Women's Health

Latest guidelines on the treatment of osteoporosis have been released that include new recommendations for the use of romosozumab (Evenity) in postmenopausal women with severe osteoporosis, but they contain caveats as to which women should – and should not – receive the drug.

The updated clinical practice guideline from the Endocrine Society is in response to the approval of romosozumab by the Food and Drug Administration (FDA) in April 2019, and more recently, by the European Medicines Agency.

It was published online February 18 in the Journal of Clinical Endocrinology & Metabolism.

In the new guidelines, committee members recommend the use of romosozumab for postmenopausal women with osteoporosis at very high risk of fracture. Candidates would include women with severe osteoporosis (T-score of less than –2.5 and a prior fracture) or women with a history of multiple vertebral fractures.

Women should be treated with romosozumab for up to 1 year, followed by an antiresorptive agent to maintain bone mineral density gains and further reduce fracture risk.

“The recommended dosage is 210 mg monthly by subcutaneous injection for 12 months,” the authors wrote.

However, and very importantly, romosozumab should not be considered for women at high risk of cardiovascular disease (CVD) or cerebrovascular disease. A high risk of CVD includes women who have had a previous myocardial infarction (MI) or stroke.

Experts questioned by Medscape Medical News stressed that romosozumab should not be a first-line, or even generally a second-line, option for osteoporosis, but it can be a considered for select patients with severe osteoporosis, taking into account CV risk.

Boxed warning

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH), there were more major adverse cardiovascular events (MACE) in the first year of the trial with romosozumab, and patients had a 31% higher risk of MACE with romosozumab, compared with the bisphosphonate alendronate.

As a result, the drug was initially rejected by a number of regulatory agencies.

In the United States and Canada, it was eventually approved with a boxed warning, which cautions against the use of the drug in patients at risk for myocardial infarction, stroke, and CVD-related death.

“Romosozumab offers promising results for postmenopausal women with severe osteoporosis or who have a history of fractures,” Clifford Rosen, MD, Maine Medical Center Research Institute in Scarborough and chair of the writing committee, said in an Endocrine Society statement. “It does, however, come with a risk of heart disease, so clinicians need to be careful when selecting patients for this therapy.”

Exact risk unknown

Asked by Medscape Medical News to comment, Kenneth Saag, MD, professor of medicine, University of Alabama at Birmingham and principle investigator of the ARCH study, said that physicians needed more data from real-world studies to resolve the issue around whether romosozumab heightens the risk of CV events in women with osteoporosis or whether that particular finding from ARCH was an artifact.

“Women who have had a recent cardiovascular event should not receive the drug,” he said, agreeing with the new guidelines.

But it remains unclear, for example, whether women who are at slightly higher risk of having a CV event by virtue of their age alone, are also at risk, he noted.

In the meantime, results from the ARCH study clearly showed that not only was romosozumab more effective than alendronate, “but it is more effective than other bone-building drugs as well,” Dr. Saag observed, and it leads to a significantly greater reduction in vertebral, nonvertebral, and hip fractures, compared with the alendronate, the current standard of care in osteoporosis.

“In patients who have very severe osteoporosis and who have had a recent fracture or who are at risk for imminent future fracture, physicians need to balance the benefit versus the risk in favor of using romosozumab,” Dr. Saag suggested.

“And while I would say most women prefer not to inject themselves, the women I have put on this medicine have all had recent fractures and they are very aware of the pain and the disability of having a broken bone, so it is something they are willing to do,” he added.
 

Not for all women

Giving his opinion, Bart Clarke, MD, of the Mayo Clinic in Rochester, Minnesota, underscored the fact that the Fracture Study in Postmenopausal Women With Osteoporosis (FRAME), again conducted in postmenopausal women, showed no increase in CV events in patients treated with romosozumab compared with placebo.

“So there are questions about what this means, because if these events really were a drug effect, then that effect would be even more evident compared with placebo and they did not see any signal of CV events [in FRAME],” said Dr. Clarke, past president of the American Society of Bone and Mineral Research.

Like everything else in medicine, “there is always some risk,” Dr. Clarke observed.

However, what physicians should do is talk to women, ensure they have not had either an MI or stroke in the last year, and if patients have severe osteoporosis and a high risk of fracture, “then we can say, here’s another option,” he suggested.

“Then, if a woman develops chest pain or shortness of breath while on the drug, [she needs] to let us know ,and then we’ll stop the drug and reassess the situation,” he added.

Dr. Clarke also pointed out that if the FDA had received further reports of CV events linked to romosozumab, physicians would know about it by now, but to his knowledge, there has been no change to the drug’s current warning label.

Furthermore, neither he nor any of his colleagues who treat metabolic bone disease at the Mayo Clinic has seen a single CV event in patients prescribed the agent.

“This is not a drug we would use as first-line for most patients, and we don’t even use it as second-line for most patients, but in people who have not responded to other drugs or who have had terrible things happen to them already, hip fracture especially, then we are saying, you can consider this, he concluded.

The guidelines were supported by the Endocrine Society. Dr. Rosen and Dr. Clarke reported no relevant financial relationships. Dr. Saag reported receiving grants and personal fees from Amgen, personal fees from Radius, and is a consultant for Amgen, Radius, Roche, and Daiichi Sankyo.

This article first appeared on Medscape.com.

Latest guidelines on the treatment of osteoporosis have been released that include new recommendations for the use of romosozumab (Evenity) in postmenopausal women with severe osteoporosis, but they contain caveats as to which women should – and should not – receive the drug.

The updated clinical practice guideline from the Endocrine Society is in response to the approval of romosozumab by the Food and Drug Administration (FDA) in April 2019, and more recently, by the European Medicines Agency.

It was published online February 18 in the Journal of Clinical Endocrinology & Metabolism.

In the new guidelines, committee members recommend the use of romosozumab for postmenopausal women with osteoporosis at very high risk of fracture. Candidates would include women with severe osteoporosis (T-score of less than –2.5 and a prior fracture) or women with a history of multiple vertebral fractures.

Women should be treated with romosozumab for up to 1 year, followed by an antiresorptive agent to maintain bone mineral density gains and further reduce fracture risk.

“The recommended dosage is 210 mg monthly by subcutaneous injection for 12 months,” the authors wrote.

However, and very importantly, romosozumab should not be considered for women at high risk of cardiovascular disease (CVD) or cerebrovascular disease. A high risk of CVD includes women who have had a previous myocardial infarction (MI) or stroke.

Experts questioned by Medscape Medical News stressed that romosozumab should not be a first-line, or even generally a second-line, option for osteoporosis, but it can be a considered for select patients with severe osteoporosis, taking into account CV risk.

Boxed warning

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH), there were more major adverse cardiovascular events (MACE) in the first year of the trial with romosozumab, and patients had a 31% higher risk of MACE with romosozumab, compared with the bisphosphonate alendronate.

As a result, the drug was initially rejected by a number of regulatory agencies.

In the United States and Canada, it was eventually approved with a boxed warning, which cautions against the use of the drug in patients at risk for myocardial infarction, stroke, and CVD-related death.

“Romosozumab offers promising results for postmenopausal women with severe osteoporosis or who have a history of fractures,” Clifford Rosen, MD, Maine Medical Center Research Institute in Scarborough and chair of the writing committee, said in an Endocrine Society statement. “It does, however, come with a risk of heart disease, so clinicians need to be careful when selecting patients for this therapy.”

Exact risk unknown

Asked by Medscape Medical News to comment, Kenneth Saag, MD, professor of medicine, University of Alabama at Birmingham and principle investigator of the ARCH study, said that physicians needed more data from real-world studies to resolve the issue around whether romosozumab heightens the risk of CV events in women with osteoporosis or whether that particular finding from ARCH was an artifact.

“Women who have had a recent cardiovascular event should not receive the drug,” he said, agreeing with the new guidelines.

But it remains unclear, for example, whether women who are at slightly higher risk of having a CV event by virtue of their age alone, are also at risk, he noted.

In the meantime, results from the ARCH study clearly showed that not only was romosozumab more effective than alendronate, “but it is more effective than other bone-building drugs as well,” Dr. Saag observed, and it leads to a significantly greater reduction in vertebral, nonvertebral, and hip fractures, compared with the alendronate, the current standard of care in osteoporosis.

“In patients who have very severe osteoporosis and who have had a recent fracture or who are at risk for imminent future fracture, physicians need to balance the benefit versus the risk in favor of using romosozumab,” Dr. Saag suggested.

“And while I would say most women prefer not to inject themselves, the women I have put on this medicine have all had recent fractures and they are very aware of the pain and the disability of having a broken bone, so it is something they are willing to do,” he added.
 

Not for all women

Giving his opinion, Bart Clarke, MD, of the Mayo Clinic in Rochester, Minnesota, underscored the fact that the Fracture Study in Postmenopausal Women With Osteoporosis (FRAME), again conducted in postmenopausal women, showed no increase in CV events in patients treated with romosozumab compared with placebo.

“So there are questions about what this means, because if these events really were a drug effect, then that effect would be even more evident compared with placebo and they did not see any signal of CV events [in FRAME],” said Dr. Clarke, past president of the American Society of Bone and Mineral Research.

Like everything else in medicine, “there is always some risk,” Dr. Clarke observed.

However, what physicians should do is talk to women, ensure they have not had either an MI or stroke in the last year, and if patients have severe osteoporosis and a high risk of fracture, “then we can say, here’s another option,” he suggested.

“Then, if a woman develops chest pain or shortness of breath while on the drug, [she needs] to let us know ,and then we’ll stop the drug and reassess the situation,” he added.

Dr. Clarke also pointed out that if the FDA had received further reports of CV events linked to romosozumab, physicians would know about it by now, but to his knowledge, there has been no change to the drug’s current warning label.

Furthermore, neither he nor any of his colleagues who treat metabolic bone disease at the Mayo Clinic has seen a single CV event in patients prescribed the agent.

“This is not a drug we would use as first-line for most patients, and we don’t even use it as second-line for most patients, but in people who have not responded to other drugs or who have had terrible things happen to them already, hip fracture especially, then we are saying, you can consider this, he concluded.

The guidelines were supported by the Endocrine Society. Dr. Rosen and Dr. Clarke reported no relevant financial relationships. Dr. Saag reported receiving grants and personal fees from Amgen, personal fees from Radius, and is a consultant for Amgen, Radius, Roche, and Daiichi Sankyo.

This article first appeared on Medscape.com.

Latest guidelines on the treatment of osteoporosis have been released that include new recommendations for the use of romosozumab (Evenity) in postmenopausal women with severe osteoporosis, but they contain caveats as to which women should – and should not – receive the drug.

The updated clinical practice guideline from the Endocrine Society is in response to the approval of romosozumab by the Food and Drug Administration (FDA) in April 2019, and more recently, by the European Medicines Agency.

It was published online February 18 in the Journal of Clinical Endocrinology & Metabolism.

In the new guidelines, committee members recommend the use of romosozumab for postmenopausal women with osteoporosis at very high risk of fracture. Candidates would include women with severe osteoporosis (T-score of less than –2.5 and a prior fracture) or women with a history of multiple vertebral fractures.

Women should be treated with romosozumab for up to 1 year, followed by an antiresorptive agent to maintain bone mineral density gains and further reduce fracture risk.

“The recommended dosage is 210 mg monthly by subcutaneous injection for 12 months,” the authors wrote.

However, and very importantly, romosozumab should not be considered for women at high risk of cardiovascular disease (CVD) or cerebrovascular disease. A high risk of CVD includes women who have had a previous myocardial infarction (MI) or stroke.

Experts questioned by Medscape Medical News stressed that romosozumab should not be a first-line, or even generally a second-line, option for osteoporosis, but it can be a considered for select patients with severe osteoporosis, taking into account CV risk.

Boxed warning

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH), there were more major adverse cardiovascular events (MACE) in the first year of the trial with romosozumab, and patients had a 31% higher risk of MACE with romosozumab, compared with the bisphosphonate alendronate.

As a result, the drug was initially rejected by a number of regulatory agencies.

In the United States and Canada, it was eventually approved with a boxed warning, which cautions against the use of the drug in patients at risk for myocardial infarction, stroke, and CVD-related death.

“Romosozumab offers promising results for postmenopausal women with severe osteoporosis or who have a history of fractures,” Clifford Rosen, MD, Maine Medical Center Research Institute in Scarborough and chair of the writing committee, said in an Endocrine Society statement. “It does, however, come with a risk of heart disease, so clinicians need to be careful when selecting patients for this therapy.”

Exact risk unknown

Asked by Medscape Medical News to comment, Kenneth Saag, MD, professor of medicine, University of Alabama at Birmingham and principle investigator of the ARCH study, said that physicians needed more data from real-world studies to resolve the issue around whether romosozumab heightens the risk of CV events in women with osteoporosis or whether that particular finding from ARCH was an artifact.

“Women who have had a recent cardiovascular event should not receive the drug,” he said, agreeing with the new guidelines.

But it remains unclear, for example, whether women who are at slightly higher risk of having a CV event by virtue of their age alone, are also at risk, he noted.

In the meantime, results from the ARCH study clearly showed that not only was romosozumab more effective than alendronate, “but it is more effective than other bone-building drugs as well,” Dr. Saag observed, and it leads to a significantly greater reduction in vertebral, nonvertebral, and hip fractures, compared with the alendronate, the current standard of care in osteoporosis.

“In patients who have very severe osteoporosis and who have had a recent fracture or who are at risk for imminent future fracture, physicians need to balance the benefit versus the risk in favor of using romosozumab,” Dr. Saag suggested.

“And while I would say most women prefer not to inject themselves, the women I have put on this medicine have all had recent fractures and they are very aware of the pain and the disability of having a broken bone, so it is something they are willing to do,” he added.
 

Not for all women

Giving his opinion, Bart Clarke, MD, of the Mayo Clinic in Rochester, Minnesota, underscored the fact that the Fracture Study in Postmenopausal Women With Osteoporosis (FRAME), again conducted in postmenopausal women, showed no increase in CV events in patients treated with romosozumab compared with placebo.

“So there are questions about what this means, because if these events really were a drug effect, then that effect would be even more evident compared with placebo and they did not see any signal of CV events [in FRAME],” said Dr. Clarke, past president of the American Society of Bone and Mineral Research.

Like everything else in medicine, “there is always some risk,” Dr. Clarke observed.

However, what physicians should do is talk to women, ensure they have not had either an MI or stroke in the last year, and if patients have severe osteoporosis and a high risk of fracture, “then we can say, here’s another option,” he suggested.

“Then, if a woman develops chest pain or shortness of breath while on the drug, [she needs] to let us know ,and then we’ll stop the drug and reassess the situation,” he added.

Dr. Clarke also pointed out that if the FDA had received further reports of CV events linked to romosozumab, physicians would know about it by now, but to his knowledge, there has been no change to the drug’s current warning label.

Furthermore, neither he nor any of his colleagues who treat metabolic bone disease at the Mayo Clinic has seen a single CV event in patients prescribed the agent.

“This is not a drug we would use as first-line for most patients, and we don’t even use it as second-line for most patients, but in people who have not responded to other drugs or who have had terrible things happen to them already, hip fracture especially, then we are saying, you can consider this, he concluded.

The guidelines were supported by the Endocrine Society. Dr. Rosen and Dr. Clarke reported no relevant financial relationships. Dr. Saag reported receiving grants and personal fees from Amgen, personal fees from Radius, and is a consultant for Amgen, Radius, Roche, and Daiichi Sankyo.

This article first appeared on Medscape.com.

For women with dense breasts, abbreviated magnetic resonance imaging was more effective than was digital breast tomosynthesis for detecting invasive breast cancer in a cross-sectional study of 1,444 women who underwent both procedures.

Dense breasts are a common reason for failed early diagnosis of breast cancer, wrote Christopher E. Comstock, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Digital breast tomosynthesis (DBT) and abbreviated breast magnetic resonance imaging (MRI) are becoming more popular as safe and cost-effective breast cancer screening options, but their effectiveness in women with dense breasts and average breast cancer risk has not been compared.

The researchers reviewed data from 1,444 women aged 40-75 years at 47 institutions in the United States and 1 in Germany. The women underwent both DBT and MRI. The primary endpoint was the detection of invasive cancers, of which 17 were identified at baseline screening. Abbreviated breast MRI detected all 17 cases of invasive cancer, compared with 7 detected by DBT. In addition, MRI detected six of seven women with ductal carcinoma in situ, while DBT identified two of the seven cases, according to the study, which was published in JAMA.

