable immunoglobulin (Ig) M and IgG antibodies that affect false positive and false negative test results, duration of infectious phase, risk of transmission, and numerous other factors.

Positive serum viral testing likely indicates virus in semen or other bodily fluids, but a negative serum viral test cannot definitively preclude virus in other bodily fluids. Zika virus likely can be passed from any combination of semen and vaginal and cervical fluids, but validating tests for these fluids are not yet available. It is not known if sperm preparation and assisted reproductive technology (ART) procedures that minimize risk of HIV transmission are effective against Zika virus or whether or not cryopreservation can destroy the virus. 

Pregnancy timing

The Centers for Disease Control and Prevention now recommends that all men with possible Zika virus exposure who are considering attempting pregnancy with their partner wait to get pregnant until at least 6 months after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic). Women with possible Zika virus exposure are recommended to wait to get pregnant until at least 8 weeks after symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic).

Women and men with possible exposure to Zika virus but without clinical symptoms of illness should consider testing for Zika viral RNA within 2 weeks of suspected exposure and wait at least 8 weeks after the last date of exposure before being re-tested. If direct viral testing (using rRT-PCR) results initially are negative, ideally, antibody testing would be obtained, if available, at 8 weeks. However, no testing paradigm will absolutely guarantee lack of Zika virus infectivity.

Virus management problems are dramatically compounded in areas endemic for Zika. Women and men who have had Zika virus disease should wait at least 6 months after illness onset to attempt reproduction. The temporal relationship between the presence of viral RNA and infectivity is not known definitively, and so the absolute duration of time to wait before attempting pregnancy is unknown. Male and female partners who become infected should avoid all forms of intimate sexual conduct or use condoms for the same 6 months. There is no evidence Zika will cause congenital infection in pregnancies initiated after resolution of maternal Zika viremia. However, any testing performed at a time other than the time of treatment might not reflect true viral status, particularly in areas of active Zika virus transmission.

Prevention

Women and men, especially those residing in areas of active Zika virus transmission, should talk with their physicians regarding pregnancy plans and avoid mosquito bites using the usual precautions: avoid mosquito areas, drain standing water, use mosquito repellent containing DEET, and use mosquito netting. Some people have gone so far as to relocate to nonendemic areas.

Those contemplating pregnancy should be advised to consider what they would do if they become exposed to or have suspected or confirmed Zika virus during pregnancy. Additional considerations are gamete or embryo cryopreservation and quarantine until a subsequent rRT-PCR test result is negative in both the male and female and at least 8 weeks have passed from gamete collection.

Patient counseling essentials

Counsel patients considering reproduction  about:  

• Zika virus as a new reproductive hazard  
• the significance of the hazard to the fetus if infected
• the areas of active transmission, and that they are constantly changing
• avoidance of Zika areas if possible
• methods of transmission through mosquito bites or sex
• avoidance of mosquito bites
• symptoms of Zika infection
• safe sex practices
• testing limitations and knowledge deficiency about Zika.

Not uncommonly, clinical situations require complex individualized management decisions regarding trade-offs of risks, especially in older patients with decreased ovarian reserve. Consultation with infectious disease and reproductive specialists should be obtained when complicated and consequential decisions have to be made.

All practitioners should inform their patients, especially those undergoing fertility treatments, about Zika, and develop language in their informed consent that conveys the gap in knowledge to these patients.

Read how obesity specifically affects reproduction in an adverse way

Obesity adversely affects reproduction, but how specifically?

Practice Committee of the American Society for Reproductive Medicine. Obesity and Reproduction: A committee opinion. Fertil Steril. 2015;104(5):1116-1126.

The prevalence of obesity has increased substantially over the past 2 decades. Almost two-thirds of women and three-fourths of men in the United States are overweight or obese (defined as a body mass index [BMI] ≥25 kg/m² and BMI ≥30 kg/m², respectively; TABLE). Nearly 50% of reproductive-age women are obese.

A disease of excess body fat and insulin resistance, obesity increases the risks of hypertension, diabetes, dyslipidemia, cardiovascular disease, sleep apnea, respiratory problems, and cancer as well as other serious health problems. While not all individuals with obesity will have infertility, obesity is associated with impaired reproduction in both women and men, adverse obstetric outcomes, and health problems in offspring. The American Society for Reproductive Medicine (ASRM) reviewed this important issue in a recent practice committee opinion.  

