Women's Health

Cervical cancer is the second most common cancer among women in lower- and middle-income countries, but universal human papillomavirus vaccination for girls would reduce new cervical cancer cases by about 90% over the next century, according to researchers.

Adding twice-lifetime cervical screening with human papillomavirus (HPV) testing would further reduce the incidence of cervical cancer, including in countries with the highest burden, the researchers reported in The Lancet.

Marc Brisson, PhD, of Laval University, Quebec City, and colleagues conducted this study using three models identified by the World Health Organization. The models were used to project reductions in cervical cancer incidence for women in 78 low- and middle-income countries based on the following HPV vaccination and screening scenarios:

• Universal girls-only vaccination at age 9 years, assuming 90% of girls vaccinated and a vaccine that is perfectly effective
• Girls-only vaccination plus cervical screening with HPV testing at age 35 years
• Girls-only vaccination plus screening at ages 35 and 45.

All three scenarios modeled would result in the elimination of cervical cancer, Dr. Brisson and colleagues found. Elimination was defined as four or fewer new cases per 100,000 women-years.

The simplest scenario, universal girls-only vaccination, was predicted to reduce age-standardized cervical cancer incidence from 19.8 cases per 100,000 women-years to 2.1 cases per 100,000 women-years (89.4% reduction) by 2120. That amounts to about 61 million potential cases avoided, with elimination targets reached in 60% of the countries studied.

HPV vaccination plus one-time screening was predicted to reduce the incidence of cervical cancer to 1.0 case per 100,000 women-years (95.0% reduction), and HPV vaccination plus twice-lifetime screening was predicted to reduce the incidence to 0.7 cases per 100,000 women-years (96.7% reduction).

Dr. Brisson and colleagues reported that, for the countries with the highest burden of cervical cancer (more than 25 cases per 100,000 women-years), adding screening would be necessary to achieve elimination.

To meet the same targets across all 78 countries, “our models predict that scale-up of both girls-only HPV vaccination and twice-lifetime screening is necessary, with 90% HPV vaccination coverage, 90% screening uptake, and long-term protection against HPV types 16, 18, 31, 33, 45, 52, and 58,” the researchers wrote.

Dr. Brisson and colleagues claimed that a strength of this study is the modeling approach, which compared three models “that have been extensively peer reviewed and validated with postvaccination surveillance data.”

The researchers acknowledged, however, that their modeling could not account for variations in sexual behavior from country to country, and the study was not designed to anticipate behavioral or technological changes that could affect cervical cancer incidence in the decades to come.

The study was funded by the WHO, the United Nations, and the Canadian and Australian governments. The WHO contributed to the study design, data analysis and interpretation, and writing of the manuscript. Two study authors reported receiving indirect industry funding for a cervical screening trial in Australia.

SOURCE: Brisson M et al. Lancet. 2020 Jan 30. doi: 10.1016/S0140-6736(20)30068-4.

Cervical cancer is the second most common cancer among women in lower- and middle-income countries, but universal human papillomavirus vaccination for girls would reduce new cervical cancer cases by about 90% over the next century, according to researchers.

Adding twice-lifetime cervical screening with human papillomavirus (HPV) testing would further reduce the incidence of cervical cancer, including in countries with the highest burden, the researchers reported in The Lancet.

Marc Brisson, PhD, of Laval University, Quebec City, and colleagues conducted this study using three models identified by the World Health Organization. The models were used to project reductions in cervical cancer incidence for women in 78 low- and middle-income countries based on the following HPV vaccination and screening scenarios:

• Universal girls-only vaccination at age 9 years, assuming 90% of girls vaccinated and a vaccine that is perfectly effective
• Girls-only vaccination plus cervical screening with HPV testing at age 35 years
• Girls-only vaccination plus screening at ages 35 and 45.

All three scenarios modeled would result in the elimination of cervical cancer, Dr. Brisson and colleagues found. Elimination was defined as four or fewer new cases per 100,000 women-years.

The simplest scenario, universal girls-only vaccination, was predicted to reduce age-standardized cervical cancer incidence from 19.8 cases per 100,000 women-years to 2.1 cases per 100,000 women-years (89.4% reduction) by 2120. That amounts to about 61 million potential cases avoided, with elimination targets reached in 60% of the countries studied.

HPV vaccination plus one-time screening was predicted to reduce the incidence of cervical cancer to 1.0 case per 100,000 women-years (95.0% reduction), and HPV vaccination plus twice-lifetime screening was predicted to reduce the incidence to 0.7 cases per 100,000 women-years (96.7% reduction).

Dr. Brisson and colleagues reported that, for the countries with the highest burden of cervical cancer (more than 25 cases per 100,000 women-years), adding screening would be necessary to achieve elimination.

To meet the same targets across all 78 countries, “our models predict that scale-up of both girls-only HPV vaccination and twice-lifetime screening is necessary, with 90% HPV vaccination coverage, 90% screening uptake, and long-term protection against HPV types 16, 18, 31, 33, 45, 52, and 58,” the researchers wrote.

Dr. Brisson and colleagues claimed that a strength of this study is the modeling approach, which compared three models “that have been extensively peer reviewed and validated with postvaccination surveillance data.”

The researchers acknowledged, however, that their modeling could not account for variations in sexual behavior from country to country, and the study was not designed to anticipate behavioral or technological changes that could affect cervical cancer incidence in the decades to come.

The study was funded by the WHO, the United Nations, and the Canadian and Australian governments. The WHO contributed to the study design, data analysis and interpretation, and writing of the manuscript. Two study authors reported receiving indirect industry funding for a cervical screening trial in Australia.

SOURCE: Brisson M et al. Lancet. 2020 Jan 30. doi: 10.1016/S0140-6736(20)30068-4.

Cervical cancer is the second most common cancer among women in lower- and middle-income countries, but universal human papillomavirus vaccination for girls would reduce new cervical cancer cases by about 90% over the next century, according to researchers.

Adding twice-lifetime cervical screening with human papillomavirus (HPV) testing would further reduce the incidence of cervical cancer, including in countries with the highest burden, the researchers reported in The Lancet.

Marc Brisson, PhD, of Laval University, Quebec City, and colleagues conducted this study using three models identified by the World Health Organization. The models were used to project reductions in cervical cancer incidence for women in 78 low- and middle-income countries based on the following HPV vaccination and screening scenarios:

• Universal girls-only vaccination at age 9 years, assuming 90% of girls vaccinated and a vaccine that is perfectly effective
• Girls-only vaccination plus cervical screening with HPV testing at age 35 years
• Girls-only vaccination plus screening at ages 35 and 45.

All three scenarios modeled would result in the elimination of cervical cancer, Dr. Brisson and colleagues found. Elimination was defined as four or fewer new cases per 100,000 women-years.

The simplest scenario, universal girls-only vaccination, was predicted to reduce age-standardized cervical cancer incidence from 19.8 cases per 100,000 women-years to 2.1 cases per 100,000 women-years (89.4% reduction) by 2120. That amounts to about 61 million potential cases avoided, with elimination targets reached in 60% of the countries studied.

HPV vaccination plus one-time screening was predicted to reduce the incidence of cervical cancer to 1.0 case per 100,000 women-years (95.0% reduction), and HPV vaccination plus twice-lifetime screening was predicted to reduce the incidence to 0.7 cases per 100,000 women-years (96.7% reduction).

Dr. Brisson and colleagues reported that, for the countries with the highest burden of cervical cancer (more than 25 cases per 100,000 women-years), adding screening would be necessary to achieve elimination.

To meet the same targets across all 78 countries, “our models predict that scale-up of both girls-only HPV vaccination and twice-lifetime screening is necessary, with 90% HPV vaccination coverage, 90% screening uptake, and long-term protection against HPV types 16, 18, 31, 33, 45, 52, and 58,” the researchers wrote.

Dr. Brisson and colleagues claimed that a strength of this study is the modeling approach, which compared three models “that have been extensively peer reviewed and validated with postvaccination surveillance data.”

The researchers acknowledged, however, that their modeling could not account for variations in sexual behavior from country to country, and the study was not designed to anticipate behavioral or technological changes that could affect cervical cancer incidence in the decades to come.

The study was funded by the WHO, the United Nations, and the Canadian and Australian governments. The WHO contributed to the study design, data analysis and interpretation, and writing of the manuscript. Two study authors reported receiving indirect industry funding for a cervical screening trial in Australia.

SOURCE: Brisson M et al. Lancet. 2020 Jan 30. doi: 10.1016/S0140-6736(20)30068-4.

Women with systemic lupus erythematosus (SLE) who experience hypertensive disorders of pregnancy may have a higher rate of cardiovascular outcomes after pregnancy, as well as a higher rate of hypertension later in life, than do those without maternal hypertension, according to findings from a Swedish population-based, longitudinal cohort study.

“Premature CVD [cardiovascular disease] is a well-documented complication in women with SLE, which is likely, at least in part, due to renal disease, prothrombotic [antiphospholipid antibodies], and systemic inflammation. Our data confirm that women who experience a hypertensive disorder in pregnancy [HDP] are at greater risk of developing hypertension after pregnancy, and that this association is also evident for women with SLE. Women with SLE and HDP were also at increased risk of CVD, particularly stroke, at young ages and should be monitored closely and consider treatment to attenuate risk,” wrote first author Julia F. Simard, ScD, of Stanford (Calif.) University and colleagues in Arthritis Care & Research.

To reach those conclusions, the researchers identified 3,340 women in the Swedish Medical Birth Register with their first singleton delivery during 1987-2012. They matched each of the 450 women with prevalent SLE from the Medical Birth Register to 5 women without SLE in the National Patient Register based on sex, birth year, calendar time, and county of residence.

During a median follow-up period of nearly 11 years, women with SLE had an unadjusted incidence rate of incident cardiovascular outcomes of 50 cases per 10,000 person-years versus 7.2 for women without SLE. Cardiovascular outcomes included fatal and nonfatal acute MI, fatal and nonfatal stroke, transient ischemic attacks, unstable angina, and heart failure. A history of HDP in women with SLE, including preeclampsia, was linked with about a twofold higher rate of cardiovascular outcomes regardless of multiple sensitivity analyses, both before and after adjusting for maternal age at delivery, county of birth, education, body mass index, and first-trimester smoking.

The researchers found that the hazard ratio for cardiovascular outcomes in women with SLE and HDP was about eight times higher than the hazard ratio for women without SLE but with HDP, but the relative rarity of cardiovascular events seen during the follow-up period, particularly among women without SLE, made it so that they “could not confirm established associations between HDP and CVD, possibly due to the relatively short follow-up time given that premenopausal CVD is rare among women free of SLE.”

HDP was associated with a threefold higher risk for incident hypertension later in life regardless of SLE status, even though the unadjusted incidence rate was 524 cases per 10,000 person-years among women with both SLE and HDP, compared with 177 per 10,000 person-years among women with HDP in the general population, which sensitivity analyses suggested “was not due to misclassification of antihypertensive use for renal disease in women with SLE nor antihypertensive use for possible HDP in subsequent pregnancies,” the researchers wrote.

Several authors reported research grants from the National Institutes of Health, the Karolinska Institute, the Swedish Research Council, Swedish Heart-Lung Foundation, Stockholm County Council, the King Gustaf V 80th Birthday Fund, the Swedish Rheumatism Association, and Ingegerd Johansson’s Foundation that helped to fund the study. All authors reported having no competing interests.

[email protected]

SOURCE: Simard JF et al. Arthritis Care Res. 2020 Jan 31. doi: 10.1002/acr.24160.

Women with systemic lupus erythematosus (SLE) who experience hypertensive disorders of pregnancy may have a higher rate of cardiovascular outcomes after pregnancy, as well as a higher rate of hypertension later in life, than do those without maternal hypertension, according to findings from a Swedish population-based, longitudinal cohort study.

“Premature CVD [cardiovascular disease] is a well-documented complication in women with SLE, which is likely, at least in part, due to renal disease, prothrombotic [antiphospholipid antibodies], and systemic inflammation. Our data confirm that women who experience a hypertensive disorder in pregnancy [HDP] are at greater risk of developing hypertension after pregnancy, and that this association is also evident for women with SLE. Women with SLE and HDP were also at increased risk of CVD, particularly stroke, at young ages and should be monitored closely and consider treatment to attenuate risk,” wrote first author Julia F. Simard, ScD, of Stanford (Calif.) University and colleagues in Arthritis Care & Research.

To reach those conclusions, the researchers identified 3,340 women in the Swedish Medical Birth Register with their first singleton delivery during 1987-2012. They matched each of the 450 women with prevalent SLE from the Medical Birth Register to 5 women without SLE in the National Patient Register based on sex, birth year, calendar time, and county of residence.

During a median follow-up period of nearly 11 years, women with SLE had an unadjusted incidence rate of incident cardiovascular outcomes of 50 cases per 10,000 person-years versus 7.2 for women without SLE. Cardiovascular outcomes included fatal and nonfatal acute MI, fatal and nonfatal stroke, transient ischemic attacks, unstable angina, and heart failure. A history of HDP in women with SLE, including preeclampsia, was linked with about a twofold higher rate of cardiovascular outcomes regardless of multiple sensitivity analyses, both before and after adjusting for maternal age at delivery, county of birth, education, body mass index, and first-trimester smoking.

The researchers found that the hazard ratio for cardiovascular outcomes in women with SLE and HDP was about eight times higher than the hazard ratio for women without SLE but with HDP, but the relative rarity of cardiovascular events seen during the follow-up period, particularly among women without SLE, made it so that they “could not confirm established associations between HDP and CVD, possibly due to the relatively short follow-up time given that premenopausal CVD is rare among women free of SLE.”

HDP was associated with a threefold higher risk for incident hypertension later in life regardless of SLE status, even though the unadjusted incidence rate was 524 cases per 10,000 person-years among women with both SLE and HDP, compared with 177 per 10,000 person-years among women with HDP in the general population, which sensitivity analyses suggested “was not due to misclassification of antihypertensive use for renal disease in women with SLE nor antihypertensive use for possible HDP in subsequent pregnancies,” the researchers wrote.

Several authors reported research grants from the National Institutes of Health, the Karolinska Institute, the Swedish Research Council, Swedish Heart-Lung Foundation, Stockholm County Council, the King Gustaf V 80th Birthday Fund, the Swedish Rheumatism Association, and Ingegerd Johansson’s Foundation that helped to fund the study. All authors reported having no competing interests.

[email protected]

SOURCE: Simard JF et al. Arthritis Care Res. 2020 Jan 31. doi: 10.1002/acr.24160.

Women with systemic lupus erythematosus (SLE) who experience hypertensive disorders of pregnancy may have a higher rate of cardiovascular outcomes after pregnancy, as well as a higher rate of hypertension later in life, than do those without maternal hypertension, according to findings from a Swedish population-based, longitudinal cohort study.

“Premature CVD [cardiovascular disease] is a well-documented complication in women with SLE, which is likely, at least in part, due to renal disease, prothrombotic [antiphospholipid antibodies], and systemic inflammation. Our data confirm that women who experience a hypertensive disorder in pregnancy [HDP] are at greater risk of developing hypertension after pregnancy, and that this association is also evident for women with SLE. Women with SLE and HDP were also at increased risk of CVD, particularly stroke, at young ages and should be monitored closely and consider treatment to attenuate risk,” wrote first author Julia F. Simard, ScD, of Stanford (Calif.) University and colleagues in Arthritis Care & Research.

To reach those conclusions, the researchers identified 3,340 women in the Swedish Medical Birth Register with their first singleton delivery during 1987-2012. They matched each of the 450 women with prevalent SLE from the Medical Birth Register to 5 women without SLE in the National Patient Register based on sex, birth year, calendar time, and county of residence.

During a median follow-up period of nearly 11 years, women with SLE had an unadjusted incidence rate of incident cardiovascular outcomes of 50 cases per 10,000 person-years versus 7.2 for women without SLE. Cardiovascular outcomes included fatal and nonfatal acute MI, fatal and nonfatal stroke, transient ischemic attacks, unstable angina, and heart failure. A history of HDP in women with SLE, including preeclampsia, was linked with about a twofold higher rate of cardiovascular outcomes regardless of multiple sensitivity analyses, both before and after adjusting for maternal age at delivery, county of birth, education, body mass index, and first-trimester smoking.

The researchers found that the hazard ratio for cardiovascular outcomes in women with SLE and HDP was about eight times higher than the hazard ratio for women without SLE but with HDP, but the relative rarity of cardiovascular events seen during the follow-up period, particularly among women without SLE, made it so that they “could not confirm established associations between HDP and CVD, possibly due to the relatively short follow-up time given that premenopausal CVD is rare among women free of SLE.”

HDP was associated with a threefold higher risk for incident hypertension later in life regardless of SLE status, even though the unadjusted incidence rate was 524 cases per 10,000 person-years among women with both SLE and HDP, compared with 177 per 10,000 person-years among women with HDP in the general population, which sensitivity analyses suggested “was not due to misclassification of antihypertensive use for renal disease in women with SLE nor antihypertensive use for possible HDP in subsequent pregnancies,” the researchers wrote.

Several authors reported research grants from the National Institutes of Health, the Karolinska Institute, the Swedish Research Council, Swedish Heart-Lung Foundation, Stockholm County Council, the King Gustaf V 80th Birthday Fund, the Swedish Rheumatism Association, and Ingegerd Johansson’s Foundation that helped to fund the study. All authors reported having no competing interests.

[email protected]

SOURCE: Simard JF et al. Arthritis Care Res. 2020 Jan 31. doi: 10.1002/acr.24160.

Considerable differences in ovarian cancer survival exist between high-income countries, especially for older women with advanced disease, according to a recent study.

The findings suggest additional research is needed to evaluate international differences in both treatment- and patient-specific factors affecting survival.

“This study [evaluated] differences in survival by age and stage at diagnosis within and across seven high-income countries,” wrote Citadel J. Cabasag, PhD, of the International Agency for Research on Cancer in Lyon, France, and colleagues. The results were published in Gynecologic Oncology.

The researchers conducted a retrospective analysis of population-based registry data from 2010 to 2014. Data were collected from 21 cancer registries located in Canada, United Kingdom, New Zealand, Norway, Ireland, Australia, and Denmark.

The cohort included 58,161 women with epithelial and nonepithelial ovarian cancer. The majority of cases were advanced stage, with a median age of 63-67 years at diagnosis, depending on the country.

The researchers compared age- and stage-specific net survival between countries at 1 and 3 years post diagnosis.

The 3-year all-ages net survival was highest for Norway (57%) and Australia (56%), followed by Denmark (54%), Canada (50%), United Kingdom (47%), New Zealand (46%), and Ireland (45%).

Most patients were diagnosed with distant disease (range, 64%-71%), with the greatest proportion of women in the 65- to 74- and 75- to 99-year age categories. The lowest 3-year age-specific survival (range, 20%-34%) was observed in the 75- to 99-year age category.

Marked differences in 3-year net survival between countries were found for women in the 75- to 99-year age group with distant disease (range, 12%-25%).

