OBG Management

Q. You argued in the debate that screening for breast cancer should start earlier than proposed in the USPSTF guidelines, as aggressive cancers are more likely to be found in younger women. The USPSTF recommends screening begin at age 50. At what age do you advocate breast cancer screening to begin?

Q. One argument against beginning screening earlier is “overdiagnosis.” How do you respond to overdiagnosis as a concern?

Q. How would you diagnosis breast cancer “just right” given the limited screening techniques (and limited understanding of DCIS)?

Q. You mentioned that you do not like the language of benefits and harms and do not use them in your practice. What alternative language do you use when counseling patients?

Q. What are your concerns with the USPSTF  C  recommendation for screening mammography among women aged 40-49?

Q. You argued in the debate that screening for breast cancer should start earlier than proposed in the USPSTF guidelines, as aggressive cancers are more likely to be found in younger women. The USPSTF recommends screening begin at age 50. At what age do you advocate breast cancer screening to begin?

Q. One argument against beginning screening earlier is “overdiagnosis.” How do you respond to overdiagnosis as a concern?

Q. How would you diagnosis breast cancer “just right” given the limited screening techniques (and limited understanding of DCIS)?

Q. You mentioned that you do not like the language of benefits and harms and do not use them in your practice. What alternative language do you use when counseling patients?

Q. What are your concerns with the USPSTF  C  recommendation for screening mammography among women aged 40-49?

Q. You argued in the debate that screening for breast cancer should start earlier than proposed in the USPSTF guidelines, as aggressive cancers are more likely to be found in younger women. The USPSTF recommends screening begin at age 50. At what age do you advocate breast cancer screening to begin?

Q. One argument against beginning screening earlier is “overdiagnosis.” How do you respond to overdiagnosis as a concern?

Q. How would you diagnosis breast cancer “just right” given the limited screening techniques (and limited understanding of DCIS)?

Q. You mentioned that you do not like the language of benefits and harms and do not use them in your practice. What alternative language do you use when counseling patients?

Q. What are your concerns with the USPSTF  C  recommendation for screening mammography among women aged 40-49?

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EXPERT COMMENTARY

Pregnancy management when delivery appears to be imminent at 22 to 26 weeks’ gestation—a window defined as the periviable period—is among the most challenging situations that obstetricians face. Expert guidance exists both at a national level in a shared guideline from the American College of Obstetricians and Gynecologists and the Society of Maternal Fetal Medicine and, ideally, at a local level where teams of obstetricians and neonatologists have considered in their facility what represents best care.¹ But whether national or local, such consensus is largely expert opinion based on a foundation limited by available evidence, which is almost always retrospective analysis of rare cases.

Among the most important yet often missing data points are outcomes of neonates born in the periviable period. Surveys suggest that obstetric care providers often underestimate the chance of survival following periviable delivery.² Understanding and weighing anticipated outcomes inform decision making regarding management and planned obstetric and neonatal interventions, including plans for neonatal resuscitation.

Not surprisingly, perhaps, survival of periviable neonates has been linked clearly to willingness to undertake resuscitation.³ Yet decisions are not and should not be all about survival. Patients and providers want to know about short- and long-term morbidity, especially neurologic health, among survivors. Available collections of morbidity and mortality data, however, often are limited by whether all cases are captured or just those from specialized centers with particular management approaches, which outcomes are included and how they are defined, and the inevitable reality that the outcome of death “competes” with the outcome of neurologic development (that is, those neonates who die are not at risk for later abnormal neurologic outcome).

Given the need for more and better information, the data from a recent study by Younge and colleagues is especially welcome. The investigators reported on survival and neurologic outcome among more than 4,000 births between 22 and 24 weeks’ gestation at 11 centers in the United States.

Details of the study

The authors compared outcomes among three 3-year epochs between 2000 and 2011 and reported that the rate of survival without neurodevelopmental impairment increased over this period while the rate of survival with such impairment did not change. This argues that the observed overall increase in survival over these 12 years was not simply a tradeoff for life with significant impairment.

Within that overall message, however, the details of the data are important. Survival without neurodevelopmental impairment did improve from epoch 1 to epoch 3, but just from 16% to 20% (95% confidence interval [CI], 18–23; P = .001). Most neonates in the 2008–2011 epoch died (64%; 95% CI, 61–66; P<.001) or were severely impaired (16%; 95% CI, 14–18; P = .29). This led the authors to conclude that “despite improvements over time, the incidence of death, neurodevelopmental impairment, and other adverse outcomes remains high.” Examined separately, outcomes for infants born at 22 0/7 to 22 6/7 weeks’ gestation were very limited and unchanged over the 3 epochs studied, with death rates of 97% to 98% and survival without neurodevelopmental impairment of just 1%. In my own practice I do not encourage neonatal resuscitation, cesarean delivery, or many other interventions at less than 23 weeks’ gestation.

By contrast, the study showed that at 24 0/7 to 24 6/7 weeks’ gestation in the 2008–2011 epoch, 55% of neonates survived and, overall, 32% of infants survived without evidence of neurodevelopmental impairment at 18 to 22 months of age.

Related Article:
Is expectant management a safe alternative to immediate delivery in patients with PPROM close to term?

Study strengths and weaknesses

It is important to note that the definition of neurodevelopmental impairment used in the Younge study included only what many would classify as severe impairment, and survivors in this cohort “without” neurodevelopmental impairment may still have had important neurologic and other health concerns. In addition, the study did not track outcomes of the children at school age or beyond, when other developmental issues may become evident. As well, the study data may not be generalizable, for it included births from just 11 specialized centers, albeit a consortium accounting for 4% to 5% of periviable births in the United States.

Nevertheless, in supporting findings from other US and European analyses, these new data will help inform counseling conversations in the years to come. Such conversations should consider options for resuscitation, palliative care, and, at less than 24 weeks’ gestation, pregnancy termination. In individual cases these and many other decisions will be informed by both specific clinical circumstances—estimated fetal weight, fetal sex, presence of infection, use of antenatal steroids—and, perhaps most important, individual and family values and preferences. Despite these new data, managing periviable gestations will remain a great and important challenge.

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.

EXPERT COMMENTARY

Pregnancy management when delivery appears to be imminent at 22 to 26 weeks’ gestation—a window defined as the periviable period—is among the most challenging situations that obstetricians face. Expert guidance exists both at a national level in a shared guideline from the American College of Obstetricians and Gynecologists and the Society of Maternal Fetal Medicine and, ideally, at a local level where teams of obstetricians and neonatologists have considered in their facility what represents best care.¹ But whether national or local, such consensus is largely expert opinion based on a foundation limited by available evidence, which is almost always retrospective analysis of rare cases.

Among the most important yet often missing data points are outcomes of neonates born in the periviable period. Surveys suggest that obstetric care providers often underestimate the chance of survival following periviable delivery.² Understanding and weighing anticipated outcomes inform decision making regarding management and planned obstetric and neonatal interventions, including plans for neonatal resuscitation.

Not surprisingly, perhaps, survival of periviable neonates has been linked clearly to willingness to undertake resuscitation.³ Yet decisions are not and should not be all about survival. Patients and providers want to know about short- and long-term morbidity, especially neurologic health, among survivors. Available collections of morbidity and mortality data, however, often are limited by whether all cases are captured or just those from specialized centers with particular management approaches, which outcomes are included and how they are defined, and the inevitable reality that the outcome of death “competes” with the outcome of neurologic development (that is, those neonates who die are not at risk for later abnormal neurologic outcome).

Given the need for more and better information, the data from a recent study by Younge and colleagues is especially welcome. The investigators reported on survival and neurologic outcome among more than 4,000 births between 22 and 24 weeks’ gestation at 11 centers in the United States.

Details of the study

The authors compared outcomes among three 3-year epochs between 2000 and 2011 and reported that the rate of survival without neurodevelopmental impairment increased over this period while the rate of survival with such impairment did not change. This argues that the observed overall increase in survival over these 12 years was not simply a tradeoff for life with significant impairment.