Menstrual cycle and ovulatory dysfunction

Menstrual cycle abnormalities are more common in women with obesity. Elevated levels of insulin in obese women suppress sex hormone−binding globulin (SHBG) which in turn reduces gonadotropin secretion due to increased production of estrogen from conversion of androgens by adipose aromatase.¹ Adipose tissue produces adipokines, which directly can suppress ovarian function.²

Ovulatory dysfunction is common among obese women; the relative risk of such dysfunction is 3.1 (95% confidence interval [CI], 2.2−4.4) among women with BMI levels >27 kg/m² versus BMI levels 20.0 to 24.9 kg/m².^3,4  Obesity decreases fecundity even in women with normal menstrual cycles.⁵ This may in part be due to altered ovulatory dynamics with reduced early follicular luteinizing hormone pulse amplitude accompanied by prolonged folliculogenesis and reduced luteal progesterone levels.⁶

Compared with normal-weight women, obese women have a lower chance of conception within 1 year of stopping contraception; about 66% of obese women conceive within 1 year of stopping contraception, compared with about 81% of women with normal weight.⁷ Results of a Dutch study of 3,029 women with regular ovulation, at least one patent tube, and a partner with a normal semen analysis indicated a direct correlation between obesity and delayed conception, with a 4% lower spontaneous pregnancy rate per kg/m2 increase in women with a BMI >29 kg/m² versus a BMI of 21 to 29 kg/m² (hazard ratio, 0.96; 95% CI, 0.91−0.99).⁸  

Assisted reproduction

Assisted reproduction in women with obesity is associated with lower success rates than in women with normal weight. A systematic review of 27 in vitro fertilization (IVF) studies (23 of which were retrospective) reveals  10% lower live-birth rate in overweight (BMI >25 kg/m²) versus normal-weight women (BMI <25 kg/m²) undergoing IVF (odds ratio [OR], 0.90; 95% CI, 0.82−1.0).⁹ Data from a meta-analysis of 33 IVF studies, including 47,967 cycles, show that, compared with women with a BMI <25 kg/m², overweight or obese women have significantly reduced rates of clinical pregnancy (relative risk [RR], 0.90; P<.0001) and live birth (RR, 0.84; P = .0002).¹⁰

Results of a retrospective study of 4,609 women undergoing first IVF or IVF/intracytoplasmic sperm injection cycles revealed impaired embryo implantation (controlling for embryo quality and transfer day), reducing the age-adjusted odds of live birth in a BMI-dependent manner by 37% (BMI, 30.0−34.9 kg/m²), 61% (BMI, 35.0−39.9 kg/m2), and 68% (BMI, >40 kg/m²) compared with women with a BMI of 18.5 to 24.9 kg/m².¹¹ In a study of 12,566 Danish couples undergoing assisted reproduction, overweight and obese ovulatory women had a 12% (95% CI, 0.79−0.99) and 25% (95% CI, 0.63−0.90) reduction in IVF-related live birth rate, respectively (referent BMI, 18.5−24.9 kg/m²), with a 2% (95% CI, 0.97−0.99) decrease in live-birth rate for every one-unit increase in BMI.¹² Putative mechanisms for these findings include altered oocyte morphology and reduced fertilization in eggs from obese women,¹³ and impaired embryo quality in women less than age 35.¹⁴ Oocytes from women with a BMI >25 kg/m² are smaller and less likely to complete development postfertilization, with embryos arrested prior to blastulation containing more triglyceride than those forming blastocysts.¹⁵

Blastocysts developed from oocytes of high-BMI women are smaller, contain fewer cells and have a higher content of triglycerides, lower glucose consumption, and altered amino acid metabolism compared with embryos of normal-weight women (BMI <24.9 kg/m2).¹⁵ Obesity may alter endometrial receptivity during IVF given the finding that third-party surrogate women with a BMI >35 kg/m² have a lower live-birth rate (25%) compared with women with a BMI <35 kg/m² (49%; P<.05).¹⁶

Pregnancy outcomes

Obesity is linked to an increased risk of miscarriage. Results of a meta-analysis of 33 IVF studies including 47,967 cycles indicated that overweight or obese women have a higher rate of miscarriage (RR, 1.31; P<.0001) than normal-weight women (BMI <25 kg/m2).¹⁷ Maternal and perinatal morbid obesity are strongly associated with obstetric and perinatal complications, including gestational diabetes, hypertension, preeclampsia, preterm delivery, shoulder dystocia, fetal distress, early neonatal death, and small- as well as large-for-gestational age infants.

Obese women who conceive by IVF are at increased risk for preeclampsia, gestational diabetes, preterm delivery, and cesarean delivery.¹³ Authors of a meta-analysis of 18 observational studies concluded that obese mothers were at increased odds of pregnancies affected by such birth defects as neural tube defects, cardiovascular anomalies, and cleft lip and palate, among others.¹⁸

In addition to being the cause of these fetal abnormalities, maternal metabolic dysfunction is linked to promoting obesity in offspring, thereby perpetuating a cycle of obesity and adverse health outcomes that include an increased risk of premature death in adult offspring in subsequent generations.¹³

Treatment for obesity

Lifestyle modification is the first-line treatment for obesity.  
Pre-fertility therapy and pregnancy goals. Targets for pregnancy should include:  

• preconception weight loss to a BMI of 35 kg/m2
• prevention of excess weight gain in pregnancy
• long-term reduction in weight.

For all obese individuals, lifestyle modifications should include a weight loss of 7% of body weight and increased physical activity to at least 150 minutes of moderate activity, such as walking, per week. Calorie restriction should be emphasized. A 500 to 1,000 kcal/day decrease from usual dietary intake is expected to result in a 1- to 2-lb weight loss per week. A low-calorie diet of 1,000 to 1,200 kcal/day can lead to an average 10% decrease in total body weight over 6 months.