“International survival differences by age groups were less stark for early-stage disease,” the researchers reported. “Interjurisdictional differences within countries were also observed.”

The researchers acknowledged a key limitation of the analysis was the use of registry data. Variability between, and incomplete data within, registries could have lowered the accuracy of the survival estimates.

“[F]urther research investigating international differences in access to and quality of treatment, and prevalence of comorbid conditions particularly in older women with advanced disease [is needed],” the researchers concluded.

The study was supported by funding provided to the International Cancer Benchmarking Partnership. The authors reported having no conflicts of interest.

SOURCE: Cabasag CJ et al. Gynecol Oncol. 2020 Jan 28. doi: 10.1016/j.ygyno.2019.12.047.

Considerable differences in ovarian cancer survival exist between high-income countries, especially for older women with advanced disease, according to a recent study.

The findings suggest additional research is needed to evaluate international differences in both treatment- and patient-specific factors affecting survival.

“This study [evaluated] differences in survival by age and stage at diagnosis within and across seven high-income countries,” wrote Citadel J. Cabasag, PhD, of the International Agency for Research on Cancer in Lyon, France, and colleagues. The results were published in Gynecologic Oncology.

The researchers conducted a retrospective analysis of population-based registry data from 2010 to 2014. Data were collected from 21 cancer registries located in Canada, United Kingdom, New Zealand, Norway, Ireland, Australia, and Denmark.

The cohort included 58,161 women with epithelial and nonepithelial ovarian cancer. The majority of cases were advanced stage, with a median age of 63-67 years at diagnosis, depending on the country.

The researchers compared age- and stage-specific net survival between countries at 1 and 3 years post diagnosis.

The 3-year all-ages net survival was highest for Norway (57%) and Australia (56%), followed by Denmark (54%), Canada (50%), United Kingdom (47%), New Zealand (46%), and Ireland (45%).

Most patients were diagnosed with distant disease (range, 64%-71%), with the greatest proportion of women in the 65- to 74- and 75- to 99-year age categories. The lowest 3-year age-specific survival (range, 20%-34%) was observed in the 75- to 99-year age category.

Marked differences in 3-year net survival between countries were found for women in the 75- to 99-year age group with distant disease (range, 12%-25%).

“International survival differences by age groups were less stark for early-stage disease,” the researchers reported. “Interjurisdictional differences within countries were also observed.”

The researchers acknowledged a key limitation of the analysis was the use of registry data. Variability between, and incomplete data within, registries could have lowered the accuracy of the survival estimates.

“[F]urther research investigating international differences in access to and quality of treatment, and prevalence of comorbid conditions particularly in older women with advanced disease [is needed],” the researchers concluded.

The study was supported by funding provided to the International Cancer Benchmarking Partnership. The authors reported having no conflicts of interest.

SOURCE: Cabasag CJ et al. Gynecol Oncol. 2020 Jan 28. doi: 10.1016/j.ygyno.2019.12.047.

Considerable differences in ovarian cancer survival exist between high-income countries, especially for older women with advanced disease, according to a recent study.

The findings suggest additional research is needed to evaluate international differences in both treatment- and patient-specific factors affecting survival.

“This study [evaluated] differences in survival by age and stage at diagnosis within and across seven high-income countries,” wrote Citadel J. Cabasag, PhD, of the International Agency for Research on Cancer in Lyon, France, and colleagues. The results were published in Gynecologic Oncology.

The researchers conducted a retrospective analysis of population-based registry data from 2010 to 2014. Data were collected from 21 cancer registries located in Canada, United Kingdom, New Zealand, Norway, Ireland, Australia, and Denmark.

The cohort included 58,161 women with epithelial and nonepithelial ovarian cancer. The majority of cases were advanced stage, with a median age of 63-67 years at diagnosis, depending on the country.

The researchers compared age- and stage-specific net survival between countries at 1 and 3 years post diagnosis.

The 3-year all-ages net survival was highest for Norway (57%) and Australia (56%), followed by Denmark (54%), Canada (50%), United Kingdom (47%), New Zealand (46%), and Ireland (45%).

Most patients were diagnosed with distant disease (range, 64%-71%), with the greatest proportion of women in the 65- to 74- and 75- to 99-year age categories. The lowest 3-year age-specific survival (range, 20%-34%) was observed in the 75- to 99-year age category.

Marked differences in 3-year net survival between countries were found for women in the 75- to 99-year age group with distant disease (range, 12%-25%).

“International survival differences by age groups were less stark for early-stage disease,” the researchers reported. “Interjurisdictional differences within countries were also observed.”

The researchers acknowledged a key limitation of the analysis was the use of registry data. Variability between, and incomplete data within, registries could have lowered the accuracy of the survival estimates.

“[F]urther research investigating international differences in access to and quality of treatment, and prevalence of comorbid conditions particularly in older women with advanced disease [is needed],” the researchers concluded.

The study was supported by funding provided to the International Cancer Benchmarking Partnership. The authors reported having no conflicts of interest.

SOURCE: Cabasag CJ et al. Gynecol Oncol. 2020 Jan 28. doi: 10.1016/j.ygyno.2019.12.047.

WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a “reasonable and safe first-line” alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there’s one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that “the primary concern” about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

“The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations],” said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and “the superiority of insulin over oral agents simply remains questionable.”

ACOG’s 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of “poor trial quality,” and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG’s committee on practice bulletins, said in an interview. “Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment.”

In its 2017 and 2018 bulletins, ACOG said that metformin is a “reasonable alternative choice” for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. “Insurance companies aren’t always covering [insulin],” said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. “It’s a challenge – no question.”

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, “because, in most studies, it does not yield outcomes equivalent to insulin or metformin,” Dr. Turrentine emphasized.
 

Glyburide’s role

Dr. Landon took issue with ACOG’s stance on the sulfonylurea. “Frankly, I think this [conclusion] is debatable,” he said. The trend in the United States – “at least after the 2017 ACOG document came out”– has been toward use of metformin over glyburide when an oral agent is [used], but “I think glyburide has been unfairly trashed. It probably still has a place.”

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which “had become the number one agent” after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, “this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous,” said Dr. Landon. “There are real problems with this and other meta-analyses.”

The authors of a 2018 multicenter, noninferiority, randomized, controlled trial of about 900 women concluded that their study failed to show that the use of glyburide, compared with insulin, does not result in a greater frequency of perinatal complications. The authors also wrote, however, that the “increase in perinatal complications [with glyburide] may be no more than 10.5%, compared with insulin” (JAMA. 2018;319[17]:1773-80).

That increase, Dr. Landon said, was “not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%.” The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide’s role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient’s GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study’s principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.
 

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the “seminal” Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk “was all driven by the Rowan study,” Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. “But this is a classic half-full, half-empty [phenomena],” Dr. Landon said. “Some people say this isn’t good, but on the other hand, 54% avoided insulin.”

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in “more than half” of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society’s view, recent meta-analyses and systemic reviews “support the efficacy and safety of oral agents,” and “although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited.”

The society says that the difference between its statement and the ACOG recommendations is “based on the values placed by different experts and providers on the available evidence,” and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is “a little more forgiving” in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. “The professional organizations don’t make it easy for [us],” he said. At this point, “insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM.”
 

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have “unknown fetal programming effects,” and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are “clearly needed,” Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan’s MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on “both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects” (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a “reasonable and safe first-line” alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there’s one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that “the primary concern” about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

“The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations],” said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and “the superiority of insulin over oral agents simply remains questionable.”

ACOG’s 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of “poor trial quality,” and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG’s committee on practice bulletins, said in an interview. “Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment.”

In its 2017 and 2018 bulletins, ACOG said that metformin is a “reasonable alternative choice” for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. “Insurance companies aren’t always covering [insulin],” said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. “It’s a challenge – no question.”

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, “because, in most studies, it does not yield outcomes equivalent to insulin or metformin,” Dr. Turrentine emphasized.
 

Glyburide’s role

Dr. Landon took issue with ACOG’s stance on the sulfonylurea. “Frankly, I think this [conclusion] is debatable,” he said. The trend in the United States – “at least after the 2017 ACOG document came out”– has been toward use of metformin over glyburide when an oral agent is [used], but “I think glyburide has been unfairly trashed. It probably still has a place.”

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which “had become the number one agent” after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, “this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous,” said Dr. Landon. “There are real problems with this and other meta-analyses.”

The authors of a 2018 multicenter, noninferiority, randomized, controlled trial of about 900 women concluded that their study failed to show that the use of glyburide, compared with insulin, does not result in a greater frequency of perinatal complications. The authors also wrote, however, that the “increase in perinatal complications [with glyburide] may be no more than 10.5%, compared with insulin” (JAMA. 2018;319[17]:1773-80).

That increase, Dr. Landon said, was “not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%.” The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide’s role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient’s GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study’s principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.
 

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the “seminal” Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk “was all driven by the Rowan study,” Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. “But this is a classic half-full, half-empty [phenomena],” Dr. Landon said. “Some people say this isn’t good, but on the other hand, 54% avoided insulin.”

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in “more than half” of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society’s view, recent meta-analyses and systemic reviews “support the efficacy and safety of oral agents,” and “although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited.”

The society says that the difference between its statement and the ACOG recommendations is “based on the values placed by different experts and providers on the available evidence,” and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is “a little more forgiving” in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. “The professional organizations don’t make it easy for [us],” he said. At this point, “insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM.”
 

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have “unknown fetal programming effects,” and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are “clearly needed,” Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan’s MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on “both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects” (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a “reasonable and safe first-line” alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there’s one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that “the primary concern” about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

“The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations],” said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and “the superiority of insulin over oral agents simply remains questionable.”

ACOG’s 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of “poor trial quality,” and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG’s committee on practice bulletins, said in an interview. “Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment.”

In its 2017 and 2018 bulletins, ACOG said that metformin is a “reasonable alternative choice” for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. “Insurance companies aren’t always covering [insulin],” said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. “It’s a challenge – no question.”

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, “because, in most studies, it does not yield outcomes equivalent to insulin or metformin,” Dr. Turrentine emphasized.
 

Glyburide’s role

Dr. Landon took issue with ACOG’s stance on the sulfonylurea. “Frankly, I think this [conclusion] is debatable,” he said. The trend in the United States – “at least after the 2017 ACOG document came out”– has been toward use of metformin over glyburide when an oral agent is [used], but “I think glyburide has been unfairly trashed. It probably still has a place.”

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which “had become the number one agent” after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, “this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous,” said Dr. Landon. “There are real problems with this and other meta-analyses.”

The authors of a 2018 multicenter, noninferiority, randomized, controlled trial of about 900 women concluded that their study failed to show that the use of glyburide, compared with insulin, does not result in a greater frequency of perinatal complications. The authors also wrote, however, that the “increase in perinatal complications [with glyburide] may be no more than 10.5%, compared with insulin” (JAMA. 2018;319[17]:1773-80).

That increase, Dr. Landon said, was “not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%.” The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide’s role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient’s GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study’s principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.
 

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the “seminal” Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk “was all driven by the Rowan study,” Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. “But this is a classic half-full, half-empty [phenomena],” Dr. Landon said. “Some people say this isn’t good, but on the other hand, 54% avoided insulin.”

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in “more than half” of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society’s view, recent meta-analyses and systemic reviews “support the efficacy and safety of oral agents,” and “although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited.”

The society says that the difference between its statement and the ACOG recommendations is “based on the values placed by different experts and providers on the available evidence,” and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is “a little more forgiving” in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. “The professional organizations don’t make it easy for [us],” he said. At this point, “insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM.”
 

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have “unknown fetal programming effects,” and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are “clearly needed,” Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan’s MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on “both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects” (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

Although the last decade has brought appropriate increased interest in the diagnosis and treatment of postpartum depression, with screening initiatives across more than 40 states in place and even new medications being brought to market for treatment, far less attention has been given to diagnosis and treatment of a particularly serious psychiatric illness: postpartum psychosis.

Postpartum psychosis is relatively rare, with an incidence of 1 in 1,000 births, but it is one of the most serious complications of modern obstetrics. Clinically, women can experience rapid mood changes, most often with the presentation that is consistent with a manic-like psychosis, with associated symptoms of delusional thinking, hallucinations, paranoia and either depression or elation, or an amalgam of these so-called “mixed symptoms.” Onset of symptoms typically is early, within 72 hours as is classically described, but may have a somewhat later time of onset in some women.

Many investigators have studied risk factors for postpartum psychosis, and it has been well established that a history of mood disorder, particularly bipolar disorder, is one of the strongest predictors of risk for postpartum psychosis. Women with histories of postpartum psychosis are at very high risk of recurrence, with as many as 70%-90% of women experiencing recurrence if not prophylaxed with an appropriate agent. From a clinical point of view, women with postpartum psychosis typically are hospitalized, given that this is both a psychiatric and potential obstetrical emergency. In fact, the data would suggest that although postpartum suicide and infanticide are not common, they can be a tragic concomitant of postpartum psychosis (Am J Psychiatry. 2016 Dec 1;173[12]:1179-88).

A great amount of interest has been placed on the etiology of postpartum psychosis, as it’s a dramatic presentation with very rapid onset in the acute postpartum period. A rich evidence base with respect to an algorithm of treatment that maximizes likelihood of full recovery or sustaining of euthymia after recovery is limited. Few studies have looked systematically at the optimum way to treat postpartum psychosis. Clinical wisdom has dictated that, given the dramatic symptoms with which these patients present, most patients are treated with lithium and an antipsychotic medication as if they have a manic-like psychosis. It may take brief or extended periods of time for patients to stabilize. Once they are stabilized, one of the most challenging questions for clinicians is how long to treat. Again, an evidence base clearly informing this question is lacking.

Over the years, many clinicians have treated patients with postpartum psychosis as if they have bipolar disorder, given the index presentation of the illness, so some of these patients are treated with antimanic drugs indefinitely. However, clinical experience from several centers that treat women with postpartum psychosis suggests that in remitted patients, a proportion of them may be able to taper and discontinue treatment, then sustain well-being for protracted periods.

One obstacle with respect to treatment of postpartum psychosis derives from the short length of stay after delivery for many women. Some women who present with symptoms of postpartum psychosis in the first 24-48 hours frequently are managed with direct admission to an inpatient psychiatric service. But others may not develop symptoms until they are home, which may place both mother and newborn at risk.

Given that the risk for recurrent postpartum psychosis is so great (70%-90%), women with histories of postpartum psychosis invariably are prophylaxed with mood stabilizer prior to delivery in a subsequent pregnancy. In our own center, we have published on the value of such prophylactic intervention, not just in women with postpartum psychosis, but in women with bipolar disorder, who are, as noted, at great risk for developing postpartum psychotic symptoms (Am J Psychiatry. 1995 Nov;152[11]:1641-5.)

Although postpartum psychosis may be rare, over the last 3 decades we have seen a substantial number of women with postpartum psychosis and have been fascinated with the spectrum of symptoms with which some women with postpartum psychotic illness present. We also have been impressed with the time required for some women to recompensate from their illness and the course of their disorder after they have seemingly remitted. Some women appear to be able to discontinue treatment as noted above; others, particularly if there is any history of bipolar disorder, need to be maintained on treatment with mood stabilizer indefinitely.

To better understand the phenomenology of postpartum psychosis, as well as the longitudinal course of the illness, in 2019, the Mass General Hospital Postpartum Psychosis Project (MGHP3) was established. The project is conducted as a hospital-based registry where women with histories of postpartum psychosis over the last decade are invited to participate in an in-depth interview to understand both symptoms and course of underlying illness. This is complemented by obtaining a sample of saliva, which is used for genetic testing to try to identify a genetic underpinning associated with postpartum psychosis, as the question of genetic etiology of postpartum psychosis is still an open one.

As part of the MGHP3 project, clinicians across the country are able to contact perinatal psychiatrists in our center with expertise in the treatment of postpartum psychosis. Our psychiatrists also can counsel clinicians on issues regarding long-term management of postpartum psychosis because for many, knowledge of precisely how to manage this disorder or the follow-up treatment may be incomplete.

From a clinical point of view, the relevant questions really include not only acute treatment, which has already been outlined, but also the issue of duration of treatment. While some patients may be able to taper and discontinue treatment after, for example, a year of being totally well, to date we are unable to know who those patients are. We tend to be more conservative in our own center and treat patients with puerperal psychosis for a more protracted period of time, usually over several years. We also ask women about their family history of bipolar disorder or postpartum psychosis. Depending on the clinical course (if the patient really has sustained euthymia), we consider slow taper and ultimate discontinuation. As always, treatment decisions are tailored to individual clinical history, course, and patient wishes.

Postpartum psychosis remains one of the most serious illnesses that we find in reproductive psychiatry, and incomplete attention has been given to this devastating illness, which we read about periodically in newspapers and magazines. Greater understanding of postpartum psychosis will lead to a more precision-like psychiatric approach, tailoring treatment to the invariable heterogeneity of this illness.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Although the last decade has brought appropriate increased interest in the diagnosis and treatment of postpartum depression, with screening initiatives across more than 40 states in place and even new medications being brought to market for treatment, far less attention has been given to diagnosis and treatment of a particularly serious psychiatric illness: postpartum psychosis.

Postpartum psychosis is relatively rare, with an incidence of 1 in 1,000 births, but it is one of the most serious complications of modern obstetrics. Clinically, women can experience rapid mood changes, most often with the presentation that is consistent with a manic-like psychosis, with associated symptoms of delusional thinking, hallucinations, paranoia and either depression or elation, or an amalgam of these so-called “mixed symptoms.” Onset of symptoms typically is early, within 72 hours as is classically described, but may have a somewhat later time of onset in some women.

Many investigators have studied risk factors for postpartum psychosis, and it has been well established that a history of mood disorder, particularly bipolar disorder, is one of the strongest predictors of risk for postpartum psychosis. Women with histories of postpartum psychosis are at very high risk of recurrence, with as many as 70%-90% of women experiencing recurrence if not prophylaxed with an appropriate agent. From a clinical point of view, women with postpartum psychosis typically are hospitalized, given that this is both a psychiatric and potential obstetrical emergency. In fact, the data would suggest that although postpartum suicide and infanticide are not common, they can be a tragic concomitant of postpartum psychosis (Am J Psychiatry. 2016 Dec 1;173[12]:1179-88).

A great amount of interest has been placed on the etiology of postpartum psychosis, as it’s a dramatic presentation with very rapid onset in the acute postpartum period. A rich evidence base with respect to an algorithm of treatment that maximizes likelihood of full recovery or sustaining of euthymia after recovery is limited. Few studies have looked systematically at the optimum way to treat postpartum psychosis. Clinical wisdom has dictated that, given the dramatic symptoms with which these patients present, most patients are treated with lithium and an antipsychotic medication as if they have a manic-like psychosis. It may take brief or extended periods of time for patients to stabilize. Once they are stabilized, one of the most challenging questions for clinicians is how long to treat. Again, an evidence base clearly informing this question is lacking.