Overall, the invasive cancer detection rate was 11.8 per 1,000 women for MRI compared with 4.8 per 1,000 women for DBT. Sensitivity for MRI and DBT was 96% vs. 39%, and specificity was 87% vs. 97%.

The rate of recommendation for further screening was not significantly different between the procedures (8% for MRI and 10% for DBT). The most common adverse events were three cases of mild allergic reactions and two cases of anxiety.

The study findings were limited by several factors including the inability to show an association between abbreviated breast MRI and breast cancer mortality and the lack of cost-effectiveness comparisons for the two procedures. Because eligibility criteria required a prior breast mammogram to see if the breasts were dense, the study compared an incidence DBT screen to a prevalence abbreviated MRI screen, Dr. Comstock and associates noted.

However, the results show a significantly increased breast cancer detection rate with abbreviated MRI, which merits additional research to examine the relationship between screening strategies and clinical outcomes for women with dense breasts, they said.

The study was supported in part by the National Cancer Institute of the National Institutes of Health, and by Bracco Diagnostics through funding to the ECOG-ACRIN Cancer Research Group. Dr. Comstock disclosed financial relationships with Bracco Diagnostics and Bayer, and three coauthors disclosed financial relationships with other imaging companies. The remaining coauthors had no relevant financial disclosures.
 

SOURCE: Comstock CK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0572.

For women with dense breasts, abbreviated magnetic resonance imaging was more effective than was digital breast tomosynthesis for detecting invasive breast cancer in a cross-sectional study of 1,444 women who underwent both procedures.

Dense breasts are a common reason for failed early diagnosis of breast cancer, wrote Christopher E. Comstock, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Digital breast tomosynthesis (DBT) and abbreviated breast magnetic resonance imaging (MRI) are becoming more popular as safe and cost-effective breast cancer screening options, but their effectiveness in women with dense breasts and average breast cancer risk has not been compared.

The researchers reviewed data from 1,444 women aged 40-75 years at 47 institutions in the United States and 1 in Germany. The women underwent both DBT and MRI. The primary endpoint was the detection of invasive cancers, of which 17 were identified at baseline screening. Abbreviated breast MRI detected all 17 cases of invasive cancer, compared with 7 detected by DBT. In addition, MRI detected six of seven women with ductal carcinoma in situ, while DBT identified two of the seven cases, according to the study, which was published in JAMA.

Overall, the invasive cancer detection rate was 11.8 per 1,000 women for MRI compared with 4.8 per 1,000 women for DBT. Sensitivity for MRI and DBT was 96% vs. 39%, and specificity was 87% vs. 97%.

The rate of recommendation for further screening was not significantly different between the procedures (8% for MRI and 10% for DBT). The most common adverse events were three cases of mild allergic reactions and two cases of anxiety.

The study findings were limited by several factors including the inability to show an association between abbreviated breast MRI and breast cancer mortality and the lack of cost-effectiveness comparisons for the two procedures. Because eligibility criteria required a prior breast mammogram to see if the breasts were dense, the study compared an incidence DBT screen to a prevalence abbreviated MRI screen, Dr. Comstock and associates noted.

However, the results show a significantly increased breast cancer detection rate with abbreviated MRI, which merits additional research to examine the relationship between screening strategies and clinical outcomes for women with dense breasts, they said.

The study was supported in part by the National Cancer Institute of the National Institutes of Health, and by Bracco Diagnostics through funding to the ECOG-ACRIN Cancer Research Group. Dr. Comstock disclosed financial relationships with Bracco Diagnostics and Bayer, and three coauthors disclosed financial relationships with other imaging companies. The remaining coauthors had no relevant financial disclosures.
 

SOURCE: Comstock CK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0572.

For women with dense breasts, abbreviated magnetic resonance imaging was more effective than was digital breast tomosynthesis for detecting invasive breast cancer in a cross-sectional study of 1,444 women who underwent both procedures.

Dense breasts are a common reason for failed early diagnosis of breast cancer, wrote Christopher E. Comstock, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Digital breast tomosynthesis (DBT) and abbreviated breast magnetic resonance imaging (MRI) are becoming more popular as safe and cost-effective breast cancer screening options, but their effectiveness in women with dense breasts and average breast cancer risk has not been compared.

The researchers reviewed data from 1,444 women aged 40-75 years at 47 institutions in the United States and 1 in Germany. The women underwent both DBT and MRI. The primary endpoint was the detection of invasive cancers, of which 17 were identified at baseline screening. Abbreviated breast MRI detected all 17 cases of invasive cancer, compared with 7 detected by DBT. In addition, MRI detected six of seven women with ductal carcinoma in situ, while DBT identified two of the seven cases, according to the study, which was published in JAMA.

Overall, the invasive cancer detection rate was 11.8 per 1,000 women for MRI compared with 4.8 per 1,000 women for DBT. Sensitivity for MRI and DBT was 96% vs. 39%, and specificity was 87% vs. 97%.

The rate of recommendation for further screening was not significantly different between the procedures (8% for MRI and 10% for DBT). The most common adverse events were three cases of mild allergic reactions and two cases of anxiety.

The study findings were limited by several factors including the inability to show an association between abbreviated breast MRI and breast cancer mortality and the lack of cost-effectiveness comparisons for the two procedures. Because eligibility criteria required a prior breast mammogram to see if the breasts were dense, the study compared an incidence DBT screen to a prevalence abbreviated MRI screen, Dr. Comstock and associates noted.

However, the results show a significantly increased breast cancer detection rate with abbreviated MRI, which merits additional research to examine the relationship between screening strategies and clinical outcomes for women with dense breasts, they said.

The study was supported in part by the National Cancer Institute of the National Institutes of Health, and by Bracco Diagnostics through funding to the ECOG-ACRIN Cancer Research Group. Dr. Comstock disclosed financial relationships with Bracco Diagnostics and Bayer, and three coauthors disclosed financial relationships with other imaging companies. The remaining coauthors had no relevant financial disclosures.
 

SOURCE: Comstock CK et al. JAMA. 2020 Feb 25. doi: 10.1001/jama.2020.0572.

Prematurity remains the leading cause of neonatal morbidity and mortality, accounting for $26 billion a year in immediate costs, despite the implementation in obstetrics of a host of risk stratification algorithms and strategies for risk reduction, including the use of some medications.

It now is questionable whether injectable 17-alpha hydroxyprogesterone caproate (Makena) truly is efficacious in women who’ve had a prior spontaneous preterm birth (sPTB) – a Food and Drug Administration advisory committee last year recommended withdrawing it from the market based on results of an FDA confirmatory study. Even if the drug were efficacious, only a small percentage of the women who have an sPTB have had a prior one. The majority of sPTB occurs among women without such a history.

Vaginal progesterone appears to confer some protection in women found to have a short cervix during the second trimester, but this approach also has limited reach: Only 9% of women with sPTB had an antecedent short cervix in a 2017 study.¹ Like a history of sPTB, screening for short cervical length is a potentially helpful strategy for risk reduction, but it is not a strategy that will significantly impact the overall rate of prematurity.

We’ve fallen short in our goals to significantly reduce the public health impact of prematurity partly because we still do not understand the exact pathways and mechanisms by which sPTB occurs. The main working paradigm for myself and many other researchers over the past 2 decades has centered on infection in the uterus triggering inflammation, followed by cervical remodeling and ripening. Research in animal models, as well as human clinical trials targeting various infections and inflammation, have led to some insights and discoveries, but no successful interventions.

In the past decade, however, our research framework for understanding sPTB incorporates new questions about immunologic, microbiological, and molecular/cellular events that happen in the cervicovaginal space. We’ve learned more about the cervicovaginal microbiota, and most recently, our research at the University of Pennsylvania has elucidated the role that nonoptimal bacteria play in disrupting the cervical endothelial barrier and initiating the process of cervical remodeling that likely precedes sPTB.

We now know that there is an association between cervicovaginal microbial communities, immune responses, and sPTB. We also know that this association is stronger in black women and may help explain some of the observed racial disparities in sPTB. Although more research is needed to determine specific therapeutic strategies, new doors are open.
 

Host immune-microbial interactions

This new research paradigm has involved stepping back and asking basic questions, such as, what do we really know about the cervicovaginal space? In actuality, we know very little. We know little about the immune function of the vaginal and cervical epithelial cells in pregnancy, for instance, and there is a large gap in knowledge regarding the biomechanics of the cervix – a remarkable organ that can change shape and function in a matter of minutes. Studies on the biomechanics of the cervix during pregnancy and in labor are still in their infancy.

However, lessons can be drawn from research on inflammatory bowel disease and other disorders involving the gut. In the gastrointestinal tract, epithelial cells have been found to act as sentinels, forming a mucosal barrier against bacterial pathogens and secreting various immune factors. Research in this field also has shown that microbes living in the gut produce metabolites; that these microbial metabolites may be the key messengers from the microbial communities to the epithelial barrier; and that the microbes, microbial metabolites, and immune responses are responsible for triggering inflammatory processes in the tissues underneath.

In 2011, Jacques Ravel, PhD, who was part of the National Institutes of Health’s Human Microbiome Project, characterized the vaginal microbiome of reproductive-age women for the first time.² His paper classified the vaginal microbial communities of approximately 400 asymptomatic women of various ethnicities into five “community state types” (CSTs) based on the predominant bacteria found in the cervicovaginal space.³

On the heels of his research, Dr. Ravel and I launched an NIH-funded study involving a prospective cohort of 2,000 women with singleton pregnancies – the Motherhood & Microbiome cohort – to look at the cervicovaginal microbiota, the local immune response, and the risk of sPTB.⁴ Cervicovaginal samples were collected at 16-20 weeks’ gestation and during two subsequent clinical visits. From this cohort, which was composed mostly of African American women (74.5%), we conducted a nested case-controlled study of 103 cases of sPTB and 432 women who delivered at term, matched for race.

We carefully adjudicated the deliveries in our 2,000-person cohort so that we homed in on sPTB as opposed to preterm births that are medically indicated for reasons such as fetal distress or preeclampsia. (Several prior studies looking at the associations between the cervicovaginal microbiome had a heterogeneous phenotyping of PTB that made it hard to draw definitive conclusions.)

Our focus in assessing the microbiome and immunologic profiles was on the samples collected at the earliest time points in pregnancy because we hoped to detect a “signature” that could predict an outcome months later. Indeed, we found that the nonoptimal microbiota, known in microbiological terms as CST IV, was associated with about a 150% increased risk of sPTB. This community comprises a dominant array of anaerobic bacteria and a paucity of Lactobacillus species.

We also found that a larger proportion of African American women, compared with non–African American women, had this nonoptimal microbiota early in pregnancy (40% vs. 15%), which is consistent with previous studies in pregnancy and nonpregnancy showing lower levels of Lactobacillus species in the cervicovaginal microbiome of African American women.

Even more interesting was the finding that, although the rate of sPTB was higher in African American women and the effect of CST IV on sPTB was stronger in these women, the risk of sPTB couldn’t be explained solely by the presence of CST IV. Some women with this nonoptimal microbiome delivered at term, whereas others with more optimal microbiome types had sPTBs. This suggests that other factors contribute to African American women having a nonoptimal microbiota and being especially predisposed to sPTB.

Through the study’s immunologic profiling, we found a significant difference in the cervicovaginal levels of an immune factor, beta-defensin 2, between African American women who delivered at term and those who had a sPTB. Women who had a sPTB, even those who had higher levels of Lactobacillus species, had lower levels of beta-defensin 2. This association was not found in non–African American women.

Beta-defensin 2 is a host-derived antimicrobial peptide that, like other antimicrobial peptides, works at epithelial-mucosal barriers to combat bacteria; we have knowledge of its action from research on the gut, as well as some studies of the vaginal space in nonpregnant women that have focused on sexually transmitted infections.

Most exciting for us was the finding that higher levels of beta-defensin 2 appeared to lower the risk of sPTB in women who had a nonoptimal cervicovaginal microbiota. There’s an interplay between the host and the microbiota, in other words, and it’s one that could be essential to manipulate as we seek to reduce sPTB.
 

The cervical epithelial barrier

In the laboratory, meanwhile, we are learning how certain microbes are mechanistically involved in the pathogenesis of sPTB. Research over the last decade has suggested that disruption or breakdown of the cervical epithelial barrier drives cervical remodeling processes that precede sPTB. The question now is, do cervicovaginal bacteria associated with sPTB, or a nonoptimal cervicovaginal microbiota, cause disruption of the vaginal and cervical epithelial barrier – and how?

Using an in vitro model system, we found that Mobiluncus curtisii/mulieris, the bacterial taxa with the strongest association with sPTB in our Motherhood & Microbiome cohort and one that has long been associated with bacterial vaginosis, had a plethora of effects. It increased cell permeability and the expression of inflammatory mediators associated with cervical epithelial breakdown, and it altered expression of microRNAs that have been associated with sPTB in human studies.

Our study on Mobiluncus has served as proof of concept to us that, not only is the bacteria associated with sPTB, but that there are multiple mechanisms by which it can disrupt the cervicovaginal barrier and lead to cervical remodeling.⁵

The findings echo previous in vitro research on Gardnerella vaginalis, another anaerobic bacterium that has been associated with bacterial vaginosis and adverse obstetric outcomes, including sPTB.⁶ Using similar models, we found that G. vaginalis disrupts the cervical epithelial barrier through diverse mechanisms including the cleavage of certain proteins, the up-regulation of proinflammatory immune mediators, and altered gene expression.

Lactobacillus crispatus, on the other hand, conferred protection to the cervical epithelial barrier in this study by mitigating various G. vaginalis–induced effects.

Learning more about host-microbe interactions and the role of microbial metabolites in these interactions, as well as the role of altered gene expression in cervical function, will help us to more fully understand the biological mechanisms regulating cervicovaginal epithelial cells. At this point, we know that, as in the gut, bacteria commonly found in the cervicovaginal space play a significant role in regulating the function of epithelial cells (in both optimal and nonoptimal microbiota), and that various bacteria associated with sPTB contribute to poor outcomes by breaking down the cervical epithelium.
 

Therapeutic implications

Our growing knowledge of the cervicovaginal microbiota does not yet support screening or any particular interventions. We don’t know, for instance, that administering probiotics or prebiotics orally or vaginally will have any effect on rates of sPTB.

Ongoing research at all levels holds promise, however, for the development of diagnostics to identify women at risk for sPTB, and for the development of therapeutic strategies that aim to modify the microbiome and/or modify the immune response. We know from other areas of medicine that there are realistic ways to modulate the immune response and/or microbiota in a system to alter risk.

We need to more thoroughly understand the risk of particular microbiota and immune response factors – and how they vary by race and ethnicity – and we need to study the cervicovaginal microbiota of women before and during pregnancy to learn whether there is something about pregnancy or even about intercourse that can change one’s microbiome to a less favorable state.

It may well be possible in the near future to identify high-risk states of nonoptimal microbiota before conception – microbiota that, in and of themselves, may not be pathogenic but that become detrimental during pregnancy – and it should be possible to screen women early in pregnancy for microbial or immune signatures or both.

The question often arises in medicine of the validity of screening without having achieved certainty about treatments. However, in obstetrics, where we have different levels of care and the ability to personalize monitoring and care, identifying those at greatest risk still has value. Ultimately, with enough investment in all levels of research (basic, translational, and clinical), we can develop interventions and therapeutics that address a biologically plausible mechanism of sPTB and, as a result, achieve significant reductions in the rate of prematurity.

Dr. Elovitz is the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia. She disclosed holding a patent on a method to determine risk of preterm birth that relates to the microbiome. Email her at obnews@mdedge.com.

References

1. JAMA. 2017 Mar 14;317(10):1047-56.

2. NIH Human Microbiome Project. https://hmpdacc.org/.

3. PNAS. 2011 Mar 15;108 (Supplement 1):4680-7.

4. Nat Commun. 2019 Mar 21. doi: 10.1038/s41467-019-09285-9.

5. Anaerobe. 2019 Nov 21. doi: 10.1016/j.anaerobe.2019.102127.

6. Front Microbiol. 2018 Oct 8. doi: 10.3389/fmicb.2018.02181.

Prematurity remains the leading cause of neonatal morbidity and mortality, accounting for $26 billion a year in immediate costs, despite the implementation in obstetrics of a host of risk stratification algorithms and strategies for risk reduction, including the use of some medications.