Within that overall message, however, the details of the data are important. Survival without neurodevelopmental impairment did improve from epoch 1 to epoch 3, but just from 16% to 20% (95% confidence interval [CI], 18–23; P = .001). Most neonates in the 2008–2011 epoch died (64%; 95% CI, 61–66; P<.001) or were severely impaired (16%; 95% CI, 14–18; P = .29). This led the authors to conclude that “despite improvements over time, the incidence of death, neurodevelopmental impairment, and other adverse outcomes remains high.” Examined separately, outcomes for infants born at 22 0/7 to 22 6/7 weeks’ gestation were very limited and unchanged over the 3 epochs studied, with death rates of 97% to 98% and survival without neurodevelopmental impairment of just 1%. In my own practice I do not encourage neonatal resuscitation, cesarean delivery, or many other interventions at less than 23 weeks’ gestation.

By contrast, the study showed that at 24 0/7 to 24 6/7 weeks’ gestation in the 2008–2011 epoch, 55% of neonates survived and, overall, 32% of infants survived without evidence of neurodevelopmental impairment at 18 to 22 months of age.

Related Article:
Is expectant management a safe alternative to immediate delivery in patients with PPROM close to term?

Study strengths and weaknesses

It is important to note that the definition of neurodevelopmental impairment used in the Younge study included only what many would classify as severe impairment, and survivors in this cohort “without” neurodevelopmental impairment may still have had important neurologic and other health concerns. In addition, the study did not track outcomes of the children at school age or beyond, when other developmental issues may become evident. As well, the study data may not be generalizable, for it included births from just 11 specialized centers, albeit a consortium accounting for 4% to 5% of periviable births in the United States.

Nevertheless, in supporting findings from other US and European analyses, these new data will help inform counseling conversations in the years to come. Such conversations should consider options for resuscitation, palliative care, and, at less than 24 weeks’ gestation, pregnancy termination. In individual cases these and many other decisions will be informed by both specific clinical circumstances—estimated fetal weight, fetal sex, presence of infection, use of antenatal steroids—and, perhaps most important, individual and family values and preferences. Despite these new data, managing periviable gestations will remain a great and important challenge.

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.

EXPERT COMMENTARY

Pregnancy management when delivery appears to be imminent at 22 to 26 weeks’ gestation—a window defined as the periviable period—is among the most challenging situations that obstetricians face. Expert guidance exists both at a national level in a shared guideline from the American College of Obstetricians and Gynecologists and the Society of Maternal Fetal Medicine and, ideally, at a local level where teams of obstetricians and neonatologists have considered in their facility what represents best care.¹ But whether national or local, such consensus is largely expert opinion based on a foundation limited by available evidence, which is almost always retrospective analysis of rare cases.

Among the most important yet often missing data points are outcomes of neonates born in the periviable period. Surveys suggest that obstetric care providers often underestimate the chance of survival following periviable delivery.² Understanding and weighing anticipated outcomes inform decision making regarding management and planned obstetric and neonatal interventions, including plans for neonatal resuscitation.

Not surprisingly, perhaps, survival of periviable neonates has been linked clearly to willingness to undertake resuscitation.³ Yet decisions are not and should not be all about survival. Patients and providers want to know about short- and long-term morbidity, especially neurologic health, among survivors. Available collections of morbidity and mortality data, however, often are limited by whether all cases are captured or just those from specialized centers with particular management approaches, which outcomes are included and how they are defined, and the inevitable reality that the outcome of death “competes” with the outcome of neurologic development (that is, those neonates who die are not at risk for later abnormal neurologic outcome).

Given the need for more and better information, the data from a recent study by Younge and colleagues is especially welcome. The investigators reported on survival and neurologic outcome among more than 4,000 births between 22 and 24 weeks’ gestation at 11 centers in the United States.

Details of the study

The authors compared outcomes among three 3-year epochs between 2000 and 2011 and reported that the rate of survival without neurodevelopmental impairment increased over this period while the rate of survival with such impairment did not change. This argues that the observed overall increase in survival over these 12 years was not simply a tradeoff for life with significant impairment.

Within that overall message, however, the details of the data are important. Survival without neurodevelopmental impairment did improve from epoch 1 to epoch 3, but just from 16% to 20% (95% confidence interval [CI], 18–23; P = .001). Most neonates in the 2008–2011 epoch died (64%; 95% CI, 61–66; P<.001) or were severely impaired (16%; 95% CI, 14–18; P = .29). This led the authors to conclude that “despite improvements over time, the incidence of death, neurodevelopmental impairment, and other adverse outcomes remains high.” Examined separately, outcomes for infants born at 22 0/7 to 22 6/7 weeks’ gestation were very limited and unchanged over the 3 epochs studied, with death rates of 97% to 98% and survival without neurodevelopmental impairment of just 1%. In my own practice I do not encourage neonatal resuscitation, cesarean delivery, or many other interventions at less than 23 weeks’ gestation.

By contrast, the study showed that at 24 0/7 to 24 6/7 weeks’ gestation in the 2008–2011 epoch, 55% of neonates survived and, overall, 32% of infants survived without evidence of neurodevelopmental impairment at 18 to 22 months of age.

Related Article:
Is expectant management a safe alternative to immediate delivery in patients with PPROM close to term?

Study strengths and weaknesses

It is important to note that the definition of neurodevelopmental impairment used in the Younge study included only what many would classify as severe impairment, and survivors in this cohort “without” neurodevelopmental impairment may still have had important neurologic and other health concerns. In addition, the study did not track outcomes of the children at school age or beyond, when other developmental issues may become evident. As well, the study data may not be generalizable, for it included births from just 11 specialized centers, albeit a consortium accounting for 4% to 5% of periviable births in the United States.

Nevertheless, in supporting findings from other US and European analyses, these new data will help inform counseling conversations in the years to come. Such conversations should consider options for resuscitation, palliative care, and, at less than 24 weeks’ gestation, pregnancy termination. In individual cases these and many other decisions will be informed by both specific clinical circumstances—estimated fetal weight, fetal sex, presence of infection, use of antenatal steroids—and, perhaps most important, individual and family values and preferences. Despite these new data, managing periviable gestations will remain a great and important challenge.

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.

Vaccination against human papillomavirus (HPV) infection and periodic cervical screening have significantly decreased the incidence of invasive cervical cancer. But cancers still exist despite the availability of these useful clinical tools, especially in women of reproductive age in developing regions of the world. In the 2016 update on cervical disease, I reviewed studies on 2 promising and novel immunotherapies for cervical cancer: HPV therapeutic vaccine and adoptive T-cell therapy. This year the focus is on remarkable advances in the field of genomics and related studies that are rapidly expanding our understanding of the molecular characteristics of cervical cancer. Rewards of this research already being explored include novel immunotherapeutic agents as well as the repurposed use of existing drugs.

But first, with regard to cervical screening and follow-up, 2 recent large studies have yielded findings that have important implications for patient management. One pertains to the monitoring of women who have persistent infection with high-risk HPV but cytology results that are negative. Its conclusion was unequivocal and very useful in the management of our patients. The other study tracked HPV screening performed every 3 years and reported on the diagnostic efficiency of this shorter interval screening strategy.

Read about persistent HPV infection and CIN

Persistent HPV infection has a higher risk than most clinicians might think

Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.

It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.

Related Article:
It is time for HPV vaccination to be considered part of routine preventive health care

Details of the study

Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.

Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.

Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.

All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.

Read about HPV-cytology cotesting

HPV−cytology cotesting every 3 years lowers population rates of cervical precancer and cancer

Silver MI, Schiffman M, Fetterman B, et al. The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen. Cancer. 2016;122(23):3682−3686.