Over the years, many clinicians have treated patients with postpartum psychosis as if they have bipolar disorder, given the index presentation of the illness, so some of these patients are treated with antimanic drugs indefinitely. However, clinical experience from several centers that treat women with postpartum psychosis suggests that in remitted patients, a proportion of them may be able to taper and discontinue treatment, then sustain well-being for protracted periods.

One obstacle with respect to treatment of postpartum psychosis derives from the short length of stay after delivery for many women. Some women who present with symptoms of postpartum psychosis in the first 24-48 hours frequently are managed with direct admission to an inpatient psychiatric service. But others may not develop symptoms until they are home, which may place both mother and newborn at risk.

Given that the risk for recurrent postpartum psychosis is so great (70%-90%), women with histories of postpartum psychosis invariably are prophylaxed with mood stabilizer prior to delivery in a subsequent pregnancy. In our own center, we have published on the value of such prophylactic intervention, not just in women with postpartum psychosis, but in women with bipolar disorder, who are, as noted, at great risk for developing postpartum psychotic symptoms (Am J Psychiatry. 1995 Nov;152[11]:1641-5.)

Although postpartum psychosis may be rare, over the last 3 decades we have seen a substantial number of women with postpartum psychosis and have been fascinated with the spectrum of symptoms with which some women with postpartum psychotic illness present. We also have been impressed with the time required for some women to recompensate from their illness and the course of their disorder after they have seemingly remitted. Some women appear to be able to discontinue treatment as noted above; others, particularly if there is any history of bipolar disorder, need to be maintained on treatment with mood stabilizer indefinitely.

To better understand the phenomenology of postpartum psychosis, as well as the longitudinal course of the illness, in 2019, the Mass General Hospital Postpartum Psychosis Project (MGHP3) was established. The project is conducted as a hospital-based registry where women with histories of postpartum psychosis over the last decade are invited to participate in an in-depth interview to understand both symptoms and course of underlying illness. This is complemented by obtaining a sample of saliva, which is used for genetic testing to try to identify a genetic underpinning associated with postpartum psychosis, as the question of genetic etiology of postpartum psychosis is still an open one.

As part of the MGHP3 project, clinicians across the country are able to contact perinatal psychiatrists in our center with expertise in the treatment of postpartum psychosis. Our psychiatrists also can counsel clinicians on issues regarding long-term management of postpartum psychosis because for many, knowledge of precisely how to manage this disorder or the follow-up treatment may be incomplete.

From a clinical point of view, the relevant questions really include not only acute treatment, which has already been outlined, but also the issue of duration of treatment. While some patients may be able to taper and discontinue treatment after, for example, a year of being totally well, to date we are unable to know who those patients are. We tend to be more conservative in our own center and treat patients with puerperal psychosis for a more protracted period of time, usually over several years. We also ask women about their family history of bipolar disorder or postpartum psychosis. Depending on the clinical course (if the patient really has sustained euthymia), we consider slow taper and ultimate discontinuation. As always, treatment decisions are tailored to individual clinical history, course, and patient wishes.

Postpartum psychosis remains one of the most serious illnesses that we find in reproductive psychiatry, and incomplete attention has been given to this devastating illness, which we read about periodically in newspapers and magazines. Greater understanding of postpartum psychosis will lead to a more precision-like psychiatric approach, tailoring treatment to the invariable heterogeneity of this illness.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Although the last decade has brought appropriate increased interest in the diagnosis and treatment of postpartum depression, with screening initiatives across more than 40 states in place and even new medications being brought to market for treatment, far less attention has been given to diagnosis and treatment of a particularly serious psychiatric illness: postpartum psychosis.

Postpartum psychosis is relatively rare, with an incidence of 1 in 1,000 births, but it is one of the most serious complications of modern obstetrics. Clinically, women can experience rapid mood changes, most often with the presentation that is consistent with a manic-like psychosis, with associated symptoms of delusional thinking, hallucinations, paranoia and either depression or elation, or an amalgam of these so-called “mixed symptoms.” Onset of symptoms typically is early, within 72 hours as is classically described, but may have a somewhat later time of onset in some women.

Many investigators have studied risk factors for postpartum psychosis, and it has been well established that a history of mood disorder, particularly bipolar disorder, is one of the strongest predictors of risk for postpartum psychosis. Women with histories of postpartum psychosis are at very high risk of recurrence, with as many as 70%-90% of women experiencing recurrence if not prophylaxed with an appropriate agent. From a clinical point of view, women with postpartum psychosis typically are hospitalized, given that this is both a psychiatric and potential obstetrical emergency. In fact, the data would suggest that although postpartum suicide and infanticide are not common, they can be a tragic concomitant of postpartum psychosis (Am J Psychiatry. 2016 Dec 1;173[12]:1179-88).

A great amount of interest has been placed on the etiology of postpartum psychosis, as it’s a dramatic presentation with very rapid onset in the acute postpartum period. A rich evidence base with respect to an algorithm of treatment that maximizes likelihood of full recovery or sustaining of euthymia after recovery is limited. Few studies have looked systematically at the optimum way to treat postpartum psychosis. Clinical wisdom has dictated that, given the dramatic symptoms with which these patients present, most patients are treated with lithium and an antipsychotic medication as if they have a manic-like psychosis. It may take brief or extended periods of time for patients to stabilize. Once they are stabilized, one of the most challenging questions for clinicians is how long to treat. Again, an evidence base clearly informing this question is lacking.

Over the years, many clinicians have treated patients with postpartum psychosis as if they have bipolar disorder, given the index presentation of the illness, so some of these patients are treated with antimanic drugs indefinitely. However, clinical experience from several centers that treat women with postpartum psychosis suggests that in remitted patients, a proportion of them may be able to taper and discontinue treatment, then sustain well-being for protracted periods.

One obstacle with respect to treatment of postpartum psychosis derives from the short length of stay after delivery for many women. Some women who present with symptoms of postpartum psychosis in the first 24-48 hours frequently are managed with direct admission to an inpatient psychiatric service. But others may not develop symptoms until they are home, which may place both mother and newborn at risk.

Given that the risk for recurrent postpartum psychosis is so great (70%-90%), women with histories of postpartum psychosis invariably are prophylaxed with mood stabilizer prior to delivery in a subsequent pregnancy. In our own center, we have published on the value of such prophylactic intervention, not just in women with postpartum psychosis, but in women with bipolar disorder, who are, as noted, at great risk for developing postpartum psychotic symptoms (Am J Psychiatry. 1995 Nov;152[11]:1641-5.)

Although postpartum psychosis may be rare, over the last 3 decades we have seen a substantial number of women with postpartum psychosis and have been fascinated with the spectrum of symptoms with which some women with postpartum psychotic illness present. We also have been impressed with the time required for some women to recompensate from their illness and the course of their disorder after they have seemingly remitted. Some women appear to be able to discontinue treatment as noted above; others, particularly if there is any history of bipolar disorder, need to be maintained on treatment with mood stabilizer indefinitely.

To better understand the phenomenology of postpartum psychosis, as well as the longitudinal course of the illness, in 2019, the Mass General Hospital Postpartum Psychosis Project (MGHP3) was established. The project is conducted as a hospital-based registry where women with histories of postpartum psychosis over the last decade are invited to participate in an in-depth interview to understand both symptoms and course of underlying illness. This is complemented by obtaining a sample of saliva, which is used for genetic testing to try to identify a genetic underpinning associated with postpartum psychosis, as the question of genetic etiology of postpartum psychosis is still an open one.

As part of the MGHP3 project, clinicians across the country are able to contact perinatal psychiatrists in our center with expertise in the treatment of postpartum psychosis. Our psychiatrists also can counsel clinicians on issues regarding long-term management of postpartum psychosis because for many, knowledge of precisely how to manage this disorder or the follow-up treatment may be incomplete.

From a clinical point of view, the relevant questions really include not only acute treatment, which has already been outlined, but also the issue of duration of treatment. While some patients may be able to taper and discontinue treatment after, for example, a year of being totally well, to date we are unable to know who those patients are. We tend to be more conservative in our own center and treat patients with puerperal psychosis for a more protracted period of time, usually over several years. We also ask women about their family history of bipolar disorder or postpartum psychosis. Depending on the clinical course (if the patient really has sustained euthymia), we consider slow taper and ultimate discontinuation. As always, treatment decisions are tailored to individual clinical history, course, and patient wishes.

Postpartum psychosis remains one of the most serious illnesses that we find in reproductive psychiatry, and incomplete attention has been given to this devastating illness, which we read about periodically in newspapers and magazines. Greater understanding of postpartum psychosis will lead to a more precision-like psychiatric approach, tailoring treatment to the invariable heterogeneity of this illness.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

According to the DSM-V, gender dysphoria in adolescents and adults “involves a difference between one’s experienced/expressed gender and assigned gender, and significant distress or problems functioning. It lasts at least 6 months,” and several other criteria must be met.¹ Many patients with gender dysphoria also identify as transgender. A “transition” or “transitioning” is a process by which individuals come to inhabit their gender identity.² A gender transition may take many forms, and only some people will choose to include medical assistance in their transition process. Although the scope of this article will not address these concerns, it should be noted that many people in the transgender and gender nonconforming community would object to the concepts of gender dysphoria and gender transition because they rely on a binary model of gender that may exclude individuals that see themselves as something other than “man or woman.”

sturti/Getty Images

There are both medical and surgical options for medical assistance in a gender transition. This article will focus on the surgical care of patients assigned female at birth who are seeking masculinizing surgical therapy. Many writers will discuss “gender-affirming” surgery, but we will use the term “gender-reaffirming” surgery because transgender patients have already affirmed their own genders and do not require surgery to inhabit this affirmation. Surgical options might include bilateral mastectomy, hysterectomy, bilateral salpingo-oophorectomy (BSO), metoidioplasty (surgical formation of a neophallus with existing genital tissue), or phalloplasty. There currently is no single surgical subspecialty that encompasses training in all forms of gender-reaffirming surgical therapies. In some areas of the country, centers of excellence have given rise to multidisciplinary teams that combine the skill sets of surgical subspecialists to provide a streamlined approach to gender-reaffirming surgery. Because of the scarcity of these integrated centers, most patients seeking gender-reaffirming surgeries will need to find individual subspecialists whose surgical training focuses on one area of the body. For example, patients seeking all possible surgical options may need a breast surgeon to perform their mastectomy, an ob.gyn. to perform their hysterectomy and BSO, a urologist to perform their metoidioplasty, and a plastic surgeon to perform their phalloplasty. In these scenarios, a general ob.gyn. may be consulted to perform a gender-reaffirming hysterectomy with BSO.

There are many reasons why transgender men might desire hysterectomy/BSO as part of their transition. Removal of the uterus and cervix eliminates concerns surrounding menstruation, pregnancy, and cervical cancer screening, all of which may add to their experience of gender dysphoria. Furthermore, removal of the ovaries may simplify long-term hormonal therapy with testosterone by eliminating the need for estrogen suppression. Lastly, a hysterectomy/BSO is a lower-risk and more cost-effective masculinizing surgery, compared with metoidioplasty or phalloplasty.

While the technical aspect of performing a hysterectomy/BSO certainly is within the scope of training for a general ob.gyn., there are several nuances of which providers should be aware when planning gender-reaffirming surgery for a transgender man. During the preoperative planning phase, it is of utmost importance to provide an environment of safety so that the focus of the preop visit is not clouded by communication mishaps between office staff and the patient. These barriers can be avoided by implementing office intake forms that give patients the opportunity to inform the health care team of their chosen name and personal pronouns upon registration for the visit.

A pelvic exam is commonly performed by ob.gyns. to determine surgical approach for a hysterectomy/BSO. When approaching transgender male patients for preoperative pelvic exams, it is important to be mindful of the fact that this type of exam may trigger gender dysphoria. While pelvic exams should be handled in sensitive fashion regardless of a patient’s gender identity, a patient who is a transgender man may benefit from some added steps in discussing the pelvic exam. One approach is to acknowledge that these exams/discussions may be especially triggering of gender dysphoria, and ask if the patient would prefer certain words to be used or not used in reference to their anatomy. As with any patient, the provider should explain the purpose of the examination and offer opportunities for the patient to have some control in the exam such as by assisting with insertion of the speculum or designating a “safe word” that would signal the provider to stop or pause the exam. In some cases, patients may not be able to tolerate the pelvic exam while awake because of the degree of gender dysphoria that the exam would induce. Providers might consider noninvasive imaging studies to help with surgical planning if they find they need more information before scheduling the operation, or they may offer a staged procedure with exam under anesthesia prior to the definitive surgery.

In conclusion, performing a gender-reaffirming hysterectomy/BSO requires thoughtful preparation to ensure a safe surgical environment for this vulnerable population. Care should be taken to plan the operation with a culturally sensitive approach.

Dr. Joyner is an assistant professor at Emory University, and is the director of gynecologic services in the Gender Center at Grady Memorial Hospital, both in Atlanta. Dr. Joyner identifies as a cisgender female and uses she/hers/her as her personal pronouns. Dr. Joey Bahng is a PGY-1 resident physician in Emory University’s gynecology & obstetrics residency program. Dr. Bahng identifies as nonbinary and uses they/them/their as their personal pronouns. Dr. Joyner and Dr. Bahng reported no relevant financial disclosures.

References

1. American Psychiatric Association. What is Gender Dysphoria? https://www.psychiatry.org/patients-families/gender-dysphoria/what-is-gender-dysphoria

2. UCSF Transgender Care. Transition Roadmap. https://transcare.ucsf.edu/transition-roadmap

According to the DSM-V, gender dysphoria in adolescents and adults “involves a difference between one’s experienced/expressed gender and assigned gender, and significant distress or problems functioning. It lasts at least 6 months,” and several other criteria must be met.¹ Many patients with gender dysphoria also identify as transgender. A “transition” or “transitioning” is a process by which individuals come to inhabit their gender identity.² A gender transition may take many forms, and only some people will choose to include medical assistance in their transition process. Although the scope of this article will not address these concerns, it should be noted that many people in the transgender and gender nonconforming community would object to the concepts of gender dysphoria and gender transition because they rely on a binary model of gender that may exclude individuals that see themselves as something other than “man or woman.”

sturti/Getty Images

There are both medical and surgical options for medical assistance in a gender transition. This article will focus on the surgical care of patients assigned female at birth who are seeking masculinizing surgical therapy. Many writers will discuss “gender-affirming” surgery, but we will use the term “gender-reaffirming” surgery because transgender patients have already affirmed their own genders and do not require surgery to inhabit this affirmation. Surgical options might include bilateral mastectomy, hysterectomy, bilateral salpingo-oophorectomy (BSO), metoidioplasty (surgical formation of a neophallus with existing genital tissue), or phalloplasty. There currently is no single surgical subspecialty that encompasses training in all forms of gender-reaffirming surgical therapies. In some areas of the country, centers of excellence have given rise to multidisciplinary teams that combine the skill sets of surgical subspecialists to provide a streamlined approach to gender-reaffirming surgery. Because of the scarcity of these integrated centers, most patients seeking gender-reaffirming surgeries will need to find individual subspecialists whose surgical training focuses on one area of the body. For example, patients seeking all possible surgical options may need a breast surgeon to perform their mastectomy, an ob.gyn. to perform their hysterectomy and BSO, a urologist to perform their metoidioplasty, and a plastic surgeon to perform their phalloplasty. In these scenarios, a general ob.gyn. may be consulted to perform a gender-reaffirming hysterectomy with BSO.

There are many reasons why transgender men might desire hysterectomy/BSO as part of their transition. Removal of the uterus and cervix eliminates concerns surrounding menstruation, pregnancy, and cervical cancer screening, all of which may add to their experience of gender dysphoria. Furthermore, removal of the ovaries may simplify long-term hormonal therapy with testosterone by eliminating the need for estrogen suppression. Lastly, a hysterectomy/BSO is a lower-risk and more cost-effective masculinizing surgery, compared with metoidioplasty or phalloplasty.

While the technical aspect of performing a hysterectomy/BSO certainly is within the scope of training for a general ob.gyn., there are several nuances of which providers should be aware when planning gender-reaffirming surgery for a transgender man. During the preoperative planning phase, it is of utmost importance to provide an environment of safety so that the focus of the preop visit is not clouded by communication mishaps between office staff and the patient. These barriers can be avoided by implementing office intake forms that give patients the opportunity to inform the health care team of their chosen name and personal pronouns upon registration for the visit.

A pelvic exam is commonly performed by ob.gyns. to determine surgical approach for a hysterectomy/BSO. When approaching transgender male patients for preoperative pelvic exams, it is important to be mindful of the fact that this type of exam may trigger gender dysphoria. While pelvic exams should be handled in sensitive fashion regardless of a patient’s gender identity, a patient who is a transgender man may benefit from some added steps in discussing the pelvic exam. One approach is to acknowledge that these exams/discussions may be especially triggering of gender dysphoria, and ask if the patient would prefer certain words to be used or not used in reference to their anatomy. As with any patient, the provider should explain the purpose of the examination and offer opportunities for the patient to have some control in the exam such as by assisting with insertion of the speculum or designating a “safe word” that would signal the provider to stop or pause the exam. In some cases, patients may not be able to tolerate the pelvic exam while awake because of the degree of gender dysphoria that the exam would induce. Providers might consider noninvasive imaging studies to help with surgical planning if they find they need more information before scheduling the operation, or they may offer a staged procedure with exam under anesthesia prior to the definitive surgery.

In conclusion, performing a gender-reaffirming hysterectomy/BSO requires thoughtful preparation to ensure a safe surgical environment for this vulnerable population. Care should be taken to plan the operation with a culturally sensitive approach.

Dr. Joyner is an assistant professor at Emory University, and is the director of gynecologic services in the Gender Center at Grady Memorial Hospital, both in Atlanta. Dr. Joyner identifies as a cisgender female and uses she/hers/her as her personal pronouns. Dr. Joey Bahng is a PGY-1 resident physician in Emory University’s gynecology & obstetrics residency program. Dr. Bahng identifies as nonbinary and uses they/them/their as their personal pronouns. Dr. Joyner and Dr. Bahng reported no relevant financial disclosures.