Adjunct supervised medical therapy or bariatric surgery can play an important role in successful weight loss prepregnancy but are not appropriate for women actively attempting conception. Importantly, pregnancy should be deferred for a minimum of 1 year after bariatric surgery. The decision to postpone pregnancy to achieve weight loss must be balanced against the risk of declining fertility with advancing age of the woman. 

Read about when to treat subclinical hypothyroidism

Optimal management of subclinical hypothyroidism in women with infertility

Practice Committee of the American Society for Reproductive Medicine. Subclinical hypothyroidism in the infertile female population: a guideline. Fertil Steril. 2015;104(3):545-553.

Thyroid disorders long have been associated with the potential for adverse reproductive outcomes. While overt hypothyroidism has been linked to infertility, increased miscarriage risk, and poor maternal and fetal outcomes, controversy has existed regarding the association between subclinical hypothyroidism (SCH) and reproductive problems. The ASRM recently published a guideline on the role of SCH in the infertile female population.  

How is subclinical hypothyroidism defined?

SCH is classically defined as a thyrotropin (TSH) level above the upper limit of normal range (4.5−5.0 mIU/L) with normal free thyroxine (FT4) levels. The National Health and Nutrition Examination Survey (NHANES III) population has been used to establish normative data for TSH for a disease-free population. These include a median serum level for TSH of 1.5 mIU/L, with the corresponding 2.5 and 97.5 percentiles of 0.41 and 6.10, respectively.¹⁹ Data from the National Academy of Clinical Biochemistry, however, reveal that 95% of individuals without evidence of thyroid disease have a TSH level <2.5 mIU/L, and that the normal reference range is skewed to the right.20 Adjusting the upper limit of the normal range to 2.5 mIU/L would result in an additional 11.8% to 14.2% of the United States population (22 to 28 million individuals) being diagnosed with hypothyroidism.

This information raises several important questions.

1. Should nonpregnant women be treated for SCH?

No. There is no benefit from the standpoint of lipid profile or alteration of cardiovascular risk in the treatment of TSH levels between 5 and 10 mIU/L and, therefore, treatment of individuals with TSH <5 mIU/L is questionable. Furthermore, the risk of overtreatment resulting in bone loss is a concern. The Endocrine Society does not recommend changing the current normal TSH range for nonpregnant women.

2. What are normal TSH levels in pregnant women?

Because human chorionic gonadotropin (hCG) can bind to and affect the TSH receptor, thereby influencing TSH values, the normal range for TSH is modified in pregnancy. The Endocrine Society recommends the following pregnancy trimester guidelines for TSH levels: 2.5 mIU/L is the recommended upper limit of normal in the first trimester, 3.0 mIU/L in the second trimester, and 3.5 mIU/L in the third trimester.

3. Is untreated SCH associated with miscarriage?

There is fair evidence that SCH, defined as a TSH level >4 mIU/L during pregnancy, is associated with miscarriage, but there is insufficient evidence that TSH levels between 2.5 and 4 mIU/L are associated with miscarriage.

4. Is untreated SCH associated with infertility?

Limited data are available to assess the effect of SCH on infertility. While a few studies show an association between SCH on unexplained infertility and ovulatory disorders, SCH does not appear to be increased in other causes of infertility.

5. Is SCH associated with adverse obstetric outcomes?

Available data reveal that SCH with TSH levels outside the normal pregnancy range are associated with an increased risk of such obstetric complications as placental abruption, preterm birth, fetal death, and preterm premature rupture of membranes (PPROM). However, it is unclear if prepregnancy TSH levels between 2.5 and 4 mIU/L are associated with adverse obstetric outcomes.

6. Does untreated SCH affect developmental outcomes in children?

The fetus is solely dependent on maternal thyroid hormone in early pregnancy because the fetal thyroid does not produce thyroid hormone before 10 to 13 weeks of gestation. Significant evidence has associated untreated maternal hypothyroidism with delayed fetal neurologic development, impaired school performance, and lower intelligence quotient (IQ) among offspring.21 There is fair evidence that SCH diagnosed in pregnancy is associated with adverse neurologic development. There is no evidence that SCH prior to pregnancy is associated with adverse neurodevelopmental outcomes. It should be noted that only one study has examined whether treatment of SCH improves developmental outcomes (measured by IQ scored at age 3 years) and no significant differences were observed in women with SCH who were treated with levothyroxine versus those who were not.²²

7. Does treatment of SCH improve miscarriage rates, live-birth rates, and/or clinical pregnancy rates?

Small randomized controlled studies of women undergoing infertility treatment and a few observational studies in the general population yield good evidence that levothyroxine treatment in women with SCH defined as TSH >4.0 mIU/L is associated with improvement in pregnancy, live birth, and miscarriage rates. There are no randomized trials assessing whether levothyroxine treatment in women with TSH levels between 2.5 and 4 mIU/L would yield similar benefits to those observed in women with TSH levels above 4 mIU/L.