It now is questionable whether injectable 17-alpha hydroxyprogesterone caproate (Makena) truly is efficacious in women who’ve had a prior spontaneous preterm birth (sPTB) – a Food and Drug Administration advisory committee last year recommended withdrawing it from the market based on results of an FDA confirmatory study. Even if the drug were efficacious, only a small percentage of the women who have an sPTB have had a prior one. The majority of sPTB occurs among women without such a history.

Vaginal progesterone appears to confer some protection in women found to have a short cervix during the second trimester, but this approach also has limited reach: Only 9% of women with sPTB had an antecedent short cervix in a 2017 study.¹ Like a history of sPTB, screening for short cervical length is a potentially helpful strategy for risk reduction, but it is not a strategy that will significantly impact the overall rate of prematurity.

We’ve fallen short in our goals to significantly reduce the public health impact of prematurity partly because we still do not understand the exact pathways and mechanisms by which sPTB occurs. The main working paradigm for myself and many other researchers over the past 2 decades has centered on infection in the uterus triggering inflammation, followed by cervical remodeling and ripening. Research in animal models, as well as human clinical trials targeting various infections and inflammation, have led to some insights and discoveries, but no successful interventions.

In the past decade, however, our research framework for understanding sPTB incorporates new questions about immunologic, microbiological, and molecular/cellular events that happen in the cervicovaginal space. We’ve learned more about the cervicovaginal microbiota, and most recently, our research at the University of Pennsylvania has elucidated the role that nonoptimal bacteria play in disrupting the cervical endothelial barrier and initiating the process of cervical remodeling that likely precedes sPTB.

We now know that there is an association between cervicovaginal microbial communities, immune responses, and sPTB. We also know that this association is stronger in black women and may help explain some of the observed racial disparities in sPTB. Although more research is needed to determine specific therapeutic strategies, new doors are open.
 

Host immune-microbial interactions

This new research paradigm has involved stepping back and asking basic questions, such as, what do we really know about the cervicovaginal space? In actuality, we know very little. We know little about the immune function of the vaginal and cervical epithelial cells in pregnancy, for instance, and there is a large gap in knowledge regarding the biomechanics of the cervix – a remarkable organ that can change shape and function in a matter of minutes. Studies on the biomechanics of the cervix during pregnancy and in labor are still in their infancy.

However, lessons can be drawn from research on inflammatory bowel disease and other disorders involving the gut. In the gastrointestinal tract, epithelial cells have been found to act as sentinels, forming a mucosal barrier against bacterial pathogens and secreting various immune factors. Research in this field also has shown that microbes living in the gut produce metabolites; that these microbial metabolites may be the key messengers from the microbial communities to the epithelial barrier; and that the microbes, microbial metabolites, and immune responses are responsible for triggering inflammatory processes in the tissues underneath.

In 2011, Jacques Ravel, PhD, who was part of the National Institutes of Health’s Human Microbiome Project, characterized the vaginal microbiome of reproductive-age women for the first time.² His paper classified the vaginal microbial communities of approximately 400 asymptomatic women of various ethnicities into five “community state types” (CSTs) based on the predominant bacteria found in the cervicovaginal space.³

On the heels of his research, Dr. Ravel and I launched an NIH-funded study involving a prospective cohort of 2,000 women with singleton pregnancies – the Motherhood & Microbiome cohort – to look at the cervicovaginal microbiota, the local immune response, and the risk of sPTB.⁴ Cervicovaginal samples were collected at 16-20 weeks’ gestation and during two subsequent clinical visits. From this cohort, which was composed mostly of African American women (74.5%), we conducted a nested case-controlled study of 103 cases of sPTB and 432 women who delivered at term, matched for race.

We carefully adjudicated the deliveries in our 2,000-person cohort so that we homed in on sPTB as opposed to preterm births that are medically indicated for reasons such as fetal distress or preeclampsia. (Several prior studies looking at the associations between the cervicovaginal microbiome had a heterogeneous phenotyping of PTB that made it hard to draw definitive conclusions.)

Our focus in assessing the microbiome and immunologic profiles was on the samples collected at the earliest time points in pregnancy because we hoped to detect a “signature” that could predict an outcome months later. Indeed, we found that the nonoptimal microbiota, known in microbiological terms as CST IV, was associated with about a 150% increased risk of sPTB. This community comprises a dominant array of anaerobic bacteria and a paucity of Lactobacillus species.

We also found that a larger proportion of African American women, compared with non–African American women, had this nonoptimal microbiota early in pregnancy (40% vs. 15%), which is consistent with previous studies in pregnancy and nonpregnancy showing lower levels of Lactobacillus species in the cervicovaginal microbiome of African American women.

Even more interesting was the finding that, although the rate of sPTB was higher in African American women and the effect of CST IV on sPTB was stronger in these women, the risk of sPTB couldn’t be explained solely by the presence of CST IV. Some women with this nonoptimal microbiome delivered at term, whereas others with more optimal microbiome types had sPTBs. This suggests that other factors contribute to African American women having a nonoptimal microbiota and being especially predisposed to sPTB.

Through the study’s immunologic profiling, we found a significant difference in the cervicovaginal levels of an immune factor, beta-defensin 2, between African American women who delivered at term and those who had a sPTB. Women who had a sPTB, even those who had higher levels of Lactobacillus species, had lower levels of beta-defensin 2. This association was not found in non–African American women.

Beta-defensin 2 is a host-derived antimicrobial peptide that, like other antimicrobial peptides, works at epithelial-mucosal barriers to combat bacteria; we have knowledge of its action from research on the gut, as well as some studies of the vaginal space in nonpregnant women that have focused on sexually transmitted infections.

Most exciting for us was the finding that higher levels of beta-defensin 2 appeared to lower the risk of sPTB in women who had a nonoptimal cervicovaginal microbiota. There’s an interplay between the host and the microbiota, in other words, and it’s one that could be essential to manipulate as we seek to reduce sPTB.
 

The cervical epithelial barrier

In the laboratory, meanwhile, we are learning how certain microbes are mechanistically involved in the pathogenesis of sPTB. Research over the last decade has suggested that disruption or breakdown of the cervical epithelial barrier drives cervical remodeling processes that precede sPTB. The question now is, do cervicovaginal bacteria associated with sPTB, or a nonoptimal cervicovaginal microbiota, cause disruption of the vaginal and cervical epithelial barrier – and how?

Using an in vitro model system, we found that Mobiluncus curtisii/mulieris, the bacterial taxa with the strongest association with sPTB in our Motherhood & Microbiome cohort and one that has long been associated with bacterial vaginosis, had a plethora of effects. It increased cell permeability and the expression of inflammatory mediators associated with cervical epithelial breakdown, and it altered expression of microRNAs that have been associated with sPTB in human studies.

Our study on Mobiluncus has served as proof of concept to us that, not only is the bacteria associated with sPTB, but that there are multiple mechanisms by which it can disrupt the cervicovaginal barrier and lead to cervical remodeling.⁵

The findings echo previous in vitro research on Gardnerella vaginalis, another anaerobic bacterium that has been associated with bacterial vaginosis and adverse obstetric outcomes, including sPTB.⁶ Using similar models, we found that G. vaginalis disrupts the cervical epithelial barrier through diverse mechanisms including the cleavage of certain proteins, the up-regulation of proinflammatory immune mediators, and altered gene expression.

Lactobacillus crispatus, on the other hand, conferred protection to the cervical epithelial barrier in this study by mitigating various G. vaginalis–induced effects.

Learning more about host-microbe interactions and the role of microbial metabolites in these interactions, as well as the role of altered gene expression in cervical function, will help us to more fully understand the biological mechanisms regulating cervicovaginal epithelial cells. At this point, we know that, as in the gut, bacteria commonly found in the cervicovaginal space play a significant role in regulating the function of epithelial cells (in both optimal and nonoptimal microbiota), and that various bacteria associated with sPTB contribute to poor outcomes by breaking down the cervical epithelium.
 

Therapeutic implications

Our growing knowledge of the cervicovaginal microbiota does not yet support screening or any particular interventions. We don’t know, for instance, that administering probiotics or prebiotics orally or vaginally will have any effect on rates of sPTB.

Ongoing research at all levels holds promise, however, for the development of diagnostics to identify women at risk for sPTB, and for the development of therapeutic strategies that aim to modify the microbiome and/or modify the immune response. We know from other areas of medicine that there are realistic ways to modulate the immune response and/or microbiota in a system to alter risk.

We need to more thoroughly understand the risk of particular microbiota and immune response factors – and how they vary by race and ethnicity – and we need to study the cervicovaginal microbiota of women before and during pregnancy to learn whether there is something about pregnancy or even about intercourse that can change one’s microbiome to a less favorable state.

It may well be possible in the near future to identify high-risk states of nonoptimal microbiota before conception – microbiota that, in and of themselves, may not be pathogenic but that become detrimental during pregnancy – and it should be possible to screen women early in pregnancy for microbial or immune signatures or both.

The question often arises in medicine of the validity of screening without having achieved certainty about treatments. However, in obstetrics, where we have different levels of care and the ability to personalize monitoring and care, identifying those at greatest risk still has value. Ultimately, with enough investment in all levels of research (basic, translational, and clinical), we can develop interventions and therapeutics that address a biologically plausible mechanism of sPTB and, as a result, achieve significant reductions in the rate of prematurity.

Dr. Elovitz is the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia. She disclosed holding a patent on a method to determine risk of preterm birth that relates to the microbiome. Email her at obnews@mdedge.com.

References

1. JAMA. 2017 Mar 14;317(10):1047-56.

2. NIH Human Microbiome Project. https://hmpdacc.org/.

3. PNAS. 2011 Mar 15;108 (Supplement 1):4680-7.

4. Nat Commun. 2019 Mar 21. doi: 10.1038/s41467-019-09285-9.

5. Anaerobe. 2019 Nov 21. doi: 10.1016/j.anaerobe.2019.102127.

6. Front Microbiol. 2018 Oct 8. doi: 10.3389/fmicb.2018.02181.

Prematurity remains the leading cause of neonatal morbidity and mortality, accounting for $26 billion a year in immediate costs, despite the implementation in obstetrics of a host of risk stratification algorithms and strategies for risk reduction, including the use of some medications.

It now is questionable whether injectable 17-alpha hydroxyprogesterone caproate (Makena) truly is efficacious in women who’ve had a prior spontaneous preterm birth (sPTB) – a Food and Drug Administration advisory committee last year recommended withdrawing it from the market based on results of an FDA confirmatory study. Even if the drug were efficacious, only a small percentage of the women who have an sPTB have had a prior one. The majority of sPTB occurs among women without such a history.

Vaginal progesterone appears to confer some protection in women found to have a short cervix during the second trimester, but this approach also has limited reach: Only 9% of women with sPTB had an antecedent short cervix in a 2017 study.¹ Like a history of sPTB, screening for short cervical length is a potentially helpful strategy for risk reduction, but it is not a strategy that will significantly impact the overall rate of prematurity.

We’ve fallen short in our goals to significantly reduce the public health impact of prematurity partly because we still do not understand the exact pathways and mechanisms by which sPTB occurs. The main working paradigm for myself and many other researchers over the past 2 decades has centered on infection in the uterus triggering inflammation, followed by cervical remodeling and ripening. Research in animal models, as well as human clinical trials targeting various infections and inflammation, have led to some insights and discoveries, but no successful interventions.

In the past decade, however, our research framework for understanding sPTB incorporates new questions about immunologic, microbiological, and molecular/cellular events that happen in the cervicovaginal space. We’ve learned more about the cervicovaginal microbiota, and most recently, our research at the University of Pennsylvania has elucidated the role that nonoptimal bacteria play in disrupting the cervical endothelial barrier and initiating the process of cervical remodeling that likely precedes sPTB.

We now know that there is an association between cervicovaginal microbial communities, immune responses, and sPTB. We also know that this association is stronger in black women and may help explain some of the observed racial disparities in sPTB. Although more research is needed to determine specific therapeutic strategies, new doors are open.
 

Host immune-microbial interactions

This new research paradigm has involved stepping back and asking basic questions, such as, what do we really know about the cervicovaginal space? In actuality, we know very little. We know little about the immune function of the vaginal and cervical epithelial cells in pregnancy, for instance, and there is a large gap in knowledge regarding the biomechanics of the cervix – a remarkable organ that can change shape and function in a matter of minutes. Studies on the biomechanics of the cervix during pregnancy and in labor are still in their infancy.

However, lessons can be drawn from research on inflammatory bowel disease and other disorders involving the gut. In the gastrointestinal tract, epithelial cells have been found to act as sentinels, forming a mucosal barrier against bacterial pathogens and secreting various immune factors. Research in this field also has shown that microbes living in the gut produce metabolites; that these microbial metabolites may be the key messengers from the microbial communities to the epithelial barrier; and that the microbes, microbial metabolites, and immune responses are responsible for triggering inflammatory processes in the tissues underneath.

In 2011, Jacques Ravel, PhD, who was part of the National Institutes of Health’s Human Microbiome Project, characterized the vaginal microbiome of reproductive-age women for the first time.² His paper classified the vaginal microbial communities of approximately 400 asymptomatic women of various ethnicities into five “community state types” (CSTs) based on the predominant bacteria found in the cervicovaginal space.³

On the heels of his research, Dr. Ravel and I launched an NIH-funded study involving a prospective cohort of 2,000 women with singleton pregnancies – the Motherhood & Microbiome cohort – to look at the cervicovaginal microbiota, the local immune response, and the risk of sPTB.⁴ Cervicovaginal samples were collected at 16-20 weeks’ gestation and during two subsequent clinical visits. From this cohort, which was composed mostly of African American women (74.5%), we conducted a nested case-controlled study of 103 cases of sPTB and 432 women who delivered at term, matched for race.

We carefully adjudicated the deliveries in our 2,000-person cohort so that we homed in on sPTB as opposed to preterm births that are medically indicated for reasons such as fetal distress or preeclampsia. (Several prior studies looking at the associations between the cervicovaginal microbiome had a heterogeneous phenotyping of PTB that made it hard to draw definitive conclusions.)

Our focus in assessing the microbiome and immunologic profiles was on the samples collected at the earliest time points in pregnancy because we hoped to detect a “signature” that could predict an outcome months later. Indeed, we found that the nonoptimal microbiota, known in microbiological terms as CST IV, was associated with about a 150% increased risk of sPTB. This community comprises a dominant array of anaerobic bacteria and a paucity of Lactobacillus species.

We also found that a larger proportion of African American women, compared with non–African American women, had this nonoptimal microbiota early in pregnancy (40% vs. 15%), which is consistent with previous studies in pregnancy and nonpregnancy showing lower levels of Lactobacillus species in the cervicovaginal microbiome of African American women.

Even more interesting was the finding that, although the rate of sPTB was higher in African American women and the effect of CST IV on sPTB was stronger in these women, the risk of sPTB couldn’t be explained solely by the presence of CST IV. Some women with this nonoptimal microbiome delivered at term, whereas others with more optimal microbiome types had sPTBs. This suggests that other factors contribute to African American women having a nonoptimal microbiota and being especially predisposed to sPTB.

Through the study’s immunologic profiling, we found a significant difference in the cervicovaginal levels of an immune factor, beta-defensin 2, between African American women who delivered at term and those who had a sPTB. Women who had a sPTB, even those who had higher levels of Lactobacillus species, had lower levels of beta-defensin 2. This association was not found in non–African American women.

Beta-defensin 2 is a host-derived antimicrobial peptide that, like other antimicrobial peptides, works at epithelial-mucosal barriers to combat bacteria; we have knowledge of its action from research on the gut, as well as some studies of the vaginal space in nonpregnant women that have focused on sexually transmitted infections.

Most exciting for us was the finding that higher levels of beta-defensin 2 appeared to lower the risk of sPTB in women who had a nonoptimal cervicovaginal microbiota. There’s an interplay between the host and the microbiota, in other words, and it’s one that could be essential to manipulate as we seek to reduce sPTB.
 

The cervical epithelial barrier

In the laboratory, meanwhile, we are learning how certain microbes are mechanistically involved in the pathogenesis of sPTB. Research over the last decade has suggested that disruption or breakdown of the cervical epithelial barrier drives cervical remodeling processes that precede sPTB. The question now is, do cervicovaginal bacteria associated with sPTB, or a nonoptimal cervicovaginal microbiota, cause disruption of the vaginal and cervical epithelial barrier – and how?