Current guidelines on screening for cervical cancer in women 30 to 65 years of age advise the preferred strategy of using cytology alone every 3 years or combining HPV testing and cytology every 5 years.¹ These guidelines, based on data available at the time they were written, were meant to offer a reasonable balance between timely detection of abnormalities and avoidance of potential harms from screening too frequently. However, many patients are reluctant to postpone repeat testing to the extent recommended. Several authorities have in fact asked that screening intervals be revisited, perhaps allowing for a range of strategies, contending that the level of protection once provided by annual screening should be the benchmark by which evolving strategies are judged.² Today, they point out, the risk of cancer doubles in the 3 years following an initial negative cytology result, and it also increases by lengthening the cotesting interval from 3 to 5 years. They additionally question the validity of using frequency of colposcopies as a surrogate to measure harms of screening, and suggest that many women would willingly accept the procedure's minimal discomfort and inconvenience to gain peace of mind.

The study by Silver and colleagues gives credence to considering a shorter cotesting interval. Since 2003, Kaiser Permanente Northern California (KPNC) has implemented 3-year cotesting. To determine actual clinical outcomes of cotesting at this interval, KPNC analyzed data on more than 1 million women in its care between 2003 and 2012. Although investigators expected that they might see decreasing efficiency in cotesting over time, they instead found an increased detection rate of precancerous lesions per woman screened in the larger of 2 study cohorts.

Related Article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Details of the study

Included were all women 30 years of age or older enrolled in this study at KPNC between 2003 and 2012 who underwent HPV−cytology cotesting every 3 years. The population in its entirety (1,065,273 women) was deemed the "open cohort" and represented KPNC's total annual experience. A subset of this population, the "closed cohort," was designed to gauge the effect of repeated screening on a fixed population and comprised only those women enrolled and initially screened between 2003 and 2004 and then followed longitudinally until 2012.

For each cohort, investigators calculated the ratios of precancer and cancer diagnoses to the total number of cotests performed on the cohort's population. The 3-year testing periods were 2004−2006, 2007−2009, and 2010−2012. Also calculated in these periods were the ratios of colposcopic biopsies to cotests and the rates of precancer diagnoses (TABLE). 

In the open cohort, the biopsy rate nearly doubled over the course of the study. Precancer diagnoses per number of cotests rose by 71.5% between the first and second testing periods (P = .001) and then eased off by 10% in the third period (P<.001). These corresponding increases throughout the study yielded a stable number of biopsies (16 to 22) needed to detect precancer.

In the closed long-term cohort, the biopsy rate rose, but not as much as in the open cohort. Precancer diagnoses per number of cotests rose by 47% between the first and second periods (P≤.001), but in the third period fell back by 28% (P<.001) to a level just above the first period results. The number of biopsies needed to detect a precancerous lesion in the closed cohort rose from 19 to 33 over the course of the study, suggesting there may have been some loss of screening efficiency in the fixed group.

Read about molecular profiling of cervical cancer

Molecular profiling of cervical cancer is revolutionizing treatment

The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.

Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.

Related Article:
2016 Update on cervical disease

How molecular profiling is paying off for cervical cancer

Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.

Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.

The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.  

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.

Vaccination against human papillomavirus (HPV) infection and periodic cervical screening have significantly decreased the incidence of invasive cervical cancer. But cancers still exist despite the availability of these useful clinical tools, especially in women of reproductive age in developing regions of the world. In the 2016 update on cervical disease, I reviewed studies on 2 promising and novel immunotherapies for cervical cancer: HPV therapeutic vaccine and adoptive T-cell therapy. This year the focus is on remarkable advances in the field of genomics and related studies that are rapidly expanding our understanding of the molecular characteristics of cervical cancer. Rewards of this research already being explored include novel immunotherapeutic agents as well as the repurposed use of existing drugs.

But first, with regard to cervical screening and follow-up, 2 recent large studies have yielded findings that have important implications for patient management. One pertains to the monitoring of women who have persistent infection with high-risk HPV but cytology results that are negative. Its conclusion was unequivocal and very useful in the management of our patients. The other study tracked HPV screening performed every 3 years and reported on the diagnostic efficiency of this shorter interval screening strategy.

Read about persistent HPV infection and CIN

Persistent HPV infection has a higher risk than most clinicians might think

Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.

It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.

Related Article:
It is time for HPV vaccination to be considered part of routine preventive health care

Details of the study

Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.

Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.

Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.

All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.

Read about HPV-cytology cotesting

HPV−cytology cotesting every 3 years lowers population rates of cervical precancer and cancer

Silver MI, Schiffman M, Fetterman B, et al. The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen. Cancer. 2016;122(23):3682−3686.

Current guidelines on screening for cervical cancer in women 30 to 65 years of age advise the preferred strategy of using cytology alone every 3 years or combining HPV testing and cytology every 5 years.¹ These guidelines, based on data available at the time they were written, were meant to offer a reasonable balance between timely detection of abnormalities and avoidance of potential harms from screening too frequently. However, many patients are reluctant to postpone repeat testing to the extent recommended. Several authorities have in fact asked that screening intervals be revisited, perhaps allowing for a range of strategies, contending that the level of protection once provided by annual screening should be the benchmark by which evolving strategies are judged.² Today, they point out, the risk of cancer doubles in the 3 years following an initial negative cytology result, and it also increases by lengthening the cotesting interval from 3 to 5 years. They additionally question the validity of using frequency of colposcopies as a surrogate to measure harms of screening, and suggest that many women would willingly accept the procedure's minimal discomfort and inconvenience to gain peace of mind.

The study by Silver and colleagues gives credence to considering a shorter cotesting interval. Since 2003, Kaiser Permanente Northern California (KPNC) has implemented 3-year cotesting. To determine actual clinical outcomes of cotesting at this interval, KPNC analyzed data on more than 1 million women in its care between 2003 and 2012. Although investigators expected that they might see decreasing efficiency in cotesting over time, they instead found an increased detection rate of precancerous lesions per woman screened in the larger of 2 study cohorts.

Related Article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Details of the study

Included were all women 30 years of age or older enrolled in this study at KPNC between 2003 and 2012 who underwent HPV−cytology cotesting every 3 years. The population in its entirety (1,065,273 women) was deemed the "open cohort" and represented KPNC's total annual experience. A subset of this population, the "closed cohort," was designed to gauge the effect of repeated screening on a fixed population and comprised only those women enrolled and initially screened between 2003 and 2004 and then followed longitudinally until 2012.

For each cohort, investigators calculated the ratios of precancer and cancer diagnoses to the total number of cotests performed on the cohort's population. The 3-year testing periods were 2004−2006, 2007−2009, and 2010−2012. Also calculated in these periods were the ratios of colposcopic biopsies to cotests and the rates of precancer diagnoses (TABLE). 

In the open cohort, the biopsy rate nearly doubled over the course of the study. Precancer diagnoses per number of cotests rose by 71.5% between the first and second testing periods (P = .001) and then eased off by 10% in the third period (P<.001). These corresponding increases throughout the study yielded a stable number of biopsies (16 to 22) needed to detect precancer.

In the closed long-term cohort, the biopsy rate rose, but not as much as in the open cohort. Precancer diagnoses per number of cotests rose by 47% between the first and second periods (P≤.001), but in the third period fell back by 28% (P<.001) to a level just above the first period results. The number of biopsies needed to detect a precancerous lesion in the closed cohort rose from 19 to 33 over the course of the study, suggesting there may have been some loss of screening efficiency in the fixed group.

Read about molecular profiling of cervical cancer

Molecular profiling of cervical cancer is revolutionizing treatment

The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.

Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.

Related Article:
2016 Update on cervical disease

How molecular profiling is paying off for cervical cancer

Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.

Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.

The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.  

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.

Vaccination against human papillomavirus (HPV) infection and periodic cervical screening have significantly decreased the incidence of invasive cervical cancer. But cancers still exist despite the availability of these useful clinical tools, especially in women of reproductive age in developing regions of the world. In the 2016 update on cervical disease, I reviewed studies on 2 promising and novel immunotherapies for cervical cancer: HPV therapeutic vaccine and adoptive T-cell therapy. This year the focus is on remarkable advances in the field of genomics and related studies that are rapidly expanding our understanding of the molecular characteristics of cervical cancer. Rewards of this research already being explored include novel immunotherapeutic agents as well as the repurposed use of existing drugs.