8. Are thyroid antibodies associated with infertility or adverse reproductive outcomes?

There is good evidence that the thyroid autoimmunity, or the presence of TPO-Ab, is associated with miscarriage and fair evidence that it is associated with infertility. Treatment with levothyroxine may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L.

9. Should there be universal screening for hypothyroidism in the first trimester of pregnancy?

Current evidence does not reveal a benefit of universal screening at this time. The American College of Obstetricians and Gynecologists does not recommend routine screening for hypothyroidism in pregnancy unless women have risk factors for thyroid disease, including a personal or family history of thyroid disease, physical findings or symptoms of goiter or hypothyroidism, type 1 diabetes mellitus, infertility, history of miscarriage or preterm delivery, and/or personal or family history of autoimmune disease.

The bottom line

SCH, defined as a TSH level greater than the upper limit of normal range (4.5&#8722;5.0 mIU/L)with normal FT4 levels, is associated with adverse reproductive outcomes including miscarriage, pregnancy complications, and delayed fetal neurodevelopment. Thyroid supplementation is beneficial; however, treatment has not been shown to improve long-term neurologic developmental outcomes in offspring. Data are limited on whether TSH values between 2.5 mIU/L and the upper range of normal are associated with adverse pregnancy outcomes and therefore treatment in this group remains controversial. Although available evidence is weak, there may be a benefit in some subgroups, and because risk is minimal, it may be reasonable to treat or to monitor levels and treat above nonpregnant and pregnancy ranges. There is fair evidence that thyroid autoimmunity (positive thyroid antibody) is associated with miscarriage and infertility. Levothyroxine therapy may improve pregnancy outcomes especially if the TSH level is above 2.5 mIU/L. While universal screening of thyroid function in pregnancy is not recommended, women at high risk for thyroid disease should be screened.23

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Patients seeking fertility care commonly ask the physician for advice regarding ways to optimize their conception attempts. While evidence from randomized controlled trials is not available, data from observational studies provide parameters that can inform patient decision making. Knowledge about the fertility window, the decline in fecundability with age, and lifestyle practices that promote conception may be helpful to clinicians and aid in their ability to guide patients.

For those patients who will not achieve conception naturally, assisted reproductive technologies (ART) offer a promising alternative. ART options have improved greatly in effectiveness and safety since Louise Brown was born in 1978. More than 5 million babies have been born globally.¹ However, even though the United States is wealthy, access to in vitro fertilization (IVF) is poor relative to many other countries, with not more than 1 in 3 people needing IVF actually receiving the treatment. Understanding the international experience enables physicians to take actions that help increase access for their patients who need IVF.

In this article we not only address ways in which your patients can optimize their natural fertility but also examine this country’s ability to offer ART options when they are needed. Without such examination, fundamental changes in societal attitudes toward infertility and payor attitudes toward reproductive care will not occur, and it is these changes, among others, that can move this country to more equitable ART access.

Increasing access to assisted reproductive technologies
Besides per capita income, the major factor affecting access to ART is the role of public funding of health care. However, effectiveness also matters. Globally, only 1 cycle in 5 results in a live birth.²³ In the United States, 1 in 3 cycles result in a live birth—even with a population of older patients than many other countries. For US patients aged 37 or younger, approximately 2 in 5 who undergo 1 ART cycle will have a baby.²³ However, these results also demonstrate that, even with the highest live-birth rates in the world, a large majority of US patients will require more than 1 cycle of IVF. Therefore, access remains critical to enable not only the first cycle but also more than 1 cycle to be attempted.

One of the reasons for the higher US pregnancy rate is that we, historically, have replaced more embryos than other countries. This is not the only, or even the major, reason for higher pregnancy rates; however, it is the major reason for a higher multiple pregnancy rate.

Physician and patient education programs to address this problem have resulted in fewer embryos being replaced, and a slight reduction in the multiple pregnancy rates, but much further progress is needed (FIGURE 1).²³

 

23

The crux of the problem: Competition for a positive result
Importantly, the major reason more embryos are replaced in the United States is that poorer access is related to a higher number of embryos replaced in order to try to get patients pregnant with fewer cycles. This pressure is created both by patients and by physicians—especially because the United States is one of the few countries that mandates the publication of clinic-specific pregnancy rates.

This government mandate changes clinical practice toward maximizing pregnancy rates because IVF clinics cannot afford, for competitive reasons, to have lower pregnancy rates than other clinics. This is unfortunate, because it has been shown that when elective single embryo transfer (eSET) is implemented, pregnancy rates do not decrease significantly but, in fact, multiple pregnancy rates drop dramatically (FIGURE 2).²³
 

 

23

The cost of IVF obviously impacts access, but the issue is more complex than it appears. IVF in the United States costs about 30% to 50% more than in other countries. But general US health care costs are also relatively even higher than that, and IVF is not expensive relative to other medical services.^24,25 Nevertheless, compared with other countries, the average US cost of a standard fresh IVF cycle is the highest as a percentage of gross national income per capita, at about 25%.²⁶ However, because of higher live birth rates, the cost-effectiveness of ART (which is the cost per live birth) in the United States is not unfavorable relative to other countries.²⁶