Using an in vitro model system, we found that Mobiluncus curtisii/mulieris, the bacterial taxa with the strongest association with sPTB in our Motherhood & Microbiome cohort and one that has long been associated with bacterial vaginosis, had a plethora of effects. It increased cell permeability and the expression of inflammatory mediators associated with cervical epithelial breakdown, and it altered expression of microRNAs that have been associated with sPTB in human studies.

Our study on Mobiluncus has served as proof of concept to us that, not only is the bacteria associated with sPTB, but that there are multiple mechanisms by which it can disrupt the cervicovaginal barrier and lead to cervical remodeling.⁵

The findings echo previous in vitro research on Gardnerella vaginalis, another anaerobic bacterium that has been associated with bacterial vaginosis and adverse obstetric outcomes, including sPTB.⁶ Using similar models, we found that G. vaginalis disrupts the cervical epithelial barrier through diverse mechanisms including the cleavage of certain proteins, the up-regulation of proinflammatory immune mediators, and altered gene expression.

Lactobacillus crispatus, on the other hand, conferred protection to the cervical epithelial barrier in this study by mitigating various G. vaginalis–induced effects.

Learning more about host-microbe interactions and the role of microbial metabolites in these interactions, as well as the role of altered gene expression in cervical function, will help us to more fully understand the biological mechanisms regulating cervicovaginal epithelial cells. At this point, we know that, as in the gut, bacteria commonly found in the cervicovaginal space play a significant role in regulating the function of epithelial cells (in both optimal and nonoptimal microbiota), and that various bacteria associated with sPTB contribute to poor outcomes by breaking down the cervical epithelium.
 

Therapeutic implications

Our growing knowledge of the cervicovaginal microbiota does not yet support screening or any particular interventions. We don’t know, for instance, that administering probiotics or prebiotics orally or vaginally will have any effect on rates of sPTB.

Ongoing research at all levels holds promise, however, for the development of diagnostics to identify women at risk for sPTB, and for the development of therapeutic strategies that aim to modify the microbiome and/or modify the immune response. We know from other areas of medicine that there are realistic ways to modulate the immune response and/or microbiota in a system to alter risk.

We need to more thoroughly understand the risk of particular microbiota and immune response factors – and how they vary by race and ethnicity – and we need to study the cervicovaginal microbiota of women before and during pregnancy to learn whether there is something about pregnancy or even about intercourse that can change one’s microbiome to a less favorable state.

It may well be possible in the near future to identify high-risk states of nonoptimal microbiota before conception – microbiota that, in and of themselves, may not be pathogenic but that become detrimental during pregnancy – and it should be possible to screen women early in pregnancy for microbial or immune signatures or both.

The question often arises in medicine of the validity of screening without having achieved certainty about treatments. However, in obstetrics, where we have different levels of care and the ability to personalize monitoring and care, identifying those at greatest risk still has value. Ultimately, with enough investment in all levels of research (basic, translational, and clinical), we can develop interventions and therapeutics that address a biologically plausible mechanism of sPTB and, as a result, achieve significant reductions in the rate of prematurity.

Dr. Elovitz is the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia. She disclosed holding a patent on a method to determine risk of preterm birth that relates to the microbiome. Email her at obnews@mdedge.com.

References

1. JAMA. 2017 Mar 14;317(10):1047-56.

2. NIH Human Microbiome Project. https://hmpdacc.org/.

3. PNAS. 2011 Mar 15;108 (Supplement 1):4680-7.

4. Nat Commun. 2019 Mar 21. doi: 10.1038/s41467-019-09285-9.

5. Anaerobe. 2019 Nov 21. doi: 10.1016/j.anaerobe.2019.102127.

6. Front Microbiol. 2018 Oct 8. doi: 10.3389/fmicb.2018.02181.

Preventing infant mortality remains a significant challenge for ob.gyns. Despite the availability of a multitude of preventive and treatment options and some of the best possible medical care offered in the world, the United States lags behind many other developed and developing countries in its rate of infant deaths, which was an estimated 5.8 deaths per 1,000 live births in 2017. We can, and must, do better.

One of the major contributing factors to infant mortality is preterm birth. Defined as birth occurring prior to 37 weeks’ gestation, preterm birth is associated with a myriad of severe neonatal sequelae: low birth weight, bacterial sepsis, neonatal hemorrhage, and respiratory distress syndrome, among others. Therefore, many within the clinical and biomedical research spheres recognize that preventing preterm birth means reducing infant deaths.

However, therein lies the conundrum. We know very little about what causes preterm birth, which renders the current therapeutic strategies – such as use of progesterone supplements or cerclage placement – good for some but not all patients. It is thus vital to continue research to unravel the underlying mechanisms of preterm birth.

A promising area of investigation is the field of microbiome research, which has made great strides in advancing our awareness of the critical role of the millions of organisms living on and within us in maintaining health and fighting disease. For example, we now realize that eradicating all the commensals in our gastrointestinal tract has unintended and very negative consequences and, for patients whose good bacteria have been eliminated, fecal transplant is a therapeutic option. Therefore, it stands to reason that the microbes found in the vagina contribute significantly to women’s overall reproductive health.

The publication of the groundbreaking study characterizing the vaginal microbiome species in reproductive-age women opened new avenues of research into how these organisms contribute to women’s health. Importantly, this work, led initially by Jacques Ravel, PhD, a professor in the department of microbiology & immunology and associate director of the Institute for Genome Sciences at the University of Maryland School of Medicine, has spawned additional investigations into the potential role of the vaginal microbiome in preterm birth.

To provide some insight into the research around how the microorganisms in the vagina may induce or prevent preterm birth is our guest author, Michal A. Elovitz, MD, the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia.

Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at obnews@mdedge.com.

Preventing infant mortality remains a significant challenge for ob.gyns. Despite the availability of a multitude of preventive and treatment options and some of the best possible medical care offered in the world, the United States lags behind many other developed and developing countries in its rate of infant deaths, which was an estimated 5.8 deaths per 1,000 live births in 2017. We can, and must, do better.

One of the major contributing factors to infant mortality is preterm birth. Defined as birth occurring prior to 37 weeks’ gestation, preterm birth is associated with a myriad of severe neonatal sequelae: low birth weight, bacterial sepsis, neonatal hemorrhage, and respiratory distress syndrome, among others. Therefore, many within the clinical and biomedical research spheres recognize that preventing preterm birth means reducing infant deaths.

However, therein lies the conundrum. We know very little about what causes preterm birth, which renders the current therapeutic strategies – such as use of progesterone supplements or cerclage placement – good for some but not all patients. It is thus vital to continue research to unravel the underlying mechanisms of preterm birth.

A promising area of investigation is the field of microbiome research, which has made great strides in advancing our awareness of the critical role of the millions of organisms living on and within us in maintaining health and fighting disease. For example, we now realize that eradicating all the commensals in our gastrointestinal tract has unintended and very negative consequences and, for patients whose good bacteria have been eliminated, fecal transplant is a therapeutic option. Therefore, it stands to reason that the microbes found in the vagina contribute significantly to women’s overall reproductive health.

The publication of the groundbreaking study characterizing the vaginal microbiome species in reproductive-age women opened new avenues of research into how these organisms contribute to women’s health. Importantly, this work, led initially by Jacques Ravel, PhD, a professor in the department of microbiology & immunology and associate director of the Institute for Genome Sciences at the University of Maryland School of Medicine, has spawned additional investigations into the potential role of the vaginal microbiome in preterm birth.

To provide some insight into the research around how the microorganisms in the vagina may induce or prevent preterm birth is our guest author, Michal A. Elovitz, MD, the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia.

Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at obnews@mdedge.com.

Preventing infant mortality remains a significant challenge for ob.gyns. Despite the availability of a multitude of preventive and treatment options and some of the best possible medical care offered in the world, the United States lags behind many other developed and developing countries in its rate of infant deaths, which was an estimated 5.8 deaths per 1,000 live births in 2017. We can, and must, do better.

One of the major contributing factors to infant mortality is preterm birth. Defined as birth occurring prior to 37 weeks’ gestation, preterm birth is associated with a myriad of severe neonatal sequelae: low birth weight, bacterial sepsis, neonatal hemorrhage, and respiratory distress syndrome, among others. Therefore, many within the clinical and biomedical research spheres recognize that preventing preterm birth means reducing infant deaths.

However, therein lies the conundrum. We know very little about what causes preterm birth, which renders the current therapeutic strategies – such as use of progesterone supplements or cerclage placement – good for some but not all patients. It is thus vital to continue research to unravel the underlying mechanisms of preterm birth.

A promising area of investigation is the field of microbiome research, which has made great strides in advancing our awareness of the critical role of the millions of organisms living on and within us in maintaining health and fighting disease. For example, we now realize that eradicating all the commensals in our gastrointestinal tract has unintended and very negative consequences and, for patients whose good bacteria have been eliminated, fecal transplant is a therapeutic option. Therefore, it stands to reason that the microbes found in the vagina contribute significantly to women’s overall reproductive health.

The publication of the groundbreaking study characterizing the vaginal microbiome species in reproductive-age women opened new avenues of research into how these organisms contribute to women’s health. Importantly, this work, led initially by Jacques Ravel, PhD, a professor in the department of microbiology & immunology and associate director of the Institute for Genome Sciences at the University of Maryland School of Medicine, has spawned additional investigations into the potential role of the vaginal microbiome in preterm birth.

To provide some insight into the research around how the microorganisms in the vagina may induce or prevent preterm birth is our guest author, Michal A. Elovitz, MD, the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia.

Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at obnews@mdedge.com.

In Rochester, N.Y., a comprehensive community initiative that raised awareness about and delivered training in the use of long-acting reversible contraceptives (LARCs) significantly upped LARC adoption among sexually active female high schoolers.

JPC-PROD/Shutterstock

Over the course of the 3-year project, LARC use rose from about 4% to 24% in this group, a statistically significant increase (P less than .0001). During the same time period, LARC use increased nationally, as well, but at a lower rate, rising from 2% to 5% for the same population, while New York state saw LARC use rise from 2% to 5%.

In New York City, where an unrelated LARC awareness campaign was conducted, LARC use went from 3% to 5% over the study period for sexually active female high school students. Comparing the trend in LARC use in Rochester to the secular trend in these control groups showed significantly higher uptake over time in Rochester (P less than .0001).

Through a series of lunch-and-learn talks given to adults who work with adolescents in community-based settings and in medical settings, the Greater Rochester LARC Initiative reached more than 1,300 individuals during July 2014-June 2017, C. Andrew Aligne, MD, MPH, of the University of Rochester (N.Y.), and coauthors reported in the American Journal of Obstetrics and Gynecology.

Of the 81 total talks delivered, 50 were in medical settings, reaching 703 attendees ranging from front-office personnel to primary care physicians, advanced practice clinicians, and nurses; the talks in community-based settings reached 662 attendees.

“We use the term ‘community detailing’ to describe the design of the intervention because it was an innovative hybrid of academic detailing and community health education,” explained Dr. Aligne and colleagues. This approach is a unique, feasible, and effective approach to unintended adolescent pregnancy programs. “The community detailing approach could be a useful complement to programs for preventing unintended adolescent pregnancy.”

The study’s primary outcome measure was LARC use among sexually active female high school students as identified by responses on the U.S. Centers for Disease Control and Statistics’ Youth Risk Behavior Survey (YRBS).

YRBS data were examined for the years 2013, 2015, and 2017, spanning the period before and after the LARC initiative was begun. A separate question about LARC use wasn’t included in the 2013 YRBS survey, so the investigators used a generous estimate that two-thirds of respondents who reported using the “other” contraceptive category for that year were using LARCs. That category was chosen by a total of 6% of respondents, and encompassed LARC use along with use of the patch, ring, diaphragm, and fertility awareness, explained Dr. Aligne and collaborators.

Addressing the problem of failure to use a condom with LARC use, Dr. Aligne and collaborators found overall low rates of dual-method use, but higher rates in Rochester than in the comparison groups. In Rochester, 78% of respondents reported that they also did not use condoms. This figure was lower than the 91% reported for the United States as a whole, and also was lower than the 93% reported in New York City and the 85% reported in New York state. No increase in sexually transmitted infections was seen in Rochester’s sexually active high school females during the study period.

“Our main finding of increased LARC use is consistent with the literature demonstrating that many sexually active young women, including adolescents, will choose LARC if they are given access not only to birth control itself, but also to accurate information about various contraceptive methods,” concluded Dr. Aligne and his associates.

A practical strength of the Greater Rochester LARC initiative was that it capitalized on existing resources, such as New York state’s preexisting program for free access to contraception and similar provisions in the Affordable Care Act. Also, local Title X clinics that were enrolled in New York’s free contraception initiative already had practitioners who were trained and able to provide same-day LARC insertion.

Pediatricians engaged in the initiative were able to receive free training from LARC manufacturers, as mandated by the Food and Drug Administration. Through collaboration with implant manufacturers, Rochester LARC Initiative staff were able to piggyback on training sessions to add education about contraception counseling and the importance of offering access to all contraception methods.

Taken as a whole, the LARC Initiative could be scaled up, wrote Dr. Aligne and his coauthors, a potential boon in the 21 states where qualifying individuals younger than 19 years of age are eligible for Medicaid reimbursement for family planning services. “Even though easy LARC access is far from universal, there are vast areas of the nation where cost need not be seen as an insurmountable barrier.” Dr. Aligne and coauthors also addressed the fraught history of reproductive justice in the United States, cautioning that universal LARC adoption was not – and should not be – the goal of such initiatives. “There is a history of reproductive coercion in the U.S. including forced sterilization of women of color; therefore, it is critical that LARC methods not be imposed on any particular group. On the other hand, LARC should not be withheld deliberately from adolescents who want it, as this is another form of injustice,” they wrote. “The goal should be to empower individuals to decide what is right for them in a context of social and reproductive justice.”

Using the nationally administered YRBS was a significant strength of the study, commented Dr. Aligne and his collaborators. “This allowed us to employ the study design of pre-post with a nonrandomized control group,” the investigators noted, adding that the “relatively rigorous” methodology reduced the risk of problems with internal validity, and also allowed comparisons between changes in Rochester and those at the state and national level.

However, the researchers acknowledged that the study was not a randomized trial, and there’s always the possibility of unknown confounders contributing to LARC uptake during the study period. Also, the YRBS is a self-report instrument and only includes those enrolled in school.

Dr. Aligne reported that his spouse received compensation for providing contraceptive implant insertion training, as did two coauthors. The LARC initiative was supported by a grant from the Greater Rochester Health Foundation.

koakes@mdedge.com

SOURCE: Aligne CA et al. Am J Obstet Gynecol. 2020 Jan 22. doi: 10.1016/j.ajog.2020.01.029.

In Rochester, N.Y., a comprehensive community initiative that raised awareness about and delivered training in the use of long-acting reversible contraceptives (LARCs) significantly upped LARC adoption among sexually active female high schoolers.

JPC-PROD/Shutterstock

Over the course of the 3-year project, LARC use rose from about 4% to 24% in this group, a statistically significant increase (P less than .0001). During the same time period, LARC use increased nationally, as well, but at a lower rate, rising from 2% to 5% for the same population, while New York state saw LARC use rise from 2% to 5%.

In New York City, where an unrelated LARC awareness campaign was conducted, LARC use went from 3% to 5% over the study period for sexually active female high school students. Comparing the trend in LARC use in Rochester to the secular trend in these control groups showed significantly higher uptake over time in Rochester (P less than .0001).

Through a series of lunch-and-learn talks given to adults who work with adolescents in community-based settings and in medical settings, the Greater Rochester LARC Initiative reached more than 1,300 individuals during July 2014-June 2017, C. Andrew Aligne, MD, MPH, of the University of Rochester (N.Y.), and coauthors reported in the American Journal of Obstetrics and Gynecology.

Of the 81 total talks delivered, 50 were in medical settings, reaching 703 attendees ranging from front-office personnel to primary care physicians, advanced practice clinicians, and nurses; the talks in community-based settings reached 662 attendees.

“We use the term ‘community detailing’ to describe the design of the intervention because it was an innovative hybrid of academic detailing and community health education,” explained Dr. Aligne and colleagues. This approach is a unique, feasible, and effective approach to unintended adolescent pregnancy programs. “The community detailing approach could be a useful complement to programs for preventing unintended adolescent pregnancy.”

The study’s primary outcome measure was LARC use among sexually active female high school students as identified by responses on the U.S. Centers for Disease Control and Statistics’ Youth Risk Behavior Survey (YRBS).