But first, with regard to cervical screening and follow-up, 2 recent large studies have yielded findings that have important implications for patient management. One pertains to the monitoring of women who have persistent infection with high-risk HPV but cytology results that are negative. Its conclusion was unequivocal and very useful in the management of our patients. The other study tracked HPV screening performed every 3 years and reported on the diagnostic efficiency of this shorter interval screening strategy.

Read about persistent HPV infection and CIN

Persistent HPV infection has a higher risk than most clinicians might think

Elfgren K, Elfström KM, Naucler P, Arnheim-Dahlström L, Dillner J. Management of women with human papillomavirus persistence: long-term follow-up of a randomized clinical trial. Am J Obstet Gynecol. 2017;216(3):264.e1-e7.

It is well known that most cases of cervical cancer arise from persistent HPV infection, with the highest percentage of cancers caused by high-risk types 16 or 18. What has been uncertain, however, is the actual degree of risk that persistent infection confers over time for the development of cervical intraepithelial neoplasia (CIN) or worse when a woman's repeated cytology reports are negative. In an analysis of a long-term double-blind, randomized, controlled screening study, Elfgren and colleagues showed that all women whose HPV infection persisted up to 7 years developed CIN grade 2 (CIN2+), while those whose infection cleared in that period, or changed genotype, had no precancerous lesions out to 13 years of follow-up.

Related Article:
It is time for HPV vaccination to be considered part of routine preventive health care

Details of the study

Between 1997 and 2000, 12,527 Swedish women between the ages of 32 and 38 years who were undergoing organized cervical cancer screening agreed to participate in a 1:1-randomized prospective trial to determine the benefit of screening with HPV and cytology (intervention group) compared with cytology screening alone (control group). However, brush sampling for HPV was performed even on women in the control group, with the samples frozen for later testing. All participants were identified in the Swedish National Cervical Screening Registry.

Women in the intervention group who initially tested positive for HPV but whose cytology test results were negative (n = 341) were invited to return a year later for repeat HPV testing; 270 women returned and 119 had type-specific HPV persistence. Of those with persistent infection, 100 agreed to undergo colposcopy; 111 women from the control group were randomly selected to undergo sham HPV testing and colposcopy, and 95 attended. Women with evident cytologic abnormalities received treatment per protocol. Those with negative cytology results were offered annual HPV testing thereafter, and each follow-up with documented type-specific HPV persistence led to repeat colposcopy. A comparable number of women from the control group had repeat colposcopies.

Although some women were lost to clinical follow-up throughout the trial, all 195 who attended the first colposcopy were followed for at least 5 years in the Swedish registry, and 191 were followed in the registry for 13 years. Of 102 women with known HPV persistence at baseline (100 in the treatment group; 2 in the randomly selected control group), 31 became HPV negative, 4 evidenced a switch in HPV type but cleared the initial infection, 27 had unknown persistence status due to missed HPV tests, and 40 had continuously type-specific persistence. Of note, persistent HPV16 infection seemed to impart a higher risk of CIN development than did persistent HPV18 infection.

All 40 participants with clinically verified continuously persistent HPV infection developed CIN2+ within 7 years of baseline documentation of persistence (FIGURE 1). Among the 27 women with unknown persistence status, risk of CIN2+ occurrence within 7 years was 50%. None of the 35 women who cleared their infection or switched HPV type developed CIN2+.

Read about HPV-cytology cotesting

HPV−cytology cotesting every 3 years lowers population rates of cervical precancer and cancer

Silver MI, Schiffman M, Fetterman B, et al. The population impact of human papillomavirus/cytology cervical cotesting at 3-year intervals: reduced cervical cancer risk and decreased yield of precancer per screen. Cancer. 2016;122(23):3682−3686.

Current guidelines on screening for cervical cancer in women 30 to 65 years of age advise the preferred strategy of using cytology alone every 3 years or combining HPV testing and cytology every 5 years.¹ These guidelines, based on data available at the time they were written, were meant to offer a reasonable balance between timely detection of abnormalities and avoidance of potential harms from screening too frequently. However, many patients are reluctant to postpone repeat testing to the extent recommended. Several authorities have in fact asked that screening intervals be revisited, perhaps allowing for a range of strategies, contending that the level of protection once provided by annual screening should be the benchmark by which evolving strategies are judged.² Today, they point out, the risk of cancer doubles in the 3 years following an initial negative cytology result, and it also increases by lengthening the cotesting interval from 3 to 5 years. They additionally question the validity of using frequency of colposcopies as a surrogate to measure harms of screening, and suggest that many women would willingly accept the procedure's minimal discomfort and inconvenience to gain peace of mind.

The study by Silver and colleagues gives credence to considering a shorter cotesting interval. Since 2003, Kaiser Permanente Northern California (KPNC) has implemented 3-year cotesting. To determine actual clinical outcomes of cotesting at this interval, KPNC analyzed data on more than 1 million women in its care between 2003 and 2012. Although investigators expected that they might see decreasing efficiency in cotesting over time, they instead found an increased detection rate of precancerous lesions per woman screened in the larger of 2 study cohorts.

Related Article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Details of the study

Included were all women 30 years of age or older enrolled in this study at KPNC between 2003 and 2012 who underwent HPV−cytology cotesting every 3 years. The population in its entirety (1,065,273 women) was deemed the "open cohort" and represented KPNC's total annual experience. A subset of this population, the "closed cohort," was designed to gauge the effect of repeated screening on a fixed population and comprised only those women enrolled and initially screened between 2003 and 2004 and then followed longitudinally until 2012.

For each cohort, investigators calculated the ratios of precancer and cancer diagnoses to the total number of cotests performed on the cohort's population. The 3-year testing periods were 2004−2006, 2007−2009, and 2010−2012. Also calculated in these periods were the ratios of colposcopic biopsies to cotests and the rates of precancer diagnoses (TABLE). 

In the open cohort, the biopsy rate nearly doubled over the course of the study. Precancer diagnoses per number of cotests rose by 71.5% between the first and second testing periods (P = .001) and then eased off by 10% in the third period (P<.001). These corresponding increases throughout the study yielded a stable number of biopsies (16 to 22) needed to detect precancer.

In the closed long-term cohort, the biopsy rate rose, but not as much as in the open cohort. Precancer diagnoses per number of cotests rose by 47% between the first and second periods (P≤.001), but in the third period fell back by 28% (P<.001) to a level just above the first period results. The number of biopsies needed to detect a precancerous lesion in the closed cohort rose from 19 to 33 over the course of the study, suggesting there may have been some loss of screening efficiency in the fixed group.

Read about molecular profiling of cervical cancer

Molecular profiling of cervical cancer is revolutionizing treatment

The Cancer Genome Atlas Research Network. Integratedgenomic and molecular characterization of cervical cancer. Nature. 2017;543(7645):378−384.

Effective treatments for cervical cancer could be close at hand, thanks to a recent explosion of knowledge at the molecular level about how specific cancers arise and what drives them other than HPV. The Cancer Genome Atlas Research Network (TCGA) recently published the results of its genomic and proteomic analyses, which yielded distinct profiles for 178 cervical cancers with important patterns common to other cancers, such as uterine and breast cancer. These recently published findings on cervical cancer highlight areas of gene and protein dysfunction it shares with these other cancers, which could open the doors for new targets for treatments already developed or in the pipeline.

Related Article:
2016 Update on cervical disease

How molecular profiling is paying off for cervical cancer

Cancers develop in any given tissue through the altered function of different genes and signaling pathways in the tissue's cells. The latest extensive investigation conducted by the TCGA network has identified significant mutations in 5 genes previously unrecognized in association with cervical cancer, bringing the total now to 14.