What matters to patients, however, is affordability, which is the net cost to patients after all subsidies relative to disposable income. US out-of-pocket costs for IVF as a percent of annual disposable income make IVF costs in the United States among the least affordable in the world. Affordability predicts utilization, as well as number of embryos transferred.²⁴ It is clear that less affordable IVF cycles result in more embryos being transferred. Broad insurance mandates result in large increases in treatment access but also significantly less aggressive treatment. More limited insurance mandates generally have little effect on IVF markets, which is why there is only a slight difference in practice behavior in mandated states because, nationally, coverage is poor (FIGURE 3).^24,27,28

 

28

We must increase access to ART by increasing funding
In summary, the economic factors that affect affordability are the cost of treatment, socioeconomic status, disposable income, government coverage, insurance coverage, and access to financing/loan programs. Access is affected by many factors, but only countries with funding arrangements that minimize out-of-pocket expenses meet expected demand of infertile patients. ART is expensive from a patient perspective, but not from a societal perspective. To increase subsidies we must:

 

• change societal attitudes toward infertility
• change payor attitudes toward reproductive care
• convince payers of cost-effectiveness
• develop effective payment plans and programs
• improve protocols (eg, eSET)
• educate patients and professionals
• use technology appropriately
• standardize treatments through research
• innovate new technologies to reduce costs
• develop patient criteria for inclusion in subsidization.

The ASRM has taken the lead in this respect in the United States by having an Access to Care Summit in September 2015, as well as an Advocacy Forum, and will continue to advocate for better coverage for infertility care. Internationally, FIGO (the International Federation of Gynecologyand Obstetrics) has taken the initiative to increase ART access, with the Committee on Reproductive Medicine distributing The FIGO Fertility Toolbox (http://www.fertilitytool.com).

World Health Organization Infertility Initiative
The World Health Organization (WHO) has, over the past 5 years, made a major initiative to increase global access to infertility diagnosis and treatment. This effort was effected through 3 major activities:

 

• rapid assessment task force
• reproductive medicine glossary
• fertility guidelines. 

The Rapid Assessment Task Force. This Task Force developed a comprehensive questionnaire for the 195 governments that belong to and adhere to WHO guidelines. This questionnaire, which is to be completed by government health departments, requires the government to document the breadth and depth of their infertility services and identify deficiencies or gaps. It is expected that the questionnaire will be distributed to all governments of the world in 2016, including the United States. The information that is received by the Task Force will be analyzed by the WHO to help develop plans for improved national infertility services globally.

The Reproductive Medicine glossary. This glossary being developed is a revision and major update of The International Committee Monitoring ART (ICMART)/WHO Glossary.²⁹ The number of definitions in the glossary is being increased 4-fold to about 300 definitions to include not only ART but also sections on clinical definitions, out‑comes, laboratory/embryology, epidemiology/public health, and andrology. While easy to overlook, definitions are essential to the accurate documentation of disease, communication among professionals, research comparisons, insurance coverage, billing and coding, and other issues.

For example, because the definition of infertility must include not only couples but also single persons, be flexible to deal with clinical versus epidemiologic and public health requirements, account for pre-existing conditions and age, and identify it as both a disease and a disability. Abortion definitions are complicated by the desire of many to call spontaneous abortion “miscarriage” and by the duration of pregnancy necessary before “delivery” of a fetus occurs. There is a desire to remove conception as a term (although it is widely used) because it is not a biological event. Pregnancy has its own complexities, including when it is initiated, which is now considered to be at the time of implantation. The glossary is expected to be published by mid-2016.

The WHO infertility guidelines. These have been an exhaustively-developed set of guidelines based on a comprehensive review and assessment of the entire literature by approximately 60 international experts working in teams with other assistants and experts using a standardized PICO (Population, Intervention, Comparators, and Outcomes of interest) system. This was a truly herculean effort. Guidelines are being finalized in the following areas: female infertility, unexplained infertility, polycystic ovary syndrome, ovarian stimulation, intrauterine insemination, ovarian hyperstimulation syndrome, IVF, and male infertility. After thorough review by the WHO, these guidelines will be published in hard copy and electronically in mid-2016.

Watch for access tools available this year
The plans are for the Task Force recommendations, the glossary, and the fertility guidelines, including The FIGO Fertility Toolbox to be presented as a comprehensive package to all of the governments of the world in 2016. This will give them the tools and encouragement to assess their fertility services and to use the WHO fertility package to improve access, effectiveness, and safety of infertility services in their respective countries.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Patients seeking fertility care commonly ask the physician for advice regarding ways to optimize their conception attempts. While evidence from randomized controlled trials is not available, data from observational studies provide parameters that can inform patient decision making. Knowledge about the fertility window, the decline in fecundability with age, and lifestyle practices that promote conception may be helpful to clinicians and aid in their ability to guide patients.