YRBS data were examined for the years 2013, 2015, and 2017, spanning the period before and after the LARC initiative was begun. A separate question about LARC use wasn’t included in the 2013 YRBS survey, so the investigators used a generous estimate that two-thirds of respondents who reported using the “other” contraceptive category for that year were using LARCs. That category was chosen by a total of 6% of respondents, and encompassed LARC use along with use of the patch, ring, diaphragm, and fertility awareness, explained Dr. Aligne and collaborators.

Addressing the problem of failure to use a condom with LARC use, Dr. Aligne and collaborators found overall low rates of dual-method use, but higher rates in Rochester than in the comparison groups. In Rochester, 78% of respondents reported that they also did not use condoms. This figure was lower than the 91% reported for the United States as a whole, and also was lower than the 93% reported in New York City and the 85% reported in New York state. No increase in sexually transmitted infections was seen in Rochester’s sexually active high school females during the study period.

“Our main finding of increased LARC use is consistent with the literature demonstrating that many sexually active young women, including adolescents, will choose LARC if they are given access not only to birth control itself, but also to accurate information about various contraceptive methods,” concluded Dr. Aligne and his associates.

A practical strength of the Greater Rochester LARC initiative was that it capitalized on existing resources, such as New York state’s preexisting program for free access to contraception and similar provisions in the Affordable Care Act. Also, local Title X clinics that were enrolled in New York’s free contraception initiative already had practitioners who were trained and able to provide same-day LARC insertion.

Pediatricians engaged in the initiative were able to receive free training from LARC manufacturers, as mandated by the Food and Drug Administration. Through collaboration with implant manufacturers, Rochester LARC Initiative staff were able to piggyback on training sessions to add education about contraception counseling and the importance of offering access to all contraception methods.

Taken as a whole, the LARC Initiative could be scaled up, wrote Dr. Aligne and his coauthors, a potential boon in the 21 states where qualifying individuals younger than 19 years of age are eligible for Medicaid reimbursement for family planning services. “Even though easy LARC access is far from universal, there are vast areas of the nation where cost need not be seen as an insurmountable barrier.” Dr. Aligne and coauthors also addressed the fraught history of reproductive justice in the United States, cautioning that universal LARC adoption was not – and should not be – the goal of such initiatives. “There is a history of reproductive coercion in the U.S. including forced sterilization of women of color; therefore, it is critical that LARC methods not be imposed on any particular group. On the other hand, LARC should not be withheld deliberately from adolescents who want it, as this is another form of injustice,” they wrote. “The goal should be to empower individuals to decide what is right for them in a context of social and reproductive justice.”

Using the nationally administered YRBS was a significant strength of the study, commented Dr. Aligne and his collaborators. “This allowed us to employ the study design of pre-post with a nonrandomized control group,” the investigators noted, adding that the “relatively rigorous” methodology reduced the risk of problems with internal validity, and also allowed comparisons between changes in Rochester and those at the state and national level.

However, the researchers acknowledged that the study was not a randomized trial, and there’s always the possibility of unknown confounders contributing to LARC uptake during the study period. Also, the YRBS is a self-report instrument and only includes those enrolled in school.

Dr. Aligne reported that his spouse received compensation for providing contraceptive implant insertion training, as did two coauthors. The LARC initiative was supported by a grant from the Greater Rochester Health Foundation.

koakes@mdedge.com

SOURCE: Aligne CA et al. Am J Obstet Gynecol. 2020 Jan 22. doi: 10.1016/j.ajog.2020.01.029.

In Rochester, N.Y., a comprehensive community initiative that raised awareness about and delivered training in the use of long-acting reversible contraceptives (LARCs) significantly upped LARC adoption among sexually active female high schoolers.

JPC-PROD/Shutterstock

Over the course of the 3-year project, LARC use rose from about 4% to 24% in this group, a statistically significant increase (P less than .0001). During the same time period, LARC use increased nationally, as well, but at a lower rate, rising from 2% to 5% for the same population, while New York state saw LARC use rise from 2% to 5%.

In New York City, where an unrelated LARC awareness campaign was conducted, LARC use went from 3% to 5% over the study period for sexually active female high school students. Comparing the trend in LARC use in Rochester to the secular trend in these control groups showed significantly higher uptake over time in Rochester (P less than .0001).

Through a series of lunch-and-learn talks given to adults who work with adolescents in community-based settings and in medical settings, the Greater Rochester LARC Initiative reached more than 1,300 individuals during July 2014-June 2017, C. Andrew Aligne, MD, MPH, of the University of Rochester (N.Y.), and coauthors reported in the American Journal of Obstetrics and Gynecology.

Of the 81 total talks delivered, 50 were in medical settings, reaching 703 attendees ranging from front-office personnel to primary care physicians, advanced practice clinicians, and nurses; the talks in community-based settings reached 662 attendees.

“We use the term ‘community detailing’ to describe the design of the intervention because it was an innovative hybrid of academic detailing and community health education,” explained Dr. Aligne and colleagues. This approach is a unique, feasible, and effective approach to unintended adolescent pregnancy programs. “The community detailing approach could be a useful complement to programs for preventing unintended adolescent pregnancy.”

The study’s primary outcome measure was LARC use among sexually active female high school students as identified by responses on the U.S. Centers for Disease Control and Statistics’ Youth Risk Behavior Survey (YRBS).

YRBS data were examined for the years 2013, 2015, and 2017, spanning the period before and after the LARC initiative was begun. A separate question about LARC use wasn’t included in the 2013 YRBS survey, so the investigators used a generous estimate that two-thirds of respondents who reported using the “other” contraceptive category for that year were using LARCs. That category was chosen by a total of 6% of respondents, and encompassed LARC use along with use of the patch, ring, diaphragm, and fertility awareness, explained Dr. Aligne and collaborators.

Addressing the problem of failure to use a condom with LARC use, Dr. Aligne and collaborators found overall low rates of dual-method use, but higher rates in Rochester than in the comparison groups. In Rochester, 78% of respondents reported that they also did not use condoms. This figure was lower than the 91% reported for the United States as a whole, and also was lower than the 93% reported in New York City and the 85% reported in New York state. No increase in sexually transmitted infections was seen in Rochester’s sexually active high school females during the study period.

“Our main finding of increased LARC use is consistent with the literature demonstrating that many sexually active young women, including adolescents, will choose LARC if they are given access not only to birth control itself, but also to accurate information about various contraceptive methods,” concluded Dr. Aligne and his associates.

A practical strength of the Greater Rochester LARC initiative was that it capitalized on existing resources, such as New York state’s preexisting program for free access to contraception and similar provisions in the Affordable Care Act. Also, local Title X clinics that were enrolled in New York’s free contraception initiative already had practitioners who were trained and able to provide same-day LARC insertion.

Pediatricians engaged in the initiative were able to receive free training from LARC manufacturers, as mandated by the Food and Drug Administration. Through collaboration with implant manufacturers, Rochester LARC Initiative staff were able to piggyback on training sessions to add education about contraception counseling and the importance of offering access to all contraception methods.

Taken as a whole, the LARC Initiative could be scaled up, wrote Dr. Aligne and his coauthors, a potential boon in the 21 states where qualifying individuals younger than 19 years of age are eligible for Medicaid reimbursement for family planning services. “Even though easy LARC access is far from universal, there are vast areas of the nation where cost need not be seen as an insurmountable barrier.” Dr. Aligne and coauthors also addressed the fraught history of reproductive justice in the United States, cautioning that universal LARC adoption was not – and should not be – the goal of such initiatives. “There is a history of reproductive coercion in the U.S. including forced sterilization of women of color; therefore, it is critical that LARC methods not be imposed on any particular group. On the other hand, LARC should not be withheld deliberately from adolescents who want it, as this is another form of injustice,” they wrote. “The goal should be to empower individuals to decide what is right for them in a context of social and reproductive justice.”

Using the nationally administered YRBS was a significant strength of the study, commented Dr. Aligne and his collaborators. “This allowed us to employ the study design of pre-post with a nonrandomized control group,” the investigators noted, adding that the “relatively rigorous” methodology reduced the risk of problems with internal validity, and also allowed comparisons between changes in Rochester and those at the state and national level.

However, the researchers acknowledged that the study was not a randomized trial, and there’s always the possibility of unknown confounders contributing to LARC uptake during the study period. Also, the YRBS is a self-report instrument and only includes those enrolled in school.

Dr. Aligne reported that his spouse received compensation for providing contraceptive implant insertion training, as did two coauthors. The LARC initiative was supported by a grant from the Greater Rochester Health Foundation.

koakes@mdedge.com

SOURCE: Aligne CA et al. Am J Obstet Gynecol. 2020 Jan 22. doi: 10.1016/j.ajog.2020.01.029.

MAUI, HAWAII – Osteoporosis affects about 15% of people with inflammatory bowel disease (IBD), but the disease pattern is different than in the general population, said gastroenterologist Millie Long, MD, from the Department of Medicine at the University of North Carolina in Chapel Hill.

In the general population, those who develop osteoporosis are typically women who are thin and postmenopausal, and family history, smoking status, and alcohol use usually play a role, Long said at the Gastroenterology Updates, IBD, Liver Disease Conference.

But in the population with IBD, the risk for osteoporosis is similar in women and men, age plays a large role, and corticosteroid use seems to be a driving factor in the development of the disease, she explained.

A previous study that looked at fractures in patients with IBD showed that the risk “is 40% greater than in the general population,” Long reported. In patients younger than 40 years, the risk for fracture was 37% higher than in the general population, and this rate increased with age.
 

Preventing fractures

Fractures to the hip and spine are linked to significant morbidity, including hospitalization, major surgery, and even death, Long noted. But they are one of the preventable downstream effects of IBD, and patients need to understand that there’s something they can do about their elevated risk.

Patients should be educated on the importance of weight-bearing exercise and quitting smoking, she said.

“We need to think of preventive measures for anyone on more than 5 mg of prednisone a day for a time period of about 3 months,” she added. “Unfortunately, most of our patients meet this criterion.”

Patients with IBD should undergo dual-energy x-ray absorptiometry (DXA) to calculate bone density and establish the need for calcium and vitamin D supplementation.

“One of the things I’m starting to do in my practice is check vitamin D levels annually on my patients. I do this in the springtime and try to optimize their levels,” Long said.
 

Higher risk for herpes zoster

The risk for infection is also elevated in patients with IBD, including the risk for herpes zoster, which is already high, affecting one in three people in the general population.

In fact, the risk for herpes zoster in patients with IBD in their 20s is similar to the risk for people in their 50s in the general population. This is “something we need to be addressing in all of our patients,” said Long.

Physicians should emphasize the need for zoster vaccination in patients at least 50 years of age, and potentially younger patients on certain therapies, she added.

But because the Shingrix shingles vaccine (GlaxoSmithKline) is so much more powerful than the previous live vaccine, some have wondered whether it could stimulate an immune response, causing the IBD to flare after vaccination, she said.

However, a recent study of IBD patients followed for 207 days after shingles vaccination showed that only one of the 67 study participants (1.5%) experienced a flare. But fever is fairly common after the shot.

“I counsel my patients that they may feel pretty wiped out for 24 hours; they may have myalgias,” Long reported. “If you have someone who has to travel for work, you want them to time this vaccination so they can have a day of rest afterward. It’s the real deal.”
 

Screening for TB

Screening to rule out latent tuberculosis (TB) is also important in IBD.

“We should be looking at whether they’ve had close contact with active TB or people from endemic areas,” said Long. “The reason we really care about this is that the risk of serious infection is doubled with anti-TNF therapy.”

The treatment of latent TB prior to the initiation of an anti-TNF “reduces the incidence of active TB by over 80%. This is why it’s imperative to screen prior to initiation, and then periodically based on risk factors,” she explained.

“It’s profound how much maintenance is required for patients with IBD,” said Christopher Stanke, MD, from the Oregon Medical Group in Eugene.

He said he is particularly struck by the collective risks for younger patients with IBD.

“Young people look to us as their only doctor. They don’t even see their primary care physicians very often. We have to take over a lot of this stuff,” he told Medscape Medical News.

And osteoporosis doesn’t often get the attention it needs in gastroenterologists’ offices, he acknowledged.

“I often check it on people as they get close to 50 or 60,” said Stanke, who added that Long’s presentation is a good reminder that younger patients, especially those who have been on steroids for a while, need more attention.

This article first appeared on Medscape.com.

MAUI, HAWAII – Osteoporosis affects about 15% of people with inflammatory bowel disease (IBD), but the disease pattern is different than in the general population, said gastroenterologist Millie Long, MD, from the Department of Medicine at the University of North Carolina in Chapel Hill.

In the general population, those who develop osteoporosis are typically women who are thin and postmenopausal, and family history, smoking status, and alcohol use usually play a role, Long said at the Gastroenterology Updates, IBD, Liver Disease Conference.

But in the population with IBD, the risk for osteoporosis is similar in women and men, age plays a large role, and corticosteroid use seems to be a driving factor in the development of the disease, she explained.

A previous study that looked at fractures in patients with IBD showed that the risk “is 40% greater than in the general population,” Long reported. In patients younger than 40 years, the risk for fracture was 37% higher than in the general population, and this rate increased with age.
 

Preventing fractures

Fractures to the hip and spine are linked to significant morbidity, including hospitalization, major surgery, and even death, Long noted. But they are one of the preventable downstream effects of IBD, and patients need to understand that there’s something they can do about their elevated risk.

Patients should be educated on the importance of weight-bearing exercise and quitting smoking, she said.

“We need to think of preventive measures for anyone on more than 5 mg of prednisone a day for a time period of about 3 months,” she added. “Unfortunately, most of our patients meet this criterion.”

Patients with IBD should undergo dual-energy x-ray absorptiometry (DXA) to calculate bone density and establish the need for calcium and vitamin D supplementation.

“One of the things I’m starting to do in my practice is check vitamin D levels annually on my patients. I do this in the springtime and try to optimize their levels,” Long said.
 

Higher risk for herpes zoster

The risk for infection is also elevated in patients with IBD, including the risk for herpes zoster, which is already high, affecting one in three people in the general population.

In fact, the risk for herpes zoster in patients with IBD in their 20s is similar to the risk for people in their 50s in the general population. This is “something we need to be addressing in all of our patients,” said Long.

Physicians should emphasize the need for zoster vaccination in patients at least 50 years of age, and potentially younger patients on certain therapies, she added.

But because the Shingrix shingles vaccine (GlaxoSmithKline) is so much more powerful than the previous live vaccine, some have wondered whether it could stimulate an immune response, causing the IBD to flare after vaccination, she said.

However, a recent study of IBD patients followed for 207 days after shingles vaccination showed that only one of the 67 study participants (1.5%) experienced a flare. But fever is fairly common after the shot.

“I counsel my patients that they may feel pretty wiped out for 24 hours; they may have myalgias,” Long reported. “If you have someone who has to travel for work, you want them to time this vaccination so they can have a day of rest afterward. It’s the real deal.”
 

Screening for TB

Screening to rule out latent tuberculosis (TB) is also important in IBD.

“We should be looking at whether they’ve had close contact with active TB or people from endemic areas,” said Long. “The reason we really care about this is that the risk of serious infection is doubled with anti-TNF therapy.”

The treatment of latent TB prior to the initiation of an anti-TNF “reduces the incidence of active TB by over 80%. This is why it’s imperative to screen prior to initiation, and then periodically based on risk factors,” she explained.

“It’s profound how much maintenance is required for patients with IBD,” said Christopher Stanke, MD, from the Oregon Medical Group in Eugene.

He said he is particularly struck by the collective risks for younger patients with IBD.

“Young people look to us as their only doctor. They don’t even see their primary care physicians very often. We have to take over a lot of this stuff,” he told Medscape Medical News.

And osteoporosis doesn’t often get the attention it needs in gastroenterologists’ offices, he acknowledged.

“I often check it on people as they get close to 50 or 60,” said Stanke, who added that Long’s presentation is a good reminder that younger patients, especially those who have been on steroids for a while, need more attention.

This article first appeared on Medscape.com.

MAUI, HAWAII – Osteoporosis affects about 15% of people with inflammatory bowel disease (IBD), but the disease pattern is different than in the general population, said gastroenterologist Millie Long, MD, from the Department of Medicine at the University of North Carolina in Chapel Hill.

In the general population, those who develop osteoporosis are typically women who are thin and postmenopausal, and family history, smoking status, and alcohol use usually play a role, Long said at the Gastroenterology Updates, IBD, Liver Disease Conference.