Several highlights are featured in the TCGA's recently published work. One discovery is the amplification of genes CD274 and PDCD1LG2, which are involved with the expression of 2 cytolytic effector genes and are therefore likely targets for immunotherapeutic strategies. Another line of exploration, whole-genome sequencing, has detected an aberration in some cervical cancer tissue with the potential for immediate application. Duplication and copy number gain of BCAR4, a noncoding RNA, facilitates cell proliferation through the HER2/HER3 pathway, a target of the tyrosine-kinase inhibitor, lapatinib, which is currently used to treat breast cancer.

The integration of data from multiple layers of analysis (FIGURE 2) is helping investigators identify variations in cancers. DNA methylation, for instance, is a means by which cells control gene expression. An analysis of this process in cervical tumor tissue has revealed additional cancer subgroups in which messenger RNA increases the transition of epithelial cells to invasive mesenchymal cells. Targeting that process in these subgroups would likely enhance the effectiveness of novel small-molecule inhibitors and some standard cytotoxic chemotherapy.  

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.

Antenatal corticosteroid treat-ment prior to preterm birth is the most important pharmacologic intervention available to obstetricians to improve newborn health. Antenatal corticosteroids reduce preterm newborn morbidity and mortality.¹ The American College of Obstetricians and Gynecologists (ACOG) recently has summarized updated recommendations for the use of antenatal steroid treatment.²

ACOG guidance includes:

• “A single course of corticosteroids is recommended for pregnant women between 24 0/7 weeks and 33 6/7 weeks of gestation, including for those with ruptured membranes and multiple gestations.” This guidance is supported by many high-quality trials and meta-analyses.¹
• A single course of corticosteroids “may be considered for pregnant women starting at 23 0/7 weeks of gestation who are at risk of preterm delivery within 7 days.”
• “A single repeat course of antenatal corticosteroids should be considered in women who are less than 34 0/7 weeks of gestation who have an imminent risk of preterm delivery within the next 7 days and whose prior course of antenatal corticosteroids was administered more than 14 days previously.” A repeat course of corticosteroids could be considered as early as 7 days from the prior dose.
• No more than 2 courses of antenatal steroids should be administered.

An important new ACOG recommendation is:

• “A single course of betamethasone is recommended for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk of preterm birth within 7 days, and who have not received a previous course of antenatal corticosteroids.”

This recommendation is based, in part, on a high-quality, randomized trial including 2,831 women at high risk for preterm birth between 34 0/7 and 36 6/7 weeks of gestation who were randomly assigned to receive a course of betamethasone or placebo. The newborn and maternal outcomes observed in this study are summarized in the TABLE.³

A few points relevant to the Antenatal Late Preterm Steroids study bear emphasizing. The women enrolled in this trial were at high risk for preterm delivery based on preterm labor with a cervical dilation of ≥3 cm or 75% effacement, spontaneous rupture of the membranes, or a planned late preterm delivery by cesarean or induction. No tocolytics were administered to women in this study, and approximately 40% of the women delivered within 24 hours of entry into the trial and only received 1 dose of corticosteroid or placebo.

Women with multiple gestations, pregestational diabetes, or a prior course of corticosteroids were not included in the trial; therefore, this study cannot guide our clinical practice for these subgroups of women. Of note, betamethasone should not be administered to women in the late preterm who have chorioamnionitis.

Related article:
When could use of antenatal corticosteroids in the late preterm birth period be beneficial?

The investigators calculated that 35 women would need to be treated to prevent one case of the primary outcome: a composite score of the use of respiratory support. Consequently, 34 fetuses who do not benefit from treatment are exposed in utero to betamethasone. Long-term follow-up of infants born to mothers participating in this study is currently underway.

A recent meta-analysis of 3 trials including 3,200 women at high risk for preterm delivery at 34 0/7 to 36 6/7 weeks of gestation reported that the corticosteroid administration reduced newborn risk for transient tachypnea of the newborn (relative risk [RR], 0.72; 95% confidence interval [CI], 0.56−0.92), severe respiratory distress syndrome (RR, 0.60; 95% CI, 0.33−0.94), and use of surfactant (RR, 0.61; 95% CI, 0.38−0.99).⁴

The recommendation to offer a single course of betamethasone for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk for preterm birth has not been embraced enthusiastically by all obstetricians. Many experts have emphasized that the known risks of late preterm betamethasone, including neonatal hypoglycemia and the unknown long-term risks of treatment, including suboptimal neurodevelopmental, cardiovascular, and metabolic outcomes should dampen enthusiasm for embracing the new ACOG recommendation.⁵ Experts also emphasize that late preterm newborns are less likely to benefit from antenatal corticosteroid treatment than babies born at less than 34 weeks. Hence, many late preterm newborns will be exposed to a potentially harmful intervention and have only a small chance of benefiting from the treatment.⁶

Many neonatologists believe that for the newborn, the benefits of maternal corticosteroid treatment outweigh the risks.^7–9 In a 30-year follow-up of 534 newborns participating in antenatal corticosteroid trials, treatment had no effect on body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, lung function, history of cardiovascular disease, educational attainment, or socioeconomic status. Corticosteroid treatment was associated with increased insulin secretion in response to a glucose load.¹⁰ In this study, the mothers received treatment at a median of 33 weeks of gestation and births occurred at a median of 35 weeks. Hence this study is relevant to the issue of late preterm corticosteroid treatment.

Balancing risks and benefits is complex. Balancing immediate benefits against long-term risks is most challenging. Regarding antenatal steroid use there are many unknowns, including optimal dose, drug formulation, and timing from treatment to delivery. In addition we need more high-quality data delineating the long-term effects of antenatal corticosteroids on childhood and adult health.

Read about 3 options to use in your practice

Consider these 3 options for your practice

As noted, the Antenatal Late Preterm Steroids trial investigators are pursuing long-term follow-up of the children born after maternal treatment with antenatal glucocorticoids. Both ACOG and the Society for Maternal-Fetal Medicine (SMFM)¹¹ recommend administration of antenatal glucocorticoids to women at high risk for late preterm delivery. However, since some experts are concerned that a great number of babies born late preterm will have been exposed to glucocorticoids, whose long-term risks are not well known, with only a few babies having a modest short-term benefit, 3 options could be considered for your clinical practice.

Related article:
Need for caution before extending the use of antenatal corticosteroids beyond 34 weeks’ gestation

Option 1

Follow the ACOG and SMFM suggestion that all women with a high risk of late preterm birth be offered antenatal corticosteroids. Counsel the mother and family about the potential risks and benefits and involve them in the decision.

Two alternative options are to limit antenatal corticosteroid treatment to subgroups of late preterm babies most likely to benefit from treatment, those born by cesarean delivery and those born at the earliest gestational ages.

Option 2

Limit the use of antenatal corticosteroids in the late preterm to women who are scheduled for a cesarean delivery for an obstetric indication between 34 0/7 weeks and 36 6/7 weeks of gestation. This approach greatly reduces the number of babies born in the late preterm that will be exposed to antenatal corticosteroids and focuses the treatment on a subset of babies who are certain to be born preterm and most likely to benefit.

Option 3

Limit the use of antenatal corticosteroids to women at high risk for preterm birth whose newborns are most likely to benefit from treatment—women at 34 0/7 to 35 6/7 weeks of gestation. Neonates born in the 34th or 35th week of gestation are at higher risk for morbidity than those born in the 36th week of gestation and are likely to derive the greatest benefit from antenatal corticosteroid treatment.^3,12

My advice

Yogi Berra advised, “It is tough to make predictions, especially about the future.” Although ACOG and SMFM have recommended administration of glucocorticoids to women at high risk for late preterm birth, many experts caution that until the long-term effects of antenatal corticosteroids are better characterized we should limit the use of corticosteroids in the late preterm.^5,6,13 My prediction is that long-term follow-up studies will not document significant adverse effects of one course of late preterm antenatal glucocorticoid treatment on children. My advice is to start offering antenatal corticosteroids to some women at high risk for late preterm delivery.