For those patients who will not achieve conception naturally, assisted reproductive technologies (ART) offer a promising alternative. ART options have improved greatly in effectiveness and safety since Louise Brown was born in 1978. More than 5 million babies have been born globally.¹ However, even though the United States is wealthy, access to in vitro fertilization (IVF) is poor relative to many other countries, with not more than 1 in 3 people needing IVF actually receiving the treatment. Understanding the international experience enables physicians to take actions that help increase access for their patients who need IVF.

In this article we not only address ways in which your patients can optimize their natural fertility but also examine this country’s ability to offer ART options when they are needed. Without such examination, fundamental changes in societal attitudes toward infertility and payor attitudes toward reproductive care will not occur, and it is these changes, among others, that can move this country to more equitable ART access.

Increasing access to assisted reproductive technologies
Besides per capita income, the major factor affecting access to ART is the role of public funding of health care. However, effectiveness also matters. Globally, only 1 cycle in 5 results in a live birth.²³ In the United States, 1 in 3 cycles result in a live birth—even with a population of older patients than many other countries. For US patients aged 37 or younger, approximately 2 in 5 who undergo 1 ART cycle will have a baby.²³ However, these results also demonstrate that, even with the highest live-birth rates in the world, a large majority of US patients will require more than 1 cycle of IVF. Therefore, access remains critical to enable not only the first cycle but also more than 1 cycle to be attempted.

One of the reasons for the higher US pregnancy rate is that we, historically, have replaced more embryos than other countries. This is not the only, or even the major, reason for higher pregnancy rates; however, it is the major reason for a higher multiple pregnancy rate.

Physician and patient education programs to address this problem have resulted in fewer embryos being replaced, and a slight reduction in the multiple pregnancy rates, but much further progress is needed (FIGURE 1).²³

 

23

The crux of the problem: Competition for a positive result
Importantly, the major reason more embryos are replaced in the United States is that poorer access is related to a higher number of embryos replaced in order to try to get patients pregnant with fewer cycles. This pressure is created both by patients and by physicians—especially because the United States is one of the few countries that mandates the publication of clinic-specific pregnancy rates.

This government mandate changes clinical practice toward maximizing pregnancy rates because IVF clinics cannot afford, for competitive reasons, to have lower pregnancy rates than other clinics. This is unfortunate, because it has been shown that when elective single embryo transfer (eSET) is implemented, pregnancy rates do not decrease significantly but, in fact, multiple pregnancy rates drop dramatically (FIGURE 2).²³
 

 

23

The cost of IVF obviously impacts access, but the issue is more complex than it appears. IVF in the United States costs about 30% to 50% more than in other countries. But general US health care costs are also relatively even higher than that, and IVF is not expensive relative to other medical services.^24,25 Nevertheless, compared with other countries, the average US cost of a standard fresh IVF cycle is the highest as a percentage of gross national income per capita, at about 25%.²⁶ However, because of higher live birth rates, the cost-effectiveness of ART (which is the cost per live birth) in the United States is not unfavorable relative to other countries.²⁶

What matters to patients, however, is affordability, which is the net cost to patients after all subsidies relative to disposable income. US out-of-pocket costs for IVF as a percent of annual disposable income make IVF costs in the United States among the least affordable in the world. Affordability predicts utilization, as well as number of embryos transferred.²⁴ It is clear that less affordable IVF cycles result in more embryos being transferred. Broad insurance mandates result in large increases in treatment access but also significantly less aggressive treatment. More limited insurance mandates generally have little effect on IVF markets, which is why there is only a slight difference in practice behavior in mandated states because, nationally, coverage is poor (FIGURE 3).^24,27,28

 

28

We must increase access to ART by increasing funding
In summary, the economic factors that affect affordability are the cost of treatment, socioeconomic status, disposable income, government coverage, insurance coverage, and access to financing/loan programs. Access is affected by many factors, but only countries with funding arrangements that minimize out-of-pocket expenses meet expected demand of infertile patients. ART is expensive from a patient perspective, but not from a societal perspective. To increase subsidies we must:

 

• change societal attitudes toward infertility
• change payor attitudes toward reproductive care
• convince payers of cost-effectiveness
• develop effective payment plans and programs
• improve protocols (eg, eSET)
• educate patients and professionals
• use technology appropriately
• standardize treatments through research
• innovate new technologies to reduce costs
• develop patient criteria for inclusion in subsidization.

The ASRM has taken the lead in this respect in the United States by having an Access to Care Summit in September 2015, as well as an Advocacy Forum, and will continue to advocate for better coverage for infertility care. Internationally, FIGO (the International Federation of Gynecologyand Obstetrics) has taken the initiative to increase ART access, with the Committee on Reproductive Medicine distributing The FIGO Fertility Toolbox (http://www.fertilitytool.com).

World Health Organization Infertility Initiative
The World Health Organization (WHO) has, over the past 5 years, made a major initiative to increase global access to infertility diagnosis and treatment. This effort was effected through 3 major activities:

 

• rapid assessment task force
• reproductive medicine glossary
• fertility guidelines. 

