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No link found between sleep position, pregnancy outcomes
such as stillbirth, small-for-gestational-age (SGA) newborns, and gestational hypertensive disorders. The finding, published in the October issue of Obstetrics & Gynecology, conflicts with previous retrospective case-control studies that suggested left-side sleeping may lead to reduced risk. The disagreement may be due to the prospective nature of the new study, which followed 8,706 women over 4 years.
Right-side or back sleeping had attracted suspicion because of its potential to compress uterine blood vessels and decrease uterine blood flow, and various public health campaigns urge pregnant women to sleep on their left side. Although case-control studies backed up those worries, those retrospective approaches can suffer from limitations including recall bias, in which grieving mothers overreport suspect sleeping behaviors, perhaps in search of an explanation for their loss.
Prospective analyses can counter some of those limitations. The researchers, led by Robert Silver, MD, of the University of Utah, Salt Lake City, conducted a secondary analysis of the nuMoM2b study, examining adverse pregnancy outcomes and risk factors. It was a multicenter observational cohort study of 8,706 nulliparous women with singleton gestations who completed two sleep questionnaires: one between 6 and 13 weeks of gestation, and one between 22 and 29 weeks.
Adverse outcomes occurred in 1,903 women, including 178 cases of both SGA and hypertensive disorders, 8 with SGA plus stillbirth, 3 with hypertensive disorders plus stillbirth, and 2 cases with all three complications.
The researchers found no association between any adverse outcomes and sleep position either at the first visit in early pregnancy (adjusted odds ratio, 1.00; 95% confidence interval, 0.89-1.14) or the third visit in midpregnancy (aOR, 0.99; 95% CI, 0.89-1.11). Propensity score matching to adjust non-left lateral positioning to the composite outcome also showed no association.
In midpregnancy, there was an association between non-left lateral sleeping and reduced risk of stillbirth (aOR, 0.27; 95% CI, 0.09-0.75). “This observation is likely spurious owing to small numbers of stillbirths, Dr. Silver and associates said.
A post hoc analysis indicated that the study was sufficiently powered to detect clinically meaningful risks; ORs of 1.2 for hypertensive disorders, 1.23 for SGA, 2.4 for stillbirth, and 1.2 for the composite outcome.
Let sleeping mothers lie
Pregnant women have enough on their minds. They shouldn’t have to worry about sleep position as well, according to Nathan Fox, MD, professor of obstetrics, gynecology, and reproductive science at Icahn School of Medicine at Mount Sinai, New York, and Emily Oster, PhD, economist at Brown University, Providence, R.I., who wrote an accompanying editorial.
It may seem harmless to direct women to sleep on their left side even if it has no benefit, but restricting a woman’s sleep options may leave her less well rested at a time when she is about to enter a period of sleep deprivation, as well as contribute to general discomfort, in their opinion.
Also, in the rare cases of a bad outcome, advice based on limited or poor quality evidence contributes to “devastating and unwarranted feelings of responsibility and guilt, and this harm to women already suffering from sadness and despair must not be minimized,” they said.
The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and grants from multiple universities. One author received research funding from Kyndermed through her institution. Another receives royalties from UpToDate.com. Dr. Fox and Dr. Oster have no relevant financial disclosures.
SOURCES: Silver RM et al. Obstet Gynecol. 2019. doi: 10.1097/AOG.0000000000003458; Fox N and Oster E. Obstet. Gynecol. 2019 Oct. doi: 10.1097/AOG.0000000000003466
such as stillbirth, small-for-gestational-age (SGA) newborns, and gestational hypertensive disorders. The finding, published in the October issue of Obstetrics & Gynecology, conflicts with previous retrospective case-control studies that suggested left-side sleeping may lead to reduced risk. The disagreement may be due to the prospective nature of the new study, which followed 8,706 women over 4 years.
Right-side or back sleeping had attracted suspicion because of its potential to compress uterine blood vessels and decrease uterine blood flow, and various public health campaigns urge pregnant women to sleep on their left side. Although case-control studies backed up those worries, those retrospective approaches can suffer from limitations including recall bias, in which grieving mothers overreport suspect sleeping behaviors, perhaps in search of an explanation for their loss.
Prospective analyses can counter some of those limitations. The researchers, led by Robert Silver, MD, of the University of Utah, Salt Lake City, conducted a secondary analysis of the nuMoM2b study, examining adverse pregnancy outcomes and risk factors. It was a multicenter observational cohort study of 8,706 nulliparous women with singleton gestations who completed two sleep questionnaires: one between 6 and 13 weeks of gestation, and one between 22 and 29 weeks.
Adverse outcomes occurred in 1,903 women, including 178 cases of both SGA and hypertensive disorders, 8 with SGA plus stillbirth, 3 with hypertensive disorders plus stillbirth, and 2 cases with all three complications.
The researchers found no association between any adverse outcomes and sleep position either at the first visit in early pregnancy (adjusted odds ratio, 1.00; 95% confidence interval, 0.89-1.14) or the third visit in midpregnancy (aOR, 0.99; 95% CI, 0.89-1.11). Propensity score matching to adjust non-left lateral positioning to the composite outcome also showed no association.
In midpregnancy, there was an association between non-left lateral sleeping and reduced risk of stillbirth (aOR, 0.27; 95% CI, 0.09-0.75). “This observation is likely spurious owing to small numbers of stillbirths, Dr. Silver and associates said.
A post hoc analysis indicated that the study was sufficiently powered to detect clinically meaningful risks; ORs of 1.2 for hypertensive disorders, 1.23 for SGA, 2.4 for stillbirth, and 1.2 for the composite outcome.
Let sleeping mothers lie
Pregnant women have enough on their minds. They shouldn’t have to worry about sleep position as well, according to Nathan Fox, MD, professor of obstetrics, gynecology, and reproductive science at Icahn School of Medicine at Mount Sinai, New York, and Emily Oster, PhD, economist at Brown University, Providence, R.I., who wrote an accompanying editorial.
It may seem harmless to direct women to sleep on their left side even if it has no benefit, but restricting a woman’s sleep options may leave her less well rested at a time when she is about to enter a period of sleep deprivation, as well as contribute to general discomfort, in their opinion.
Also, in the rare cases of a bad outcome, advice based on limited or poor quality evidence contributes to “devastating and unwarranted feelings of responsibility and guilt, and this harm to women already suffering from sadness and despair must not be minimized,” they said.
The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and grants from multiple universities. One author received research funding from Kyndermed through her institution. Another receives royalties from UpToDate.com. Dr. Fox and Dr. Oster have no relevant financial disclosures.
SOURCES: Silver RM et al. Obstet Gynecol. 2019. doi: 10.1097/AOG.0000000000003458; Fox N and Oster E. Obstet. Gynecol. 2019 Oct. doi: 10.1097/AOG.0000000000003466
such as stillbirth, small-for-gestational-age (SGA) newborns, and gestational hypertensive disorders. The finding, published in the October issue of Obstetrics & Gynecology, conflicts with previous retrospective case-control studies that suggested left-side sleeping may lead to reduced risk. The disagreement may be due to the prospective nature of the new study, which followed 8,706 women over 4 years.
Right-side or back sleeping had attracted suspicion because of its potential to compress uterine blood vessels and decrease uterine blood flow, and various public health campaigns urge pregnant women to sleep on their left side. Although case-control studies backed up those worries, those retrospective approaches can suffer from limitations including recall bias, in which grieving mothers overreport suspect sleeping behaviors, perhaps in search of an explanation for their loss.
Prospective analyses can counter some of those limitations. The researchers, led by Robert Silver, MD, of the University of Utah, Salt Lake City, conducted a secondary analysis of the nuMoM2b study, examining adverse pregnancy outcomes and risk factors. It was a multicenter observational cohort study of 8,706 nulliparous women with singleton gestations who completed two sleep questionnaires: one between 6 and 13 weeks of gestation, and one between 22 and 29 weeks.
Adverse outcomes occurred in 1,903 women, including 178 cases of both SGA and hypertensive disorders, 8 with SGA plus stillbirth, 3 with hypertensive disorders plus stillbirth, and 2 cases with all three complications.
The researchers found no association between any adverse outcomes and sleep position either at the first visit in early pregnancy (adjusted odds ratio, 1.00; 95% confidence interval, 0.89-1.14) or the third visit in midpregnancy (aOR, 0.99; 95% CI, 0.89-1.11). Propensity score matching to adjust non-left lateral positioning to the composite outcome also showed no association.
In midpregnancy, there was an association between non-left lateral sleeping and reduced risk of stillbirth (aOR, 0.27; 95% CI, 0.09-0.75). “This observation is likely spurious owing to small numbers of stillbirths, Dr. Silver and associates said.
A post hoc analysis indicated that the study was sufficiently powered to detect clinically meaningful risks; ORs of 1.2 for hypertensive disorders, 1.23 for SGA, 2.4 for stillbirth, and 1.2 for the composite outcome.
Let sleeping mothers lie
Pregnant women have enough on their minds. They shouldn’t have to worry about sleep position as well, according to Nathan Fox, MD, professor of obstetrics, gynecology, and reproductive science at Icahn School of Medicine at Mount Sinai, New York, and Emily Oster, PhD, economist at Brown University, Providence, R.I., who wrote an accompanying editorial.
It may seem harmless to direct women to sleep on their left side even if it has no benefit, but restricting a woman’s sleep options may leave her less well rested at a time when she is about to enter a period of sleep deprivation, as well as contribute to general discomfort, in their opinion.
Also, in the rare cases of a bad outcome, advice based on limited or poor quality evidence contributes to “devastating and unwarranted feelings of responsibility and guilt, and this harm to women already suffering from sadness and despair must not be minimized,” they said.
The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and grants from multiple universities. One author received research funding from Kyndermed through her institution. Another receives royalties from UpToDate.com. Dr. Fox and Dr. Oster have no relevant financial disclosures.
SOURCES: Silver RM et al. Obstet Gynecol. 2019. doi: 10.1097/AOG.0000000000003458; Fox N and Oster E. Obstet. Gynecol. 2019 Oct. doi: 10.1097/AOG.0000000000003466
FROM OBSTETRICS & GYNECOLOGY
Remember that preeclampsia has a ‘fourth trimester’
NEW ORLEANS – according to Natalie Bello, MD, a cardiologist and assistant professor of medicine at Columbia University in New York.
In medical school, “they told me that you deliver the placenta, and the preeclampsia goes away. Not the case. Postpartum preeclampsia is a real thing. We are seeing a lot of it at our sites, which have a lot of underserved women who hadn’t had great prenatal care” elsewhere, she said.
Headache and visual changes in association with hypertension during what’s been dubbed “the fourth trimester” raise suspicions. Women can progress rapidly to eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), but sometimes providers don’t recognize what’s going on because they don’t know women have recently given birth. “We can do better; we should be doing better. Please always ask women if they’ve delivered recently,” Dr. Bello said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
Hypertension should resolve within 6 weeks of delivery, and blood pressure should be back to baseline by 3 months. To make sure that happens, BP should be checked within a few days of birth and regularly thereafter. It can be tough to get busy and tired new moms back into the office, but “they’ll do whatever it takes” to get their baby to a pediatric appointment, so maybe having pediatricians involved in checking blood pressure would help, she said.
The cutoff point for hypertension in pregnancy is 140/90 mm Hg, and it’s considered severe when values hit 160/110 mm Hg or higher. Evidence is strong for treating severe hypertension to reduce strokes, placental abruptions, and other problems, but the data for treating nonsevere hypertension are less clear, Dr. Bello explained.
The Chronic Hypertension and Pregnancy (CHAP) trial is expected to fill the evidence gap in a few years; women are being randomized to start treatment at either 140/90 mm Hg or 160/105 mm Hg. Meanwhile, the American College of Obstetricians and Gynecologists recently suggested that treatment of nonsevere hypertension might be appropriate in the setting of comorbidities and renal dysfunction (Obstet Gynecol. 2019 Jan;133[1]:e26-e50).