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.

Antenatal corticosteroid treat-ment prior to preterm birth is the most important pharmacologic intervention available to obstetricians to improve newborn health. Antenatal corticosteroids reduce preterm newborn morbidity and mortality.¹ The American College of Obstetricians and Gynecologists (ACOG) recently has summarized updated recommendations for the use of antenatal steroid treatment.²

ACOG guidance includes:

• “A single course of corticosteroids is recommended for pregnant women between 24 0/7 weeks and 33 6/7 weeks of gestation, including for those with ruptured membranes and multiple gestations.” This guidance is supported by many high-quality trials and meta-analyses.¹
• A single course of corticosteroids “may be considered for pregnant women starting at 23 0/7 weeks of gestation who are at risk of preterm delivery within 7 days.”
• “A single repeat course of antenatal corticosteroids should be considered in women who are less than 34 0/7 weeks of gestation who have an imminent risk of preterm delivery within the next 7 days and whose prior course of antenatal corticosteroids was administered more than 14 days previously.” A repeat course of corticosteroids could be considered as early as 7 days from the prior dose.
• No more than 2 courses of antenatal steroids should be administered.

An important new ACOG recommendation is:

• “A single course of betamethasone is recommended for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk of preterm birth within 7 days, and who have not received a previous course of antenatal corticosteroids.”

This recommendation is based, in part, on a high-quality, randomized trial including 2,831 women at high risk for preterm birth between 34 0/7 and 36 6/7 weeks of gestation who were randomly assigned to receive a course of betamethasone or placebo. The newborn and maternal outcomes observed in this study are summarized in the TABLE.³

A few points relevant to the Antenatal Late Preterm Steroids study bear emphasizing. The women enrolled in this trial were at high risk for preterm delivery based on preterm labor with a cervical dilation of ≥3 cm or 75% effacement, spontaneous rupture of the membranes, or a planned late preterm delivery by cesarean or induction. No tocolytics were administered to women in this study, and approximately 40% of the women delivered within 24 hours of entry into the trial and only received 1 dose of corticosteroid or placebo.

Women with multiple gestations, pregestational diabetes, or a prior course of corticosteroids were not included in the trial; therefore, this study cannot guide our clinical practice for these subgroups of women. Of note, betamethasone should not be administered to women in the late preterm who have chorioamnionitis.

Related article:
When could use of antenatal corticosteroids in the late preterm birth period be beneficial?

The investigators calculated that 35 women would need to be treated to prevent one case of the primary outcome: a composite score of the use of respiratory support. Consequently, 34 fetuses who do not benefit from treatment are exposed in utero to betamethasone. Long-term follow-up of infants born to mothers participating in this study is currently underway.

A recent meta-analysis of 3 trials including 3,200 women at high risk for preterm delivery at 34 0/7 to 36 6/7 weeks of gestation reported that the corticosteroid administration reduced newborn risk for transient tachypnea of the newborn (relative risk [RR], 0.72; 95% confidence interval [CI], 0.56−0.92), severe respiratory distress syndrome (RR, 0.60; 95% CI, 0.33−0.94), and use of surfactant (RR, 0.61; 95% CI, 0.38−0.99).⁴

The recommendation to offer a single course of betamethasone for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk for preterm birth has not been embraced enthusiastically by all obstetricians. Many experts have emphasized that the known risks of late preterm betamethasone, including neonatal hypoglycemia and the unknown long-term risks of treatment, including suboptimal neurodevelopmental, cardiovascular, and metabolic outcomes should dampen enthusiasm for embracing the new ACOG recommendation.⁵ Experts also emphasize that late preterm newborns are less likely to benefit from antenatal corticosteroid treatment than babies born at less than 34 weeks. Hence, many late preterm newborns will be exposed to a potentially harmful intervention and have only a small chance of benefiting from the treatment.⁶

Many neonatologists believe that for the newborn, the benefits of maternal corticosteroid treatment outweigh the risks.^7–9 In a 30-year follow-up of 534 newborns participating in antenatal corticosteroid trials, treatment had no effect on body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, lung function, history of cardiovascular disease, educational attainment, or socioeconomic status. Corticosteroid treatment was associated with increased insulin secretion in response to a glucose load.¹⁰ In this study, the mothers received treatment at a median of 33 weeks of gestation and births occurred at a median of 35 weeks. Hence this study is relevant to the issue of late preterm corticosteroid treatment.

Balancing risks and benefits is complex. Balancing immediate benefits against long-term risks is most challenging. Regarding antenatal steroid use there are many unknowns, including optimal dose, drug formulation, and timing from treatment to delivery. In addition we need more high-quality data delineating the long-term effects of antenatal corticosteroids on childhood and adult health.

Read about 3 options to use in your practice

Consider these 3 options for your practice

As noted, the Antenatal Late Preterm Steroids trial investigators are pursuing long-term follow-up of the children born after maternal treatment with antenatal glucocorticoids. Both ACOG and the Society for Maternal-Fetal Medicine (SMFM)¹¹ recommend administration of antenatal glucocorticoids to women at high risk for late preterm delivery. However, since some experts are concerned that a great number of babies born late preterm will have been exposed to glucocorticoids, whose long-term risks are not well known, with only a few babies having a modest short-term benefit, 3 options could be considered for your clinical practice.

Related article:
Need for caution before extending the use of antenatal corticosteroids beyond 34 weeks’ gestation

Option 1

Follow the ACOG and SMFM suggestion that all women with a high risk of late preterm birth be offered antenatal corticosteroids. Counsel the mother and family about the potential risks and benefits and involve them in the decision.

Two alternative options are to limit antenatal corticosteroid treatment to subgroups of late preterm babies most likely to benefit from treatment, those born by cesarean delivery and those born at the earliest gestational ages.

Option 2

Limit the use of antenatal corticosteroids in the late preterm to women who are scheduled for a cesarean delivery for an obstetric indication between 34 0/7 weeks and 36 6/7 weeks of gestation. This approach greatly reduces the number of babies born in the late preterm that will be exposed to antenatal corticosteroids and focuses the treatment on a subset of babies who are certain to be born preterm and most likely to benefit.

Option 3

Limit the use of antenatal corticosteroids to women at high risk for preterm birth whose newborns are most likely to benefit from treatment—women at 34 0/7 to 35 6/7 weeks of gestation. Neonates born in the 34th or 35th week of gestation are at higher risk for morbidity than those born in the 36th week of gestation and are likely to derive the greatest benefit from antenatal corticosteroid treatment.^3,12

My advice

Yogi Berra advised, “It is tough to make predictions, especially about the future.” Although ACOG and SMFM have recommended administration of glucocorticoids to women at high risk for late preterm birth, many experts caution that until the long-term effects of antenatal corticosteroids are better characterized we should limit the use of corticosteroids in the late preterm.^5,6,13 My prediction is that long-term follow-up studies will not document significant adverse effects of one course of late preterm antenatal glucocorticoid treatment on children. My advice is to start offering antenatal corticosteroids to some women at high risk for late preterm delivery.

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.

Antenatal corticosteroid treat-ment prior to preterm birth is the most important pharmacologic intervention available to obstetricians to improve newborn health. Antenatal corticosteroids reduce preterm newborn morbidity and mortality.¹ The American College of Obstetricians and Gynecologists (ACOG) recently has summarized updated recommendations for the use of antenatal steroid treatment.²

ACOG guidance includes:

• “A single course of corticosteroids is recommended for pregnant women between 24 0/7 weeks and 33 6/7 weeks of gestation, including for those with ruptured membranes and multiple gestations.” This guidance is supported by many high-quality trials and meta-analyses.¹
• A single course of corticosteroids “may be considered for pregnant women starting at 23 0/7 weeks of gestation who are at risk of preterm delivery within 7 days.”
• “A single repeat course of antenatal corticosteroids should be considered in women who are less than 34 0/7 weeks of gestation who have an imminent risk of preterm delivery within the next 7 days and whose prior course of antenatal corticosteroids was administered more than 14 days previously.” A repeat course of corticosteroids could be considered as early as 7 days from the prior dose.
• No more than 2 courses of antenatal steroids should be administered.