References

1. American Psychiatric Association. What is Gender Dysphoria? https://www.psychiatry.org/patients-families/gender-dysphoria/what-is-gender-dysphoria

2. UCSF Transgender Care. Transition Roadmap. https://transcare.ucsf.edu/transition-roadmap

According to the DSM-V, gender dysphoria in adolescents and adults “involves a difference between one’s experienced/expressed gender and assigned gender, and significant distress or problems functioning. It lasts at least 6 months,” and several other criteria must be met.¹ Many patients with gender dysphoria also identify as transgender. A “transition” or “transitioning” is a process by which individuals come to inhabit their gender identity.² A gender transition may take many forms, and only some people will choose to include medical assistance in their transition process. Although the scope of this article will not address these concerns, it should be noted that many people in the transgender and gender nonconforming community would object to the concepts of gender dysphoria and gender transition because they rely on a binary model of gender that may exclude individuals that see themselves as something other than “man or woman.”

sturti/Getty Images

There are both medical and surgical options for medical assistance in a gender transition. This article will focus on the surgical care of patients assigned female at birth who are seeking masculinizing surgical therapy. Many writers will discuss “gender-affirming” surgery, but we will use the term “gender-reaffirming” surgery because transgender patients have already affirmed their own genders and do not require surgery to inhabit this affirmation. Surgical options might include bilateral mastectomy, hysterectomy, bilateral salpingo-oophorectomy (BSO), metoidioplasty (surgical formation of a neophallus with existing genital tissue), or phalloplasty. There currently is no single surgical subspecialty that encompasses training in all forms of gender-reaffirming surgical therapies. In some areas of the country, centers of excellence have given rise to multidisciplinary teams that combine the skill sets of surgical subspecialists to provide a streamlined approach to gender-reaffirming surgery. Because of the scarcity of these integrated centers, most patients seeking gender-reaffirming surgeries will need to find individual subspecialists whose surgical training focuses on one area of the body. For example, patients seeking all possible surgical options may need a breast surgeon to perform their mastectomy, an ob.gyn. to perform their hysterectomy and BSO, a urologist to perform their metoidioplasty, and a plastic surgeon to perform their phalloplasty. In these scenarios, a general ob.gyn. may be consulted to perform a gender-reaffirming hysterectomy with BSO.

There are many reasons why transgender men might desire hysterectomy/BSO as part of their transition. Removal of the uterus and cervix eliminates concerns surrounding menstruation, pregnancy, and cervical cancer screening, all of which may add to their experience of gender dysphoria. Furthermore, removal of the ovaries may simplify long-term hormonal therapy with testosterone by eliminating the need for estrogen suppression. Lastly, a hysterectomy/BSO is a lower-risk and more cost-effective masculinizing surgery, compared with metoidioplasty or phalloplasty.

While the technical aspect of performing a hysterectomy/BSO certainly is within the scope of training for a general ob.gyn., there are several nuances of which providers should be aware when planning gender-reaffirming surgery for a transgender man. During the preoperative planning phase, it is of utmost importance to provide an environment of safety so that the focus of the preop visit is not clouded by communication mishaps between office staff and the patient. These barriers can be avoided by implementing office intake forms that give patients the opportunity to inform the health care team of their chosen name and personal pronouns upon registration for the visit.

A pelvic exam is commonly performed by ob.gyns. to determine surgical approach for a hysterectomy/BSO. When approaching transgender male patients for preoperative pelvic exams, it is important to be mindful of the fact that this type of exam may trigger gender dysphoria. While pelvic exams should be handled in sensitive fashion regardless of a patient’s gender identity, a patient who is a transgender man may benefit from some added steps in discussing the pelvic exam. One approach is to acknowledge that these exams/discussions may be especially triggering of gender dysphoria, and ask if the patient would prefer certain words to be used or not used in reference to their anatomy. As with any patient, the provider should explain the purpose of the examination and offer opportunities for the patient to have some control in the exam such as by assisting with insertion of the speculum or designating a “safe word” that would signal the provider to stop or pause the exam. In some cases, patients may not be able to tolerate the pelvic exam while awake because of the degree of gender dysphoria that the exam would induce. Providers might consider noninvasive imaging studies to help with surgical planning if they find they need more information before scheduling the operation, or they may offer a staged procedure with exam under anesthesia prior to the definitive surgery.

In conclusion, performing a gender-reaffirming hysterectomy/BSO requires thoughtful preparation to ensure a safe surgical environment for this vulnerable population. Care should be taken to plan the operation with a culturally sensitive approach.

Dr. Joyner is an assistant professor at Emory University, and is the director of gynecologic services in the Gender Center at Grady Memorial Hospital, both in Atlanta. Dr. Joyner identifies as a cisgender female and uses she/hers/her as her personal pronouns. Dr. Joey Bahng is a PGY-1 resident physician in Emory University’s gynecology & obstetrics residency program. Dr. Bahng identifies as nonbinary and uses they/them/their as their personal pronouns. Dr. Joyner and Dr. Bahng reported no relevant financial disclosures.

References

1. American Psychiatric Association. What is Gender Dysphoria? https://www.psychiatry.org/patients-families/gender-dysphoria/what-is-gender-dysphoria

2. UCSF Transgender Care. Transition Roadmap. https://transcare.ucsf.edu/transition-roadmap

Molar pregnancy is an uncommon but serious condition that affects young women of reproductive age. The diagnosis and management of molar pregnancy is familiar to most gynecologists. However, in the days and weeks following evacuation of molar pregnancy, clinicians face a critical time period in which they must be vigilant for the development of postmolar gestational trophoblastic neoplasia (GTN). If recognized early and treated appropriately, it almost always can be cured; however, errors or delays in the management of this condition can have catastrophic consequences for patients, including decreasing the likelihood of cure. Here we will review some of the steps and actions that can be taken immediately following the diagnosis of a molar pregnancy to expeditiously identify postmolar GTN and ensure patients are appropriately prepared for further consultation and intervention.

Postmolar GTN includes the diagnoses of invasive mole and choriocarcinoma that contain highly atypical trophoblasts with the capacity for local invasion and metastasis. Typically, the diagnosis is made clinically and not distinguished with histology. While molar pregnancies are a benign condition, invasive moles and choriocarcinoma are malignant conditions in which the molar tissue infiltrates the uterine myometrium, vasculature, and frequently is associated with hematogenous spread with distant metastases. It is a highly chemosensitive disease, and cure with chemotherapy typically is achieved with the ability to preserve fertility if desired even in advanced stage disease.¹

After evacuation of a molar pregnancy, gynecologists should be on alert for the development of postmolar GTN if the following known risk factors are present: a history of a prior GTN diagnosis, complete mole on pathology (as opposed to partial mole), serum human chorionic gonadotropin (hCG) levels greater than 100,000 mIU/mL, age greater than 40 years, an enlarged uterus or large ovarian theca lutein cysts, and slow to normalize (more than 2 months) hCG. Symptoms for the development of postmolar GTN include persistent vaginal bleeding after evacuation, a persistently enlarged or enlarging uterine size, and adnexal masses. Ultimately, the diagnosis is made through plateaued or rising serum hCG assessments.² (See graphic.)

Following the evacuation of a molar pregnancy, hCG levels should be drawn at the same laboratory every 1-2 weeks until normalization and then three consecutive normal values. Once this has been achieved, hCG levels should be tested once at 3 months and again at 6 months. During this 6 month period, patients should use reliable contraception, ideally, and through oral contraceptive pills that suppress the secretion of pituitary hCG if not contraindicated. Should a woman become pregnant during this 6-month surveillance, it becomes impossible to rule out occult postmolar GTN.

Typically after evacuation of a molar pregnancy, there is rapid fall in hCG levels, but this does not occur when the molar pregnancy has become invasive or is associated with choriocarcinoma. In these cases, after an initial drop in hCG levels, there is an observed rise or plateau in levels (as defined in the accompanying table), and this establishes the diagnosis of postmolar GTN. It is common for hCG to fall in fits and starts, rather than have a smooth, consistent diminution, and this can be worrying for gynecologists; however, provided there is a consistent reduction in values in accordance with the stated definitions, observation can continue.

Another source of confusion and concern is an HCG level that fails to completely normalize during observation, yet reaches a very low level. If this is observed, clinicians should consider the diagnosis of quiescent hCG, pituitary hCG, or phantom hCG.³ These can be difficult to distinguish from postmolar GTN, and consultation with a gynecologic oncologist with experience in the diagnosis and management of these rare tumors is helpful to determine if the persistent low levels in hCG require intervention.

Once a clinician has observed a plateau or rise in hCG levels, a gynecologic examination should be performed because the lower genital tract is a common site for metastatic postmolar GTN. If during this evaluation, a suspicious lesion is identified (typically a blue-black, slightly raised, hemorrhagic-appearing lesion), it should not be biopsied, but rather assumed to be a metastatic site. The vasculature of metastatic sites is extremely fragile, and biopsy or disruption can result in catastrophic hemorrhage, even from very small lesions.

In addition to physical examination, several diagnostic studies should be performed which may expedite the triage and management of the case. A pelvic ultrasound should evaluate the endometrial cavity for a new viable pregnancy, and residual molar tissue; sometimes, myometrial invasion consistent with an invasive mole can be appreciated. Chest x-ray or CT scan should be ordered to evaluate for pulmonary metastatic lesions. Additionally, CT scans of the abdomen and pelvis should be ordered, and if lung metastases are present, brain imaging with either MRI or CT scan also should be obtained. These imaging studies will provide the necessary information to stage the GTN (as metastatic or not).

Treatment for postmolar GTN is determined based on further prognostic categorization (“high risk” or “low risk”) in accordance with the WHO classification, which is derived using several prognostic clinical variables including age, antecedent pregnancy, interval from index pregnancy, pretreatment hCG, largest tumor size, sites and number of metastases, and response to previous chemotherapy.⁴ These assignments are necessary to determine whether single-agent or multiagent chemotherapy should be prescribed.

Laboratory studies are helpful to obtain at this time and include metabolic panels (which can ensure that renal and hepatic function are within normal limits in anticipation of future chemotherapy), and complete blood count ,which can establish viable bone marrow function prior to chemotherapy.

Once postmolar GTN has been diagnosed, it is most appropriate to refer the patient to a gynecologic oncologist with experience in the treatment of these relatively rare malignancies. At that point, the patient will be formally staged, and offered treatment based on these staging results.

Among women with low-risk, nonmetastatic GTN who desire future fertility it is appropriate to offer a repeat dilation and curettage (D&C) procedure rather than immediately proceeding with chemotherapy. Approximately two-thirds of women with low risk disease can avoid chemotherapy with repeat curettage.⁵ Risk factors for needing chemotherapy after repeat D&C include the presence of trophoblastic disease in the pathology specimen and urinary hCG levels greater than 1,500 mIU/mL at the time of curettage. In my experience, many women appreciate this option to potentially avoid toxic chemotherapy.

For women with low-risk, nonmetastatic postmolar GTN who do not desire future fertility, and hope to avoid chemotherapy, hysterectomy also is a reasonable first option. This can be performed via either minimally invasive, laparotomy, or vaginal route. If performing a minimally invasive procedure in the setting of GTN, there should be caution or avoidance of use of a uterine manipulator because the uterine wall typically is soft and prone to perforation, and bleeding can be significant secondary to disruption of the tumor.

If repeat D&C or hysterectomy are adopted instead of chemotherapy, it is important that patients are very closely monitored post operatively to ensure normalization of their hCG levels (as described above). If it fails to normalize, restaging scans and examinations should be performed, and referral for the appropriate chemotherapy regimen should be initiated without delay.

Postmolar GTN is a serious condition that usually can be cured with chemotherapy or, if appropriate, surgery. Gynecologists should be vigilant for the development of postmolar GTN following evacuation of a molar pregnancy, and refer to a gynecologic oncologist when criteria are met to ensure that overtreatment is avoided and essential therapy is ensured.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].

References

1. Lancet Oncol. 2007 Aug;8(8):715-24.

2. J Natl Compr Canc Netw. 2019 Nov 1;17(11):1374-91.

3. Gynecol Oncol. 2009 Mar;112(3):663-72.

4. World Health Organ Tech Rep Ser. 1983;692:7-81.

5. Obstet Gynecol. 2016;128(3):535-42.

Molar pregnancy is an uncommon but serious condition that affects young women of reproductive age. The diagnosis and management of molar pregnancy is familiar to most gynecologists. However, in the days and weeks following evacuation of molar pregnancy, clinicians face a critical time period in which they must be vigilant for the development of postmolar gestational trophoblastic neoplasia (GTN). If recognized early and treated appropriately, it almost always can be cured; however, errors or delays in the management of this condition can have catastrophic consequences for patients, including decreasing the likelihood of cure. Here we will review some of the steps and actions that can be taken immediately following the diagnosis of a molar pregnancy to expeditiously identify postmolar GTN and ensure patients are appropriately prepared for further consultation and intervention.

Postmolar GTN includes the diagnoses of invasive mole and choriocarcinoma that contain highly atypical trophoblasts with the capacity for local invasion and metastasis. Typically, the diagnosis is made clinically and not distinguished with histology. While molar pregnancies are a benign condition, invasive moles and choriocarcinoma are malignant conditions in which the molar tissue infiltrates the uterine myometrium, vasculature, and frequently is associated with hematogenous spread with distant metastases. It is a highly chemosensitive disease, and cure with chemotherapy typically is achieved with the ability to preserve fertility if desired even in advanced stage disease.¹

After evacuation of a molar pregnancy, gynecologists should be on alert for the development of postmolar GTN if the following known risk factors are present: a history of a prior GTN diagnosis, complete mole on pathology (as opposed to partial mole), serum human chorionic gonadotropin (hCG) levels greater than 100,000 mIU/mL, age greater than 40 years, an enlarged uterus or large ovarian theca lutein cysts, and slow to normalize (more than 2 months) hCG. Symptoms for the development of postmolar GTN include persistent vaginal bleeding after evacuation, a persistently enlarged or enlarging uterine size, and adnexal masses. Ultimately, the diagnosis is made through plateaued or rising serum hCG assessments.² (See graphic.)

Following the evacuation of a molar pregnancy, hCG levels should be drawn at the same laboratory every 1-2 weeks until normalization and then three consecutive normal values. Once this has been achieved, hCG levels should be tested once at 3 months and again at 6 months. During this 6 month period, patients should use reliable contraception, ideally, and through oral contraceptive pills that suppress the secretion of pituitary hCG if not contraindicated. Should a woman become pregnant during this 6-month surveillance, it becomes impossible to rule out occult postmolar GTN.

Typically after evacuation of a molar pregnancy, there is rapid fall in hCG levels, but this does not occur when the molar pregnancy has become invasive or is associated with choriocarcinoma. In these cases, after an initial drop in hCG levels, there is an observed rise or plateau in levels (as defined in the accompanying table), and this establishes the diagnosis of postmolar GTN. It is common for hCG to fall in fits and starts, rather than have a smooth, consistent diminution, and this can be worrying for gynecologists; however, provided there is a consistent reduction in values in accordance with the stated definitions, observation can continue.

Another source of confusion and concern is an HCG level that fails to completely normalize during observation, yet reaches a very low level. If this is observed, clinicians should consider the diagnosis of quiescent hCG, pituitary hCG, or phantom hCG.³ These can be difficult to distinguish from postmolar GTN, and consultation with a gynecologic oncologist with experience in the diagnosis and management of these rare tumors is helpful to determine if the persistent low levels in hCG require intervention.

Once a clinician has observed a plateau or rise in hCG levels, a gynecologic examination should be performed because the lower genital tract is a common site for metastatic postmolar GTN. If during this evaluation, a suspicious lesion is identified (typically a blue-black, slightly raised, hemorrhagic-appearing lesion), it should not be biopsied, but rather assumed to be a metastatic site. The vasculature of metastatic sites is extremely fragile, and biopsy or disruption can result in catastrophic hemorrhage, even from very small lesions.

In addition to physical examination, several diagnostic studies should be performed which may expedite the triage and management of the case. A pelvic ultrasound should evaluate the endometrial cavity for a new viable pregnancy, and residual molar tissue; sometimes, myometrial invasion consistent with an invasive mole can be appreciated. Chest x-ray or CT scan should be ordered to evaluate for pulmonary metastatic lesions. Additionally, CT scans of the abdomen and pelvis should be ordered, and if lung metastases are present, brain imaging with either MRI or CT scan also should be obtained. These imaging studies will provide the necessary information to stage the GTN (as metastatic or not).

Treatment for postmolar GTN is determined based on further prognostic categorization (“high risk” or “low risk”) in accordance with the WHO classification, which is derived using several prognostic clinical variables including age, antecedent pregnancy, interval from index pregnancy, pretreatment hCG, largest tumor size, sites and number of metastases, and response to previous chemotherapy.⁴ These assignments are necessary to determine whether single-agent or multiagent chemotherapy should be prescribed.

Laboratory studies are helpful to obtain at this time and include metabolic panels (which can ensure that renal and hepatic function are within normal limits in anticipation of future chemotherapy), and complete blood count ,which can establish viable bone marrow function prior to chemotherapy.

Once postmolar GTN has been diagnosed, it is most appropriate to refer the patient to a gynecologic oncologist with experience in the treatment of these relatively rare malignancies. At that point, the patient will be formally staged, and offered treatment based on these staging results.

Among women with low-risk, nonmetastatic GTN who desire future fertility it is appropriate to offer a repeat dilation and curettage (D&C) procedure rather than immediately proceeding with chemotherapy. Approximately two-thirds of women with low risk disease can avoid chemotherapy with repeat curettage.⁵ Risk factors for needing chemotherapy after repeat D&C include the presence of trophoblastic disease in the pathology specimen and urinary hCG levels greater than 1,500 mIU/mL at the time of curettage. In my experience, many women appreciate this option to potentially avoid toxic chemotherapy.

For women with low-risk, nonmetastatic postmolar GTN who do not desire future fertility, and hope to avoid chemotherapy, hysterectomy also is a reasonable first option. This can be performed via either minimally invasive, laparotomy, or vaginal route. If performing a minimally invasive procedure in the setting of GTN, there should be caution or avoidance of use of a uterine manipulator because the uterine wall typically is soft and prone to perforation, and bleeding can be significant secondary to disruption of the tumor.

If repeat D&C or hysterectomy are adopted instead of chemotherapy, it is important that patients are very closely monitored post operatively to ensure normalization of their hCG levels (as described above). If it fails to normalize, restaging scans and examinations should be performed, and referral for the appropriate chemotherapy regimen should be initiated without delay.

Postmolar GTN is a serious condition that usually can be cured with chemotherapy or, if appropriate, surgery. Gynecologists should be vigilant for the development of postmolar GTN following evacuation of a molar pregnancy, and refer to a gynecologic oncologist when criteria are met to ensure that overtreatment is avoided and essential therapy is ensured.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].

References

1. Lancet Oncol. 2007 Aug;8(8):715-24.

2. J Natl Compr Canc Netw. 2019 Nov 1;17(11):1374-91.

3. Gynecol Oncol. 2009 Mar;112(3):663-72.

4. World Health Organ Tech Rep Ser. 1983;692:7-81.

5. Obstet Gynecol. 2016;128(3):535-42.

Molar pregnancy is an uncommon but serious condition that affects young women of reproductive age. The diagnosis and management of molar pregnancy is familiar to most gynecologists. However, in the days and weeks following evacuation of molar pregnancy, clinicians face a critical time period in which they must be vigilant for the development of postmolar gestational trophoblastic neoplasia (GTN). If recognized early and treated appropriately, it almost always can be cured; however, errors or delays in the management of this condition can have catastrophic consequences for patients, including decreasing the likelihood of cure. Here we will review some of the steps and actions that can be taken immediately following the diagnosis of a molar pregnancy to expeditiously identify postmolar GTN and ensure patients are appropriately prepared for further consultation and intervention.