But in the population with IBD, the risk for osteoporosis is similar in women and men, age plays a large role, and corticosteroid use seems to be a driving factor in the development of the disease, she explained.

A previous study that looked at fractures in patients with IBD showed that the risk “is 40% greater than in the general population,” Long reported. In patients younger than 40 years, the risk for fracture was 37% higher than in the general population, and this rate increased with age.
 

Preventing fractures

Fractures to the hip and spine are linked to significant morbidity, including hospitalization, major surgery, and even death, Long noted. But they are one of the preventable downstream effects of IBD, and patients need to understand that there’s something they can do about their elevated risk.

Patients should be educated on the importance of weight-bearing exercise and quitting smoking, she said.

“We need to think of preventive measures for anyone on more than 5 mg of prednisone a day for a time period of about 3 months,” she added. “Unfortunately, most of our patients meet this criterion.”

Patients with IBD should undergo dual-energy x-ray absorptiometry (DXA) to calculate bone density and establish the need for calcium and vitamin D supplementation.

“One of the things I’m starting to do in my practice is check vitamin D levels annually on my patients. I do this in the springtime and try to optimize their levels,” Long said.
 

Higher risk for herpes zoster

The risk for infection is also elevated in patients with IBD, including the risk for herpes zoster, which is already high, affecting one in three people in the general population.

In fact, the risk for herpes zoster in patients with IBD in their 20s is similar to the risk for people in their 50s in the general population. This is “something we need to be addressing in all of our patients,” said Long.

Physicians should emphasize the need for zoster vaccination in patients at least 50 years of age, and potentially younger patients on certain therapies, she added.

But because the Shingrix shingles vaccine (GlaxoSmithKline) is so much more powerful than the previous live vaccine, some have wondered whether it could stimulate an immune response, causing the IBD to flare after vaccination, she said.

However, a recent study of IBD patients followed for 207 days after shingles vaccination showed that only one of the 67 study participants (1.5%) experienced a flare. But fever is fairly common after the shot.

“I counsel my patients that they may feel pretty wiped out for 24 hours; they may have myalgias,” Long reported. “If you have someone who has to travel for work, you want them to time this vaccination so they can have a day of rest afterward. It’s the real deal.”
 

Screening for TB

Screening to rule out latent tuberculosis (TB) is also important in IBD.

“We should be looking at whether they’ve had close contact with active TB or people from endemic areas,” said Long. “The reason we really care about this is that the risk of serious infection is doubled with anti-TNF therapy.”

The treatment of latent TB prior to the initiation of an anti-TNF “reduces the incidence of active TB by over 80%. This is why it’s imperative to screen prior to initiation, and then periodically based on risk factors,” she explained.

“It’s profound how much maintenance is required for patients with IBD,” said Christopher Stanke, MD, from the Oregon Medical Group in Eugene.

He said he is particularly struck by the collective risks for younger patients with IBD.

“Young people look to us as their only doctor. They don’t even see their primary care physicians very often. We have to take over a lot of this stuff,” he told Medscape Medical News.

And osteoporosis doesn’t often get the attention it needs in gastroenterologists’ offices, he acknowledged.

“I often check it on people as they get close to 50 or 60,” said Stanke, who added that Long’s presentation is a good reminder that younger patients, especially those who have been on steroids for a while, need more attention.

This article first appeared on Medscape.com.

Children exposed to macrolides during the first trimester of pregnancy had an increased risk of major malformations, compared with first-trimester penicillin exposure, according to an observational study.

Creatas Images

Use of antibiotics is common in pregnancy, and macrolides commonly are used if a penicillin allergy is reported.

Hypospadias and other genital malformations also were more likely with exposure during any trimester to macrolides, although this association lost significance when limited to the first trimester. The researchers did not identify any associations with macrolides exposure and neurodevelopmental disorders.

The observational study could not establish causality, but the researchers calculated an estimate of likely excess malformations if the association were found to be causal: “For every 1,000 mothers prescribed macrolides instead of penicillins during the first trimester, an additional 4.1 children would have cardiovascular malformations,” Heng Fan, a PhD student at the University College London, and colleagues wrote in the BMJ. “The corresponding figures for prescriptions during any trimester and genital malformations would be 1.7.”

The researchers used records from the U.K. Clinical Practice Research Datalink to analyze outcomes in 104,605 children born between 1990 and 2016 to mothers who received at least one prescription of erythromycin, clarithromycin, azithromycin, or penicillin monotherapy between their fourth week of pregnancy and delivery. Women prescribed any known teratogenic medications were excluded.

The majority of the mothers (92%) had been prescribed penicillin once, and 8% were prescribed a macrolide antibiotic once during pregnancy.

The researchers tallied and calculated the children’s risk of major malformations; cerebral palsy; epilepsy; ADHD; autism spectrum disorder; and any nervous, cardiovascular, gastrointestinal, genital, or urinary malformations. The children were tracked through a median 6 years of age.

In comparing risk of malformations or neurodevelopmental disorders among children, the researchers chose to compare exposure to macrolides and penicillin to reduce the likelihood of confounding by indication for infections. (They also included two negative control groups: unexposed siblings and women prescribed antibiotics before conception.) The authors acknowledged, however, that residual confounding still may occur “if macrolides were prescribed for specific indications (e.g., chlamydia), or when potential risk factors for malformations or neurodevelopmental outcomes differed between treatment groups.”

The overall rate of malformations was 22 per 1,000 children prenatally exposed to macrolides (28 in first trimester and 20 in second or third trimester) and 17 per 1,000 children prenatally exposed to penicillin. The risk and type of malformations varied, however, according to the trimester.

The researchers made adjustments to account for differences in a wide range of maternal factors: age at delivery, calendar year of delivery, alcohol misuse, illegal drug use, tobacco use, obesity, hypertension, diabetes, anxiety, depression, and epilepsy. They also adjusted for parity, multiples, and chronic medical treatments, as well as genitourinary tract infections or STIs during pregnancy, both of which are linked to preterm labor.

Compared with children exposed to penicillin during the first trimester of pregnancy, risk of malformations was 1.6 times greater in those exposed to macrolides in the first trimester (risk ratio, 1.55; 28 vs. 18 per 1,000). Erythromycin exposure in the first trimester also was linked to a 50% greater likelihood of any major malformation compared with penicillin (RR, 1.5; 27 vs. 18 per 1,000).

Cardiovascular malformations in particular were more likely in those exposed to macrolides (11 per 1,000), compared with penicillin (7 per 1,000) in the first trimester (RR, 1.62). Meanwhile, genital malformations, primarily hypospadias, occurred more frequently in children whose mothers were prescribed macrolides (5 per 1,000), compared with penicillin (3 per 1,000) in any trimester (RR, 1.58).

No increased risk of major malformations was associated with macrolides prescribed only in the second or third trimester, although a borderline significant association existed with gastrointestinal malformations. The authors also found no links between macrolides exposure and increased risk of cerebral palsy, epilepsy, ADHD, or autism spectrum disorder.

The findings did not change in several sensitivity analyses, including one that restricted analysis to antibiotics prescribed only for respiratory tract infections.

Dr. Fan and associates discussed several potential biological mechanisms for causation, including the arrhythmic effect of macrolides that may relate to cardiovascular malformations or contribute to fetal hypoxia. They noted that “macrolide prescribing during pregnancy warrants caution,” and recommend including on drug safety labels “that there is uncertainty about the safety of macrolides, including erythromycin” and alternative antibiotics should be used when possible.

Iris Krishna, MD, MPH, assistant professor of maternal-fetal medicine at Emory University, Atlanta, agreed with the study authors that use of macrolides in the first trimester warrants further investigation, and if an appropriate alternative antibiotic is available, then it should be preferentially considered when treating infections in the first trimester.

“However, if macrolides are the only treatment option, pregnant women can be reassured that the absolute risk of a birth defect is low, and this should not discourage them from taking a macrolide when needed as untreated infections pose a greater risk in pregnancy,” she said in an interview.

“This study does not establish that macrolide antibiotics cause birth defects, but it suggests a potential association. Previous studies examining the use of macrolides, such as erythromycin, have not demonstrated a consistent pattern of birth defects, and heart defects identified were classified as mostly mild. The authors suggest that the potential biologic mechanism based on rat models may be that macrolides might induce fetal cardiac arrhythmias and short-term fetal hypoxia. This study was underpowered to examine macrolide exposure for specific malformations. To avoid underpowered comparisons, the authors’ categorized malformations by organ systems, so the spectrum of cardiac defects is unclear,” commented Dr. Krishna, who also is a member of the Ob.Gyn. News editorial advisory board.

“Current recommendations for macrolide antibiotic use in pregnancy in the second and third trimester of pregnancy, and in particular when used for obstetric indications, such as prelabor rupture of membranes to prolong the latency period to delivery, should not be altered based on the findings of this study,” she concluded.

The research was funded by Child Health Research CIO Trust, the China Scholarship Council, Health Data Research UK, and the National Institute for Health Research. Dr. Fan and associates had no industry disclosures. Dr. Krishna had no relevant financial disclosures.

SOURCE: Fan H et al. BMJ. 2020;368:m331.

Children exposed to macrolides during the first trimester of pregnancy had an increased risk of major malformations, compared with first-trimester penicillin exposure, according to an observational study.

Creatas Images

Use of antibiotics is common in pregnancy, and macrolides commonly are used if a penicillin allergy is reported.

Hypospadias and other genital malformations also were more likely with exposure during any trimester to macrolides, although this association lost significance when limited to the first trimester. The researchers did not identify any associations with macrolides exposure and neurodevelopmental disorders.

The observational study could not establish causality, but the researchers calculated an estimate of likely excess malformations if the association were found to be causal: “For every 1,000 mothers prescribed macrolides instead of penicillins during the first trimester, an additional 4.1 children would have cardiovascular malformations,” Heng Fan, a PhD student at the University College London, and colleagues wrote in the BMJ. “The corresponding figures for prescriptions during any trimester and genital malformations would be 1.7.”

The researchers used records from the U.K. Clinical Practice Research Datalink to analyze outcomes in 104,605 children born between 1990 and 2016 to mothers who received at least one prescription of erythromycin, clarithromycin, azithromycin, or penicillin monotherapy between their fourth week of pregnancy and delivery. Women prescribed any known teratogenic medications were excluded.

The majority of the mothers (92%) had been prescribed penicillin once, and 8% were prescribed a macrolide antibiotic once during pregnancy.

The researchers tallied and calculated the children’s risk of major malformations; cerebral palsy; epilepsy; ADHD; autism spectrum disorder; and any nervous, cardiovascular, gastrointestinal, genital, or urinary malformations. The children were tracked through a median 6 years of age.

In comparing risk of malformations or neurodevelopmental disorders among children, the researchers chose to compare exposure to macrolides and penicillin to reduce the likelihood of confounding by indication for infections. (They also included two negative control groups: unexposed siblings and women prescribed antibiotics before conception.) The authors acknowledged, however, that residual confounding still may occur “if macrolides were prescribed for specific indications (e.g., chlamydia), or when potential risk factors for malformations or neurodevelopmental outcomes differed between treatment groups.”

The overall rate of malformations was 22 per 1,000 children prenatally exposed to macrolides (28 in first trimester and 20 in second or third trimester) and 17 per 1,000 children prenatally exposed to penicillin. The risk and type of malformations varied, however, according to the trimester.

The researchers made adjustments to account for differences in a wide range of maternal factors: age at delivery, calendar year of delivery, alcohol misuse, illegal drug use, tobacco use, obesity, hypertension, diabetes, anxiety, depression, and epilepsy. They also adjusted for parity, multiples, and chronic medical treatments, as well as genitourinary tract infections or STIs during pregnancy, both of which are linked to preterm labor.

Compared with children exposed to penicillin during the first trimester of pregnancy, risk of malformations was 1.6 times greater in those exposed to macrolides in the first trimester (risk ratio, 1.55; 28 vs. 18 per 1,000). Erythromycin exposure in the first trimester also was linked to a 50% greater likelihood of any major malformation compared with penicillin (RR, 1.5; 27 vs. 18 per 1,000).

Cardiovascular malformations in particular were more likely in those exposed to macrolides (11 per 1,000), compared with penicillin (7 per 1,000) in the first trimester (RR, 1.62). Meanwhile, genital malformations, primarily hypospadias, occurred more frequently in children whose mothers were prescribed macrolides (5 per 1,000), compared with penicillin (3 per 1,000) in any trimester (RR, 1.58).

No increased risk of major malformations was associated with macrolides prescribed only in the second or third trimester, although a borderline significant association existed with gastrointestinal malformations. The authors also found no links between macrolides exposure and increased risk of cerebral palsy, epilepsy, ADHD, or autism spectrum disorder.

The findings did not change in several sensitivity analyses, including one that restricted analysis to antibiotics prescribed only for respiratory tract infections.

Dr. Fan and associates discussed several potential biological mechanisms for causation, including the arrhythmic effect of macrolides that may relate to cardiovascular malformations or contribute to fetal hypoxia. They noted that “macrolide prescribing during pregnancy warrants caution,” and recommend including on drug safety labels “that there is uncertainty about the safety of macrolides, including erythromycin” and alternative antibiotics should be used when possible.

Iris Krishna, MD, MPH, assistant professor of maternal-fetal medicine at Emory University, Atlanta, agreed with the study authors that use of macrolides in the first trimester warrants further investigation, and if an appropriate alternative antibiotic is available, then it should be preferentially considered when treating infections in the first trimester.

“However, if macrolides are the only treatment option, pregnant women can be reassured that the absolute risk of a birth defect is low, and this should not discourage them from taking a macrolide when needed as untreated infections pose a greater risk in pregnancy,” she said in an interview.

“This study does not establish that macrolide antibiotics cause birth defects, but it suggests a potential association. Previous studies examining the use of macrolides, such as erythromycin, have not demonstrated a consistent pattern of birth defects, and heart defects identified were classified as mostly mild. The authors suggest that the potential biologic mechanism based on rat models may be that macrolides might induce fetal cardiac arrhythmias and short-term fetal hypoxia. This study was underpowered to examine macrolide exposure for specific malformations. To avoid underpowered comparisons, the authors’ categorized malformations by organ systems, so the spectrum of cardiac defects is unclear,” commented Dr. Krishna, who also is a member of the Ob.Gyn. News editorial advisory board.

“Current recommendations for macrolide antibiotic use in pregnancy in the second and third trimester of pregnancy, and in particular when used for obstetric indications, such as prelabor rupture of membranes to prolong the latency period to delivery, should not be altered based on the findings of this study,” she concluded.

The research was funded by Child Health Research CIO Trust, the China Scholarship Council, Health Data Research UK, and the National Institute for Health Research. Dr. Fan and associates had no industry disclosures. Dr. Krishna had no relevant financial disclosures.

SOURCE: Fan H et al. BMJ. 2020;368:m331.

Children exposed to macrolides during the first trimester of pregnancy had an increased risk of major malformations, compared with first-trimester penicillin exposure, according to an observational study.

Creatas Images

Use of antibiotics is common in pregnancy, and macrolides commonly are used if a penicillin allergy is reported.

Hypospadias and other genital malformations also were more likely with exposure during any trimester to macrolides, although this association lost significance when limited to the first trimester. The researchers did not identify any associations with macrolides exposure and neurodevelopmental disorders.

The observational study could not establish causality, but the researchers calculated an estimate of likely excess malformations if the association were found to be causal: “For every 1,000 mothers prescribed macrolides instead of penicillins during the first trimester, an additional 4.1 children would have cardiovascular malformations,” Heng Fan, a PhD student at the University College London, and colleagues wrote in the BMJ. “The corresponding figures for prescriptions during any trimester and genital malformations would be 1.7.”

The researchers used records from the U.K. Clinical Practice Research Datalink to analyze outcomes in 104,605 children born between 1990 and 2016 to mothers who received at least one prescription of erythromycin, clarithromycin, azithromycin, or penicillin monotherapy between their fourth week of pregnancy and delivery. Women prescribed any known teratogenic medications were excluded.

The majority of the mothers (92%) had been prescribed penicillin once, and 8% were prescribed a macrolide antibiotic once during pregnancy.

The researchers tallied and calculated the children’s risk of major malformations; cerebral palsy; epilepsy; ADHD; autism spectrum disorder; and any nervous, cardiovascular, gastrointestinal, genital, or urinary malformations. The children were tracked through a median 6 years of age.