Dr. Bello prefers treating with extended-release calcium channel blocker nifedipine over the beta-blocker labetalol. “We think it is a little more effective,” and the once daily dosing, instead of two or three times a day, helps with compliance. Thiazide diuretics and hydralazine are also in her arsenal, but hydralazine shouldn’t be used in isolation because of its reflex tachycardia risk. The old standby, the antiadrenergic methyldopa, has fallen out of favor because of depression and other concerns. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and mineralocorticoid receptor antagonists shouldn’t be used in pregnancy, she said.
Intravenous labetalol and short-acting oral nifedipine are the mainstays for urgent, severe hypertension, along with high-dose intravenous magnesium, especially for seizure control. IV hydralazine or nitroglycerin are other options, the latter particularly for pulmonary edema. “Be careful of synergistic hypotension with magnesium and nifedipine,” Dr. Bello said.
Dr. Bello didn’t have any industry disclosures.
NEW ORLEANS – according to Natalie Bello, MD, a cardiologist and assistant professor of medicine at Columbia University in New York.
In medical school, “they told me that you deliver the placenta, and the preeclampsia goes away. Not the case. Postpartum preeclampsia is a real thing. We are seeing a lot of it at our sites, which have a lot of underserved women who hadn’t had great prenatal care” elsewhere, she said.
Headache and visual changes in association with hypertension during what’s been dubbed “the fourth trimester” raise suspicions. Women can progress rapidly to eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), but sometimes providers don’t recognize what’s going on because they don’t know women have recently given birth. “We can do better; we should be doing better. Please always ask women if they’ve delivered recently,” Dr. Bello said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
Hypertension should resolve within 6 weeks of delivery, and blood pressure should be back to baseline by 3 months. To make sure that happens, BP should be checked within a few days of birth and regularly thereafter. It can be tough to get busy and tired new moms back into the office, but “they’ll do whatever it takes” to get their baby to a pediatric appointment, so maybe having pediatricians involved in checking blood pressure would help, she said.
The cutoff point for hypertension in pregnancy is 140/90 mm Hg, and it’s considered severe when values hit 160/110 mm Hg or higher. Evidence is strong for treating severe hypertension to reduce strokes, placental abruptions, and other problems, but the data for treating nonsevere hypertension are less clear, Dr. Bello explained.
The Chronic Hypertension and Pregnancy (CHAP) trial is expected to fill the evidence gap in a few years; women are being randomized to start treatment at either 140/90 mm Hg or 160/105 mm Hg. Meanwhile, the American College of Obstetricians and Gynecologists recently suggested that treatment of nonsevere hypertension might be appropriate in the setting of comorbidities and renal dysfunction (Obstet Gynecol. 2019 Jan;133[1]:e26-e50).
Dr. Bello prefers treating with extended-release calcium channel blocker nifedipine over the beta-blocker labetalol. “We think it is a little more effective,” and the once daily dosing, instead of two or three times a day, helps with compliance. Thiazide diuretics and hydralazine are also in her arsenal, but hydralazine shouldn’t be used in isolation because of its reflex tachycardia risk. The old standby, the antiadrenergic methyldopa, has fallen out of favor because of depression and other concerns. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and mineralocorticoid receptor antagonists shouldn’t be used in pregnancy, she said.
Intravenous labetalol and short-acting oral nifedipine are the mainstays for urgent, severe hypertension, along with high-dose intravenous magnesium, especially for seizure control. IV hydralazine or nitroglycerin are other options, the latter particularly for pulmonary edema. “Be careful of synergistic hypotension with magnesium and nifedipine,” Dr. Bello said.
Dr. Bello didn’t have any industry disclosures.
NEW ORLEANS – according to Natalie Bello, MD, a cardiologist and assistant professor of medicine at Columbia University in New York.
In medical school, “they told me that you deliver the placenta, and the preeclampsia goes away. Not the case. Postpartum preeclampsia is a real thing. We are seeing a lot of it at our sites, which have a lot of underserved women who hadn’t had great prenatal care” elsewhere, she said.
Headache and visual changes in association with hypertension during what’s been dubbed “the fourth trimester” raise suspicions. Women can progress rapidly to eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), but sometimes providers don’t recognize what’s going on because they don’t know women have recently given birth. “We can do better; we should be doing better. Please always ask women if they’ve delivered recently,” Dr. Bello said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
Hypertension should resolve within 6 weeks of delivery, and blood pressure should be back to baseline by 3 months. To make sure that happens, BP should be checked within a few days of birth and regularly thereafter. It can be tough to get busy and tired new moms back into the office, but “they’ll do whatever it takes” to get their baby to a pediatric appointment, so maybe having pediatricians involved in checking blood pressure would help, she said.
The cutoff point for hypertension in pregnancy is 140/90 mm Hg, and it’s considered severe when values hit 160/110 mm Hg or higher. Evidence is strong for treating severe hypertension to reduce strokes, placental abruptions, and other problems, but the data for treating nonsevere hypertension are less clear, Dr. Bello explained.
The Chronic Hypertension and Pregnancy (CHAP) trial is expected to fill the evidence gap in a few years; women are being randomized to start treatment at either 140/90 mm Hg or 160/105 mm Hg. Meanwhile, the American College of Obstetricians and Gynecologists recently suggested that treatment of nonsevere hypertension might be appropriate in the setting of comorbidities and renal dysfunction (Obstet Gynecol. 2019 Jan;133[1]:e26-e50).
Dr. Bello prefers treating with extended-release calcium channel blocker nifedipine over the beta-blocker labetalol. “We think it is a little more effective,” and the once daily dosing, instead of two or three times a day, helps with compliance. Thiazide diuretics and hydralazine are also in her arsenal, but hydralazine shouldn’t be used in isolation because of its reflex tachycardia risk. The old standby, the antiadrenergic methyldopa, has fallen out of favor because of depression and other concerns. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and mineralocorticoid receptor antagonists shouldn’t be used in pregnancy, she said.
Intravenous labetalol and short-acting oral nifedipine are the mainstays for urgent, severe hypertension, along with high-dose intravenous magnesium, especially for seizure control. IV hydralazine or nitroglycerin are other options, the latter particularly for pulmonary edema. “Be careful of synergistic hypotension with magnesium and nifedipine,” Dr. Bello said.
Dr. Bello didn’t have any industry disclosures.
EXPERT ANALYSIS FROM JOINT HYPERTENSION 2019
Subchorionic hematomas not associated with adverse pregnancy outcomes
Subchorionic hematomas in the first trimester were not associated with adverse pregnancy outcomes after 20 weeks’ gestation in singleton pregnancies, according to Mackenzie N. Naert of the Icahn School of Medicine at Mount Sinai, New York, and associates.
The investigators conducted a retrospective study, published in Obstetrics & Gynecology, of all women who presented for prenatal care before 14 weeks’ gestation at a single maternal-fetal medicine practice between January 2015 and December 2017. Of the 2,172 women with singleton pregnancies included in the analysis, 389 (18%) had a subchorionic hematoma.
Women with subchorionic hematomas were more likely to have their first ultrasound at an earlier gestational age (8 5/7 weeks vs. 9 6/7 weeks; P less than .001) and to have vaginal bleeding at the time of the ultrasound exam (32% vs. 8%; P less than .001). No other differences in baseline characteristics were observed, and after univariable analysis, subchorionic hematoma was not associated with any of the measured adverse outcomes, such as preterm birth, low birth weight, preeclampsia, gestational hypertension, placental disruption, intrauterine fetal death, cesarean section, blood transfusion, or antepartum admission.
In a regression analysis that included subchorionic hematoma, vaginal bleeding, and gestational age at ultrasound examination, vaginal bleeding had an independent association with preterm birth at less than 37 weeks’ gestation (adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.6) and birth weight less than the 10th percentile (aOR, 1.8; 95% CI, 1.2-2.6). No independent association was found for subchorionic hematoma.
“Most subchorionic hematomas present during the first trimester resolved by the second trimester,” the investigators wrote. “Therefore, women diagnosed with a first-trimester subchorionic hematoma should be reassured that their rate of adverse pregnancy outcomes at more than 20 weeks of gestation is not affected by the presence of the subchorionic hematoma. Additionally, we have previously shown that first-trimester subchorionic hematoma is not associated with pregnancy loss at less than 20 weeks of gestation.”
The authors reported no conflicts of interest.
SOURCE: Naert MN et al. Obstet Gynecol. 2019 Sep 10. doi: 10.1097/AOG.0000000000003487.
Subchorionic hematomas in the first trimester were not associated with adverse pregnancy outcomes after 20 weeks’ gestation in singleton pregnancies, according to Mackenzie N. Naert of the Icahn School of Medicine at Mount Sinai, New York, and associates.
The investigators conducted a retrospective study, published in Obstetrics & Gynecology, of all women who presented for prenatal care before 14 weeks’ gestation at a single maternal-fetal medicine practice between January 2015 and December 2017. Of the 2,172 women with singleton pregnancies included in the analysis, 389 (18%) had a subchorionic hematoma.
Women with subchorionic hematomas were more likely to have their first ultrasound at an earlier gestational age (8 5/7 weeks vs. 9 6/7 weeks; P less than .001) and to have vaginal bleeding at the time of the ultrasound exam (32% vs. 8%; P less than .001). No other differences in baseline characteristics were observed, and after univariable analysis, subchorionic hematoma was not associated with any of the measured adverse outcomes, such as preterm birth, low birth weight, preeclampsia, gestational hypertension, placental disruption, intrauterine fetal death, cesarean section, blood transfusion, or antepartum admission.
In a regression analysis that included subchorionic hematoma, vaginal bleeding, and gestational age at ultrasound examination, vaginal bleeding had an independent association with preterm birth at less than 37 weeks’ gestation (adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.6) and birth weight less than the 10th percentile (aOR, 1.8; 95% CI, 1.2-2.6). No independent association was found for subchorionic hematoma.
“Most subchorionic hematomas present during the first trimester resolved by the second trimester,” the investigators wrote. “Therefore, women diagnosed with a first-trimester subchorionic hematoma should be reassured that their rate of adverse pregnancy outcomes at more than 20 weeks of gestation is not affected by the presence of the subchorionic hematoma. Additionally, we have previously shown that first-trimester subchorionic hematoma is not associated with pregnancy loss at less than 20 weeks of gestation.”
The authors reported no conflicts of interest.
SOURCE: Naert MN et al. Obstet Gynecol. 2019 Sep 10. doi: 10.1097/AOG.0000000000003487.
Subchorionic hematomas in the first trimester were not associated with adverse pregnancy outcomes after 20 weeks’ gestation in singleton pregnancies, according to Mackenzie N. Naert of the Icahn School of Medicine at Mount Sinai, New York, and associates.
The investigators conducted a retrospective study, published in Obstetrics & Gynecology, of all women who presented for prenatal care before 14 weeks’ gestation at a single maternal-fetal medicine practice between January 2015 and December 2017. Of the 2,172 women with singleton pregnancies included in the analysis, 389 (18%) had a subchorionic hematoma.
Women with subchorionic hematomas were more likely to have their first ultrasound at an earlier gestational age (8 5/7 weeks vs. 9 6/7 weeks; P less than .001) and to have vaginal bleeding at the time of the ultrasound exam (32% vs. 8%; P less than .001). No other differences in baseline characteristics were observed, and after univariable analysis, subchorionic hematoma was not associated with any of the measured adverse outcomes, such as preterm birth, low birth weight, preeclampsia, gestational hypertension, placental disruption, intrauterine fetal death, cesarean section, blood transfusion, or antepartum admission.
In a regression analysis that included subchorionic hematoma, vaginal bleeding, and gestational age at ultrasound examination, vaginal bleeding had an independent association with preterm birth at less than 37 weeks’ gestation (adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.6) and birth weight less than the 10th percentile (aOR, 1.8; 95% CI, 1.2-2.6). No independent association was found for subchorionic hematoma.