Postmolar GTN includes the diagnoses of invasive mole and choriocarcinoma that contain highly atypical trophoblasts with the capacity for local invasion and metastasis. Typically, the diagnosis is made clinically and not distinguished with histology. While molar pregnancies are a benign condition, invasive moles and choriocarcinoma are malignant conditions in which the molar tissue infiltrates the uterine myometrium, vasculature, and frequently is associated with hematogenous spread with distant metastases. It is a highly chemosensitive disease, and cure with chemotherapy typically is achieved with the ability to preserve fertility if desired even in advanced stage disease.¹

After evacuation of a molar pregnancy, gynecologists should be on alert for the development of postmolar GTN if the following known risk factors are present: a history of a prior GTN diagnosis, complete mole on pathology (as opposed to partial mole), serum human chorionic gonadotropin (hCG) levels greater than 100,000 mIU/mL, age greater than 40 years, an enlarged uterus or large ovarian theca lutein cysts, and slow to normalize (more than 2 months) hCG. Symptoms for the development of postmolar GTN include persistent vaginal bleeding after evacuation, a persistently enlarged or enlarging uterine size, and adnexal masses. Ultimately, the diagnosis is made through plateaued or rising serum hCG assessments.² (See graphic.)

Following the evacuation of a molar pregnancy, hCG levels should be drawn at the same laboratory every 1-2 weeks until normalization and then three consecutive normal values. Once this has been achieved, hCG levels should be tested once at 3 months and again at 6 months. During this 6 month period, patients should use reliable contraception, ideally, and through oral contraceptive pills that suppress the secretion of pituitary hCG if not contraindicated. Should a woman become pregnant during this 6-month surveillance, it becomes impossible to rule out occult postmolar GTN.

Typically after evacuation of a molar pregnancy, there is rapid fall in hCG levels, but this does not occur when the molar pregnancy has become invasive or is associated with choriocarcinoma. In these cases, after an initial drop in hCG levels, there is an observed rise or plateau in levels (as defined in the accompanying table), and this establishes the diagnosis of postmolar GTN. It is common for hCG to fall in fits and starts, rather than have a smooth, consistent diminution, and this can be worrying for gynecologists; however, provided there is a consistent reduction in values in accordance with the stated definitions, observation can continue.

Another source of confusion and concern is an HCG level that fails to completely normalize during observation, yet reaches a very low level. If this is observed, clinicians should consider the diagnosis of quiescent hCG, pituitary hCG, or phantom hCG.³ These can be difficult to distinguish from postmolar GTN, and consultation with a gynecologic oncologist with experience in the diagnosis and management of these rare tumors is helpful to determine if the persistent low levels in hCG require intervention.

Once a clinician has observed a plateau or rise in hCG levels, a gynecologic examination should be performed because the lower genital tract is a common site for metastatic postmolar GTN. If during this evaluation, a suspicious lesion is identified (typically a blue-black, slightly raised, hemorrhagic-appearing lesion), it should not be biopsied, but rather assumed to be a metastatic site. The vasculature of metastatic sites is extremely fragile, and biopsy or disruption can result in catastrophic hemorrhage, even from very small lesions.

In addition to physical examination, several diagnostic studies should be performed which may expedite the triage and management of the case. A pelvic ultrasound should evaluate the endometrial cavity for a new viable pregnancy, and residual molar tissue; sometimes, myometrial invasion consistent with an invasive mole can be appreciated. Chest x-ray or CT scan should be ordered to evaluate for pulmonary metastatic lesions. Additionally, CT scans of the abdomen and pelvis should be ordered, and if lung metastases are present, brain imaging with either MRI or CT scan also should be obtained. These imaging studies will provide the necessary information to stage the GTN (as metastatic or not).

Treatment for postmolar GTN is determined based on further prognostic categorization (“high risk” or “low risk”) in accordance with the WHO classification, which is derived using several prognostic clinical variables including age, antecedent pregnancy, interval from index pregnancy, pretreatment hCG, largest tumor size, sites and number of metastases, and response to previous chemotherapy.⁴ These assignments are necessary to determine whether single-agent or multiagent chemotherapy should be prescribed.

Laboratory studies are helpful to obtain at this time and include metabolic panels (which can ensure that renal and hepatic function are within normal limits in anticipation of future chemotherapy), and complete blood count ,which can establish viable bone marrow function prior to chemotherapy.

Once postmolar GTN has been diagnosed, it is most appropriate to refer the patient to a gynecologic oncologist with experience in the treatment of these relatively rare malignancies. At that point, the patient will be formally staged, and offered treatment based on these staging results.

Among women with low-risk, nonmetastatic GTN who desire future fertility it is appropriate to offer a repeat dilation and curettage (D&C) procedure rather than immediately proceeding with chemotherapy. Approximately two-thirds of women with low risk disease can avoid chemotherapy with repeat curettage.⁵ Risk factors for needing chemotherapy after repeat D&C include the presence of trophoblastic disease in the pathology specimen and urinary hCG levels greater than 1,500 mIU/mL at the time of curettage. In my experience, many women appreciate this option to potentially avoid toxic chemotherapy.

For women with low-risk, nonmetastatic postmolar GTN who do not desire future fertility, and hope to avoid chemotherapy, hysterectomy also is a reasonable first option. This can be performed via either minimally invasive, laparotomy, or vaginal route. If performing a minimally invasive procedure in the setting of GTN, there should be caution or avoidance of use of a uterine manipulator because the uterine wall typically is soft and prone to perforation, and bleeding can be significant secondary to disruption of the tumor.

If repeat D&C or hysterectomy are adopted instead of chemotherapy, it is important that patients are very closely monitored post operatively to ensure normalization of their hCG levels (as described above). If it fails to normalize, restaging scans and examinations should be performed, and referral for the appropriate chemotherapy regimen should be initiated without delay.

Postmolar GTN is a serious condition that usually can be cured with chemotherapy or, if appropriate, surgery. Gynecologists should be vigilant for the development of postmolar GTN following evacuation of a molar pregnancy, and refer to a gynecologic oncologist when criteria are met to ensure that overtreatment is avoided and essential therapy is ensured.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email her at [email protected].

References

1. Lancet Oncol. 2007 Aug;8(8):715-24.

2. J Natl Compr Canc Netw. 2019 Nov 1;17(11):1374-91.

3. Gynecol Oncol. 2009 Mar;112(3):663-72.

4. World Health Organ Tech Rep Ser. 1983;692:7-81.

5. Obstet Gynecol. 2016;128(3):535-42.

Modafinil exposure during pregnancy was associated with an approximately tripled risk of congenital malformations in a large Danish registry-based study.

Modafinil (Provigil) is commonly prescribed to address daytime sleepiness in narcolepsy and multiple sclerosis. An interim postmarketing safety analysis showed increased rates of major malformation in modafinil-exposed pregnancies, so the manufacturer issued an alert advising health care professionals of this safety signal in June 2019, wrote Per Damkier, MD, PhD, corresponding author of a JAMA research letter reporting the Danish study results. The postmarketing study had shown a major malformation rate of about 15% in modafinil-exposed pregnancies, much higher than the 3% background rate.

Dr. Damkier and Anne Broe, MD, PhD, both of the department of clinical biochemistry and pharmacology at Odense (Denmark) University Hospital, compared outcomes for pregnant women who were prescribed modafinil at any point during the first trimester of pregnancy with those who were prescribed an active comparator, methylphenidate, as well as with those who had neither exposure. Methylphenidate is not associated with congenital malformations and is used for indications similar to modafinil.

Looking at all pregnancies for whom complete records existed in Danish health registries between 2004 and 2017, the investigators found 49 modafinil-exposed pregnancies, 963 methylphenidate-exposed pregnancies, and 828,644 pregnancies with neither exposure.

Six major congenital malformations occurred in the modafinil-exposed group for an absolute risk of 12%. Major malformations occurred in 43 (4.5%) of the methylphenidate-exposed group and 32,466 (3.9%) of the unexposed group.

Using the extensive data available in public registries, the authors were able to perform logistic regression to adjust for concomitant use of other psychotropic medication; comorbidities such as diabetes and hypertension; and demographic and anthropometric measures such as maternal age, smoking status, and body mass index.

After this statistical adjustment, the researchers found that modafinil exposure during the first trimester of pregnancy was associated with an odds ratio of 3.4 (95% confidence interval, 1.2-9.7) for major congenital malformation, compared with first-trimester methylphenidate exposure. Compared with the unexposed cohort, modafinil-exposed pregnancies had an adjusted odds ratio of 2.7 (95% CI, 1.1-6.9) for major congenital malformation.

A total of 13 (27%) women who took modafinil had multiple sclerosis, but the authors excluded women who’d received a prescription for the multiple sclerosis drug teriflunomide (Aubagio), a known teratogen. Sleep disorders were reported for 39% of modafinil users, compared with 4.5% of methylphenidate users. Rates of psychoactive drug use were 41% for the modafinil group and 30% for the methylphenidate group.

The authors acknowledged the possibility of residual confounders affecting their results, and of the statistical problems with the very small sample size of modafinil-exposed pregnancies. Also, actual medication use – rather than prescription redemption – wasn’t captured in the study.

The study was partially funded by the Novo Nordisk Foundation. The authors reported no conflicts of interest.

[email protected]

SOURCE: Damkier P, Broe A. JAMA. 2020;323(4):374-6.

Modafinil exposure during pregnancy was associated with an approximately tripled risk of congenital malformations in a large Danish registry-based study.

Modafinil (Provigil) is commonly prescribed to address daytime sleepiness in narcolepsy and multiple sclerosis. An interim postmarketing safety analysis showed increased rates of major malformation in modafinil-exposed pregnancies, so the manufacturer issued an alert advising health care professionals of this safety signal in June 2019, wrote Per Damkier, MD, PhD, corresponding author of a JAMA research letter reporting the Danish study results. The postmarketing study had shown a major malformation rate of about 15% in modafinil-exposed pregnancies, much higher than the 3% background rate.

Dr. Damkier and Anne Broe, MD, PhD, both of the department of clinical biochemistry and pharmacology at Odense (Denmark) University Hospital, compared outcomes for pregnant women who were prescribed modafinil at any point during the first trimester of pregnancy with those who were prescribed an active comparator, methylphenidate, as well as with those who had neither exposure. Methylphenidate is not associated with congenital malformations and is used for indications similar to modafinil.

Looking at all pregnancies for whom complete records existed in Danish health registries between 2004 and 2017, the investigators found 49 modafinil-exposed pregnancies, 963 methylphenidate-exposed pregnancies, and 828,644 pregnancies with neither exposure.

Six major congenital malformations occurred in the modafinil-exposed group for an absolute risk of 12%. Major malformations occurred in 43 (4.5%) of the methylphenidate-exposed group and 32,466 (3.9%) of the unexposed group.

Using the extensive data available in public registries, the authors were able to perform logistic regression to adjust for concomitant use of other psychotropic medication; comorbidities such as diabetes and hypertension; and demographic and anthropometric measures such as maternal age, smoking status, and body mass index.

After this statistical adjustment, the researchers found that modafinil exposure during the first trimester of pregnancy was associated with an odds ratio of 3.4 (95% confidence interval, 1.2-9.7) for major congenital malformation, compared with first-trimester methylphenidate exposure. Compared with the unexposed cohort, modafinil-exposed pregnancies had an adjusted odds ratio of 2.7 (95% CI, 1.1-6.9) for major congenital malformation.

A total of 13 (27%) women who took modafinil had multiple sclerosis, but the authors excluded women who’d received a prescription for the multiple sclerosis drug teriflunomide (Aubagio), a known teratogen. Sleep disorders were reported for 39% of modafinil users, compared with 4.5% of methylphenidate users. Rates of psychoactive drug use were 41% for the modafinil group and 30% for the methylphenidate group.

The authors acknowledged the possibility of residual confounders affecting their results, and of the statistical problems with the very small sample size of modafinil-exposed pregnancies. Also, actual medication use – rather than prescription redemption – wasn’t captured in the study.

The study was partially funded by the Novo Nordisk Foundation. The authors reported no conflicts of interest.

[email protected]

SOURCE: Damkier P, Broe A. JAMA. 2020;323(4):374-6.

Modafinil exposure during pregnancy was associated with an approximately tripled risk of congenital malformations in a large Danish registry-based study.

Modafinil (Provigil) is commonly prescribed to address daytime sleepiness in narcolepsy and multiple sclerosis. An interim postmarketing safety analysis showed increased rates of major malformation in modafinil-exposed pregnancies, so the manufacturer issued an alert advising health care professionals of this safety signal in June 2019, wrote Per Damkier, MD, PhD, corresponding author of a JAMA research letter reporting the Danish study results. The postmarketing study had shown a major malformation rate of about 15% in modafinil-exposed pregnancies, much higher than the 3% background rate.

Dr. Damkier and Anne Broe, MD, PhD, both of the department of clinical biochemistry and pharmacology at Odense (Denmark) University Hospital, compared outcomes for pregnant women who were prescribed modafinil at any point during the first trimester of pregnancy with those who were prescribed an active comparator, methylphenidate, as well as with those who had neither exposure. Methylphenidate is not associated with congenital malformations and is used for indications similar to modafinil.

Looking at all pregnancies for whom complete records existed in Danish health registries between 2004 and 2017, the investigators found 49 modafinil-exposed pregnancies, 963 methylphenidate-exposed pregnancies, and 828,644 pregnancies with neither exposure.

Six major congenital malformations occurred in the modafinil-exposed group for an absolute risk of 12%. Major malformations occurred in 43 (4.5%) of the methylphenidate-exposed group and 32,466 (3.9%) of the unexposed group.

Using the extensive data available in public registries, the authors were able to perform logistic regression to adjust for concomitant use of other psychotropic medication; comorbidities such as diabetes and hypertension; and demographic and anthropometric measures such as maternal age, smoking status, and body mass index.

After this statistical adjustment, the researchers found that modafinil exposure during the first trimester of pregnancy was associated with an odds ratio of 3.4 (95% confidence interval, 1.2-9.7) for major congenital malformation, compared with first-trimester methylphenidate exposure. Compared with the unexposed cohort, modafinil-exposed pregnancies had an adjusted odds ratio of 2.7 (95% CI, 1.1-6.9) for major congenital malformation.

A total of 13 (27%) women who took modafinil had multiple sclerosis, but the authors excluded women who’d received a prescription for the multiple sclerosis drug teriflunomide (Aubagio), a known teratogen. Sleep disorders were reported for 39% of modafinil users, compared with 4.5% of methylphenidate users. Rates of psychoactive drug use were 41% for the modafinil group and 30% for the methylphenidate group.

The authors acknowledged the possibility of residual confounders affecting their results, and of the statistical problems with the very small sample size of modafinil-exposed pregnancies. Also, actual medication use – rather than prescription redemption – wasn’t captured in the study.

The study was partially funded by the Novo Nordisk Foundation. The authors reported no conflicts of interest.

[email protected]

SOURCE: Damkier P, Broe A. JAMA. 2020;323(4):374-6.

CASE

A 30-year-old G2P2 woman presents for a well-woman visit and reports 6 months of premenstrual symptoms including irritability, depression, breast pain, and headaches. She is not taking any medications or hormonal contraceptives. She is sexually active and currently not interested in becoming pregnant. She asks what you can do for her symptoms, as they are affecting her life at home and at work.

Symptoms and definitions vary

Although more than 150 premenstrual symptoms have been reported, the most common psychological and behavioral ones are mood swings, depression, anxiety, irritability, crying, social withdrawal, forgetfulness, and problems concentrating.^1-3 The most common physical symptoms are fatigue, abdominal bloating, weight gain, breast tenderness, acne, change in appetite or food cravings, edema, headache, and gastrointestinal upset. The etiology of these symptoms is usually multifactorial, with some combination of hormonal, neurotransmitter, lifestyle, environmental, and psychosocial factors playing a role.

Premenstrual disorder. In reviewing diagnostic criteria for the various premenstrual syndromes and disorders from different organizations (eg, the International Society for Premenstrual Disorders; the American College of Obstetricians and Gynecologists; the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), there is agreement on the following criteria for premenstrual syndrome (PMS)^4-6:

• The woman must be ovulating. (Women who no longer menstruate [eg, because of hysterectomy or endometrial ablation] can have premenstrual disorders as long as ovarian function remains intact.)
• The woman experiences a constellation of disabling physical and/or psychological symptoms that appears in the luteal phase of her menstrual cycle.
• The symptoms improve soon after the onset of menses.
• There is a symptom-free interval before ovulation.
• There is prospective documentation of symptoms for at least 2 consecutive cycles.
• The symptoms are sufficient in severity to affect activities of daily living and/or important relationships.

Premenstrual dysphoric disorder. PMDD is another common premenstrual disorder. It is distinguished by significant premenstrual psychological symptoms and requires the presence of marked affective lability, marked irritability or anger, markedly depressed mood, and/or marked anxiety (TABLE 1).⁷

Exacerbation of other ailments. Another premenstrual disorder is the premenstrual exacerbation of underlying chronic medical or psychological problems such as migraines, seizures, asthma, diabetes, irritable bowel syndrome, fibromyalgia, anxiety, or depression.

Differences in interpretation lead to variations in prevalence

Differences in the interpretation of significant premenstrual symptoms have led to variations in estimated prevalence. For example, 80% to 95% of women report premenstrual symptoms, but only 30% to 40% meet criteria for PMS and only 3% to 8% meet criteria for PMDD.⁸ Many women who report premenstrual symptoms in a retrospective questionnaire do not meet criteria for PMS or PMDD based on prospective symptom charting. The Daily Record of Severity of Problems (DRSP), a prospective tracking tool for premenstrual symptoms, is sensitive and specific for diagnosing PMS and PMDD if administered on the first day of menstruation.⁹

Ask about symptoms and use a tracking tool

When you see a woman for a well-woman visit or a gynecologic problem, inquire about physical/emotional symptoms and their severity during the week that precedes menstruation. If a patient reports few symptoms of a mild nature, then no further work-up is needed.

Continue to: If patients report significant...

Women who no longer menstruate can have premenstrual disorders as long as ovarian function remains intact.

If patients report significant premenstrual symptoms, recommend the use of a tool to track the symptoms. Older tools such as the DRSP and the Premenstrual Symptoms Screening Tool (PSST), newer symptom diaries that can be used for both PMS and PMDD,and questionnaires that have been used in research situations can be time consuming and difficult for patients to complete.^10-12 Instead, physicians can easily construct their own charting tool, as we did for patients to use when tracking their most bothersome symptoms (FIGURE 1). Tracking helps to confirm the diagnosis and helps you and the patient focus on treatment goals.