The Rapid Assessment Task Force. This Task Force developed a comprehensive questionnaire for the 195 governments that belong to and adhere to WHO guidelines. This questionnaire, which is to be completed by government health departments, requires the government to document the breadth and depth of their infertility services and identify deficiencies or gaps. It is expected that the questionnaire will be distributed to all governments of the world in 2016, including the United States. The information that is received by the Task Force will be analyzed by the WHO to help develop plans for improved national infertility services globally.

The Reproductive Medicine glossary. This glossary being developed is a revision and major update of The International Committee Monitoring ART (ICMART)/WHO Glossary.²⁹ The number of definitions in the glossary is being increased 4-fold to about 300 definitions to include not only ART but also sections on clinical definitions, out‑comes, laboratory/embryology, epidemiology/public health, and andrology. While easy to overlook, definitions are essential to the accurate documentation of disease, communication among professionals, research comparisons, insurance coverage, billing and coding, and other issues.

For example, because the definition of infertility must include not only couples but also single persons, be flexible to deal with clinical versus epidemiologic and public health requirements, account for pre-existing conditions and age, and identify it as both a disease and a disability. Abortion definitions are complicated by the desire of many to call spontaneous abortion “miscarriage” and by the duration of pregnancy necessary before “delivery” of a fetus occurs. There is a desire to remove conception as a term (although it is widely used) because it is not a biological event. Pregnancy has its own complexities, including when it is initiated, which is now considered to be at the time of implantation. The glossary is expected to be published by mid-2016.

The WHO infertility guidelines. These have been an exhaustively-developed set of guidelines based on a comprehensive review and assessment of the entire literature by approximately 60 international experts working in teams with other assistants and experts using a standardized PICO (Population, Intervention, Comparators, and Outcomes of interest) system. This was a truly herculean effort. Guidelines are being finalized in the following areas: female infertility, unexplained infertility, polycystic ovary syndrome, ovarian stimulation, intrauterine insemination, ovarian hyperstimulation syndrome, IVF, and male infertility. After thorough review by the WHO, these guidelines will be published in hard copy and electronically in mid-2016.

Watch for access tools available this year
The plans are for the Task Force recommendations, the glossary, and the fertility guidelines, including The FIGO Fertility Toolbox to be presented as a comprehensive package to all of the governments of the world in 2016. This will give them the tools and encouragement to assess their fertility services and to use the WHO fertility package to improve access, effectiveness, and safety of infertility services in their respective countries.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

Patients seeking fertility care commonly ask the physician for advice regarding ways to optimize their conception attempts. While evidence from randomized controlled trials is not available, data from observational studies provide parameters that can inform patient decision making. Knowledge about the fertility window, the decline in fecundability with age, and lifestyle practices that promote conception may be helpful to clinicians and aid in their ability to guide patients.

For those patients who will not achieve conception naturally, assisted reproductive technologies (ART) offer a promising alternative. ART options have improved greatly in effectiveness and safety since Louise Brown was born in 1978. More than 5 million babies have been born globally.¹ However, even though the United States is wealthy, access to in vitro fertilization (IVF) is poor relative to many other countries, with not more than 1 in 3 people needing IVF actually receiving the treatment. Understanding the international experience enables physicians to take actions that help increase access for their patients who need IVF.

In this article we not only address ways in which your patients can optimize their natural fertility but also examine this country’s ability to offer ART options when they are needed. Without such examination, fundamental changes in societal attitudes toward infertility and payor attitudes toward reproductive care will not occur, and it is these changes, among others, that can move this country to more equitable ART access.

Increasing access to assisted reproductive technologies
Besides per capita income, the major factor affecting access to ART is the role of public funding of health care. However, effectiveness also matters. Globally, only 1 cycle in 5 results in a live birth.²³ In the United States, 1 in 3 cycles result in a live birth—even with a population of older patients than many other countries. For US patients aged 37 or younger, approximately 2 in 5 who undergo 1 ART cycle will have a baby.²³ However, these results also demonstrate that, even with the highest live-birth rates in the world, a large majority of US patients will require more than 1 cycle of IVF. Therefore, access remains critical to enable not only the first cycle but also more than 1 cycle to be attempted.

One of the reasons for the higher US pregnancy rate is that we, historically, have replaced more embryos than other countries. This is not the only, or even the major, reason for higher pregnancy rates; however, it is the major reason for a higher multiple pregnancy rate.

Physician and patient education programs to address this problem have resulted in fewer embryos being replaced, and a slight reduction in the multiple pregnancy rates, but much further progress is needed (FIGURE 1).²³

 

23

The crux of the problem: Competition for a positive result
Importantly, the major reason more embryos are replaced in the United States is that poorer access is related to a higher number of embryos replaced in order to try to get patients pregnant with fewer cycles. This pressure is created both by patients and by physicians—especially because the United States is one of the few countries that mandates the publication of clinic-specific pregnancy rates.