An important new ACOG recommendation is:

• “A single course of betamethasone is recommended for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk of preterm birth within 7 days, and who have not received a previous course of antenatal corticosteroids.”

This recommendation is based, in part, on a high-quality, randomized trial including 2,831 women at high risk for preterm birth between 34 0/7 and 36 6/7 weeks of gestation who were randomly assigned to receive a course of betamethasone or placebo. The newborn and maternal outcomes observed in this study are summarized in the TABLE.³

A few points relevant to the Antenatal Late Preterm Steroids study bear emphasizing. The women enrolled in this trial were at high risk for preterm delivery based on preterm labor with a cervical dilation of ≥3 cm or 75% effacement, spontaneous rupture of the membranes, or a planned late preterm delivery by cesarean or induction. No tocolytics were administered to women in this study, and approximately 40% of the women delivered within 24 hours of entry into the trial and only received 1 dose of corticosteroid or placebo.

Women with multiple gestations, pregestational diabetes, or a prior course of corticosteroids were not included in the trial; therefore, this study cannot guide our clinical practice for these subgroups of women. Of note, betamethasone should not be administered to women in the late preterm who have chorioamnionitis.

Related article:
When could use of antenatal corticosteroids in the late preterm birth period be beneficial?

The investigators calculated that 35 women would need to be treated to prevent one case of the primary outcome: a composite score of the use of respiratory support. Consequently, 34 fetuses who do not benefit from treatment are exposed in utero to betamethasone. Long-term follow-up of infants born to mothers participating in this study is currently underway.

A recent meta-analysis of 3 trials including 3,200 women at high risk for preterm delivery at 34 0/7 to 36 6/7 weeks of gestation reported that the corticosteroid administration reduced newborn risk for transient tachypnea of the newborn (relative risk [RR], 0.72; 95% confidence interval [CI], 0.56−0.92), severe respiratory distress syndrome (RR, 0.60; 95% CI, 0.33−0.94), and use of surfactant (RR, 0.61; 95% CI, 0.38−0.99).⁴

The recommendation to offer a single course of betamethasone for pregnant women between 34 0/7 and 36 6/7 weeks of gestation at risk for preterm birth has not been embraced enthusiastically by all obstetricians. Many experts have emphasized that the known risks of late preterm betamethasone, including neonatal hypoglycemia and the unknown long-term risks of treatment, including suboptimal neurodevelopmental, cardiovascular, and metabolic outcomes should dampen enthusiasm for embracing the new ACOG recommendation.⁵ Experts also emphasize that late preterm newborns are less likely to benefit from antenatal corticosteroid treatment than babies born at less than 34 weeks. Hence, many late preterm newborns will be exposed to a potentially harmful intervention and have only a small chance of benefiting from the treatment.⁶

Many neonatologists believe that for the newborn, the benefits of maternal corticosteroid treatment outweigh the risks.^7–9 In a 30-year follow-up of 534 newborns participating in antenatal corticosteroid trials, treatment had no effect on body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, lung function, history of cardiovascular disease, educational attainment, or socioeconomic status. Corticosteroid treatment was associated with increased insulin secretion in response to a glucose load.¹⁰ In this study, the mothers received treatment at a median of 33 weeks of gestation and births occurred at a median of 35 weeks. Hence this study is relevant to the issue of late preterm corticosteroid treatment.

Balancing risks and benefits is complex. Balancing immediate benefits against long-term risks is most challenging. Regarding antenatal steroid use there are many unknowns, including optimal dose, drug formulation, and timing from treatment to delivery. In addition we need more high-quality data delineating the long-term effects of antenatal corticosteroids on childhood and adult health.

Read about 3 options to use in your practice

Consider these 3 options for your practice

As noted, the Antenatal Late Preterm Steroids trial investigators are pursuing long-term follow-up of the children born after maternal treatment with antenatal glucocorticoids. Both ACOG and the Society for Maternal-Fetal Medicine (SMFM)¹¹ recommend administration of antenatal glucocorticoids to women at high risk for late preterm delivery. However, since some experts are concerned that a great number of babies born late preterm will have been exposed to glucocorticoids, whose long-term risks are not well known, with only a few babies having a modest short-term benefit, 3 options could be considered for your clinical practice.

Related article:
Need for caution before extending the use of antenatal corticosteroids beyond 34 weeks’ gestation

Option 1

Follow the ACOG and SMFM suggestion that all women with a high risk of late preterm birth be offered antenatal corticosteroids. Counsel the mother and family about the potential risks and benefits and involve them in the decision.

Two alternative options are to limit antenatal corticosteroid treatment to subgroups of late preterm babies most likely to benefit from treatment, those born by cesarean delivery and those born at the earliest gestational ages.

Option 2

Limit the use of antenatal corticosteroids in the late preterm to women who are scheduled for a cesarean delivery for an obstetric indication between 34 0/7 weeks and 36 6/7 weeks of gestation. This approach greatly reduces the number of babies born in the late preterm that will be exposed to antenatal corticosteroids and focuses the treatment on a subset of babies who are certain to be born preterm and most likely to benefit.

Option 3

Limit the use of antenatal corticosteroids to women at high risk for preterm birth whose newborns are most likely to benefit from treatment—women at 34 0/7 to 35 6/7 weeks of gestation. Neonates born in the 34th or 35th week of gestation are at higher risk for morbidity than those born in the 36th week of gestation and are likely to derive the greatest benefit from antenatal corticosteroid treatment.^3,12

My advice

Yogi Berra advised, “It is tough to make predictions, especially about the future.” Although ACOG and SMFM have recommended administration of glucocorticoids to women at high risk for late preterm birth, many experts caution that until the long-term effects of antenatal corticosteroids are better characterized we should limit the use of corticosteroids in the late preterm.^5,6,13 My prediction is that long-term follow-up studies will not document significant adverse effects of one course of late preterm antenatal glucocorticoid treatment on children. My advice is to start offering antenatal corticosteroids to some women at high risk for late preterm delivery.

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.

A) Didelphys uterus INCORRECT

A didelphys uterus occurs as a result of complete nonfusion of the Müllerian duct, resulting in duplicated uterine horns, duplicated cervices, and occasionally the proximal vagina, which is often associated with a transverse or longitudinal vaginal septum.^1,2 Fusion anomalies (didelphys and bicornuate) can be differentiated from resorption anomalies (septate and arcuate) on ultrasonography (US) by a deep fundal cleft (>1 cm).¹ 3D US is highly accurate in identifying Müllerian duct anomalies (MDAs), it correlates well with magnetic resonance imaging (MRI), and it is more cost effective and accessible.³ For the didelphys uterus, 3D US obtained coronal to the uterine fundus often demonstrates widely divergent uterine horns separated by a deep serosal fundal cleft (>1 cm) and noncommunicating endometrial cavities with 2 cervices.¹ Identifying a duplicated vaginal canal can help differentiate a didelphys uterus from a bicornuate bicollis uterus.¹

B) Unicornuate uterus INCORRECT

A unicornuate uterus results from arrested development of one Müllerian duct and normal development of the other. There are 4 different subtypes: no rudimentary horn, rudimentary horn without endometrial cavity, rudimentary horn with communicating endometrial cavity, and rudimentary horn with noncommunicating uterine cavity.¹ Renal anomalies, especially renal agenesis when present, are usually ipsilateral to the rudimentary horn.¹ On US, unicornuate uterus appears as a lobular oblong (banana-shaped) structure away from the midline. The rudimentary horn is often difficult to identify and, when seen, the presence or absence of endometrium is an important finding.¹