“Most subchorionic hematomas present during the first trimester resolved by the second trimester,” the investigators wrote. “Therefore, women diagnosed with a first-trimester subchorionic hematoma should be reassured that their rate of adverse pregnancy outcomes at more than 20 weeks of gestation is not affected by the presence of the subchorionic hematoma. Additionally, we have previously shown that first-trimester subchorionic hematoma is not associated with pregnancy loss at less than 20 weeks of gestation.”
The authors reported no conflicts of interest.
SOURCE: Naert MN et al. Obstet Gynecol. 2019 Sep 10. doi: 10.1097/AOG.0000000000003487.
FROM OBSTETRICS AND GYNECOLOGY
Drug doses for heart failure could possibly be halved for women
Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.
“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.
Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”
In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.
HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)
For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.
“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”
The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.
“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.
In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).
The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.
SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.
Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.
“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.
Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”
In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.
HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)
For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.
“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”
The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.
“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.
In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).
The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.
SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.
Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.
“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.
Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”
In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.
HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)
For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.
“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”
The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.
“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.
In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).
The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.
SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.
FROM THE LANCET
No decrease in preterm birth with n-3 fatty acid supplements
according to data published in the New England Journal of Medicine.
Maria Makrides, PhD, of the South Australian Health and Medical Research Institute, North Adelaide, and coauthors wrote there is evidence that n-3 long-chain polyunsaturated fatty acids play an essential role in labor initiation.
“Typical Western diets are relatively low in n-3 long-chain polyunsaturated fatty acids, which leads to a predominance of 2-series prostaglandin substrate in the fetoplacental unit and potentially confers a predisposition to preterm delivery,” they wrote, adding that epidemiologic studies have suggested associations between lower fish consumption in pregnancy and a higher rate of preterm delivery.
In a multicenter, double-blind trial, 5,517 women were randomized to either a daily fish oil supplement containing 900 mg of n-3 long-chain polyunsaturated fatty acids or vegetable oil capsules, from before 20 weeks’ gestation until 34 weeks’ gestation or delivery.
Among the 5,486 pregnancies included in the final analysis, there were no differences between the intervention and control groups in the primary outcome of early preterm delivery, which occurred in 2.2% of pregnancies in the n-3 fatty acid group and 2% of the control group (P = 0.5).
The study also saw no significant differences between the two groups in other outcomes such as the rates of preterm delivery, preterm spontaneous labor, postterm induction, or gestational age at delivery. Similarly, there were no apparent effects of supplementation on maternal and neonatal outcomes including low birth weight, admission to neonatal intensive care, gestational diabetes, postpartum hemorrhage, or preeclampsia.
The analysis did suggest a greater incidence of infants born very large for gestational age – with a birth weight above the 97th percentile – among women in the fatty acid supplement group, but this did not correspond to an increased rate of interventions such as cesarean section or postterm induction.
The authors commented that their finding of more very-large-for-gestational-age babies added to the debate about whether n-3 long-chain polyunsaturated fatty acid supplementation did have a direct impact on fetal growth, although they also noted that it could be a chance finding.
There were also no significant differences between the two groups in serious adverse events, including miscarriage.
The authors noted that the baseline level of n-3 long-chain polyunsaturated fatty acids in the women enrolled in trial may have been higher than in previous studies.
The study was supported by the Australian National Health and Medical Research Council and the Thyne Reid Foundation, with in-kind support from Croda UK and Efamol/Wassen UK. Two authors declared advisory board fees from private industry, and one also declared a patent relating to fatty acids in research. No other conflicts of interest were declared.
SOURCE: Makrides M et al. N Engl J Med. 2019;381:1035-45.
according to data published in the New England Journal of Medicine.
Maria Makrides, PhD, of the South Australian Health and Medical Research Institute, North Adelaide, and coauthors wrote there is evidence that n-3 long-chain polyunsaturated fatty acids play an essential role in labor initiation.
“Typical Western diets are relatively low in n-3 long-chain polyunsaturated fatty acids, which leads to a predominance of 2-series prostaglandin substrate in the fetoplacental unit and potentially confers a predisposition to preterm delivery,” they wrote, adding that epidemiologic studies have suggested associations between lower fish consumption in pregnancy and a higher rate of preterm delivery.
In a multicenter, double-blind trial, 5,517 women were randomized to either a daily fish oil supplement containing 900 mg of n-3 long-chain polyunsaturated fatty acids or vegetable oil capsules, from before 20 weeks’ gestation until 34 weeks’ gestation or delivery.
Among the 5,486 pregnancies included in the final analysis, there were no differences between the intervention and control groups in the primary outcome of early preterm delivery, which occurred in 2.2% of pregnancies in the n-3 fatty acid group and 2% of the control group (P = 0.5).
The study also saw no significant differences between the two groups in other outcomes such as the rates of preterm delivery, preterm spontaneous labor, postterm induction, or gestational age at delivery. Similarly, there were no apparent effects of supplementation on maternal and neonatal outcomes including low birth weight, admission to neonatal intensive care, gestational diabetes, postpartum hemorrhage, or preeclampsia.
The analysis did suggest a greater incidence of infants born very large for gestational age – with a birth weight above the 97th percentile – among women in the fatty acid supplement group, but this did not correspond to an increased rate of interventions such as cesarean section or postterm induction.
The authors commented that their finding of more very-large-for-gestational-age babies added to the debate about whether n-3 long-chain polyunsaturated fatty acid supplementation did have a direct impact on fetal growth, although they also noted that it could be a chance finding.
There were also no significant differences between the two groups in serious adverse events, including miscarriage.
The authors noted that the baseline level of n-3 long-chain polyunsaturated fatty acids in the women enrolled in trial may have been higher than in previous studies.
The study was supported by the Australian National Health and Medical Research Council and the Thyne Reid Foundation, with in-kind support from Croda UK and Efamol/Wassen UK. Two authors declared advisory board fees from private industry, and one also declared a patent relating to fatty acids in research. No other conflicts of interest were declared.
SOURCE: Makrides M et al. N Engl J Med. 2019;381:1035-45.
according to data published in the New England Journal of Medicine.
Maria Makrides, PhD, of the South Australian Health and Medical Research Institute, North Adelaide, and coauthors wrote there is evidence that n-3 long-chain polyunsaturated fatty acids play an essential role in labor initiation.
“Typical Western diets are relatively low in n-3 long-chain polyunsaturated fatty acids, which leads to a predominance of 2-series prostaglandin substrate in the fetoplacental unit and potentially confers a predisposition to preterm delivery,” they wrote, adding that epidemiologic studies have suggested associations between lower fish consumption in pregnancy and a higher rate of preterm delivery.
In a multicenter, double-blind trial, 5,517 women were randomized to either a daily fish oil supplement containing 900 mg of n-3 long-chain polyunsaturated fatty acids or vegetable oil capsules, from before 20 weeks’ gestation until 34 weeks’ gestation or delivery.
Among the 5,486 pregnancies included in the final analysis, there were no differences between the intervention and control groups in the primary outcome of early preterm delivery, which occurred in 2.2% of pregnancies in the n-3 fatty acid group and 2% of the control group (P = 0.5).
The study also saw no significant differences between the two groups in other outcomes such as the rates of preterm delivery, preterm spontaneous labor, postterm induction, or gestational age at delivery. Similarly, there were no apparent effects of supplementation on maternal and neonatal outcomes including low birth weight, admission to neonatal intensive care, gestational diabetes, postpartum hemorrhage, or preeclampsia.
The analysis did suggest a greater incidence of infants born very large for gestational age – with a birth weight above the 97th percentile – among women in the fatty acid supplement group, but this did not correspond to an increased rate of interventions such as cesarean section or postterm induction.
The authors commented that their finding of more very-large-for-gestational-age babies added to the debate about whether n-3 long-chain polyunsaturated fatty acid supplementation did have a direct impact on fetal growth, although they also noted that it could be a chance finding.
There were also no significant differences between the two groups in serious adverse events, including miscarriage.
The authors noted that the baseline level of n-3 long-chain polyunsaturated fatty acids in the women enrolled in trial may have been higher than in previous studies.
The study was supported by the Australian National Health and Medical Research Council and the Thyne Reid Foundation, with in-kind support from Croda UK and Efamol/Wassen UK. Two authors declared advisory board fees from private industry, and one also declared a patent relating to fatty acids in research. No other conflicts of interest were declared.
SOURCE: Makrides M et al. N Engl J Med. 2019;381:1035-45.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: No decrease in preterm birth was seen with n-3 fatty acid supplementation during pregnancy, compared with controls.
Major finding: Early preterm delivery occurred in 2.2% of pregnancies in the n-3 fatty acid group and 2% of the control group (P = 0.5).
Study details: A multicenter, double-blind trial in 5,517 women.
Disclosures: The study was supported by the Australian National Health and Medical Research Council and the Thyne Reid Foundation, with in-kind support from Croda UK and Efamol/Wassen UK. Two authors declared advisory board fees from private industry, and one also declared a patent relating to fatty acids in research. No other conflicts of interest were declared.
Source: Makrides M et al. N Engl J Med. 2019;381:1035-45.
Use of genetic testing for congenital heart defect management
The average student in America learns that genes form the building blocks of what makes us human by the time they receive their high school diploma. Indeed, the completion of the Human Genome Project in 2003 paved the way for our genetic makeup, much like our medical history, to become a routine part of our health care. For example, our faculty at the University of Maryland School of Medicine discovered an important gene – CYP2C19 – which is involved in the metabolism of the antiplatelet medicine clopidogrel (Plavix). Although most people have this gene, some don’t. Therefore, when we manage a patient with coronary disease, we use a genetic screen to determine whether that patient has CYP2C19 and then modify therapy based on these results.
Our genes also have become commodities – from companies willing to analyze our genes to determine our racial and ethnic ancestry or propensity for certain diseases to those that can sequence the family dog’s genes.
Advances in genomics similarly have impacted ob.gyn. practice. Because of rapidly evolving gene analysis tools, we can now, for example, noninvasively test a developing fetus’s risk for chromosomal abnormalities and determine a baby’s sex by merely examining fetal DNA in a pregnant woman’s bloodstream. Although not diagnostic, these gene-based prenatal screening tests have reduced the need for unnecessary, costly, and highly invasive procedures for many of our patients.
Importantly, our recognition that certain genes can confer a higher risk of disease has meant that performing a prenatal genetic evaluation can greatly inform the mother and her care team about potential problems her baby may have that may require additional management. For babies who have congenital heart defects, a genetic evaluation performed in addition to sonographic examination can provide ob.gyns. with crucial details to enhance pregnancy management and postnatal care decisions.
The importance of genetic testing and analysis in the detection, treatment, and prevention of congenital heart defects is the topic of part two of this two-part Master Class series authored by Shifa Turan, MD, associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine and director of the Fetal Heart Program at the University of Maryland Medical Center. By using a combination of three- and four-dimensional ultrasound with gene assays, Dr. Turan and her colleagues can greatly enhance and personalize the care they deliver to their patients.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
The average student in America learns that genes form the building blocks of what makes us human by the time they receive their high school diploma. Indeed, the completion of the Human Genome Project in 2003 paved the way for our genetic makeup, much like our medical history, to become a routine part of our health care. For example, our faculty at the University of Maryland School of Medicine discovered an important gene – CYP2C19 – which is involved in the metabolism of the antiplatelet medicine clopidogrel (Plavix). Although most people have this gene, some don’t. Therefore, when we manage a patient with coronary disease, we use a genetic screen to determine whether that patient has CYP2C19 and then modify therapy based on these results.
Our genes also have become commodities – from companies willing to analyze our genes to determine our racial and ethnic ancestry or propensity for certain diseases to those that can sequence the family dog’s genes.
Advances in genomics similarly have impacted ob.gyn. practice. Because of rapidly evolving gene analysis tools, we can now, for example, noninvasively test a developing fetus’s risk for chromosomal abnormalities and determine a baby’s sex by merely examining fetal DNA in a pregnant woman’s bloodstream. Although not diagnostic, these gene-based prenatal screening tests have reduced the need for unnecessary, costly, and highly invasive procedures for many of our patients.