Keep in mind other diagnoses (eg, anemia, thyroid disorders, perimenopause, anxiety, depression, eating disorders, substance abuse) that can cause or exacerbate the psychological/physical symptoms the patient is reporting. If you suspect any of these other diagnoses, laboratory evaluation (eg, complete blood count, thyroid-stimulating hormone level or other hormonal testing, urine drug screen, etc) may be warranted to rule out other etiologies for the reported symptoms.

Develop a Tx plan that ­considers symptoms, family-planning needs

Focus treatment on the patient’s predominant symptoms whether they are physical, psychological, or mixed (FIGURE 2). The patient’s preferences regarding family planning are another important consideration. Women who are using a fertility awareness–based method of family planning may not desire a contraceptive hormonal treatment for their premenstrual disorder. Also, patients may have cultural and/or religious beliefs that need to be respected.

Although the definitions for PMS and PMDD require at least 2 cycles of prospective documentation of symptoms, dietary and lifestyle changes can begin immediately. Regular follow-up to document improvement of symptoms is important; using the patient’s symptoms charting tool can help with this.

Focus on diet and lifestyle right away

Experts in the field of PMS/PMDD suggest that simple dietary changes may be a reasonable first step to help improve symptoms. Researchers have found that diets high in fiber, vegetables, and whole grains are inversely related to PMS.¹³ Older studies have suggested an increased prevalence and severity of PMS with increased caffeine intake; however, a newer study found no such association.¹⁴

Continue to: A case-control study nested...

Focus treatment on the patient’s predominant symptoms, whether they are physical, psychological, or mixed.

A case-control study nested within the Nurses’ Health Study II cohort showed that a high intake of both dietary calcium and vitamin D prevented the development of PMS in women ages 27 to 44.¹⁵ B vitamins, such as thiamine and riboflavin, from food sources have been associated with a lower risk of PMS.¹⁶ A variety of older clinical studies showed benefit from aerobic exercise on PMS symptoms,^17-19 but a newer cross-sectional study of young adult women found no association between physical activity and the prevalence of PMS.²⁰ Acupuncture has demonstrated efficacy for the treatment of the physical symptoms of PMS and PMDD, but more rigorous studies are needed.^21,22 Cognitive behavioral therapy has been studied as a treatment, but data to support this approach are limited so it cannot be recommended at this time.²³

Make the most of supplements—especially calcium

Calcium is the nutritional supplement with the most evidence to support its use to relieve symptoms of PMS and PMDD (TABLE 2^21,22,24-45). Research indicates that disturbances in calcium regulation and calcium deficiency may be responsible for various premenstrual symptoms. One study showed that, compared with placebo, women who took 1200 mg/d calcium carbonate for 3 menstrual cycles had a 48% decrease in both somatic and affective symptoms.²⁴ Another trial demonstrated improvement in PMS symptoms of early tiredness, appetite changes, and depression with calcium therapy.²⁵

Pyridoxine (vitamin B6) has potential benefit in treating PMS due to its ability to increase levels of serotonin, norepinephrine, histamine, dopamine, and taurine.²⁶ An older systematic review showed benefit for symptoms associated with PMS, but the authors concluded that larger randomized controlled trials (RCTs) were needed before definitive recommendations could be made.²⁷

Chasteberry. A number of studies have evaluated the effect of vitex agnus castus (VAC), commonly referred to as chasteberry, on PMS and PMDD symptoms. The exact mechanism of VAC is unknown, but in vitro studies show binding of VAC extracts to dopamine-2 receptors and opioid receptors, and an affinity for estrogen receptors.²⁸

A recent meta-analysis concluded that VAC extracts are not superior to selective serotonin reuptake inhibitors (SSRIs) or oral contraceptives (OCs) for PMS/PMDD.²⁸ The authors suggested a possible benefit of VAC compared with placebo or other nutritional supplements; however, the studies supporting its use are limited by small sample size and potential bias.

Continue to: Magnesium

Magnesium. Many small studies have evaluated the role of other herbal and nutritional supplements for the treatment of PMS/PMDD. A systematic review of studies on the effect of magnesium supplementation on anxiety and stress showed that magnesium may have a potential role in the treatment of the premenstrual symptom of anxiety.²⁹ Other studies have demonstrated a potential role in the treatment of premenstrual migraine.^30,31

Vitamin E has demonstrated benefit in the treatment of cyclic mastalgia; however, evidence for using vitamin E for mood and depressive symptoms associated with PMS and PMDD is inconsistent.^32-34 Other studies involving vitamin D, St. John’s wort, black cohosh, evening primrose oil, saffron, and ginkgo biloba either showed these agents to be nonefficacious in relieving PMS/PMDD symptoms or to require more data before they can be recommended for use.^34,46

Patient doesn’t respond? Start an SSRI

Pharmacotherapy with antidepressants is typically reserved for those who do not respond to nonpharmacologic therapies and are experiencing more moderate to severe symptoms of PMS or PMDD. Reduced levels of serotonin and serotonergic activity in the brain may be linked to symptoms of PMS and PMDD.⁴⁷ Studies have shown SSRIs to be effective in reducing many psychological symptoms (eg, depression, anxiety, lethargy, irritability) and some physical symptoms (eg, headache, breast tenderness, muscle or joint pain) associated with PMS and PMDD.

A Cochrane review of 31 RCTs compared various SSRIs to placebo. When taken either continuously or intermittently (administration during luteal phase), SSRIs were similarly effective in relieving symptoms when compared with placebo.³⁵ Psychological symptoms are more likely to improve with both low and moderate doses of SSRIs, while physical symptoms may only improve with moderate or higher doses. A direct comparison of the various SSRIs for the treatment of PMS or PMDD is lacking; therefore, the selection of SSRI may be based on patient characteristics and preference.

The benefits of SSRIs are noted much earlier in the treatment of PMS/PMDD than they are observed in their use for depression or anxiety.³⁶ This suggests that the mechanism by which SSRIs relieve PMS/PMDD symptoms is different than that for depression or anxiety. Intermittent dosing capitalizes upon the rapid effect seen with these medications and the cyclical nature of these disorders. In most studies, the benefit of intermittent dosing is similar to continuous dosing; however, one meta-analysis did note that continuous dosing had a larger effect.³⁷

Continue to: The doses of SSRIs...

Although the definitions for PMS and PMDD require at least 2 cycles of prospective documentation of symptoms, diet and lifestyle changes can begin immediately.

The doses of SSRIs used in most PMS/PMDD trials were lower than those typically used for the treatment of depression and anxiety. The withdrawal effect that can be seen with abrupt cessation of SSRIs has not been reported in the intermittent-dosing studies for PMS/PMDD.³⁸ While this might imply a more tolerable safety profile, the most common adverse effects reported in trials were still as expected: sleep disturbances, headache, nausea, and sexual dysfunction. It is important to note that SSRIs should be used with caution during pregnancy, and paroxetine should be avoided in women considering pregnancy in the near future.

Other antidepressant classes have been studied to a lesser extent than SSRIs. Continuously dosed venlafaxine, a serotonin and norepinephrine reuptake inhibitor, demonstrated efficacy in PMS/PMDD treatment when compared with placebo within the first cycle of therapy.³⁹ The response seen was comparable to that associated with SSRI treatments in other trials.

Buspirone, an anxiolytic with serotonin receptor activity that is different from that of the SSRIs, demonstrated efficacy in reducing the symptom of irritability.⁴⁸ Buspirone may have a role to play in those presenting with irritability as a primary symptom or in those who are unable to tolerate the adverse effects of SSRIs. Tricyclic antidepressants, bupropion, and alprazolam have either limited data regarding efficacy or are associated with adverse effects that limit their use.³⁸

Hormonal treatments may be worth considering

One commonly prescribed hormonal therapy for PMS and PMDD is continuous OCs. A 2012 Cochrane review of OCs containing drospirenone evaluated 5 trials and a total of 1920 women.⁴⁰ Two placebo-controlled trials of women with severe premenstrual symptoms (PMDD) showed improvement after 3 months of taking daily drospirenone 3 mg with ethinyl estradiol 20 mcg, compared with placebo.

While experiencing greater benefit, these groups also experienced significantly more adverse effects including nausea, intermenstrual bleeding, and breast pain. The respective odds ratios for the 3 adverse effects were 3.15 (95% confidence interval [CI], 1.90-5.22), 4.92 (95% CI, 3.03-7.96), and 2.67 (95% CI, 1.50-4.78). The review concluded that drospirenone 3 mg with ethinyl estradiol 20 mcg may help in the treatment of severe premenstrual symptoms (PMDD) but that it is unknown whether this treatment is appropriate for patients with less severe premenstrual symptoms.

Continue to: Another multicenter RCT

Another multicenter RCT evaluated women with PMDD who received levonorgestrel 90 mcg with ethinyl estradiol 20 mcg or placebo daily for 112 days.⁴¹ Symptoms were recorded utilizing the DRSP. Significantly more women taking the daily combination hormone (52%) than placebo (40%) had a positive response (≥ 50% improvement in the DRSP 7-day late luteal phase score and Clinical Global Impression of Severity score of ≥ 1 improvement, evaluated at the last “on-therapy” cycle [P = .025]). Twenty-three of 186 patients in the treatment arm dropped out because of adverse effects.

Noncontraceptive estrogen-containing preparations. Hormone therapy preparations containing lower doses of estrogen than seen in OC preparations have also been studied for PMS management. A 2017 Cochrane review of noncontraceptive estrogen-containing preparations found very low-quality evidence to support the effectiveness of continuous estrogen (transdermal patches or subcutaneous implants) plus progestogen.⁴⁹

Progesterone. The cyclic use of progesterone in the luteal phase has been reviewed as a hormonal treatment for PMS. A 2012 Cochrane review of the efficacy of progesterone for PMS was inconclusive; however, route of administration, dose, and duration differed across studies.⁴²

Another systematic review of 10 trials involving 531 women concluded that progesterone was no better than placebo in the treatment of PMS.⁴³ However, it should be noted that each trial evaluated a different dose of progesterone, and all but 1 of the trials administered progesterone by using the calendar method to predict the beginning of the luteal phase. The only trial to use an objective confirmation of ovulation prior to beginning progesterone therapy did demonstrate significant improvement in premenstrual symptoms.

This 1985 study by Dennerstein et al⁴⁴ prescribed progesterone for 10 days of each menstrual cycle starting 3 days after ovulation. In each cycle, ovulation was confirmed by determinations of urinary 24-hour pregnanediol and total estrogen concentrations. Progesterone was then prescribed during the objectively identified luteal phase, resulting in significant improvement in symptoms.

Continue to: Another study evaluated...

The benefits of SSRIs are noted much earlier in the treatment of PMS/PMDD than they are observed in their use for depression or anxiety.

Another study evaluated the post-ovulatory progesterone profiles of 77 women with symptoms of PMS and found lower levels of progesterone and a sharper rate of decline in the women with PMS vs the control group.⁴⁵ Subsequent progesterone treatment during the objectively identified luteal phase significantly improved PMS symptoms. These studies would seem to suggest that progesterone replacement when administered during an objectively identified luteal phase may offer some benefit in the treatment of PMS, but larger RCTs are needed to confirm this.

CASE

You provide the patient with diet and lifestyle education as well as a recommendation for calcium supplementation. The patient agrees to prospectively chart her most significant premenstrual symptoms. You review additional treatment options including SSRI medications and hormonal approaches. She is using a fertility awareness–based method of family planning that allows her to confidently identify her luteal phase. She agrees to take sertraline 50 mg/d during the luteal phase of her cycle. At her follow-up office visit 3 months later, she reports improvement in her premenstrual symptoms. Her charting of symptoms confirms this.

CORRESPONDENCE
Peter Danis, MD, Mercy Family Medicine St. Louis, 12680 Olive Boulevard, St. Louis, MO 63141; [email protected].

CASE

A 30-year-old G2P2 woman presents for a well-woman visit and reports 6 months of premenstrual symptoms including irritability, depression, breast pain, and headaches. She is not taking any medications or hormonal contraceptives. She is sexually active and currently not interested in becoming pregnant. She asks what you can do for her symptoms, as they are affecting her life at home and at work.

Symptoms and definitions vary

Although more than 150 premenstrual symptoms have been reported, the most common psychological and behavioral ones are mood swings, depression, anxiety, irritability, crying, social withdrawal, forgetfulness, and problems concentrating.^1-3 The most common physical symptoms are fatigue, abdominal bloating, weight gain, breast tenderness, acne, change in appetite or food cravings, edema, headache, and gastrointestinal upset. The etiology of these symptoms is usually multifactorial, with some combination of hormonal, neurotransmitter, lifestyle, environmental, and psychosocial factors playing a role.

Premenstrual disorder. In reviewing diagnostic criteria for the various premenstrual syndromes and disorders from different organizations (eg, the International Society for Premenstrual Disorders; the American College of Obstetricians and Gynecologists; the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), there is agreement on the following criteria for premenstrual syndrome (PMS)^4-6:

• The woman must be ovulating. (Women who no longer menstruate [eg, because of hysterectomy or endometrial ablation] can have premenstrual disorders as long as ovarian function remains intact.)
• The woman experiences a constellation of disabling physical and/or psychological symptoms that appears in the luteal phase of her menstrual cycle.
• The symptoms improve soon after the onset of menses.
• There is a symptom-free interval before ovulation.
• There is prospective documentation of symptoms for at least 2 consecutive cycles.
• The symptoms are sufficient in severity to affect activities of daily living and/or important relationships.

Premenstrual dysphoric disorder. PMDD is another common premenstrual disorder. It is distinguished by significant premenstrual psychological symptoms and requires the presence of marked affective lability, marked irritability or anger, markedly depressed mood, and/or marked anxiety (TABLE 1).⁷

Exacerbation of other ailments. Another premenstrual disorder is the premenstrual exacerbation of underlying chronic medical or psychological problems such as migraines, seizures, asthma, diabetes, irritable bowel syndrome, fibromyalgia, anxiety, or depression.

Differences in interpretation lead to variations in prevalence

Differences in the interpretation of significant premenstrual symptoms have led to variations in estimated prevalence. For example, 80% to 95% of women report premenstrual symptoms, but only 30% to 40% meet criteria for PMS and only 3% to 8% meet criteria for PMDD.⁸ Many women who report premenstrual symptoms in a retrospective questionnaire do not meet criteria for PMS or PMDD based on prospective symptom charting. The Daily Record of Severity of Problems (DRSP), a prospective tracking tool for premenstrual symptoms, is sensitive and specific for diagnosing PMS and PMDD if administered on the first day of menstruation.⁹

Ask about symptoms and use a tracking tool

When you see a woman for a well-woman visit or a gynecologic problem, inquire about physical/emotional symptoms and their severity during the week that precedes menstruation. If a patient reports few symptoms of a mild nature, then no further work-up is needed.

Continue to: If patients report significant...

Women who no longer menstruate can have premenstrual disorders as long as ovarian function remains intact.

If patients report significant premenstrual symptoms, recommend the use of a tool to track the symptoms. Older tools such as the DRSP and the Premenstrual Symptoms Screening Tool (PSST), newer symptom diaries that can be used for both PMS and PMDD,and questionnaires that have been used in research situations can be time consuming and difficult for patients to complete.^10-12 Instead, physicians can easily construct their own charting tool, as we did for patients to use when tracking their most bothersome symptoms (FIGURE 1). Tracking helps to confirm the diagnosis and helps you and the patient focus on treatment goals.

Keep in mind other diagnoses (eg, anemia, thyroid disorders, perimenopause, anxiety, depression, eating disorders, substance abuse) that can cause or exacerbate the psychological/physical symptoms the patient is reporting. If you suspect any of these other diagnoses, laboratory evaluation (eg, complete blood count, thyroid-stimulating hormone level or other hormonal testing, urine drug screen, etc) may be warranted to rule out other etiologies for the reported symptoms.

Develop a Tx plan that ­considers symptoms, family-planning needs

Focus treatment on the patient’s predominant symptoms whether they are physical, psychological, or mixed (FIGURE 2). The patient’s preferences regarding family planning are another important consideration. Women who are using a fertility awareness–based method of family planning may not desire a contraceptive hormonal treatment for their premenstrual disorder. Also, patients may have cultural and/or religious beliefs that need to be respected.

Although the definitions for PMS and PMDD require at least 2 cycles of prospective documentation of symptoms, dietary and lifestyle changes can begin immediately. Regular follow-up to document improvement of symptoms is important; using the patient’s symptoms charting tool can help with this.

Focus on diet and lifestyle right away

Experts in the field of PMS/PMDD suggest that simple dietary changes may be a reasonable first step to help improve symptoms. Researchers have found that diets high in fiber, vegetables, and whole grains are inversely related to PMS.¹³ Older studies have suggested an increased prevalence and severity of PMS with increased caffeine intake; however, a newer study found no such association.¹⁴

Continue to: A case-control study nested...

Focus treatment on the patient’s predominant symptoms, whether they are physical, psychological, or mixed.

A case-control study nested within the Nurses’ Health Study II cohort showed that a high intake of both dietary calcium and vitamin D prevented the development of PMS in women ages 27 to 44.¹⁵ B vitamins, such as thiamine and riboflavin, from food sources have been associated with a lower risk of PMS.¹⁶ A variety of older clinical studies showed benefit from aerobic exercise on PMS symptoms,^17-19 but a newer cross-sectional study of young adult women found no association between physical activity and the prevalence of PMS.²⁰ Acupuncture has demonstrated efficacy for the treatment of the physical symptoms of PMS and PMDD, but more rigorous studies are needed.^21,22 Cognitive behavioral therapy has been studied as a treatment, but data to support this approach are limited so it cannot be recommended at this time.²³

Make the most of supplements—especially calcium

Calcium is the nutritional supplement with the most evidence to support its use to relieve symptoms of PMS and PMDD (TABLE 2^21,22,24-45). Research indicates that disturbances in calcium regulation and calcium deficiency may be responsible for various premenstrual symptoms. One study showed that, compared with placebo, women who took 1200 mg/d calcium carbonate for 3 menstrual cycles had a 48% decrease in both somatic and affective symptoms.²⁴ Another trial demonstrated improvement in PMS symptoms of early tiredness, appetite changes, and depression with calcium therapy.²⁵

Pyridoxine (vitamin B6) has potential benefit in treating PMS due to its ability to increase levels of serotonin, norepinephrine, histamine, dopamine, and taurine.²⁶ An older systematic review showed benefit for symptoms associated with PMS, but the authors concluded that larger randomized controlled trials (RCTs) were needed before definitive recommendations could be made.²⁷

Chasteberry. A number of studies have evaluated the effect of vitex agnus castus (VAC), commonly referred to as chasteberry, on PMS and PMDD symptoms. The exact mechanism of VAC is unknown, but in vitro studies show binding of VAC extracts to dopamine-2 receptors and opioid receptors, and an affinity for estrogen receptors.²⁸

A recent meta-analysis concluded that VAC extracts are not superior to selective serotonin reuptake inhibitors (SSRIs) or oral contraceptives (OCs) for PMS/PMDD.²⁸ The authors suggested a possible benefit of VAC compared with placebo or other nutritional supplements; however, the studies supporting its use are limited by small sample size and potential bias.