In comparing risk of malformations or neurodevelopmental disorders among children, the researchers chose to compare exposure to macrolides and penicillin to reduce the likelihood of confounding by indication for infections. (They also included two negative control groups: unexposed siblings and women prescribed antibiotics before conception.) The authors acknowledged, however, that residual confounding still may occur “if macrolides were prescribed for specific indications (e.g., chlamydia), or when potential risk factors for malformations or neurodevelopmental outcomes differed between treatment groups.”

The overall rate of malformations was 22 per 1,000 children prenatally exposed to macrolides (28 in first trimester and 20 in second or third trimester) and 17 per 1,000 children prenatally exposed to penicillin. The risk and type of malformations varied, however, according to the trimester.

The researchers made adjustments to account for differences in a wide range of maternal factors: age at delivery, calendar year of delivery, alcohol misuse, illegal drug use, tobacco use, obesity, hypertension, diabetes, anxiety, depression, and epilepsy. They also adjusted for parity, multiples, and chronic medical treatments, as well as genitourinary tract infections or STIs during pregnancy, both of which are linked to preterm labor.

Compared with children exposed to penicillin during the first trimester of pregnancy, risk of malformations was 1.6 times greater in those exposed to macrolides in the first trimester (risk ratio, 1.55; 28 vs. 18 per 1,000). Erythromycin exposure in the first trimester also was linked to a 50% greater likelihood of any major malformation compared with penicillin (RR, 1.5; 27 vs. 18 per 1,000).

Cardiovascular malformations in particular were more likely in those exposed to macrolides (11 per 1,000), compared with penicillin (7 per 1,000) in the first trimester (RR, 1.62). Meanwhile, genital malformations, primarily hypospadias, occurred more frequently in children whose mothers were prescribed macrolides (5 per 1,000), compared with penicillin (3 per 1,000) in any trimester (RR, 1.58).

No increased risk of major malformations was associated with macrolides prescribed only in the second or third trimester, although a borderline significant association existed with gastrointestinal malformations. The authors also found no links between macrolides exposure and increased risk of cerebral palsy, epilepsy, ADHD, or autism spectrum disorder.

The findings did not change in several sensitivity analyses, including one that restricted analysis to antibiotics prescribed only for respiratory tract infections.

Dr. Fan and associates discussed several potential biological mechanisms for causation, including the arrhythmic effect of macrolides that may relate to cardiovascular malformations or contribute to fetal hypoxia. They noted that “macrolide prescribing during pregnancy warrants caution,” and recommend including on drug safety labels “that there is uncertainty about the safety of macrolides, including erythromycin” and alternative antibiotics should be used when possible.

Iris Krishna, MD, MPH, assistant professor of maternal-fetal medicine at Emory University, Atlanta, agreed with the study authors that use of macrolides in the first trimester warrants further investigation, and if an appropriate alternative antibiotic is available, then it should be preferentially considered when treating infections in the first trimester.

“However, if macrolides are the only treatment option, pregnant women can be reassured that the absolute risk of a birth defect is low, and this should not discourage them from taking a macrolide when needed as untreated infections pose a greater risk in pregnancy,” she said in an interview.

“This study does not establish that macrolide antibiotics cause birth defects, but it suggests a potential association. Previous studies examining the use of macrolides, such as erythromycin, have not demonstrated a consistent pattern of birth defects, and heart defects identified were classified as mostly mild. The authors suggest that the potential biologic mechanism based on rat models may be that macrolides might induce fetal cardiac arrhythmias and short-term fetal hypoxia. This study was underpowered to examine macrolide exposure for specific malformations. To avoid underpowered comparisons, the authors’ categorized malformations by organ systems, so the spectrum of cardiac defects is unclear,” commented Dr. Krishna, who also is a member of the Ob.Gyn. News editorial advisory board.

“Current recommendations for macrolide antibiotic use in pregnancy in the second and third trimester of pregnancy, and in particular when used for obstetric indications, such as prelabor rupture of membranes to prolong the latency period to delivery, should not be altered based on the findings of this study,” she concluded.

The research was funded by Child Health Research CIO Trust, the China Scholarship Council, Health Data Research UK, and the National Institute for Health Research. Dr. Fan and associates had no industry disclosures. Dr. Krishna had no relevant financial disclosures.

SOURCE: Fan H et al. BMJ. 2020;368:m331.

Women who had gestational diabetes mellitus had an increased risk for later type 2 diabetes if they carried certain genetic risk factors for the disease, according to a new analysis in BMJ Open Diabetes Research & Care of data from two independent populations.

A higher genetic risk score (GRS) had a modest association with developing type 2 diabetes, but a healthier diet may mitigate this risk, as Mengying Li, PhD, and her colleagues found for participants in the Nurses’ Health Study and members of the Danish National Birth Cohort who developed gestational diabetes mellitus (GDM).

Of 1,884 white women with a history of GDM in the Nurses’ Health Study II (NHSII), 446 (23.7%) went on to develop type 2 diabetes, and of the 550 women who had GDM in the Danish National Birth Cohort (DNBC), 155 (28.2%) developed the disease. The researchers calculated a GRS for type 2 diabetes for the full cohort. Genome-wide association studies completed in European populations were used to identify 59 single-nucleotide polymorphisms (SNPs) associated with the disease.

Dr. Li, an epidemiologist and postdoctoral researcher at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md., and her coauthors found that women whose GRS was in the highest quartile had a relative risk of 1.19 for type 2 diabetes. The relative risks for the three lower quartiles were 1.25, 0.97, and 1.00, respectively (P value for trend = .02). For each increase of five risk alleles in the GRS, NHSII participants had a 7% increased risk for type 2 diabetes, and DNBC participants saw a 9% increased risk.

Comparing these findings with other studies looking at genetic risk and type 2 diabetes in the general population, Dr. Li and her coauthors noted that the increase in relative risk for type 2 disease with increase in GRS was actually slightly weaker in the GDM cohort they studied. “The smaller effect size among women with GDM likely reflects an already higher baseline genetic risk for [type 2 diabetes] than the general population, as we have demonstrated,” they explained.

Though 11 individual SNPs had a significant individual association with the risk for type 2 diabetes initially, that association disappeared after correction for a false-discovery rate. Dr. Li and her coinvestigators conducted a sensitivity analysis that included only 42 SNPs that were later definitively associated with type 2 disease and they saw essentially unchanged results.

The researchers also investigated how dietary quality affected the GRS–type 2 diabetes association by dichotomizing self-reported diet quality in both cohorts into healthier diet quality and less healthy diet quality. They found a tighter association between GRS and type 2 diabetes for women with diet quality below the median, whereas women with higher diet quality did not have such a strong association between GRS and type 2 disease. The researchers wrote that there was “suggestive evidence that a healthful diet might mitigate the excessive risk of T2D [type 2 diabetes] related to greater genetic susceptibility, which supports public health efforts of encouraging a healthful diet” for diabetes prevention in this high-risk population.

Patients in the NHSII were followed for a mean 21.3 years, and those in the DNBC were followed for a mean 12.7 years. Mean age at index pregnancy was 30.5 years for the NHSII cohort and 31.7 for the DNBC cohort. In the NHSII cohort, just 8.4% of participants reported smoking before pregnancy, compared with 26.4% of those in the DNBC cohort. The NHSII cohort participants, wrote Dr. Li and her coauthors, “were also less likely to have a family history of diabetes, less likely to smoke, and be leaner than women in the DNBC.”

Dr. Li and her coauthors noted that, “despite being the largest genetic study by far on [type 2 diabetes] among women with GDM, our study may not be sufficiently powered to examine the associations of individual T2D SNPs in relation to the risk of developing T2D.” Another limitation was that for the Danish cohort, information about diet was drawn from a one-time questionnaire administered between 9 and 16 years after the index pregnancy, so full data about dietary quality over time was not available. Also of note is that the study included only white participants, limiting generalizability to women of color. The authors called for expanding this research into more racially diverse populations.

The study was supported by the National Institutes of Health. The authors reported that they had no conflicts of interest.

SOURCE: Li M et al. BMJ Open Diab Res Care. 2020 Feb 13. doi: 10.1136/bmjdrc-2019-000850.

Women who had gestational diabetes mellitus had an increased risk for later type 2 diabetes if they carried certain genetic risk factors for the disease, according to a new analysis in BMJ Open Diabetes Research & Care of data from two independent populations.

A higher genetic risk score (GRS) had a modest association with developing type 2 diabetes, but a healthier diet may mitigate this risk, as Mengying Li, PhD, and her colleagues found for participants in the Nurses’ Health Study and members of the Danish National Birth Cohort who developed gestational diabetes mellitus (GDM).

Of 1,884 white women with a history of GDM in the Nurses’ Health Study II (NHSII), 446 (23.7%) went on to develop type 2 diabetes, and of the 550 women who had GDM in the Danish National Birth Cohort (DNBC), 155 (28.2%) developed the disease. The researchers calculated a GRS for type 2 diabetes for the full cohort. Genome-wide association studies completed in European populations were used to identify 59 single-nucleotide polymorphisms (SNPs) associated with the disease.

Dr. Li, an epidemiologist and postdoctoral researcher at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md., and her coauthors found that women whose GRS was in the highest quartile had a relative risk of 1.19 for type 2 diabetes. The relative risks for the three lower quartiles were 1.25, 0.97, and 1.00, respectively (P value for trend = .02). For each increase of five risk alleles in the GRS, NHSII participants had a 7% increased risk for type 2 diabetes, and DNBC participants saw a 9% increased risk.

Comparing these findings with other studies looking at genetic risk and type 2 diabetes in the general population, Dr. Li and her coauthors noted that the increase in relative risk for type 2 disease with increase in GRS was actually slightly weaker in the GDM cohort they studied. “The smaller effect size among women with GDM likely reflects an already higher baseline genetic risk for [type 2 diabetes] than the general population, as we have demonstrated,” they explained.

Though 11 individual SNPs had a significant individual association with the risk for type 2 diabetes initially, that association disappeared after correction for a false-discovery rate. Dr. Li and her coinvestigators conducted a sensitivity analysis that included only 42 SNPs that were later definitively associated with type 2 disease and they saw essentially unchanged results.

The researchers also investigated how dietary quality affected the GRS–type 2 diabetes association by dichotomizing self-reported diet quality in both cohorts into healthier diet quality and less healthy diet quality. They found a tighter association between GRS and type 2 diabetes for women with diet quality below the median, whereas women with higher diet quality did not have such a strong association between GRS and type 2 disease. The researchers wrote that there was “suggestive evidence that a healthful diet might mitigate the excessive risk of T2D [type 2 diabetes] related to greater genetic susceptibility, which supports public health efforts of encouraging a healthful diet” for diabetes prevention in this high-risk population.

Patients in the NHSII were followed for a mean 21.3 years, and those in the DNBC were followed for a mean 12.7 years. Mean age at index pregnancy was 30.5 years for the NHSII cohort and 31.7 for the DNBC cohort. In the NHSII cohort, just 8.4% of participants reported smoking before pregnancy, compared with 26.4% of those in the DNBC cohort. The NHSII cohort participants, wrote Dr. Li and her coauthors, “were also less likely to have a family history of diabetes, less likely to smoke, and be leaner than women in the DNBC.”

Dr. Li and her coauthors noted that, “despite being the largest genetic study by far on [type 2 diabetes] among women with GDM, our study may not be sufficiently powered to examine the associations of individual T2D SNPs in relation to the risk of developing T2D.” Another limitation was that for the Danish cohort, information about diet was drawn from a one-time questionnaire administered between 9 and 16 years after the index pregnancy, so full data about dietary quality over time was not available. Also of note is that the study included only white participants, limiting generalizability to women of color. The authors called for expanding this research into more racially diverse populations.

The study was supported by the National Institutes of Health. The authors reported that they had no conflicts of interest.

SOURCE: Li M et al. BMJ Open Diab Res Care. 2020 Feb 13. doi: 10.1136/bmjdrc-2019-000850.

Women who had gestational diabetes mellitus had an increased risk for later type 2 diabetes if they carried certain genetic risk factors for the disease, according to a new analysis in BMJ Open Diabetes Research & Care of data from two independent populations.

A higher genetic risk score (GRS) had a modest association with developing type 2 diabetes, but a healthier diet may mitigate this risk, as Mengying Li, PhD, and her colleagues found for participants in the Nurses’ Health Study and members of the Danish National Birth Cohort who developed gestational diabetes mellitus (GDM).

Of 1,884 white women with a history of GDM in the Nurses’ Health Study II (NHSII), 446 (23.7%) went on to develop type 2 diabetes, and of the 550 women who had GDM in the Danish National Birth Cohort (DNBC), 155 (28.2%) developed the disease. The researchers calculated a GRS for type 2 diabetes for the full cohort. Genome-wide association studies completed in European populations were used to identify 59 single-nucleotide polymorphisms (SNPs) associated with the disease.

Dr. Li, an epidemiologist and postdoctoral researcher at the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Md., and her coauthors found that women whose GRS was in the highest quartile had a relative risk of 1.19 for type 2 diabetes. The relative risks for the three lower quartiles were 1.25, 0.97, and 1.00, respectively (P value for trend = .02). For each increase of five risk alleles in the GRS, NHSII participants had a 7% increased risk for type 2 diabetes, and DNBC participants saw a 9% increased risk.

Comparing these findings with other studies looking at genetic risk and type 2 diabetes in the general population, Dr. Li and her coauthors noted that the increase in relative risk for type 2 disease with increase in GRS was actually slightly weaker in the GDM cohort they studied. “The smaller effect size among women with GDM likely reflects an already higher baseline genetic risk for [type 2 diabetes] than the general population, as we have demonstrated,” they explained.

Though 11 individual SNPs had a significant individual association with the risk for type 2 diabetes initially, that association disappeared after correction for a false-discovery rate. Dr. Li and her coinvestigators conducted a sensitivity analysis that included only 42 SNPs that were later definitively associated with type 2 disease and they saw essentially unchanged results.

The researchers also investigated how dietary quality affected the GRS–type 2 diabetes association by dichotomizing self-reported diet quality in both cohorts into healthier diet quality and less healthy diet quality. They found a tighter association between GRS and type 2 diabetes for women with diet quality below the median, whereas women with higher diet quality did not have such a strong association between GRS and type 2 disease. The researchers wrote that there was “suggestive evidence that a healthful diet might mitigate the excessive risk of T2D [type 2 diabetes] related to greater genetic susceptibility, which supports public health efforts of encouraging a healthful diet” for diabetes prevention in this high-risk population.

Patients in the NHSII were followed for a mean 21.3 years, and those in the DNBC were followed for a mean 12.7 years. Mean age at index pregnancy was 30.5 years for the NHSII cohort and 31.7 for the DNBC cohort. In the NHSII cohort, just 8.4% of participants reported smoking before pregnancy, compared with 26.4% of those in the DNBC cohort. The NHSII cohort participants, wrote Dr. Li and her coauthors, “were also less likely to have a family history of diabetes, less likely to smoke, and be leaner than women in the DNBC.”

Dr. Li and her coauthors noted that, “despite being the largest genetic study by far on [type 2 diabetes] among women with GDM, our study may not be sufficiently powered to examine the associations of individual T2D SNPs in relation to the risk of developing T2D.” Another limitation was that for the Danish cohort, information about diet was drawn from a one-time questionnaire administered between 9 and 16 years after the index pregnancy, so full data about dietary quality over time was not available. Also of note is that the study included only white participants, limiting generalizability to women of color. The authors called for expanding this research into more racially diverse populations.

The study was supported by the National Institutes of Health. The authors reported that they had no conflicts of interest.

SOURCE: Li M et al. BMJ Open Diab Res Care. 2020 Feb 13. doi: 10.1136/bmjdrc-2019-000850.

Researchers have identified 24 common genetic variants that may be associated with a greater risk of developing endometrial cancer.

SilverV/Thinkstock

The 24 single-nucleotide polymorphisms (SNPs) were detected in genes that function in transcriptional regulation, cell survival, and estrogen metabolism.

“Understanding genetic predisposition to endometrial cancer could facilitate personalized risk assessment with a view to targeted prevention and screening interventions,” wrote Cemsel Bafligil, of the University of Manchester (England) and her coinvestigators. The group’s findings were published in the Journal of Medical Genetics.

The researchers searched major databases for primary studies that evaluated associations between endometrial cancer and SNPs. After applying the search criteria, 453 eligible records were found, and 149 of these were included in the study.