Importantly, our recognition that certain genes can confer a higher risk of disease has meant that performing a prenatal genetic evaluation can greatly inform the mother and her care team about potential problems her baby may have that may require additional management. For babies who have congenital heart defects, a genetic evaluation performed in addition to sonographic examination can provide ob.gyns. with crucial details to enhance pregnancy management and postnatal care decisions.
The importance of genetic testing and analysis in the detection, treatment, and prevention of congenital heart defects is the topic of part two of this two-part Master Class series authored by Shifa Turan, MD, associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine and director of the Fetal Heart Program at the University of Maryland Medical Center. By using a combination of three- and four-dimensional ultrasound with gene assays, Dr. Turan and her colleagues can greatly enhance and personalize the care they deliver to their patients.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
The average student in America learns that genes form the building blocks of what makes us human by the time they receive their high school diploma. Indeed, the completion of the Human Genome Project in 2003 paved the way for our genetic makeup, much like our medical history, to become a routine part of our health care. For example, our faculty at the University of Maryland School of Medicine discovered an important gene – CYP2C19 – which is involved in the metabolism of the antiplatelet medicine clopidogrel (Plavix). Although most people have this gene, some don’t. Therefore, when we manage a patient with coronary disease, we use a genetic screen to determine whether that patient has CYP2C19 and then modify therapy based on these results.
Our genes also have become commodities – from companies willing to analyze our genes to determine our racial and ethnic ancestry or propensity for certain diseases to those that can sequence the family dog’s genes.
Advances in genomics similarly have impacted ob.gyn. practice. Because of rapidly evolving gene analysis tools, we can now, for example, noninvasively test a developing fetus’s risk for chromosomal abnormalities and determine a baby’s sex by merely examining fetal DNA in a pregnant woman’s bloodstream. Although not diagnostic, these gene-based prenatal screening tests have reduced the need for unnecessary, costly, and highly invasive procedures for many of our patients.
Importantly, our recognition that certain genes can confer a higher risk of disease has meant that performing a prenatal genetic evaluation can greatly inform the mother and her care team about potential problems her baby may have that may require additional management. For babies who have congenital heart defects, a genetic evaluation performed in addition to sonographic examination can provide ob.gyns. with crucial details to enhance pregnancy management and postnatal care decisions.
The importance of genetic testing and analysis in the detection, treatment, and prevention of congenital heart defects is the topic of part two of this two-part Master Class series authored by Shifa Turan, MD, associate professor of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine and director of the Fetal Heart Program at the University of Maryland Medical Center. By using a combination of three- and four-dimensional ultrasound with gene assays, Dr. Turan and her colleagues can greatly enhance and personalize the care they deliver to their patients.
Dr. Reece, who specializes in maternal-fetal medicine, is executive vice president for medical affairs at the University of Maryland School of Medicine, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. He is the medical editor of this column. He said he had no relevant financial disclosures. Contact him at [email protected].
Genetic assessment for CHD: Case-specific, stepwise
Congenital heart defects (CHDs) are etiologically heterogeneous, but in recent years it has become clear that genetics plays a larger role in the development of CHDs than was previously thought. Research has been shifting from a focus on risk – estimating the magnitude of increased risk, for instance, based on maternal or familial risk factors – to a focus on the etiology of cardiac defects.
In practice, advances in genetic testing technologies have made the underlying causes of CHDs increasingly detectable. Chromosomal microarray analysis (CMA) – technology that detects significantly more and smaller changes in the amount of chromosomal material than traditional karyotype – has been proven to increase the diagnostic yield in cases of isolated CHDs and CHDs with extracardiac anomalies. Targeted next-generation sequencing also is now available as an additional approach in selective cases, and a clinically viable option for whole-exome sequencing is fast approaching.
For researchers, genetic evaluation carries the potential to unravel remaining mysteries about underlying causes of CHDs – to provide pathological insights and identify potential therapeutic targets. Currently, about 6 % of the total pie of presumed genetic determinants of CHDs is attributed to chromosomal anomalies, 10% to copy number variants, and 12% to single-gene defects. The remaining 72% of etiology, approximately, is undetermined.
As Helen Taussig, MD, (known as the founder of pediatric cardiology) once said, common cardiac malformations occurring in otherwise “normal” individuals “must be genetic in origin.”1 Greater use of genetic testing – and in particular, of whole-exome sequencing – will drive down this “undetermined” piece of the genetics pie.
For clinicians and patients, prenatal genetic evaluation can inform clinical management, guiding decisions on the mode, timing, and location of delivery. Genetic assessments help guide the neonatal health care team in taking optimal care of the infant, and the surgeon in preparing for neonatal surgeries and postsurgical complications.
In a recent analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database, prenatal diagnosis was associated with a lower overall prevalence of major preoperative risk factors for cardiac surgery.2 Surgical outcomes themselves also have been shown to be better after the prenatal diagnosis of complex CHDs, mainly because of improvements in perioperative care.3
When genetic etiology is elucidated, the cardiologist also is better able to counsel patients about anticipated challenges – such as the propensity, with certain genetic variants of CHD, to develop neurodevelopmental delays or other cardiac complications – and to target patient follow-up. Patients also can make informed decisions about termination or continuation of a current pregnancy and about family planning in the future.
Fortunately, advances in genetics technology have paralleled technological advancements in ultrasound. As I discussed in part one of this two-part Master Class series, it is now possible to detect many major CHDs well before 16 weeks’ gestation. Checking the structure of the fetal heart at the first-trimester screening and sonography (11-14 weeks of gestation) offers the opportunity for early genetic assessment, counseling, and planning when anomalies are detected.
A personalized approach
There has been growing interest in recent years in CMA for the prenatal genetic workup of CHDs. Microarray targets chromosomal regions at a much higher resolution than traditional karyotype. Traditional karyotype assesses both changes in chromosome number as well as more subtle structural changes such as chromosomal deletions and duplications. CMA finds what traditional karyotype identifies, but in addition, it identifies much smaller, clinically relevant chromosomal deletions and duplications that are not detected by karyotype performed with or without fluorescence in-situ hybridization (FISH). FISH uses DNA probes that carry fluorescent tags to detect chromosomal DNA.
At our center, we studied the prenatal genetic test results of 145 fetuses diagnosed with CHDs. Each case involved FISH for aneuploidy/karyotype, followed by CMA in cases of a negative karyotype result. CMA increased the diagnostic yield in cases of CHD by 19.8% overall – 17.4% in cases of isolated CHD and 24.5% in cases of CHD plus extracardiac anomalies.4
Indeed, although a microarray costs more and takes an additional 2 weeks to run, CMA should be strongly considered as first-line testing for the prenatal genetic evaluation of fetuses with major structural cardiac abnormalities detected by ultrasound. However, there still are cases in which a karyotype might be sufficient. For instance, if I see that a fetus has an atrial-ventricular septal defect on a prenatal ultrasound, and there are markers for trisomy 21, 13, or 18, or Turner’s syndrome (45 XO), I usually recommend a karyotype or FISH rather than an initial CMA. If the karyotype is abnormal – which is likely in such a scenario – there isn’t a need for more extensive testing.
Similarly, when there is high suspicion for DiGeorge syndrome (the 22q11.2 deletion, which often includes cleft palate and aortic arch abnormalities), usually it is most appropriate to perform a FISH test.
CMA is the preferred first modality, however, when prenatal imaging suggests severe CHD – for instance, when there are signs of hypoplastic left heart syndrome or tetralogy of Fallot (a conotruncal defect) – or complex CHD with extracardiac anomalies. In these cases, there is a high likelihood of detecting a small deletion or duplication that would be missed with karyotype.
In the past decade, karyotype and CMA have become the major methods used in our practice. However, targeted next‐generation sequencing and whole‐exome sequencing may become more widely used because these technologies enable rapid analysis of a large number of gene sequences and facilitate discovery of novel causative genes in many genetic diseases that cause CHDs.
Currently, targeted next-generation sequencing has mainly been used in the postnatal setting, and there are limited data available on its prenatal use. Compared with whole-exome sequencing, which sequences all of the protein-coding regions of the genome, targeted next-generation sequencing panels select regions of genes that are known to be associated with diseases of interest.
For CHDs, some perinatal centers have begun using a customized gene panel that targets 77 CHD-associated genes. This particular panel has been shown to be useful in addition to current methods and is an effective tool for prenatal genetic diagnosis.5
Whole-exome sequencing is currently expensive and time consuming. While sometimes it is used in the postnatal context, it is not yet part of routine practice as a prenatal diagnostic tool. As technology advances this will change – early in the next decade, I believe. For now, whole-exome sequencing may be an option for some patients who want to know more when severe CHD is evident on ultrasound and there are negative results from CMA or targeted sequencing. We have diagnosed some rare genetic syndromes using whole-exome sequencing; these diagnoses helped us to better manage the pregnancies.
These choices are part of the case-specific, stepwise approach to genetic evaluation that we take in our fetal heart program. Our goal is to pursue information that will be accurate and valuable for the patient and clinicians, in the most cost-effective and timely manner.
Limitations of noninvasive screening
In our fetal heart program we see increasing numbers of referred patients who have chosen noninvasive cell-free fetal DNA screening (cfDNA) after a cardiac anomaly is detected on ultrasound examination, and who believe that their “low risk” results demonstrate very little or no risk of CHD. Many of these patients express a belief that noninvasive testing is highly sensitive and accurate for fetal anomalies, including CHDs, and are not easily convinced of the value of other genetic tests.
We recently conducted a retrospective chart analysis (unpublished) in which we found that 41% of cases of CHD with abnormal genetics results were not detectable by cfDNA screening.
In the case of atrial-ventricular septal defects and conotruncal abnormalities that often are more associated with common aneuploidies (trisomy 21, 18, 13, and 45 XO), a “high-risk” result from cfDNA screening may offer the family and cardiology/neonatal team some guidance, but a “low-risk” result does not eliminate the risk of a microarray abnormality and thus may provide false reassurance.
Other research has shown that noninvasive screening will miss up to 7.3% of karyotype abnormalities in pregnancies at high risk for common aneuploidies.6
While invasive testing poses a very small risk of miscarriage, it is hard without such testing to elucidate the potential genetic etiologies of CHDs and truly understand the problems. We must take time to thoughtfully counsel patients who decline invasive testing about the limitations of cfDNA screening for CHDs and other anomalies.
Dr. Turan is an associate professor of obstetrics, gynecology, and reproductive sciences, and director of the fetal heart program at the University of Maryland School of Medicine and director of the Fetal Heart Program at the University of Maryland Medical Center. Dr. Turan reported that she has no disclosures relevant to this Master Class. Email her at [email protected].
References
1. J Am Coll Cardiol. 1988 Oct;12(4):1079-86.
2. Pediatr Cardiol. 2019 Mar;40(3):489-96.
3. Ann Pediatr Cardiol. 2017 May-Aug;10(2):126-30.
4. Eur J Obstet Gynecol Reprod Biol 2018;221:172-76.
5. Ultrasound Obstet Gynecol. 2018 Aug;52(2):205-11.
6. PLoS One. 2016 Jan 15;11(1):e0146794.
Congenital heart defects (CHDs) are etiologically heterogeneous, but in recent years it has become clear that genetics plays a larger role in the development of CHDs than was previously thought. Research has been shifting from a focus on risk – estimating the magnitude of increased risk, for instance, based on maternal or familial risk factors – to a focus on the etiology of cardiac defects.
In practice, advances in genetic testing technologies have made the underlying causes of CHDs increasingly detectable. Chromosomal microarray analysis (CMA) – technology that detects significantly more and smaller changes in the amount of chromosomal material than traditional karyotype – has been proven to increase the diagnostic yield in cases of isolated CHDs and CHDs with extracardiac anomalies. Targeted next-generation sequencing also is now available as an additional approach in selective cases, and a clinically viable option for whole-exome sequencing is fast approaching.
For researchers, genetic evaluation carries the potential to unravel remaining mysteries about underlying causes of CHDs – to provide pathological insights and identify potential therapeutic targets. Currently, about 6 % of the total pie of presumed genetic determinants of CHDs is attributed to chromosomal anomalies, 10% to copy number variants, and 12% to single-gene defects. The remaining 72% of etiology, approximately, is undetermined.