Continue to: Magnesium

Magnesium. Many small studies have evaluated the role of other herbal and nutritional supplements for the treatment of PMS/PMDD. A systematic review of studies on the effect of magnesium supplementation on anxiety and stress showed that magnesium may have a potential role in the treatment of the premenstrual symptom of anxiety.²⁹ Other studies have demonstrated a potential role in the treatment of premenstrual migraine.^30,31

Vitamin E has demonstrated benefit in the treatment of cyclic mastalgia; however, evidence for using vitamin E for mood and depressive symptoms associated with PMS and PMDD is inconsistent.^32-34 Other studies involving vitamin D, St. John’s wort, black cohosh, evening primrose oil, saffron, and ginkgo biloba either showed these agents to be nonefficacious in relieving PMS/PMDD symptoms or to require more data before they can be recommended for use.^34,46

Patient doesn’t respond? Start an SSRI

Pharmacotherapy with antidepressants is typically reserved for those who do not respond to nonpharmacologic therapies and are experiencing more moderate to severe symptoms of PMS or PMDD. Reduced levels of serotonin and serotonergic activity in the brain may be linked to symptoms of PMS and PMDD.⁴⁷ Studies have shown SSRIs to be effective in reducing many psychological symptoms (eg, depression, anxiety, lethargy, irritability) and some physical symptoms (eg, headache, breast tenderness, muscle or joint pain) associated with PMS and PMDD.

A Cochrane review of 31 RCTs compared various SSRIs to placebo. When taken either continuously or intermittently (administration during luteal phase), SSRIs were similarly effective in relieving symptoms when compared with placebo.³⁵ Psychological symptoms are more likely to improve with both low and moderate doses of SSRIs, while physical symptoms may only improve with moderate or higher doses. A direct comparison of the various SSRIs for the treatment of PMS or PMDD is lacking; therefore, the selection of SSRI may be based on patient characteristics and preference.

The benefits of SSRIs are noted much earlier in the treatment of PMS/PMDD than they are observed in their use for depression or anxiety.³⁶ This suggests that the mechanism by which SSRIs relieve PMS/PMDD symptoms is different than that for depression or anxiety. Intermittent dosing capitalizes upon the rapid effect seen with these medications and the cyclical nature of these disorders. In most studies, the benefit of intermittent dosing is similar to continuous dosing; however, one meta-analysis did note that continuous dosing had a larger effect.³⁷

Continue to: The doses of SSRIs...

Although the definitions for PMS and PMDD require at least 2 cycles of prospective documentation of symptoms, diet and lifestyle changes can begin immediately.

The doses of SSRIs used in most PMS/PMDD trials were lower than those typically used for the treatment of depression and anxiety. The withdrawal effect that can be seen with abrupt cessation of SSRIs has not been reported in the intermittent-dosing studies for PMS/PMDD.³⁸ While this might imply a more tolerable safety profile, the most common adverse effects reported in trials were still as expected: sleep disturbances, headache, nausea, and sexual dysfunction. It is important to note that SSRIs should be used with caution during pregnancy, and paroxetine should be avoided in women considering pregnancy in the near future.

Other antidepressant classes have been studied to a lesser extent than SSRIs. Continuously dosed venlafaxine, a serotonin and norepinephrine reuptake inhibitor, demonstrated efficacy in PMS/PMDD treatment when compared with placebo within the first cycle of therapy.³⁹ The response seen was comparable to that associated with SSRI treatments in other trials.

Buspirone, an anxiolytic with serotonin receptor activity that is different from that of the SSRIs, demonstrated efficacy in reducing the symptom of irritability.⁴⁸ Buspirone may have a role to play in those presenting with irritability as a primary symptom or in those who are unable to tolerate the adverse effects of SSRIs. Tricyclic antidepressants, bupropion, and alprazolam have either limited data regarding efficacy or are associated with adverse effects that limit their use.³⁸

Hormonal treatments may be worth considering

One commonly prescribed hormonal therapy for PMS and PMDD is continuous OCs. A 2012 Cochrane review of OCs containing drospirenone evaluated 5 trials and a total of 1920 women.⁴⁰ Two placebo-controlled trials of women with severe premenstrual symptoms (PMDD) showed improvement after 3 months of taking daily drospirenone 3 mg with ethinyl estradiol 20 mcg, compared with placebo.

While experiencing greater benefit, these groups also experienced significantly more adverse effects including nausea, intermenstrual bleeding, and breast pain. The respective odds ratios for the 3 adverse effects were 3.15 (95% confidence interval [CI], 1.90-5.22), 4.92 (95% CI, 3.03-7.96), and 2.67 (95% CI, 1.50-4.78). The review concluded that drospirenone 3 mg with ethinyl estradiol 20 mcg may help in the treatment of severe premenstrual symptoms (PMDD) but that it is unknown whether this treatment is appropriate for patients with less severe premenstrual symptoms.

Continue to: Another multicenter RCT

Another multicenter RCT evaluated women with PMDD who received levonorgestrel 90 mcg with ethinyl estradiol 20 mcg or placebo daily for 112 days.⁴¹ Symptoms were recorded utilizing the DRSP. Significantly more women taking the daily combination hormone (52%) than placebo (40%) had a positive response (≥ 50% improvement in the DRSP 7-day late luteal phase score and Clinical Global Impression of Severity score of ≥ 1 improvement, evaluated at the last “on-therapy” cycle [P = .025]). Twenty-three of 186 patients in the treatment arm dropped out because of adverse effects.

Noncontraceptive estrogen-containing preparations. Hormone therapy preparations containing lower doses of estrogen than seen in OC preparations have also been studied for PMS management. A 2017 Cochrane review of noncontraceptive estrogen-containing preparations found very low-quality evidence to support the effectiveness of continuous estrogen (transdermal patches or subcutaneous implants) plus progestogen.⁴⁹

Progesterone. The cyclic use of progesterone in the luteal phase has been reviewed as a hormonal treatment for PMS. A 2012 Cochrane review of the efficacy of progesterone for PMS was inconclusive; however, route of administration, dose, and duration differed across studies.⁴²

Another systematic review of 10 trials involving 531 women concluded that progesterone was no better than placebo in the treatment of PMS.⁴³ However, it should be noted that each trial evaluated a different dose of progesterone, and all but 1 of the trials administered progesterone by using the calendar method to predict the beginning of the luteal phase. The only trial to use an objective confirmation of ovulation prior to beginning progesterone therapy did demonstrate significant improvement in premenstrual symptoms.

This 1985 study by Dennerstein et al⁴⁴ prescribed progesterone for 10 days of each menstrual cycle starting 3 days after ovulation. In each cycle, ovulation was confirmed by determinations of urinary 24-hour pregnanediol and total estrogen concentrations. Progesterone was then prescribed during the objectively identified luteal phase, resulting in significant improvement in symptoms.

Continue to: Another study evaluated...

The benefits of SSRIs are noted much earlier in the treatment of PMS/PMDD than they are observed in their use for depression or anxiety.

Another study evaluated the post-ovulatory progesterone profiles of 77 women with symptoms of PMS and found lower levels of progesterone and a sharper rate of decline in the women with PMS vs the control group.⁴⁵ Subsequent progesterone treatment during the objectively identified luteal phase significantly improved PMS symptoms. These studies would seem to suggest that progesterone replacement when administered during an objectively identified luteal phase may offer some benefit in the treatment of PMS, but larger RCTs are needed to confirm this.

CASE

You provide the patient with diet and lifestyle education as well as a recommendation for calcium supplementation. The patient agrees to prospectively chart her most significant premenstrual symptoms. You review additional treatment options including SSRI medications and hormonal approaches. She is using a fertility awareness–based method of family planning that allows her to confidently identify her luteal phase. She agrees to take sertraline 50 mg/d during the luteal phase of her cycle. At her follow-up office visit 3 months later, she reports improvement in her premenstrual symptoms. Her charting of symptoms confirms this.

CORRESPONDENCE
Peter Danis, MD, Mercy Family Medicine St. Louis, 12680 Olive Boulevard, St. Louis, MO 63141; [email protected].

CASE

A 30-year-old G2P2 woman presents for a well-woman visit and reports 6 months of premenstrual symptoms including irritability, depression, breast pain, and headaches. She is not taking any medications or hormonal contraceptives. She is sexually active and currently not interested in becoming pregnant. She asks what you can do for her symptoms, as they are affecting her life at home and at work.

Symptoms and definitions vary

Although more than 150 premenstrual symptoms have been reported, the most common psychological and behavioral ones are mood swings, depression, anxiety, irritability, crying, social withdrawal, forgetfulness, and problems concentrating.^1-3 The most common physical symptoms are fatigue, abdominal bloating, weight gain, breast tenderness, acne, change in appetite or food cravings, edema, headache, and gastrointestinal upset. The etiology of these symptoms is usually multifactorial, with some combination of hormonal, neurotransmitter, lifestyle, environmental, and psychosocial factors playing a role.

Premenstrual disorder. In reviewing diagnostic criteria for the various premenstrual syndromes and disorders from different organizations (eg, the International Society for Premenstrual Disorders; the American College of Obstetricians and Gynecologists; the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), there is agreement on the following criteria for premenstrual syndrome (PMS)^4-6:

• The woman must be ovulating. (Women who no longer menstruate [eg, because of hysterectomy or endometrial ablation] can have premenstrual disorders as long as ovarian function remains intact.)
• The woman experiences a constellation of disabling physical and/or psychological symptoms that appears in the luteal phase of her menstrual cycle.
• The symptoms improve soon after the onset of menses.
• There is a symptom-free interval before ovulation.
• There is prospective documentation of symptoms for at least 2 consecutive cycles.
• The symptoms are sufficient in severity to affect activities of daily living and/or important relationships.

Premenstrual dysphoric disorder. PMDD is another common premenstrual disorder. It is distinguished by significant premenstrual psychological symptoms and requires the presence of marked affective lability, marked irritability or anger, markedly depressed mood, and/or marked anxiety (TABLE 1).⁷

Exacerbation of other ailments. Another premenstrual disorder is the premenstrual exacerbation of underlying chronic medical or psychological problems such as migraines, seizures, asthma, diabetes, irritable bowel syndrome, fibromyalgia, anxiety, or depression.

Differences in interpretation lead to variations in prevalence

Differences in the interpretation of significant premenstrual symptoms have led to variations in estimated prevalence. For example, 80% to 95% of women report premenstrual symptoms, but only 30% to 40% meet criteria for PMS and only 3% to 8% meet criteria for PMDD.⁸ Many women who report premenstrual symptoms in a retrospective questionnaire do not meet criteria for PMS or PMDD based on prospective symptom charting. The Daily Record of Severity of Problems (DRSP), a prospective tracking tool for premenstrual symptoms, is sensitive and specific for diagnosing PMS and PMDD if administered on the first day of menstruation.⁹

Ask about symptoms and use a tracking tool

When you see a woman for a well-woman visit or a gynecologic problem, inquire about physical/emotional symptoms and their severity during the week that precedes menstruation. If a patient reports few symptoms of a mild nature, then no further work-up is needed.

Continue to: If patients report significant...

Women who no longer menstruate can have premenstrual disorders as long as ovarian function remains intact.

If patients report significant premenstrual symptoms, recommend the use of a tool to track the symptoms. Older tools such as the DRSP and the Premenstrual Symptoms Screening Tool (PSST), newer symptom diaries that can be used for both PMS and PMDD,and questionnaires that have been used in research situations can be time consuming and difficult for patients to complete.^10-12 Instead, physicians can easily construct their own charting tool, as we did for patients to use when tracking their most bothersome symptoms (FIGURE 1). Tracking helps to confirm the diagnosis and helps you and the patient focus on treatment goals.

Keep in mind other diagnoses (eg, anemia, thyroid disorders, perimenopause, anxiety, depression, eating disorders, substance abuse) that can cause or exacerbate the psychological/physical symptoms the patient is reporting. If you suspect any of these other diagnoses, laboratory evaluation (eg, complete blood count, thyroid-stimulating hormone level or other hormonal testing, urine drug screen, etc) may be warranted to rule out other etiologies for the reported symptoms.

Develop a Tx plan that ­considers symptoms, family-planning needs

Focus treatment on the patient’s predominant symptoms whether they are physical, psychological, or mixed (FIGURE 2). The patient’s preferences regarding family planning are another important consideration. Women who are using a fertility awareness–based method of family planning may not desire a contraceptive hormonal treatment for their premenstrual disorder. Also, patients may have cultural and/or religious beliefs that need to be respected.

Although the definitions for PMS and PMDD require at least 2 cycles of prospective documentation of symptoms, dietary and lifestyle changes can begin immediately. Regular follow-up to document improvement of symptoms is important; using the patient’s symptoms charting tool can help with this.

Focus on diet and lifestyle right away

Experts in the field of PMS/PMDD suggest that simple dietary changes may be a reasonable first step to help improve symptoms. Researchers have found that diets high in fiber, vegetables, and whole grains are inversely related to PMS.¹³ Older studies have suggested an increased prevalence and severity of PMS with increased caffeine intake; however, a newer study found no such association.¹⁴

Continue to: A case-control study nested...

Focus treatment on the patient’s predominant symptoms, whether they are physical, psychological, or mixed.

A case-control study nested within the Nurses’ Health Study II cohort showed that a high intake of both dietary calcium and vitamin D prevented the development of PMS in women ages 27 to 44.¹⁵ B vitamins, such as thiamine and riboflavin, from food sources have been associated with a lower risk of PMS.¹⁶ A variety of older clinical studies showed benefit from aerobic exercise on PMS symptoms,^17-19 but a newer cross-sectional study of young adult women found no association between physical activity and the prevalence of PMS.²⁰ Acupuncture has demonstrated efficacy for the treatment of the physical symptoms of PMS and PMDD, but more rigorous studies are needed.^21,22 Cognitive behavioral therapy has been studied as a treatment, but data to support this approach are limited so it cannot be recommended at this time.²³

Make the most of supplements—especially calcium

Calcium is the nutritional supplement with the most evidence to support its use to relieve symptoms of PMS and PMDD (TABLE 2^21,22,24-45). Research indicates that disturbances in calcium regulation and calcium deficiency may be responsible for various premenstrual symptoms. One study showed that, compared with placebo, women who took 1200 mg/d calcium carbonate for 3 menstrual cycles had a 48% decrease in both somatic and affective symptoms.²⁴ Another trial demonstrated improvement in PMS symptoms of early tiredness, appetite changes, and depression with calcium therapy.²⁵

Pyridoxine (vitamin B6) has potential benefit in treating PMS due to its ability to increase levels of serotonin, norepinephrine, histamine, dopamine, and taurine.²⁶ An older systematic review showed benefit for symptoms associated with PMS, but the authors concluded that larger randomized controlled trials (RCTs) were needed before definitive recommendations could be made.²⁷

Chasteberry. A number of studies have evaluated the effect of vitex agnus castus (VAC), commonly referred to as chasteberry, on PMS and PMDD symptoms. The exact mechanism of VAC is unknown, but in vitro studies show binding of VAC extracts to dopamine-2 receptors and opioid receptors, and an affinity for estrogen receptors.²⁸

A recent meta-analysis concluded that VAC extracts are not superior to selective serotonin reuptake inhibitors (SSRIs) or oral contraceptives (OCs) for PMS/PMDD.²⁸ The authors suggested a possible benefit of VAC compared with placebo or other nutritional supplements; however, the studies supporting its use are limited by small sample size and potential bias.

Continue to: Magnesium

Magnesium. Many small studies have evaluated the role of other herbal and nutritional supplements for the treatment of PMS/PMDD. A systematic review of studies on the effect of magnesium supplementation on anxiety and stress showed that magnesium may have a potential role in the treatment of the premenstrual symptom of anxiety.²⁹ Other studies have demonstrated a potential role in the treatment of premenstrual migraine.^30,31

Vitamin E has demonstrated benefit in the treatment of cyclic mastalgia; however, evidence for using vitamin E for mood and depressive symptoms associated with PMS and PMDD is inconsistent.^32-34 Other studies involving vitamin D, St. John’s wort, black cohosh, evening primrose oil, saffron, and ginkgo biloba either showed these agents to be nonefficacious in relieving PMS/PMDD symptoms or to require more data before they can be recommended for use.^34,46

Patient doesn’t respond? Start an SSRI

Pharmacotherapy with antidepressants is typically reserved for those who do not respond to nonpharmacologic therapies and are experiencing more moderate to severe symptoms of PMS or PMDD. Reduced levels of serotonin and serotonergic activity in the brain may be linked to symptoms of PMS and PMDD.⁴⁷ Studies have shown SSRIs to be effective in reducing many psychological symptoms (eg, depression, anxiety, lethargy, irritability) and some physical symptoms (eg, headache, breast tenderness, muscle or joint pain) associated with PMS and PMDD.

A Cochrane review of 31 RCTs compared various SSRIs to placebo. When taken either continuously or intermittently (administration during luteal phase), SSRIs were similarly effective in relieving symptoms when compared with placebo.³⁵ Psychological symptoms are more likely to improve with both low and moderate doses of SSRIs, while physical symptoms may only improve with moderate or higher doses. A direct comparison of the various SSRIs for the treatment of PMS or PMDD is lacking; therefore, the selection of SSRI may be based on patient characteristics and preference.

The benefits of SSRIs are noted much earlier in the treatment of PMS/PMDD than they are observed in their use for depression or anxiety.³⁶ This suggests that the mechanism by which SSRIs relieve PMS/PMDD symptoms is different than that for depression or anxiety. Intermittent dosing capitalizes upon the rapid effect seen with these medications and the cyclical nature of these disorders. In most studies, the benefit of intermittent dosing is similar to continuous dosing; however, one meta-analysis did note that continuous dosing had a larger effect.³⁷

Continue to: The doses of SSRIs...

Although the definitions for PMS and PMDD require at least 2 cycles of prospective documentation of symptoms, diet and lifestyle changes can begin immediately.

The doses of SSRIs used in most PMS/PMDD trials were lower than those typically used for the treatment of depression and anxiety. The withdrawal effect that can be seen with abrupt cessation of SSRIs has not been reported in the intermittent-dosing studies for PMS/PMDD.³⁸ While this might imply a more tolerable safety profile, the most common adverse effects reported in trials were still as expected: sleep disturbances, headache, nausea, and sexual dysfunction. It is important to note that SSRIs should be used with caution during pregnancy, and paroxetine should be avoided in women considering pregnancy in the near future.

Other antidepressant classes have been studied to a lesser extent than SSRIs. Continuously dosed venlafaxine, a serotonin and norepinephrine reuptake inhibitor, demonstrated efficacy in PMS/PMDD treatment when compared with placebo within the first cycle of therapy.³⁹ The response seen was comparable to that associated with SSRI treatments in other trials.