The majority of records were genome-wide association studies, case-control studies, and meta-analyses. Various data, including study type, ethnicity, and endometrial cancer type, were extracted and included in the qualitative synthesis.

After analysis, the researchers identified 24 independent genetic variants associated with a higher risk of developing endometrial cancer, and SNPs in 6 genes – CYP19A1, SOX4, HNF1B, MYC, KLF, and EIF2AK – showed a strong association.

The researchers also estimated the predictive value of the identified SNPs using a theoretical polygenic risk score model. They found that women with genome-wide significant SNPs had double the risk of developing endometrial cancer (relative risk, 2.09), and women with all 24 SNPs had a three-fold greater risk of developing the disease (RR, 3.16).

“The importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate,” the researchers noted.

They also acknowledged that a key limitation of this study was the ethnic homogeneity of the cohort, with most patients being of European descent. As a result, the findings may not be fully representative of other ethnic groups.

“The multiplicative effects of these SNPs could be used in a PRS [polygenic risk score] to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer,” the researchers concluded.

The National Institute for Health Research Manchester Biomedical Research Centre funded the study. The authors reported having no conflicts of interest.

SOURCE: Bafligil C et al. J Med Genet. 2020 Feb 17. doi: 10.1136/jmedgenet-2019-106529.

Researchers have identified 24 common genetic variants that may be associated with a greater risk of developing endometrial cancer.

SilverV/Thinkstock

The 24 single-nucleotide polymorphisms (SNPs) were detected in genes that function in transcriptional regulation, cell survival, and estrogen metabolism.

“Understanding genetic predisposition to endometrial cancer could facilitate personalized risk assessment with a view to targeted prevention and screening interventions,” wrote Cemsel Bafligil, of the University of Manchester (England) and her coinvestigators. The group’s findings were published in the Journal of Medical Genetics.

The researchers searched major databases for primary studies that evaluated associations between endometrial cancer and SNPs. After applying the search criteria, 453 eligible records were found, and 149 of these were included in the study.

The majority of records were genome-wide association studies, case-control studies, and meta-analyses. Various data, including study type, ethnicity, and endometrial cancer type, were extracted and included in the qualitative synthesis.

After analysis, the researchers identified 24 independent genetic variants associated with a higher risk of developing endometrial cancer, and SNPs in 6 genes – CYP19A1, SOX4, HNF1B, MYC, KLF, and EIF2AK – showed a strong association.

The researchers also estimated the predictive value of the identified SNPs using a theoretical polygenic risk score model. They found that women with genome-wide significant SNPs had double the risk of developing endometrial cancer (relative risk, 2.09), and women with all 24 SNPs had a three-fold greater risk of developing the disease (RR, 3.16).

“The importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate,” the researchers noted.

They also acknowledged that a key limitation of this study was the ethnic homogeneity of the cohort, with most patients being of European descent. As a result, the findings may not be fully representative of other ethnic groups.

“The multiplicative effects of these SNPs could be used in a PRS [polygenic risk score] to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer,” the researchers concluded.

The National Institute for Health Research Manchester Biomedical Research Centre funded the study. The authors reported having no conflicts of interest.

SOURCE: Bafligil C et al. J Med Genet. 2020 Feb 17. doi: 10.1136/jmedgenet-2019-106529.

Researchers have identified 24 common genetic variants that may be associated with a greater risk of developing endometrial cancer.

SilverV/Thinkstock

The 24 single-nucleotide polymorphisms (SNPs) were detected in genes that function in transcriptional regulation, cell survival, and estrogen metabolism.

“Understanding genetic predisposition to endometrial cancer could facilitate personalized risk assessment with a view to targeted prevention and screening interventions,” wrote Cemsel Bafligil, of the University of Manchester (England) and her coinvestigators. The group’s findings were published in the Journal of Medical Genetics.

The researchers searched major databases for primary studies that evaluated associations between endometrial cancer and SNPs. After applying the search criteria, 453 eligible records were found, and 149 of these were included in the study.

The majority of records were genome-wide association studies, case-control studies, and meta-analyses. Various data, including study type, ethnicity, and endometrial cancer type, were extracted and included in the qualitative synthesis.

After analysis, the researchers identified 24 independent genetic variants associated with a higher risk of developing endometrial cancer, and SNPs in 6 genes – CYP19A1, SOX4, HNF1B, MYC, KLF, and EIF2AK – showed a strong association.

The researchers also estimated the predictive value of the identified SNPs using a theoretical polygenic risk score model. They found that women with genome-wide significant SNPs had double the risk of developing endometrial cancer (relative risk, 2.09), and women with all 24 SNPs had a three-fold greater risk of developing the disease (RR, 3.16).

“The importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate,” the researchers noted.

They also acknowledged that a key limitation of this study was the ethnic homogeneity of the cohort, with most patients being of European descent. As a result, the findings may not be fully representative of other ethnic groups.

“The multiplicative effects of these SNPs could be used in a PRS [polygenic risk score] to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer,” the researchers concluded.

The National Institute for Health Research Manchester Biomedical Research Centre funded the study. The authors reported having no conflicts of interest.

SOURCE: Bafligil C et al. J Med Genet. 2020 Feb 17. doi: 10.1136/jmedgenet-2019-106529.

The total number of hysterectomies performed during residency training has declined significantly since 2008, despite an increase in laparoscopic hysterectomies performed, according to a new analysis of data from graduating ob.gyn. residents that has implications for the structure of resident education.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The investigators abstracted case log data from the Accreditation Council for Graduate Medical Education (ACGME) database to assess trends in residents’ operative experience and found decreases in abdominal and vaginal cases but an increase in experience with laparoscopic hysterectomy.

The median number of abdominal hysterectomies performed per resident over 4 years of training decreased by 57% between 2002-2003 and 2017-2018 (from 85 cases to 37), and the median number of vaginal hysterectomies decreased by 36% (from 31 to 20 cases).

Laparoscopic hysterectomy increased by 115% from a median of 20 procedures in 2008-2009 to 43 in 2017-2018. Even so, the median total number of hysterectomies per resident decreased by 6%, from 112 to 105 procedures during those two time periods. (Data on total hysterectomy and laparoscopic hysterectomy were not collected by ACGME until 2008.)

While the absolute decrease in the total number of hysterectomies is “relatively small,” the trend “raises questions about what the appropriate number of hysterectomies per graduating resident should be,” Gregory M. Gressel, MD, MSc, of the Montefiore Medical Center, New York, and coauthors wrote in Obstetrics & Gynecology.

“These data point,” they wrote, “to the necessity of maximizing surgical exposure in the face of a declining availability of procedures and the importance of reflecting on which (and how many) procedures an obstetrics and gynecology resident needs to complete before entering clinical practice.”

The training numbers parallel an increased use of laparoscopic hysterectomy in the United States and other countries, as well as a well-documented decline in the total number of hysterectomies performed in the United States, the latter of which is driven largely by the availability and increasing use of alternatives to the procedure (such as hormone therapy, endometrial ablation, and uterine artery embolization).

Hysterectomy still is a “core procedure of gynecologic surgery,” however, and is “at the heart of surgical training in obstetrics and gynecology,” as surgical techniques developed from learning hysterectomy “are applied broadly in the pelvis,” Saketh R. Guntupalli, MD, wrote in an accompanying editorial.

Dr. Guntupalli, of the University of Colorado at Aurora, Denver, was involved in a survey of fellowship program directors, published in 2015, that found only 20% of first-year fellows were able to independently perform a vaginal hysterectomy and 46% to independently perform an abdominal hysterectomy (Obstet Gynecol. 2015;126:559-68).

This and other research suggest that fellowship training is “used to address deficiencies in residency training rather than to develop new, specialized surgical skills,” he wrote. Given a dearth of fellowship positions in ob.gyn., “it is impossible to adequately use those avenues to train the number of competent surgeons necessary to address the surgical needs of women’s health in the United States.”

To address such concerns, some residency programs have instituted resident tracking to direct more hysterectomy cases toward those residents who plan to pursue surgical subspecialties. The Cleveland Clinic, Dr. Guntupalli noted, has tried the latter approach “with success.”

An increase in the number of accredited training programs and a decrease in the number of residents per program also might help to improve surgical exposure for residents, Dr. Gressel and associates wrote. Over the 16-year study period, the number of graduating residents increased significantly (by 12 per year) and the number of residency programs decreased significantly (0.52 fewer programs per year).

Additionally, Dr. Guntupalli wrote, regulatory bodies may need to reevaluate how competencies are assessed, and whether minimal numbers of cases “continue to carry the same weight as they did in previous generations.”

In the study, one coauthor is a full-time employee of ACGME, and another receives funds as a director for the American Board of Obstetrics and Gynecology. The remaining authors had no relevant financial disclosures. There was no outside funding for the study. Dr. Guntupalli said he had no conflicts of interest.

SOURCES: Gressel GM et al. Obstet Gynecol. 2020 Feb;135(2):268-73; Guntupalli SR. Obstet Gynecol 2020 Feb;135(2):266-7.

The total number of hysterectomies performed during residency training has declined significantly since 2008, despite an increase in laparoscopic hysterectomies performed, according to a new analysis of data from graduating ob.gyn. residents that has implications for the structure of resident education.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The investigators abstracted case log data from the Accreditation Council for Graduate Medical Education (ACGME) database to assess trends in residents’ operative experience and found decreases in abdominal and vaginal cases but an increase in experience with laparoscopic hysterectomy.

The median number of abdominal hysterectomies performed per resident over 4 years of training decreased by 57% between 2002-2003 and 2017-2018 (from 85 cases to 37), and the median number of vaginal hysterectomies decreased by 36% (from 31 to 20 cases).

Laparoscopic hysterectomy increased by 115% from a median of 20 procedures in 2008-2009 to 43 in 2017-2018. Even so, the median total number of hysterectomies per resident decreased by 6%, from 112 to 105 procedures during those two time periods. (Data on total hysterectomy and laparoscopic hysterectomy were not collected by ACGME until 2008.)

While the absolute decrease in the total number of hysterectomies is “relatively small,” the trend “raises questions about what the appropriate number of hysterectomies per graduating resident should be,” Gregory M. Gressel, MD, MSc, of the Montefiore Medical Center, New York, and coauthors wrote in Obstetrics & Gynecology.

“These data point,” they wrote, “to the necessity of maximizing surgical exposure in the face of a declining availability of procedures and the importance of reflecting on which (and how many) procedures an obstetrics and gynecology resident needs to complete before entering clinical practice.”

The training numbers parallel an increased use of laparoscopic hysterectomy in the United States and other countries, as well as a well-documented decline in the total number of hysterectomies performed in the United States, the latter of which is driven largely by the availability and increasing use of alternatives to the procedure (such as hormone therapy, endometrial ablation, and uterine artery embolization).

Hysterectomy still is a “core procedure of gynecologic surgery,” however, and is “at the heart of surgical training in obstetrics and gynecology,” as surgical techniques developed from learning hysterectomy “are applied broadly in the pelvis,” Saketh R. Guntupalli, MD, wrote in an accompanying editorial.

Dr. Guntupalli, of the University of Colorado at Aurora, Denver, was involved in a survey of fellowship program directors, published in 2015, that found only 20% of first-year fellows were able to independently perform a vaginal hysterectomy and 46% to independently perform an abdominal hysterectomy (Obstet Gynecol. 2015;126:559-68).

This and other research suggest that fellowship training is “used to address deficiencies in residency training rather than to develop new, specialized surgical skills,” he wrote. Given a dearth of fellowship positions in ob.gyn., “it is impossible to adequately use those avenues to train the number of competent surgeons necessary to address the surgical needs of women’s health in the United States.”

To address such concerns, some residency programs have instituted resident tracking to direct more hysterectomy cases toward those residents who plan to pursue surgical subspecialties. The Cleveland Clinic, Dr. Guntupalli noted, has tried the latter approach “with success.”

An increase in the number of accredited training programs and a decrease in the number of residents per program also might help to improve surgical exposure for residents, Dr. Gressel and associates wrote. Over the 16-year study period, the number of graduating residents increased significantly (by 12 per year) and the number of residency programs decreased significantly (0.52 fewer programs per year).

Additionally, Dr. Guntupalli wrote, regulatory bodies may need to reevaluate how competencies are assessed, and whether minimal numbers of cases “continue to carry the same weight as they did in previous generations.”

In the study, one coauthor is a full-time employee of ACGME, and another receives funds as a director for the American Board of Obstetrics and Gynecology. The remaining authors had no relevant financial disclosures. There was no outside funding for the study. Dr. Guntupalli said he had no conflicts of interest.

SOURCES: Gressel GM et al. Obstet Gynecol. 2020 Feb;135(2):268-73; Guntupalli SR. Obstet Gynecol 2020 Feb;135(2):266-7.

The total number of hysterectomies performed during residency training has declined significantly since 2008, despite an increase in laparoscopic hysterectomies performed, according to a new analysis of data from graduating ob.gyn. residents that has implications for the structure of resident education.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The investigators abstracted case log data from the Accreditation Council for Graduate Medical Education (ACGME) database to assess trends in residents’ operative experience and found decreases in abdominal and vaginal cases but an increase in experience with laparoscopic hysterectomy.

The median number of abdominal hysterectomies performed per resident over 4 years of training decreased by 57% between 2002-2003 and 2017-2018 (from 85 cases to 37), and the median number of vaginal hysterectomies decreased by 36% (from 31 to 20 cases).

Laparoscopic hysterectomy increased by 115% from a median of 20 procedures in 2008-2009 to 43 in 2017-2018. Even so, the median total number of hysterectomies per resident decreased by 6%, from 112 to 105 procedures during those two time periods. (Data on total hysterectomy and laparoscopic hysterectomy were not collected by ACGME until 2008.)

While the absolute decrease in the total number of hysterectomies is “relatively small,” the trend “raises questions about what the appropriate number of hysterectomies per graduating resident should be,” Gregory M. Gressel, MD, MSc, of the Montefiore Medical Center, New York, and coauthors wrote in Obstetrics & Gynecology.

“These data point,” they wrote, “to the necessity of maximizing surgical exposure in the face of a declining availability of procedures and the importance of reflecting on which (and how many) procedures an obstetrics and gynecology resident needs to complete before entering clinical practice.”

The training numbers parallel an increased use of laparoscopic hysterectomy in the United States and other countries, as well as a well-documented decline in the total number of hysterectomies performed in the United States, the latter of which is driven largely by the availability and increasing use of alternatives to the procedure (such as hormone therapy, endometrial ablation, and uterine artery embolization).

Hysterectomy still is a “core procedure of gynecologic surgery,” however, and is “at the heart of surgical training in obstetrics and gynecology,” as surgical techniques developed from learning hysterectomy “are applied broadly in the pelvis,” Saketh R. Guntupalli, MD, wrote in an accompanying editorial.

Dr. Guntupalli, of the University of Colorado at Aurora, Denver, was involved in a survey of fellowship program directors, published in 2015, that found only 20% of first-year fellows were able to independently perform a vaginal hysterectomy and 46% to independently perform an abdominal hysterectomy (Obstet Gynecol. 2015;126:559-68).

This and other research suggest that fellowship training is “used to address deficiencies in residency training rather than to develop new, specialized surgical skills,” he wrote. Given a dearth of fellowship positions in ob.gyn., “it is impossible to adequately use those avenues to train the number of competent surgeons necessary to address the surgical needs of women’s health in the United States.”

To address such concerns, some residency programs have instituted resident tracking to direct more hysterectomy cases toward those residents who plan to pursue surgical subspecialties. The Cleveland Clinic, Dr. Guntupalli noted, has tried the latter approach “with success.”

An increase in the number of accredited training programs and a decrease in the number of residents per program also might help to improve surgical exposure for residents, Dr. Gressel and associates wrote. Over the 16-year study period, the number of graduating residents increased significantly (by 12 per year) and the number of residency programs decreased significantly (0.52 fewer programs per year).

Additionally, Dr. Guntupalli wrote, regulatory bodies may need to reevaluate how competencies are assessed, and whether minimal numbers of cases “continue to carry the same weight as they did in previous generations.”

In the study, one coauthor is a full-time employee of ACGME, and another receives funds as a director for the American Board of Obstetrics and Gynecology. The remaining authors had no relevant financial disclosures. There was no outside funding for the study. Dr. Guntupalli said he had no conflicts of interest.

SOURCES: Gressel GM et al. Obstet Gynecol. 2020 Feb;135(2):268-73; Guntupalli SR. Obstet Gynecol 2020 Feb;135(2):266-7.