As Helen Taussig, MD, (known as the founder of pediatric cardiology) once said, common cardiac malformations occurring in otherwise “normal” individuals “must be genetic in origin.”1 Greater use of genetic testing – and in particular, of whole-exome sequencing – will drive down this “undetermined” piece of the genetics pie.
For clinicians and patients, prenatal genetic evaluation can inform clinical management, guiding decisions on the mode, timing, and location of delivery. Genetic assessments help guide the neonatal health care team in taking optimal care of the infant, and the surgeon in preparing for neonatal surgeries and postsurgical complications.
In a recent analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database, prenatal diagnosis was associated with a lower overall prevalence of major preoperative risk factors for cardiac surgery.2 Surgical outcomes themselves also have been shown to be better after the prenatal diagnosis of complex CHDs, mainly because of improvements in perioperative care.3
When genetic etiology is elucidated, the cardiologist also is better able to counsel patients about anticipated challenges – such as the propensity, with certain genetic variants of CHD, to develop neurodevelopmental delays or other cardiac complications – and to target patient follow-up. Patients also can make informed decisions about termination or continuation of a current pregnancy and about family planning in the future.
Fortunately, advances in genetics technology have paralleled technological advancements in ultrasound. As I discussed in part one of this two-part Master Class series, it is now possible to detect many major CHDs well before 16 weeks’ gestation. Checking the structure of the fetal heart at the first-trimester screening and sonography (11-14 weeks of gestation) offers the opportunity for early genetic assessment, counseling, and planning when anomalies are detected.
A personalized approach
There has been growing interest in recent years in CMA for the prenatal genetic workup of CHDs. Microarray targets chromosomal regions at a much higher resolution than traditional karyotype. Traditional karyotype assesses both changes in chromosome number as well as more subtle structural changes such as chromosomal deletions and duplications. CMA finds what traditional karyotype identifies, but in addition, it identifies much smaller, clinically relevant chromosomal deletions and duplications that are not detected by karyotype performed with or without fluorescence in-situ hybridization (FISH). FISH uses DNA probes that carry fluorescent tags to detect chromosomal DNA.
At our center, we studied the prenatal genetic test results of 145 fetuses diagnosed with CHDs. Each case involved FISH for aneuploidy/karyotype, followed by CMA in cases of a negative karyotype result. CMA increased the diagnostic yield in cases of CHD by 19.8% overall – 17.4% in cases of isolated CHD and 24.5% in cases of CHD plus extracardiac anomalies.4
Indeed, although a microarray costs more and takes an additional 2 weeks to run, CMA should be strongly considered as first-line testing for the prenatal genetic evaluation of fetuses with major structural cardiac abnormalities detected by ultrasound. However, there still are cases in which a karyotype might be sufficient. For instance, if I see that a fetus has an atrial-ventricular septal defect on a prenatal ultrasound, and there are markers for trisomy 21, 13, or 18, or Turner’s syndrome (45 XO), I usually recommend a karyotype or FISH rather than an initial CMA. If the karyotype is abnormal – which is likely in such a scenario – there isn’t a need for more extensive testing.
Similarly, when there is high suspicion for DiGeorge syndrome (the 22q11.2 deletion, which often includes cleft palate and aortic arch abnormalities), usually it is most appropriate to perform a FISH test.
CMA is the preferred first modality, however, when prenatal imaging suggests severe CHD – for instance, when there are signs of hypoplastic left heart syndrome or tetralogy of Fallot (a conotruncal defect) – or complex CHD with extracardiac anomalies. In these cases, there is a high likelihood of detecting a small deletion or duplication that would be missed with karyotype.
In the past decade, karyotype and CMA have become the major methods used in our practice. However, targeted next‐generation sequencing and whole‐exome sequencing may become more widely used because these technologies enable rapid analysis of a large number of gene sequences and facilitate discovery of novel causative genes in many genetic diseases that cause CHDs.
Currently, targeted next-generation sequencing has mainly been used in the postnatal setting, and there are limited data available on its prenatal use. Compared with whole-exome sequencing, which sequences all of the protein-coding regions of the genome, targeted next-generation sequencing panels select regions of genes that are known to be associated with diseases of interest.
For CHDs, some perinatal centers have begun using a customized gene panel that targets 77 CHD-associated genes. This particular panel has been shown to be useful in addition to current methods and is an effective tool for prenatal genetic diagnosis.5
Whole-exome sequencing is currently expensive and time consuming. While sometimes it is used in the postnatal context, it is not yet part of routine practice as a prenatal diagnostic tool. As technology advances this will change – early in the next decade, I believe. For now, whole-exome sequencing may be an option for some patients who want to know more when severe CHD is evident on ultrasound and there are negative results from CMA or targeted sequencing. We have diagnosed some rare genetic syndromes using whole-exome sequencing; these diagnoses helped us to better manage the pregnancies.
These choices are part of the case-specific, stepwise approach to genetic evaluation that we take in our fetal heart program. Our goal is to pursue information that will be accurate and valuable for the patient and clinicians, in the most cost-effective and timely manner.
Limitations of noninvasive screening
In our fetal heart program we see increasing numbers of referred patients who have chosen noninvasive cell-free fetal DNA screening (cfDNA) after a cardiac anomaly is detected on ultrasound examination, and who believe that their “low risk” results demonstrate very little or no risk of CHD. Many of these patients express a belief that noninvasive testing is highly sensitive and accurate for fetal anomalies, including CHDs, and are not easily convinced of the value of other genetic tests.
We recently conducted a retrospective chart analysis (unpublished) in which we found that 41% of cases of CHD with abnormal genetics results were not detectable by cfDNA screening.
In the case of atrial-ventricular septal defects and conotruncal abnormalities that often are more associated with common aneuploidies (trisomy 21, 18, 13, and 45 XO), a “high-risk” result from cfDNA screening may offer the family and cardiology/neonatal team some guidance, but a “low-risk” result does not eliminate the risk of a microarray abnormality and thus may provide false reassurance.
Other research has shown that noninvasive screening will miss up to 7.3% of karyotype abnormalities in pregnancies at high risk for common aneuploidies.6
While invasive testing poses a very small risk of miscarriage, it is hard without such testing to elucidate the potential genetic etiologies of CHDs and truly understand the problems. We must take time to thoughtfully counsel patients who decline invasive testing about the limitations of cfDNA screening for CHDs and other anomalies.
Dr. Turan is an associate professor of obstetrics, gynecology, and reproductive sciences, and director of the fetal heart program at the University of Maryland School of Medicine and director of the Fetal Heart Program at the University of Maryland Medical Center. Dr. Turan reported that she has no disclosures relevant to this Master Class. Email her at [email protected].
References
1. J Am Coll Cardiol. 1988 Oct;12(4):1079-86.
2. Pediatr Cardiol. 2019 Mar;40(3):489-96.
3. Ann Pediatr Cardiol. 2017 May-Aug;10(2):126-30.
4. Eur J Obstet Gynecol Reprod Biol 2018;221:172-76.
5. Ultrasound Obstet Gynecol. 2018 Aug;52(2):205-11.
6. PLoS One. 2016 Jan 15;11(1):e0146794.
Congenital heart defects (CHDs) are etiologically heterogeneous, but in recent years it has become clear that genetics plays a larger role in the development of CHDs than was previously thought. Research has been shifting from a focus on risk – estimating the magnitude of increased risk, for instance, based on maternal or familial risk factors – to a focus on the etiology of cardiac defects.
In practice, advances in genetic testing technologies have made the underlying causes of CHDs increasingly detectable. Chromosomal microarray analysis (CMA) – technology that detects significantly more and smaller changes in the amount of chromosomal material than traditional karyotype – has been proven to increase the diagnostic yield in cases of isolated CHDs and CHDs with extracardiac anomalies. Targeted next-generation sequencing also is now available as an additional approach in selective cases, and a clinically viable option for whole-exome sequencing is fast approaching.
For researchers, genetic evaluation carries the potential to unravel remaining mysteries about underlying causes of CHDs – to provide pathological insights and identify potential therapeutic targets. Currently, about 6 % of the total pie of presumed genetic determinants of CHDs is attributed to chromosomal anomalies, 10% to copy number variants, and 12% to single-gene defects. The remaining 72% of etiology, approximately, is undetermined.
As Helen Taussig, MD, (known as the founder of pediatric cardiology) once said, common cardiac malformations occurring in otherwise “normal” individuals “must be genetic in origin.”1 Greater use of genetic testing – and in particular, of whole-exome sequencing – will drive down this “undetermined” piece of the genetics pie.
For clinicians and patients, prenatal genetic evaluation can inform clinical management, guiding decisions on the mode, timing, and location of delivery. Genetic assessments help guide the neonatal health care team in taking optimal care of the infant, and the surgeon in preparing for neonatal surgeries and postsurgical complications.
In a recent analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database, prenatal diagnosis was associated with a lower overall prevalence of major preoperative risk factors for cardiac surgery.2 Surgical outcomes themselves also have been shown to be better after the prenatal diagnosis of complex CHDs, mainly because of improvements in perioperative care.3
When genetic etiology is elucidated, the cardiologist also is better able to counsel patients about anticipated challenges – such as the propensity, with certain genetic variants of CHD, to develop neurodevelopmental delays or other cardiac complications – and to target patient follow-up. Patients also can make informed decisions about termination or continuation of a current pregnancy and about family planning in the future.
Fortunately, advances in genetics technology have paralleled technological advancements in ultrasound. As I discussed in part one of this two-part Master Class series, it is now possible to detect many major CHDs well before 16 weeks’ gestation. Checking the structure of the fetal heart at the first-trimester screening and sonography (11-14 weeks of gestation) offers the opportunity for early genetic assessment, counseling, and planning when anomalies are detected.
A personalized approach
There has been growing interest in recent years in CMA for the prenatal genetic workup of CHDs. Microarray targets chromosomal regions at a much higher resolution than traditional karyotype. Traditional karyotype assesses both changes in chromosome number as well as more subtle structural changes such as chromosomal deletions and duplications. CMA finds what traditional karyotype identifies, but in addition, it identifies much smaller, clinically relevant chromosomal deletions and duplications that are not detected by karyotype performed with or without fluorescence in-situ hybridization (FISH). FISH uses DNA probes that carry fluorescent tags to detect chromosomal DNA.
At our center, we studied the prenatal genetic test results of 145 fetuses diagnosed with CHDs. Each case involved FISH for aneuploidy/karyotype, followed by CMA in cases of a negative karyotype result. CMA increased the diagnostic yield in cases of CHD by 19.8% overall – 17.4% in cases of isolated CHD and 24.5% in cases of CHD plus extracardiac anomalies.4
Indeed, although a microarray costs more and takes an additional 2 weeks to run, CMA should be strongly considered as first-line testing for the prenatal genetic evaluation of fetuses with major structural cardiac abnormalities detected by ultrasound. However, there still are cases in which a karyotype might be sufficient. For instance, if I see that a fetus has an atrial-ventricular septal defect on a prenatal ultrasound, and there are markers for trisomy 21, 13, or 18, or Turner’s syndrome (45 XO), I usually recommend a karyotype or FISH rather than an initial CMA. If the karyotype is abnormal – which is likely in such a scenario – there isn’t a need for more extensive testing.
Similarly, when there is high suspicion for DiGeorge syndrome (the 22q11.2 deletion, which often includes cleft palate and aortic arch abnormalities), usually it is most appropriate to perform a FISH test.
CMA is the preferred first modality, however, when prenatal imaging suggests severe CHD – for instance, when there are signs of hypoplastic left heart syndrome or tetralogy of Fallot (a conotruncal defect) – or complex CHD with extracardiac anomalies. In these cases, there is a high likelihood of detecting a small deletion or duplication that would be missed with karyotype.