Buspirone, an anxiolytic with serotonin receptor activity that is different from that of the SSRIs, demonstrated efficacy in reducing the symptom of irritability.⁴⁸ Buspirone may have a role to play in those presenting with irritability as a primary symptom or in those who are unable to tolerate the adverse effects of SSRIs. Tricyclic antidepressants, bupropion, and alprazolam have either limited data regarding efficacy or are associated with adverse effects that limit their use.³⁸

Hormonal treatments may be worth considering

One commonly prescribed hormonal therapy for PMS and PMDD is continuous OCs. A 2012 Cochrane review of OCs containing drospirenone evaluated 5 trials and a total of 1920 women.⁴⁰ Two placebo-controlled trials of women with severe premenstrual symptoms (PMDD) showed improvement after 3 months of taking daily drospirenone 3 mg with ethinyl estradiol 20 mcg, compared with placebo.

While experiencing greater benefit, these groups also experienced significantly more adverse effects including nausea, intermenstrual bleeding, and breast pain. The respective odds ratios for the 3 adverse effects were 3.15 (95% confidence interval [CI], 1.90-5.22), 4.92 (95% CI, 3.03-7.96), and 2.67 (95% CI, 1.50-4.78). The review concluded that drospirenone 3 mg with ethinyl estradiol 20 mcg may help in the treatment of severe premenstrual symptoms (PMDD) but that it is unknown whether this treatment is appropriate for patients with less severe premenstrual symptoms.

Continue to: Another multicenter RCT

Another multicenter RCT evaluated women with PMDD who received levonorgestrel 90 mcg with ethinyl estradiol 20 mcg or placebo daily for 112 days.⁴¹ Symptoms were recorded utilizing the DRSP. Significantly more women taking the daily combination hormone (52%) than placebo (40%) had a positive response (≥ 50% improvement in the DRSP 7-day late luteal phase score and Clinical Global Impression of Severity score of ≥ 1 improvement, evaluated at the last “on-therapy” cycle [P = .025]). Twenty-three of 186 patients in the treatment arm dropped out because of adverse effects.

Noncontraceptive estrogen-containing preparations. Hormone therapy preparations containing lower doses of estrogen than seen in OC preparations have also been studied for PMS management. A 2017 Cochrane review of noncontraceptive estrogen-containing preparations found very low-quality evidence to support the effectiveness of continuous estrogen (transdermal patches or subcutaneous implants) plus progestogen.⁴⁹

Progesterone. The cyclic use of progesterone in the luteal phase has been reviewed as a hormonal treatment for PMS. A 2012 Cochrane review of the efficacy of progesterone for PMS was inconclusive; however, route of administration, dose, and duration differed across studies.⁴²

Another systematic review of 10 trials involving 531 women concluded that progesterone was no better than placebo in the treatment of PMS.⁴³ However, it should be noted that each trial evaluated a different dose of progesterone, and all but 1 of the trials administered progesterone by using the calendar method to predict the beginning of the luteal phase. The only trial to use an objective confirmation of ovulation prior to beginning progesterone therapy did demonstrate significant improvement in premenstrual symptoms.

This 1985 study by Dennerstein et al⁴⁴ prescribed progesterone for 10 days of each menstrual cycle starting 3 days after ovulation. In each cycle, ovulation was confirmed by determinations of urinary 24-hour pregnanediol and total estrogen concentrations. Progesterone was then prescribed during the objectively identified luteal phase, resulting in significant improvement in symptoms.

Continue to: Another study evaluated...

The benefits of SSRIs are noted much earlier in the treatment of PMS/PMDD than they are observed in their use for depression or anxiety.

Another study evaluated the post-ovulatory progesterone profiles of 77 women with symptoms of PMS and found lower levels of progesterone and a sharper rate of decline in the women with PMS vs the control group.⁴⁵ Subsequent progesterone treatment during the objectively identified luteal phase significantly improved PMS symptoms. These studies would seem to suggest that progesterone replacement when administered during an objectively identified luteal phase may offer some benefit in the treatment of PMS, but larger RCTs are needed to confirm this.

CASE

You provide the patient with diet and lifestyle education as well as a recommendation for calcium supplementation. The patient agrees to prospectively chart her most significant premenstrual symptoms. You review additional treatment options including SSRI medications and hormonal approaches. She is using a fertility awareness–based method of family planning that allows her to confidently identify her luteal phase. She agrees to take sertraline 50 mg/d during the luteal phase of her cycle. At her follow-up office visit 3 months later, she reports improvement in her premenstrual symptoms. Her charting of symptoms confirms this.

CORRESPONDENCE
Peter Danis, MD, Mercy Family Medicine St. Louis, 12680 Olive Boulevard, St. Louis, MO 63141; [email protected].

A Washington Post article on depression after miscarriage is a reminder that, although couples can suffer deeply from such a loss, there still are ways to provide them with meaningful support (“After miscarriage, I was rocked by depression. Like many other women, I didn’t get follow-up care for this loss,” by Katie C. Reilly, Nov 30, 2019).

Carlo107/Getty Images

Psychiatrists who focus on reproductive psychiatry and collaborative care are trying to change the current therapeutic landscape and improve practitioner awareness and treatment. Ob.gyns. managing patients who have experienced reproductive loss, especially early-term loss, may not immediately refer couples to a therapist or psychiatrist, but we can change this. Practitioners who focus on reproductive health – both physical and mental – are trying to better understand such couples’ experiences, increase their access to care, develop preventative care strategies, and improve provider education.

At the outset, providers who treat patients who have experienced a perinatal loss must recognize that not all individuals will feel that a loss is tragic. Instead, patient reactions occur along a spectrum, and there is no “correct” way to process a loss. A couple’s reaction may depend on a variety of factors, including how late or early in pregnancy the loss occurs, whether the pregnancy is planned or unplanned, and what other psychosocial stressors, such as unstable housing, limited income, and few social supports, may exist. Not every patient experiencing grief, even profoundly, will shed tears; we need to be open to all potential reactions and be mindful when a person may need additional support.

According to the Washington Post article, even though 50% of miscarriages are due to chromosomal abnormalities, women still feel ultimately responsible for the loss. As a society we are bombarded with “experts” in the media telling us the best way, the right way, the healthiest way to live. This barrage of advice distorts our views of what it really means to be a good parent and subtly conveys the idea that mothers are solely responsible for any bad pregnancy outcomes. I remember being fearful of causing unintentional harm to my unborn baby during my own pregnancy. What if I accidentally ate something that would affect her development? Is exposure to second-hand smoke as I walk down the street harming her? How bad would it be if I just had one cup of coffee? My doubts caused quite a bit of distress for me, which is a mild form of the distress I see when counseling couples after their miscarriages.

The article’s author also expressed concern about the emotional sterility of the environment in which miscarriages usually occur: a hospital ED. EDs are designed to promote a level of detachment and to quell any stress for the clinicians so that they can calmly handle unexpected health crises. EDs are not primarily designed to provide patients with emotional support, nor should they be. However, we still can make some improvements to existing ED design to better address couples’ emotional needs. For example, some EDs have placed mental health clinicians on staff, others call patients post discharge to address concerns, and some EDs even provide patients access to mental health trauma teams. Such services are not found in all EDs, and even those that exist may just scratch the surface of what is needed, but they are a step in the right direction. Providing this level of auxiliary care directly from the ED increases patients’ ability to access mental health support in the place where miscarriages are most likely to be first diagnosed and managed.

The American College of Obstetricians and Gynecologists already is trying to fill in the missing pieces when it comes to identifying mood symptoms following miscarriage. One of the key recommendations from the May 2018 Committee Opinion on Redefining the Postpartum Visit is that every woman who has experienced a miscarriage, stillbirth, or neonatal death should receive follow-up care. Mental health is a suggested component of the postpartum care plan. Some outpatient ob.gyn. practices and inpatient units are using screening tools to identify postpartum depression. For example, the Edinburgh Postnatal Depression Scale can be utilized following a miscarriage to help providers identify symptoms of depression and anxiety.

However, advancements in screening practices are only the tip of the iceberg of helping patients following miscarriage. A major question is how do we provide treatment? The trend in psychiatry over the past decade has been toward collaborative care, models that embed psychiatrists and other mental health clinicians in ob.gyn. practices to help guide the diagnosis and treatment of mental health problems. Some psychiatrists practice a co-located model in which they see patients alongside their ob.gyn. colleagues, whereas other psychiatrists treat a larger number of patients by using chart reviews for medication management while relying on behavioral health care managers for counseling and monitoring. Using this model of mental health care, more patients have access to services that are provided in a location familiar to them.

Another step in the right direction is the October 2019 launch of The National Curriculum in Reproductive Psychiatry (NCRP), which provides free educational material for psychiatry faculty and residents to enhance education on topics related to reproductive psychiatry, including miscarriage, loss, and development of trauma disorders. NCRP aspires to develop educational materials for ob.gyn. residents.

In the past we may have missed the mark in recognizing and treating the trauma that prenatal loss can cause, but we are trying to improve our approaches. More and more couples are sharing their experiences and advocating for themselves and others, often creating change in medical practice, and doctors are starting to listen. As any clinician knows, changes to standards of care can take several years to disseminate into general practice, but this gap between knowledge and treatment is now in the forefront of our minds. I am hopeful that we will continue to make advances and provide better care to our patients who have endured the loss of a pregnancy.
 

Dr. Latorre is an assistant professor in the department of psychiatry at the University of Maryland School of Medicine. She has reported no relevant financial disclosures. Email her at [email protected].

A Washington Post article on depression after miscarriage is a reminder that, although couples can suffer deeply from such a loss, there still are ways to provide them with meaningful support (“After miscarriage, I was rocked by depression. Like many other women, I didn’t get follow-up care for this loss,” by Katie C. Reilly, Nov 30, 2019).

Carlo107/Getty Images

Psychiatrists who focus on reproductive psychiatry and collaborative care are trying to change the current therapeutic landscape and improve practitioner awareness and treatment. Ob.gyns. managing patients who have experienced reproductive loss, especially early-term loss, may not immediately refer couples to a therapist or psychiatrist, but we can change this. Practitioners who focus on reproductive health – both physical and mental – are trying to better understand such couples’ experiences, increase their access to care, develop preventative care strategies, and improve provider education.

At the outset, providers who treat patients who have experienced a perinatal loss must recognize that not all individuals will feel that a loss is tragic. Instead, patient reactions occur along a spectrum, and there is no “correct” way to process a loss. A couple’s reaction may depend on a variety of factors, including how late or early in pregnancy the loss occurs, whether the pregnancy is planned or unplanned, and what other psychosocial stressors, such as unstable housing, limited income, and few social supports, may exist. Not every patient experiencing grief, even profoundly, will shed tears; we need to be open to all potential reactions and be mindful when a person may need additional support.

According to the Washington Post article, even though 50% of miscarriages are due to chromosomal abnormalities, women still feel ultimately responsible for the loss. As a society we are bombarded with “experts” in the media telling us the best way, the right way, the healthiest way to live. This barrage of advice distorts our views of what it really means to be a good parent and subtly conveys the idea that mothers are solely responsible for any bad pregnancy outcomes. I remember being fearful of causing unintentional harm to my unborn baby during my own pregnancy. What if I accidentally ate something that would affect her development? Is exposure to second-hand smoke as I walk down the street harming her? How bad would it be if I just had one cup of coffee? My doubts caused quite a bit of distress for me, which is a mild form of the distress I see when counseling couples after their miscarriages.

The article’s author also expressed concern about the emotional sterility of the environment in which miscarriages usually occur: a hospital ED. EDs are designed to promote a level of detachment and to quell any stress for the clinicians so that they can calmly handle unexpected health crises. EDs are not primarily designed to provide patients with emotional support, nor should they be. However, we still can make some improvements to existing ED design to better address couples’ emotional needs. For example, some EDs have placed mental health clinicians on staff, others call patients post discharge to address concerns, and some EDs even provide patients access to mental health trauma teams. Such services are not found in all EDs, and even those that exist may just scratch the surface of what is needed, but they are a step in the right direction. Providing this level of auxiliary care directly from the ED increases patients’ ability to access mental health support in the place where miscarriages are most likely to be first diagnosed and managed.

The American College of Obstetricians and Gynecologists already is trying to fill in the missing pieces when it comes to identifying mood symptoms following miscarriage. One of the key recommendations from the May 2018 Committee Opinion on Redefining the Postpartum Visit is that every woman who has experienced a miscarriage, stillbirth, or neonatal death should receive follow-up care. Mental health is a suggested component of the postpartum care plan. Some outpatient ob.gyn. practices and inpatient units are using screening tools to identify postpartum depression. For example, the Edinburgh Postnatal Depression Scale can be utilized following a miscarriage to help providers identify symptoms of depression and anxiety.

However, advancements in screening practices are only the tip of the iceberg of helping patients following miscarriage. A major question is how do we provide treatment? The trend in psychiatry over the past decade has been toward collaborative care, models that embed psychiatrists and other mental health clinicians in ob.gyn. practices to help guide the diagnosis and treatment of mental health problems. Some psychiatrists practice a co-located model in which they see patients alongside their ob.gyn. colleagues, whereas other psychiatrists treat a larger number of patients by using chart reviews for medication management while relying on behavioral health care managers for counseling and monitoring. Using this model of mental health care, more patients have access to services that are provided in a location familiar to them.

Another step in the right direction is the October 2019 launch of The National Curriculum in Reproductive Psychiatry (NCRP), which provides free educational material for psychiatry faculty and residents to enhance education on topics related to reproductive psychiatry, including miscarriage, loss, and development of trauma disorders. NCRP aspires to develop educational materials for ob.gyn. residents.

In the past we may have missed the mark in recognizing and treating the trauma that prenatal loss can cause, but we are trying to improve our approaches. More and more couples are sharing their experiences and advocating for themselves and others, often creating change in medical practice, and doctors are starting to listen. As any clinician knows, changes to standards of care can take several years to disseminate into general practice, but this gap between knowledge and treatment is now in the forefront of our minds. I am hopeful that we will continue to make advances and provide better care to our patients who have endured the loss of a pregnancy.
 

Dr. Latorre is an assistant professor in the department of psychiatry at the University of Maryland School of Medicine. She has reported no relevant financial disclosures. Email her at [email protected].

A Washington Post article on depression after miscarriage is a reminder that, although couples can suffer deeply from such a loss, there still are ways to provide them with meaningful support (“After miscarriage, I was rocked by depression. Like many other women, I didn’t get follow-up care for this loss,” by Katie C. Reilly, Nov 30, 2019).

Carlo107/Getty Images

Psychiatrists who focus on reproductive psychiatry and collaborative care are trying to change the current therapeutic landscape and improve practitioner awareness and treatment. Ob.gyns. managing patients who have experienced reproductive loss, especially early-term loss, may not immediately refer couples to a therapist or psychiatrist, but we can change this. Practitioners who focus on reproductive health – both physical and mental – are trying to better understand such couples’ experiences, increase their access to care, develop preventative care strategies, and improve provider education.

At the outset, providers who treat patients who have experienced a perinatal loss must recognize that not all individuals will feel that a loss is tragic. Instead, patient reactions occur along a spectrum, and there is no “correct” way to process a loss. A couple’s reaction may depend on a variety of factors, including how late or early in pregnancy the loss occurs, whether the pregnancy is planned or unplanned, and what other psychosocial stressors, such as unstable housing, limited income, and few social supports, may exist. Not every patient experiencing grief, even profoundly, will shed tears; we need to be open to all potential reactions and be mindful when a person may need additional support.

According to the Washington Post article, even though 50% of miscarriages are due to chromosomal abnormalities, women still feel ultimately responsible for the loss. As a society we are bombarded with “experts” in the media telling us the best way, the right way, the healthiest way to live. This barrage of advice distorts our views of what it really means to be a good parent and subtly conveys the idea that mothers are solely responsible for any bad pregnancy outcomes. I remember being fearful of causing unintentional harm to my unborn baby during my own pregnancy. What if I accidentally ate something that would affect her development? Is exposure to second-hand smoke as I walk down the street harming her? How bad would it be if I just had one cup of coffee? My doubts caused quite a bit of distress for me, which is a mild form of the distress I see when counseling couples after their miscarriages.

The article’s author also expressed concern about the emotional sterility of the environment in which miscarriages usually occur: a hospital ED. EDs are designed to promote a level of detachment and to quell any stress for the clinicians so that they can calmly handle unexpected health crises. EDs are not primarily designed to provide patients with emotional support, nor should they be. However, we still can make some improvements to existing ED design to better address couples’ emotional needs. For example, some EDs have placed mental health clinicians on staff, others call patients post discharge to address concerns, and some EDs even provide patients access to mental health trauma teams. Such services are not found in all EDs, and even those that exist may just scratch the surface of what is needed, but they are a step in the right direction. Providing this level of auxiliary care directly from the ED increases patients’ ability to access mental health support in the place where miscarriages are most likely to be first diagnosed and managed.

The American College of Obstetricians and Gynecologists already is trying to fill in the missing pieces when it comes to identifying mood symptoms following miscarriage. One of the key recommendations from the May 2018 Committee Opinion on Redefining the Postpartum Visit is that every woman who has experienced a miscarriage, stillbirth, or neonatal death should receive follow-up care. Mental health is a suggested component of the postpartum care plan. Some outpatient ob.gyn. practices and inpatient units are using screening tools to identify postpartum depression. For example, the Edinburgh Postnatal Depression Scale can be utilized following a miscarriage to help providers identify symptoms of depression and anxiety.

However, advancements in screening practices are only the tip of the iceberg of helping patients following miscarriage. A major question is how do we provide treatment? The trend in psychiatry over the past decade has been toward collaborative care, models that embed psychiatrists and other mental health clinicians in ob.gyn. practices to help guide the diagnosis and treatment of mental health problems. Some psychiatrists practice a co-located model in which they see patients alongside their ob.gyn. colleagues, whereas other psychiatrists treat a larger number of patients by using chart reviews for medication management while relying on behavioral health care managers for counseling and monitoring. Using this model of mental health care, more patients have access to services that are provided in a location familiar to them.

Another step in the right direction is the October 2019 launch of The National Curriculum in Reproductive Psychiatry (NCRP), which provides free educational material for psychiatry faculty and residents to enhance education on topics related to reproductive psychiatry, including miscarriage, loss, and development of trauma disorders. NCRP aspires to develop educational materials for ob.gyn. residents.

In the past we may have missed the mark in recognizing and treating the trauma that prenatal loss can cause, but we are trying to improve our approaches. More and more couples are sharing their experiences and advocating for themselves and others, often creating change in medical practice, and doctors are starting to listen. As any clinician knows, changes to standards of care can take several years to disseminate into general practice, but this gap between knowledge and treatment is now in the forefront of our minds. I am hopeful that we will continue to make advances and provide better care to our patients who have endured the loss of a pregnancy.
 

Dr. Latorre is an assistant professor in the department of psychiatry at the University of Maryland School of Medicine. She has reported no relevant financial disclosures. Email her at [email protected].