This government mandate changes clinical practice toward maximizing pregnancy rates because IVF clinics cannot afford, for competitive reasons, to have lower pregnancy rates than other clinics. This is unfortunate, because it has been shown that when elective single embryo transfer (eSET) is implemented, pregnancy rates do not decrease significantly but, in fact, multiple pregnancy rates drop dramatically (FIGURE 2).²³
 

 

23

The cost of IVF obviously impacts access, but the issue is more complex than it appears. IVF in the United States costs about 30% to 50% more than in other countries. But general US health care costs are also relatively even higher than that, and IVF is not expensive relative to other medical services.^24,25 Nevertheless, compared with other countries, the average US cost of a standard fresh IVF cycle is the highest as a percentage of gross national income per capita, at about 25%.²⁶ However, because of higher live birth rates, the cost-effectiveness of ART (which is the cost per live birth) in the United States is not unfavorable relative to other countries.²⁶

What matters to patients, however, is affordability, which is the net cost to patients after all subsidies relative to disposable income. US out-of-pocket costs for IVF as a percent of annual disposable income make IVF costs in the United States among the least affordable in the world. Affordability predicts utilization, as well as number of embryos transferred.²⁴ It is clear that less affordable IVF cycles result in more embryos being transferred. Broad insurance mandates result in large increases in treatment access but also significantly less aggressive treatment. More limited insurance mandates generally have little effect on IVF markets, which is why there is only a slight difference in practice behavior in mandated states because, nationally, coverage is poor (FIGURE 3).^24,27,28

 

28

We must increase access to ART by increasing funding
In summary, the economic factors that affect affordability are the cost of treatment, socioeconomic status, disposable income, government coverage, insurance coverage, and access to financing/loan programs. Access is affected by many factors, but only countries with funding arrangements that minimize out-of-pocket expenses meet expected demand of infertile patients. ART is expensive from a patient perspective, but not from a societal perspective. To increase subsidies we must:

 

• change societal attitudes toward infertility
• change payor attitudes toward reproductive care
• convince payers of cost-effectiveness
• develop effective payment plans and programs
• improve protocols (eg, eSET)
• educate patients and professionals
• use technology appropriately
• standardize treatments through research
• innovate new technologies to reduce costs
• develop patient criteria for inclusion in subsidization.

The ASRM has taken the lead in this respect in the United States by having an Access to Care Summit in September 2015, as well as an Advocacy Forum, and will continue to advocate for better coverage for infertility care. Internationally, FIGO (the International Federation of Gynecologyand Obstetrics) has taken the initiative to increase ART access, with the Committee on Reproductive Medicine distributing The FIGO Fertility Toolbox (http://www.fertilitytool.com).

World Health Organization Infertility Initiative
The World Health Organization (WHO) has, over the past 5 years, made a major initiative to increase global access to infertility diagnosis and treatment. This effort was effected through 3 major activities:

 

• rapid assessment task force
• reproductive medicine glossary
• fertility guidelines. 

The Rapid Assessment Task Force. This Task Force developed a comprehensive questionnaire for the 195 governments that belong to and adhere to WHO guidelines. This questionnaire, which is to be completed by government health departments, requires the government to document the breadth and depth of their infertility services and identify deficiencies or gaps. It is expected that the questionnaire will be distributed to all governments of the world in 2016, including the United States. The information that is received by the Task Force will be analyzed by the WHO to help develop plans for improved national infertility services globally.

The Reproductive Medicine glossary. This glossary being developed is a revision and major update of The International Committee Monitoring ART (ICMART)/WHO Glossary.²⁹ The number of definitions in the glossary is being increased 4-fold to about 300 definitions to include not only ART but also sections on clinical definitions, out‑comes, laboratory/embryology, epidemiology/public health, and andrology. While easy to overlook, definitions are essential to the accurate documentation of disease, communication among professionals, research comparisons, insurance coverage, billing and coding, and other issues.

For example, because the definition of infertility must include not only couples but also single persons, be flexible to deal with clinical versus epidemiologic and public health requirements, account for pre-existing conditions and age, and identify it as both a disease and a disability. Abortion definitions are complicated by the desire of many to call spontaneous abortion “miscarriage” and by the duration of pregnancy necessary before “delivery” of a fetus occurs. There is a desire to remove conception as a term (although it is widely used) because it is not a biological event. Pregnancy has its own complexities, including when it is initiated, which is now considered to be at the time of implantation. The glossary is expected to be published by mid-2016.

The WHO infertility guidelines. These have been an exhaustively-developed set of guidelines based on a comprehensive review and assessment of the entire literature by approximately 60 international experts working in teams with other assistants and experts using a standardized PICO (Population, Intervention, Comparators, and Outcomes of interest) system. This was a truly herculean effort. Guidelines are being finalized in the following areas: female infertility, unexplained infertility, polycystic ovary syndrome, ovarian stimulation, intrauterine insemination, ovarian hyperstimulation syndrome, IVF, and male infertility. After thorough review by the WHO, these guidelines will be published in hard copy and electronically in mid-2016.

Watch for access tools available this year
The plans are for the Task Force recommendations, the glossary, and the fertility guidelines, including The FIGO Fertility Toolbox to be presented as a comprehensive package to all of the governments of the world in 2016. This will give them the tools and encouragement to assess their fertility services and to use the WHO fertility package to improve access, effectiveness, and safety of infertility services in their respective countries.

Share your thoughts! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.