In the past decade, karyotype and CMA have become the major methods used in our practice. However, targeted next‐generation sequencing and whole‐exome sequencing may become more widely used because these technologies enable rapid analysis of a large number of gene sequences and facilitate discovery of novel causative genes in many genetic diseases that cause CHDs.
Currently, targeted next-generation sequencing has mainly been used in the postnatal setting, and there are limited data available on its prenatal use. Compared with whole-exome sequencing, which sequences all of the protein-coding regions of the genome, targeted next-generation sequencing panels select regions of genes that are known to be associated with diseases of interest.
For CHDs, some perinatal centers have begun using a customized gene panel that targets 77 CHD-associated genes. This particular panel has been shown to be useful in addition to current methods and is an effective tool for prenatal genetic diagnosis.5
Whole-exome sequencing is currently expensive and time consuming. While sometimes it is used in the postnatal context, it is not yet part of routine practice as a prenatal diagnostic tool. As technology advances this will change – early in the next decade, I believe. For now, whole-exome sequencing may be an option for some patients who want to know more when severe CHD is evident on ultrasound and there are negative results from CMA or targeted sequencing. We have diagnosed some rare genetic syndromes using whole-exome sequencing; these diagnoses helped us to better manage the pregnancies.
These choices are part of the case-specific, stepwise approach to genetic evaluation that we take in our fetal heart program. Our goal is to pursue information that will be accurate and valuable for the patient and clinicians, in the most cost-effective and timely manner.
Limitations of noninvasive screening
In our fetal heart program we see increasing numbers of referred patients who have chosen noninvasive cell-free fetal DNA screening (cfDNA) after a cardiac anomaly is detected on ultrasound examination, and who believe that their “low risk” results demonstrate very little or no risk of CHD. Many of these patients express a belief that noninvasive testing is highly sensitive and accurate for fetal anomalies, including CHDs, and are not easily convinced of the value of other genetic tests.
We recently conducted a retrospective chart analysis (unpublished) in which we found that 41% of cases of CHD with abnormal genetics results were not detectable by cfDNA screening.
In the case of atrial-ventricular septal defects and conotruncal abnormalities that often are more associated with common aneuploidies (trisomy 21, 18, 13, and 45 XO), a “high-risk” result from cfDNA screening may offer the family and cardiology/neonatal team some guidance, but a “low-risk” result does not eliminate the risk of a microarray abnormality and thus may provide false reassurance.
Other research has shown that noninvasive screening will miss up to 7.3% of karyotype abnormalities in pregnancies at high risk for common aneuploidies.6
While invasive testing poses a very small risk of miscarriage, it is hard without such testing to elucidate the potential genetic etiologies of CHDs and truly understand the problems. We must take time to thoughtfully counsel patients who decline invasive testing about the limitations of cfDNA screening for CHDs and other anomalies.
Dr. Turan is an associate professor of obstetrics, gynecology, and reproductive sciences, and director of the fetal heart program at the University of Maryland School of Medicine and director of the Fetal Heart Program at the University of Maryland Medical Center. Dr. Turan reported that she has no disclosures relevant to this Master Class. Email her at [email protected].
References
1. J Am Coll Cardiol. 1988 Oct;12(4):1079-86.
2. Pediatr Cardiol. 2019 Mar;40(3):489-96.
3. Ann Pediatr Cardiol. 2017 May-Aug;10(2):126-30.
4. Eur J Obstet Gynecol Reprod Biol 2018;221:172-76.
5. Ultrasound Obstet Gynecol. 2018 Aug;52(2):205-11.
6. PLoS One. 2016 Jan 15;11(1):e0146794.
Try testosterone for some women with sexual dysfunction, but not others
A new international position statement on testosterone therapy for women concludes that a trial of testosterone is appropriate for postmenopausal women with hypoactive sexual desire dysfunction (HSDD) and that its use for any other condition, symptom, or reason is not supported by available evidence.
The seven-page position statement, developed by an international task force of experts from the Endocrine Society, the American College of Gynecologists and Obstetricians, and multiple other medical societies, also emphasized that blood concentrations of testosterone should approximate premenopausal physiological conditions.
“When testosterone therapy is given, the resultant blood levels should not be above those seen in healthy young women,” said lead author Susan Ruth Davis, PhD, MBBS, of Monash University in Melbourne, Australia, in a press release issued by the Endocrine Society. Dr. Davis is president of the International Menopause Society, which coordinated the panel.
The statement was published in the Journal of Clinical Endocrinology & Metabolism and three other medical journals.
Margaret E. Wierman, MD, who represented the Endocrine Society on the task force, said in an interview that there has been “growing concern about testosterone being prescribed for a variety of signs and symptoms without data to support” such use. At the same time, there is significant concern about the ongoing lack of approved formulations licensed specifically for women, she said.
In part, the statement is about a renewed “call to industry to make some [female-specific] formulations so that we can examine other potential roles of testosterone in women,” said Dr. Wierman, professor of medicine and physiology at the University of Colorado at Denver, Aurora, and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center in Aurora.
“Testosterone may be useful [for indications other than HSDD], but we don’t know. There may be no [breast or cardiovascular disease risk], but we don’t know,” she said. “And without a formulation to study potential benefits and risks, it’s good to be cautious. It’s good to really outline where we have data and where we don’t.”
The Endocrine Society’s 2014 clinical practice guideline on androgen therapy in women, for which Dr. Wierman was the lead author, also recommended against the off-label use of testosterone for sexual dysfunction other than HSDD or for any other reason, such as cognitive, cardiovascular, metabolic, or bone health. As with the new statement, the society’s position statement was guided by an international, multisociety task force, albeit a smaller one.
For the new global position statement, the task force’s review of evidence includes a recently published systematic review and meta-analysis of randomized controlled trial data – of at least 12 weeks’ duration – on the use of testosterone for sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. Some of the data from the randomized controlled trials were unpublished.
The meta-analysis, led by Dr. Davis and published in July in the Lancet Diabetes & Endocrinology, found that, compared with placebo or a comparator (such as estrogen, with or without progesterone), testosterone in either oral or transdermal form significantly improved sexual function in postmenopausal women. However, data about the effects of testosterone for other indications, its long-term safety, and its use in premenopausal women, were insufficient for drawing any conclusions (Lancet Diabetes Endocrinol. 2019 Jul 25. doi: 10.1016/S2213-8587[19]30189-5).
In addition, testosterone administered orally – but not nonorally (patch or cream) – was associated with adverse lipid profiles, Dr. Davis and her colleagues reported.
Another systematic review and meta-analysis, published in Fertility and Sterility in 2017 and included in the task force’s evidence review, focused specifically on transdermal testosterone for menopausal women with HSDD, with or without estrogen and progestin therapy. It also showed short-term efficacy in terms of improvement in sexual function, as well as short-term safety (Fertil Steril. 2017;107(2):475-82).
The new position statement warns about the lack of long-term safety data, stating that “safety data for testosterone in physiologic doses are not available beyond 24 months of treatment.”
In the short term, testosterone therapy for postmenopausal women (in doses approximating testosterone concentrations for premenopausal women), is associated with mild increases in acne and body/facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change. Short-term transdermal therapy also does not seem to affect breast cancer risk or have any significant effects on lipid profiles, the statement says.
The panel points out, however, that randomized controlled trials with testosterone therapy have excluded women who are at high risk of cardiometabolic disease, and that women with a previous diagnosis of breast cancer have also been excluded from randomized trials of testosterone in women with HSDD. This is a “big issue,” said Dr. Wierman, and means that recommendations regarding the effect of testosterone in postmenopausal women with HSDD may not be generalizable to possible at-risk subpopulations.
The panel endorsed testosterone therapy specifically for women with HSDD because most of the studies reporting on sexual function have recruited women with diagnosed HSDD. Demonstrated benefits of testosterone in these cases include improved sexual desire, arousal, orgasm, and pleasure, and reduced concerns and distress about sex. HSDD should be diagnosed after formal biopsychosocial assessment, the statement notes.
“We don’t completely understand the control of sexual function in women, but it’s very dependent on estrogen status. And it’s also dependent on psychosocial factors, emotional health, relationship issues, and physical issues,” Dr. Wierman said in the interview.
“In practice, we look at all these issues, and we first optimize estrogen status. Once that’s done, and we’ve looked at all the other components of sexual function, then we can consider off-label use of testosterone,” she said. “If there’s no response in 3-6 months, we stop it.”
Testosterone levels do not correlate with sexual dysfunction, Dr. Wierman emphasized, and direct assays for the measurement of total and free testosterone are unreliable. The statement acknowledges that but still recommends measurement of testosterone using direct assays, in cases in which liquid/gas chromatography and tandem mass spectrometry assay (which has “high accuracy and reproducibility”) are not available. This is “to exclude high baseline concentrations and also to exclude supraphysiological concentrations during treatment,” the panel said.
Most endocrinologists and other experts who prescribe testosterone therapy for women use an approved male formulation off label and adjust it – an approach that the panel says is reasonable as long as hormone concentrations are “maintained in the physiologic female range.”
Compounded “bioidentical” testosterone therapy “cannot be recommended for the treatment of HSDD because of the lack of evidence for safety and efficacy,” the statement says.
“A big concern of many endocrinologists,” Dr. Wierman added, “is the recent explosion of using pharmacological levels of both estrogen and testosterone in either [injections] or pellets.” The Endocrine Society and other societies have alerted the Food and Drug Administration to “this new cottage industry, which may have significant side effects and risks for our patients,” she said.
Dr. Wierman reported received funding from Corcept Therapeutics, Novartis, and the Cancer League of Colorado, and honoraria or consultation fees from Pfizer to review ASPIRE grant applications for studies of acromegaly as well as Endocrine Society honorarium for teaching in the Endocrine Board Review and Clinical Endocrine Update. Dr. Davis reported receiving funding from a National Health and Medical Research Council Project Grant, a National Breast Foundation accelerator grant, and the Grollo-Ruzenne Foundation, as well as honoraria from Besins and Pfizer Australia. She has been a consultant to Besins Healthcare, Mayne Pharmaceuticals, Lawley Pharmaceuticals, and Que Oncology. Disclosures for other authors of the position statement are listed with the statement.
SOURCE: Davis SR et al. J Clin Endocrinol Metab. 2019 Sep 2. doi: 10.1210/jc.2019-01603.
A new international position statement on testosterone therapy for women concludes that a trial of testosterone is appropriate for postmenopausal women with hypoactive sexual desire dysfunction (HSDD) and that its use for any other condition, symptom, or reason is not supported by available evidence.
The seven-page position statement, developed by an international task force of experts from the Endocrine Society, the American College of Gynecologists and Obstetricians, and multiple other medical societies, also emphasized that blood concentrations of testosterone should approximate premenopausal physiological conditions.
“When testosterone therapy is given, the resultant blood levels should not be above those seen in healthy young women,” said lead author Susan Ruth Davis, PhD, MBBS, of Monash University in Melbourne, Australia, in a press release issued by the Endocrine Society. Dr. Davis is president of the International Menopause Society, which coordinated the panel.
The statement was published in the Journal of Clinical Endocrinology & Metabolism and three other medical journals.
Margaret E. Wierman, MD, who represented the Endocrine Society on the task force, said in an interview that there has been “growing concern about testosterone being prescribed for a variety of signs and symptoms without data to support” such use. At the same time, there is significant concern about the ongoing lack of approved formulations licensed specifically for women, she said.
In part, the statement is about a renewed “call to industry to make some [female-specific] formulations so that we can examine other potential roles of testosterone in women,” said Dr. Wierman, professor of medicine and physiology at the University of Colorado at Denver, Aurora, and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center in Aurora.
“Testosterone may be useful [for indications other than HSDD], but we don’t know. There may be no [breast or cardiovascular disease risk], but we don’t know,” she said. “And without a formulation to study potential benefits and risks, it’s good to be cautious. It’s good to really outline where we have data and where we don’t.”
The Endocrine Society’s 2014 clinical practice guideline on androgen therapy in women, for which Dr. Wierman was the lead author, also recommended against the off-label use of testosterone for sexual dysfunction other than HSDD or for any other reason, such as cognitive, cardiovascular, metabolic, or bone health. As with the new statement, the society’s position statement was guided by an international, multisociety task force, albeit a smaller one.