C) Partial septate uterus CORRECT

A septate uterus is a result of a resorption anomaly. The septum may be partial (subseptate) or complete secondary to failure of resorption of the uterovaginal septum. A complete septum extends to the external cervical os and occasionally to the vagina.¹ US demonstrates interruption of the myometrium by a hypoechoic fibrous septum and/or a muscular septum which is isoechoic to the myometrium and arises midline from the fundus.¹ 3D US often clearly delineates the septum and improves visualization of the external fundal contour.² The external fundal contour in septate uterus is convex (little or no serosal fundal cleft) and the apex is greater than 5 mm above the interostial line compared with a bicornuate or didelphys uterus, where the apex is less than 5 mm from the interostial line.^1,2 Additionally, the intercornual distance is less than 4 cm.⁴ A septate uterus with duplicated cervix can appear similar to a bicornuate bicollis uterus and can be correctly diagnosed by evaluating the external fundal contour.¹

D) Arcuate uterus INCORRECT

The arcuate uterus also represents a resorption anomaly as a sequela of near-complete resorption of the uterovaginal septum.¹ On 3D US, the fundal indentation in an arcuate uterus is well delineated and appears broad based with an obtuse angle at the most central point, which can help differentiate it from a septate uterus that has an acute angle.^2,3 Both an arcuate and a septate uterus have a normal external (serosal) fundal contour.^2,3 With an arcuate uterus, the length of the vertical measurement from the tubal ostia line, which is drawn horizontally between the tubal ostia to the fundal midline component of the endometrial cavity, is 1 cm or less. With a septate uterus, this vertical distance is greater than 1 cm.

A) Didelphys uterus INCORRECT

A didelphys uterus occurs as a result of complete nonfusion of the Müllerian duct, resulting in duplicated uterine horns, duplicated cervices, and occasionally the proximal vagina, which is often associated with a transverse or longitudinal vaginal septum.^1,2 Fusion anomalies (didelphys and bicornuate) can be differentiated from resorption anomalies (septate and arcuate) on ultrasonography (US) by a deep fundal cleft (>1 cm).¹ 3D US is highly accurate in identifying Müllerian duct anomalies (MDAs), it correlates well with magnetic resonance imaging (MRI), and it is more cost effective and accessible.³ For the didelphys uterus, 3D US obtained coronal to the uterine fundus often demonstrates widely divergent uterine horns separated by a deep serosal fundal cleft (>1 cm) and noncommunicating endometrial cavities with 2 cervices.¹ Identifying a duplicated vaginal canal can help differentiate a didelphys uterus from a bicornuate bicollis uterus.¹

B) Unicornuate uterus INCORRECT

A unicornuate uterus results from arrested development of one Müllerian duct and normal development of the other. There are 4 different subtypes: no rudimentary horn, rudimentary horn without endometrial cavity, rudimentary horn with communicating endometrial cavity, and rudimentary horn with noncommunicating uterine cavity.¹ Renal anomalies, especially renal agenesis when present, are usually ipsilateral to the rudimentary horn.¹ On US, unicornuate uterus appears as a lobular oblong (banana-shaped) structure away from the midline. The rudimentary horn is often difficult to identify and, when seen, the presence or absence of endometrium is an important finding.¹

C) Partial septate uterus CORRECT

A septate uterus is a result of a resorption anomaly. The septum may be partial (subseptate) or complete secondary to failure of resorption of the uterovaginal septum. A complete septum extends to the external cervical os and occasionally to the vagina.¹ US demonstrates interruption of the myometrium by a hypoechoic fibrous septum and/or a muscular septum which is isoechoic to the myometrium and arises midline from the fundus.¹ 3D US often clearly delineates the septum and improves visualization of the external fundal contour.² The external fundal contour in septate uterus is convex (little or no serosal fundal cleft) and the apex is greater than 5 mm above the interostial line compared with a bicornuate or didelphys uterus, where the apex is less than 5 mm from the interostial line.^1,2 Additionally, the intercornual distance is less than 4 cm.⁴ A septate uterus with duplicated cervix can appear similar to a bicornuate bicollis uterus and can be correctly diagnosed by evaluating the external fundal contour.¹

D) Arcuate uterus INCORRECT

The arcuate uterus also represents a resorption anomaly as a sequela of near-complete resorption of the uterovaginal septum.¹ On 3D US, the fundal indentation in an arcuate uterus is well delineated and appears broad based with an obtuse angle at the most central point, which can help differentiate it from a septate uterus that has an acute angle.^2,3 Both an arcuate and a septate uterus have a normal external (serosal) fundal contour.^2,3 With an arcuate uterus, the length of the vertical measurement from the tubal ostia line, which is drawn horizontally between the tubal ostia to the fundal midline component of the endometrial cavity, is 1 cm or less. With a septate uterus, this vertical distance is greater than 1 cm.

A) Didelphys uterus INCORRECT

A didelphys uterus occurs as a result of complete nonfusion of the Müllerian duct, resulting in duplicated uterine horns, duplicated cervices, and occasionally the proximal vagina, which is often associated with a transverse or longitudinal vaginal septum.^1,2 Fusion anomalies (didelphys and bicornuate) can be differentiated from resorption anomalies (septate and arcuate) on ultrasonography (US) by a deep fundal cleft (>1 cm).¹ 3D US is highly accurate in identifying Müllerian duct anomalies (MDAs), it correlates well with magnetic resonance imaging (MRI), and it is more cost effective and accessible.³ For the didelphys uterus, 3D US obtained coronal to the uterine fundus often demonstrates widely divergent uterine horns separated by a deep serosal fundal cleft (>1 cm) and noncommunicating endometrial cavities with 2 cervices.¹ Identifying a duplicated vaginal canal can help differentiate a didelphys uterus from a bicornuate bicollis uterus.¹

B) Unicornuate uterus INCORRECT

A unicornuate uterus results from arrested development of one Müllerian duct and normal development of the other. There are 4 different subtypes: no rudimentary horn, rudimentary horn without endometrial cavity, rudimentary horn with communicating endometrial cavity, and rudimentary horn with noncommunicating uterine cavity.¹ Renal anomalies, especially renal agenesis when present, are usually ipsilateral to the rudimentary horn.¹ On US, unicornuate uterus appears as a lobular oblong (banana-shaped) structure away from the midline. The rudimentary horn is often difficult to identify and, when seen, the presence or absence of endometrium is an important finding.¹

C) Partial septate uterus CORRECT

A septate uterus is a result of a resorption anomaly. The septum may be partial (subseptate) or complete secondary to failure of resorption of the uterovaginal septum. A complete septum extends to the external cervical os and occasionally to the vagina.¹ US demonstrates interruption of the myometrium by a hypoechoic fibrous septum and/or a muscular septum which is isoechoic to the myometrium and arises midline from the fundus.¹ 3D US often clearly delineates the septum and improves visualization of the external fundal contour.² The external fundal contour in septate uterus is convex (little or no serosal fundal cleft) and the apex is greater than 5 mm above the interostial line compared with a bicornuate or didelphys uterus, where the apex is less than 5 mm from the interostial line.^1,2 Additionally, the intercornual distance is less than 4 cm.⁴ A septate uterus with duplicated cervix can appear similar to a bicornuate bicollis uterus and can be correctly diagnosed by evaluating the external fundal contour.¹

D) Arcuate uterus INCORRECT

The arcuate uterus also represents a resorption anomaly as a sequela of near-complete resorption of the uterovaginal septum.¹ On 3D US, the fundal indentation in an arcuate uterus is well delineated and appears broad based with an obtuse angle at the most central point, which can help differentiate it from a septate uterus that has an acute angle.^2,3 Both an arcuate and a septate uterus have a normal external (serosal) fundal contour.^2,3 With an arcuate uterus, the length of the vertical measurement from the tubal ostia line, which is drawn horizontally between the tubal ostia to the fundal midline component of the endometrial cavity, is 1 cm or less. With a septate uterus, this vertical distance is greater than 1 cm.