For the new global position statement, the task force’s review of evidence includes a recently published systematic review and meta-analysis of randomized controlled trial data – of at least 12 weeks’ duration – on the use of testosterone for sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. Some of the data from the randomized controlled trials were unpublished.
The meta-analysis, led by Dr. Davis and published in July in the Lancet Diabetes & Endocrinology, found that, compared with placebo or a comparator (such as estrogen, with or without progesterone), testosterone in either oral or transdermal form significantly improved sexual function in postmenopausal women. However, data about the effects of testosterone for other indications, its long-term safety, and its use in premenopausal women, were insufficient for drawing any conclusions (Lancet Diabetes Endocrinol. 2019 Jul 25. doi: 10.1016/S2213-8587[19]30189-5).
In addition, testosterone administered orally – but not nonorally (patch or cream) – was associated with adverse lipid profiles, Dr. Davis and her colleagues reported.
Another systematic review and meta-analysis, published in Fertility and Sterility in 2017 and included in the task force’s evidence review, focused specifically on transdermal testosterone for menopausal women with HSDD, with or without estrogen and progestin therapy. It also showed short-term efficacy in terms of improvement in sexual function, as well as short-term safety (Fertil Steril. 2017;107(2):475-82).
The new position statement warns about the lack of long-term safety data, stating that “safety data for testosterone in physiologic doses are not available beyond 24 months of treatment.”
In the short term, testosterone therapy for postmenopausal women (in doses approximating testosterone concentrations for premenopausal women), is associated with mild increases in acne and body/facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change. Short-term transdermal therapy also does not seem to affect breast cancer risk or have any significant effects on lipid profiles, the statement says.
The panel points out, however, that randomized controlled trials with testosterone therapy have excluded women who are at high risk of cardiometabolic disease, and that women with a previous diagnosis of breast cancer have also been excluded from randomized trials of testosterone in women with HSDD. This is a “big issue,” said Dr. Wierman, and means that recommendations regarding the effect of testosterone in postmenopausal women with HSDD may not be generalizable to possible at-risk subpopulations.
The panel endorsed testosterone therapy specifically for women with HSDD because most of the studies reporting on sexual function have recruited women with diagnosed HSDD. Demonstrated benefits of testosterone in these cases include improved sexual desire, arousal, orgasm, and pleasure, and reduced concerns and distress about sex. HSDD should be diagnosed after formal biopsychosocial assessment, the statement notes.
“We don’t completely understand the control of sexual function in women, but it’s very dependent on estrogen status. And it’s also dependent on psychosocial factors, emotional health, relationship issues, and physical issues,” Dr. Wierman said in the interview.
“In practice, we look at all these issues, and we first optimize estrogen status. Once that’s done, and we’ve looked at all the other components of sexual function, then we can consider off-label use of testosterone,” she said. “If there’s no response in 3-6 months, we stop it.”
Testosterone levels do not correlate with sexual dysfunction, Dr. Wierman emphasized, and direct assays for the measurement of total and free testosterone are unreliable. The statement acknowledges that but still recommends measurement of testosterone using direct assays, in cases in which liquid/gas chromatography and tandem mass spectrometry assay (which has “high accuracy and reproducibility”) are not available. This is “to exclude high baseline concentrations and also to exclude supraphysiological concentrations during treatment,” the panel said.
Most endocrinologists and other experts who prescribe testosterone therapy for women use an approved male formulation off label and adjust it – an approach that the panel says is reasonable as long as hormone concentrations are “maintained in the physiologic female range.”
Compounded “bioidentical” testosterone therapy “cannot be recommended for the treatment of HSDD because of the lack of evidence for safety and efficacy,” the statement says.
“A big concern of many endocrinologists,” Dr. Wierman added, “is the recent explosion of using pharmacological levels of both estrogen and testosterone in either [injections] or pellets.” The Endocrine Society and other societies have alerted the Food and Drug Administration to “this new cottage industry, which may have significant side effects and risks for our patients,” she said.
Dr. Wierman reported received funding from Corcept Therapeutics, Novartis, and the Cancer League of Colorado, and honoraria or consultation fees from Pfizer to review ASPIRE grant applications for studies of acromegaly as well as Endocrine Society honorarium for teaching in the Endocrine Board Review and Clinical Endocrine Update. Dr. Davis reported receiving funding from a National Health and Medical Research Council Project Grant, a National Breast Foundation accelerator grant, and the Grollo-Ruzenne Foundation, as well as honoraria from Besins and Pfizer Australia. She has been a consultant to Besins Healthcare, Mayne Pharmaceuticals, Lawley Pharmaceuticals, and Que Oncology. Disclosures for other authors of the position statement are listed with the statement.
SOURCE: Davis SR et al. J Clin Endocrinol Metab. 2019 Sep 2. doi: 10.1210/jc.2019-01603.
A new international position statement on testosterone therapy for women concludes that a trial of testosterone is appropriate for postmenopausal women with hypoactive sexual desire dysfunction (HSDD) and that its use for any other condition, symptom, or reason is not supported by available evidence.
The seven-page position statement, developed by an international task force of experts from the Endocrine Society, the American College of Gynecologists and Obstetricians, and multiple other medical societies, also emphasized that blood concentrations of testosterone should approximate premenopausal physiological conditions.
“When testosterone therapy is given, the resultant blood levels should not be above those seen in healthy young women,” said lead author Susan Ruth Davis, PhD, MBBS, of Monash University in Melbourne, Australia, in a press release issued by the Endocrine Society. Dr. Davis is president of the International Menopause Society, which coordinated the panel.
The statement was published in the Journal of Clinical Endocrinology & Metabolism and three other medical journals.
Margaret E. Wierman, MD, who represented the Endocrine Society on the task force, said in an interview that there has been “growing concern about testosterone being prescribed for a variety of signs and symptoms without data to support” such use. At the same time, there is significant concern about the ongoing lack of approved formulations licensed specifically for women, she said.
In part, the statement is about a renewed “call to industry to make some [female-specific] formulations so that we can examine other potential roles of testosterone in women,” said Dr. Wierman, professor of medicine and physiology at the University of Colorado at Denver, Aurora, and chief of endocrinology at the Rocky Mountain Regional Veterans Affairs Medical Center in Aurora.
“Testosterone may be useful [for indications other than HSDD], but we don’t know. There may be no [breast or cardiovascular disease risk], but we don’t know,” she said. “And without a formulation to study potential benefits and risks, it’s good to be cautious. It’s good to really outline where we have data and where we don’t.”
The Endocrine Society’s 2014 clinical practice guideline on androgen therapy in women, for which Dr. Wierman was the lead author, also recommended against the off-label use of testosterone for sexual dysfunction other than HSDD or for any other reason, such as cognitive, cardiovascular, metabolic, or bone health. As with the new statement, the society’s position statement was guided by an international, multisociety task force, albeit a smaller one.
For the new global position statement, the task force’s review of evidence includes a recently published systematic review and meta-analysis of randomized controlled trial data – of at least 12 weeks’ duration – on the use of testosterone for sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. Some of the data from the randomized controlled trials were unpublished.
The meta-analysis, led by Dr. Davis and published in July in the Lancet Diabetes & Endocrinology, found that, compared with placebo or a comparator (such as estrogen, with or without progesterone), testosterone in either oral or transdermal form significantly improved sexual function in postmenopausal women. However, data about the effects of testosterone for other indications, its long-term safety, and its use in premenopausal women, were insufficient for drawing any conclusions (Lancet Diabetes Endocrinol. 2019 Jul 25. doi: 10.1016/S2213-8587[19]30189-5).
In addition, testosterone administered orally – but not nonorally (patch or cream) – was associated with adverse lipid profiles, Dr. Davis and her colleagues reported.
Another systematic review and meta-analysis, published in Fertility and Sterility in 2017 and included in the task force’s evidence review, focused specifically on transdermal testosterone for menopausal women with HSDD, with or without estrogen and progestin therapy. It also showed short-term efficacy in terms of improvement in sexual function, as well as short-term safety (Fertil Steril. 2017;107(2):475-82).
The new position statement warns about the lack of long-term safety data, stating that “safety data for testosterone in physiologic doses are not available beyond 24 months of treatment.”
In the short term, testosterone therapy for postmenopausal women (in doses approximating testosterone concentrations for premenopausal women), is associated with mild increases in acne and body/facial hair growth in some women, but not with alopecia, clitoromegaly, or voice change. Short-term transdermal therapy also does not seem to affect breast cancer risk or have any significant effects on lipid profiles, the statement says.
The panel points out, however, that randomized controlled trials with testosterone therapy have excluded women who are at high risk of cardiometabolic disease, and that women with a previous diagnosis of breast cancer have also been excluded from randomized trials of testosterone in women with HSDD. This is a “big issue,” said Dr. Wierman, and means that recommendations regarding the effect of testosterone in postmenopausal women with HSDD may not be generalizable to possible at-risk subpopulations.
The panel endorsed testosterone therapy specifically for women with HSDD because most of the studies reporting on sexual function have recruited women with diagnosed HSDD. Demonstrated benefits of testosterone in these cases include improved sexual desire, arousal, orgasm, and pleasure, and reduced concerns and distress about sex. HSDD should be diagnosed after formal biopsychosocial assessment, the statement notes.
“We don’t completely understand the control of sexual function in women, but it’s very dependent on estrogen status. And it’s also dependent on psychosocial factors, emotional health, relationship issues, and physical issues,” Dr. Wierman said in the interview.
“In practice, we look at all these issues, and we first optimize estrogen status. Once that’s done, and we’ve looked at all the other components of sexual function, then we can consider off-label use of testosterone,” she said. “If there’s no response in 3-6 months, we stop it.”
Testosterone levels do not correlate with sexual dysfunction, Dr. Wierman emphasized, and direct assays for the measurement of total and free testosterone are unreliable. The statement acknowledges that but still recommends measurement of testosterone using direct assays, in cases in which liquid/gas chromatography and tandem mass spectrometry assay (which has “high accuracy and reproducibility”) are not available. This is “to exclude high baseline concentrations and also to exclude supraphysiological concentrations during treatment,” the panel said.
Most endocrinologists and other experts who prescribe testosterone therapy for women use an approved male formulation off label and adjust it – an approach that the panel says is reasonable as long as hormone concentrations are “maintained in the physiologic female range.”
Compounded “bioidentical” testosterone therapy “cannot be recommended for the treatment of HSDD because of the lack of evidence for safety and efficacy,” the statement says.
“A big concern of many endocrinologists,” Dr. Wierman added, “is the recent explosion of using pharmacological levels of both estrogen and testosterone in either [injections] or pellets.” The Endocrine Society and other societies have alerted the Food and Drug Administration to “this new cottage industry, which may have significant side effects and risks for our patients,” she said.
Dr. Wierman reported received funding from Corcept Therapeutics, Novartis, and the Cancer League of Colorado, and honoraria or consultation fees from Pfizer to review ASPIRE grant applications for studies of acromegaly as well as Endocrine Society honorarium for teaching in the Endocrine Board Review and Clinical Endocrine Update. Dr. Davis reported receiving funding from a National Health and Medical Research Council Project Grant, a National Breast Foundation accelerator grant, and the Grollo-Ruzenne Foundation, as well as honoraria from Besins and Pfizer Australia. She has been a consultant to Besins Healthcare, Mayne Pharmaceuticals, Lawley Pharmaceuticals, and Que Oncology. Disclosures for other authors of the position statement are listed with the statement.
SOURCE: Davis SR et al. J Clin Endocrinol Metab. 2019 Sep 2. doi: 10.1210/jc.2019-01603.
FROM JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Zulresso: Hope and lingering questions
The last decade has brought increasing awareness of the need to effectively screen for postpartum depression, with a majority of states across the country now having some sort of formal program by which women are screened for mood disorder during the postnatal period, typically with scales such as the Edinburgh Postnatal Depression Scale (EPDS).
In addition to effective screening is a pressing need for effective referral networks of clinicians who have both the expertise and time to manage the 10%-15% of women who have been identified and who suffer from postpartum psychiatric disorders – both postpartum mood and anxiety disorders. Several studies have suggested that only a small percentage of postpartum women who score with clinically significant level of depressive symptoms actually get to a clinician or, if they do get to a clinician, receive adequate treatment restoring their emotional well-being (J Clin Psychiatry. 2016 Sep;77[9]:1189-200).
Zulresso (brexanolone), a novel new antidepressant medication which recently received Food and Drug Administration approval for the treatment of postpartum depression, is a first-in-class molecule to get such approval. Zulresso is a neurosteroid, an analogue of allopregnanolone and a GABAA receptor–positive allosteric modulator, a primary inhibitory neurotransmitter in the brain.
There is every reason to believe that, as a class, this group of neurosteroid molecules are effective in treating depression in other populations aside from women with postpartum depression and hence may not be specific to the postpartum period. For example, recent presentations of preliminary data suggest other neurosteroids such as zuranolone (an oral medication also developed by Sage Therapeutics) is effective for both men and women who have major depression in addition to women suffering from postpartum depression.
Zulresso is approved through a Risk Evaluation and Mitigation Strategy–restricted program and, per that protocol, needs to be administered by a health care provider in a recognized health care setting intravenously over 2.5 days (60 hours). Because of concerns regarding increased sedation, continuous pulse oximetry is required, and this is outlined in a boxed warning in the prescribing information. Zulresso has been classified by the Drug Enforcement Administration (DEA) as a Schedule IV injection and is subject to the prescribing regulations for a controlled substance.
Since Zulresso’s approval, my colleagues and I at the Center for Women’s Mental Health have received numerous queries from patients and colleagues about our clinical impression of this new molecule with a different mechanism of action – a welcome addition to the antidepressant pharmacopeia. The question posed to us essentially is: Where does brexanolone fit into our algorithm for treating women who suffer from postpartum depression? And frequently, the follow-up query is: Because subjects in the clinical trials for this medication included women who had onset of depression either late in pregnancy or during the postpartum period, how specific is brexanolone with respect to being a targeted therapy for postpartum depression, compared with depression encountered in other clinical settings.
What clearly can be stated is that Zulresso has a rapid onset of action and was demonstrated across clinical trials to have sustained benefit up to 30 days after IV administration. The question is whether patients have sustained benefit after 30 days or if this is a medicine to be considered as a “bridge” to other treatment. Data answering that critical clinical question are unavailable at this time. From a clinical standpoint, do patients receive this treatment and get sent home on antidepressants, as we would for patients who receive ECT, often discharging them with prophylactic antidepressants to sustain the benefit of the treatment? Or do patients receive this new medicine with the clinician providing close follow-up, assuming a wait-and-see approach? Because data informing the answer to that question are not available, this decision will be made empirically, frequently factoring in the patient’s past clinical history where presumably more liberal use of antidepressant immediately after the administration of Zulresso will be pursued in those with histories of highly recurrent major depression.
So where might this new medicine fit into the treatment of postpartum depression of moderate severity, or modest to moderate severity? It should be kept in mind that for patients with mild to moderate postpartum depression, there are data supporting the efficacy of cognitive-behavioral therapy (CBT). CBT frequently is pursued with concurrent mobilization of substantial social support with good outcomes. In patients with more severe postpartum depression, there are data supporting the use of antidepressants, and in these patients as well, use of established support from the ever-growing network of community-based support groups and services can be particularly helpful. It is unlikely that Zulresso will be a first-line medication for the treatment of postpartum depression, but it may be particularly appropriate for patients with severe illness who have not responded to other interventions.
Other practical considerations regarding use of Zulresso include the requirement that the medicine be administered in hospitals that have established clinical infrastructure to accommodate this particular population of patients and where pharmacists and other relevant parties in hospitals have accepted the medicine into its drug formulary. While coverage by various insurance policies may vary, the cost of this new medication is substantial, between $24,000 and $34,000 per treatment, according to reports.
Where Zulresso fits into the pharmacopeia for treating postpartum depression may fall well beyond the issues of efficacy. Given all of the attention to this first-in-class medicine, Zulresso has reinforced the growing interest in the substantial prevalence and the morbidity associated with postpartum depression. It is hard to imagine Zulresso being used in cases of more mild to moderate depression, in which there is nonemergent opportunity to pursue options that do not require a new mom to absent herself from homelife with a newborn. However, in picking cases of severe new onset or recurrence of depression in postpartum women, the rapid onset of benefit that was noted within days could be an extraordinary relief and be the beginning of a road to wellness for some women.
Ultimately, the collaboration of patients with their doctors, the realities of cost, and the acceptability of use in various clinical settings will determine how Zulresso is incorporated into seeking treatment to mitigate the suffering associated with postpartum depression. We at the Center for Women’s Mental Health are interested in user experience with respect to this medicine and welcome comments from both patients and their doctors at [email protected].
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. This center was an investigator site for one of the studies supported by Sage Therapeutics, the manufacturer of Zulresso. Dr. Cohen is also the Edmund and Carroll Carpenter professor of psychiatry at Harvard Medical School, also in Boston. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
The last decade has brought increasing awareness of the need to effectively screen for postpartum depression, with a majority of states across the country now having some sort of formal program by which women are screened for mood disorder during the postnatal period, typically with scales such as the Edinburgh Postnatal Depression Scale (EPDS).
In addition to effective screening is a pressing need for effective referral networks of clinicians who have both the expertise and time to manage the 10%-15% of women who have been identified and who suffer from postpartum psychiatric disorders – both postpartum mood and anxiety disorders. Several studies have suggested that only a small percentage of postpartum women who score with clinically significant level of depressive symptoms actually get to a clinician or, if they do get to a clinician, receive adequate treatment restoring their emotional well-being (J Clin Psychiatry. 2016 Sep;77[9]:1189-200).
Zulresso (brexanolone), a novel new antidepressant medication which recently received Food and Drug Administration approval for the treatment of postpartum depression, is a first-in-class molecule to get such approval. Zulresso is a neurosteroid, an analogue of allopregnanolone and a GABAA receptor–positive allosteric modulator, a primary inhibitory neurotransmitter in the brain.
There is every reason to believe that, as a class, this group of neurosteroid molecules are effective in treating depression in other populations aside from women with postpartum depression and hence may not be specific to the postpartum period. For example, recent presentations of preliminary data suggest other neurosteroids such as zuranolone (an oral medication also developed by Sage Therapeutics) is effective for both men and women who have major depression in addition to women suffering from postpartum depression.
Zulresso is approved through a Risk Evaluation and Mitigation Strategy–restricted program and, per that protocol, needs to be administered by a health care provider in a recognized health care setting intravenously over 2.5 days (60 hours). Because of concerns regarding increased sedation, continuous pulse oximetry is required, and this is outlined in a boxed warning in the prescribing information. Zulresso has been classified by the Drug Enforcement Administration (DEA) as a Schedule IV injection and is subject to the prescribing regulations for a controlled substance.
Since Zulresso’s approval, my colleagues and I at the Center for Women’s Mental Health have received numerous queries from patients and colleagues about our clinical impression of this new molecule with a different mechanism of action – a welcome addition to the antidepressant pharmacopeia. The question posed to us essentially is: Where does brexanolone fit into our algorithm for treating women who suffer from postpartum depression? And frequently, the follow-up query is: Because subjects in the clinical trials for this medication included women who had onset of depression either late in pregnancy or during the postpartum period, how specific is brexanolone with respect to being a targeted therapy for postpartum depression, compared with depression encountered in other clinical settings.
What clearly can be stated is that Zulresso has a rapid onset of action and was demonstrated across clinical trials to have sustained benefit up to 30 days after IV administration. The question is whether patients have sustained benefit after 30 days or if this is a medicine to be considered as a “bridge” to other treatment. Data answering that critical clinical question are unavailable at this time. From a clinical standpoint, do patients receive this treatment and get sent home on antidepressants, as we would for patients who receive ECT, often discharging them with prophylactic antidepressants to sustain the benefit of the treatment? Or do patients receive this new medicine with the clinician providing close follow-up, assuming a wait-and-see approach? Because data informing the answer to that question are not available, this decision will be made empirically, frequently factoring in the patient’s past clinical history where presumably more liberal use of antidepressant immediately after the administration of Zulresso will be pursued in those with histories of highly recurrent major depression.
So where might this new medicine fit into the treatment of postpartum depression of moderate severity, or modest to moderate severity? It should be kept in mind that for patients with mild to moderate postpartum depression, there are data supporting the efficacy of cognitive-behavioral therapy (CBT). CBT frequently is pursued with concurrent mobilization of substantial social support with good outcomes. In patients with more severe postpartum depression, there are data supporting the use of antidepressants, and in these patients as well, use of established support from the ever-growing network of community-based support groups and services can be particularly helpful. It is unlikely that Zulresso will be a first-line medication for the treatment of postpartum depression, but it may be particularly appropriate for patients with severe illness who have not responded to other interventions.
Other practical considerations regarding use of Zulresso include the requirement that the medicine be administered in hospitals that have established clinical infrastructure to accommodate this particular population of patients and where pharmacists and other relevant parties in hospitals have accepted the medicine into its drug formulary. While coverage by various insurance policies may vary, the cost of this new medication is substantial, between $24,000 and $34,000 per treatment, according to reports.
Where Zulresso fits into the pharmacopeia for treating postpartum depression may fall well beyond the issues of efficacy. Given all of the attention to this first-in-class medicine, Zulresso has reinforced the growing interest in the substantial prevalence and the morbidity associated with postpartum depression. It is hard to imagine Zulresso being used in cases of more mild to moderate depression, in which there is nonemergent opportunity to pursue options that do not require a new mom to absent herself from homelife with a newborn. However, in picking cases of severe new onset or recurrence of depression in postpartum women, the rapid onset of benefit that was noted within days could be an extraordinary relief and be the beginning of a road to wellness for some women.
Ultimately, the collaboration of patients with their doctors, the realities of cost, and the acceptability of use in various clinical settings will determine how Zulresso is incorporated into seeking treatment to mitigate the suffering associated with postpartum depression. We at the Center for Women’s Mental Health are interested in user experience with respect to this medicine and welcome comments from both patients and their doctors at [email protected].
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. This center was an investigator site for one of the studies supported by Sage Therapeutics, the manufacturer of Zulresso. Dr. Cohen is also the Edmund and Carroll Carpenter professor of psychiatry at Harvard Medical School, also in Boston. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
The last decade has brought increasing awareness of the need to effectively screen for postpartum depression, with a majority of states across the country now having some sort of formal program by which women are screened for mood disorder during the postnatal period, typically with scales such as the Edinburgh Postnatal Depression Scale (EPDS).
In addition to effective screening is a pressing need for effective referral networks of clinicians who have both the expertise and time to manage the 10%-15% of women who have been identified and who suffer from postpartum psychiatric disorders – both postpartum mood and anxiety disorders. Several studies have suggested that only a small percentage of postpartum women who score with clinically significant level of depressive symptoms actually get to a clinician or, if they do get to a clinician, receive adequate treatment restoring their emotional well-being (J Clin Psychiatry. 2016 Sep;77[9]:1189-200).
Zulresso (brexanolone), a novel new antidepressant medication which recently received Food and Drug Administration approval for the treatment of postpartum depression, is a first-in-class molecule to get such approval. Zulresso is a neurosteroid, an analogue of allopregnanolone and a GABAA receptor–positive allosteric modulator, a primary inhibitory neurotransmitter in the brain.
There is every reason to believe that, as a class, this group of neurosteroid molecules are effective in treating depression in other populations aside from women with postpartum depression and hence may not be specific to the postpartum period. For example, recent presentations of preliminary data suggest other neurosteroids such as zuranolone (an oral medication also developed by Sage Therapeutics) is effective for both men and women who have major depression in addition to women suffering from postpartum depression.
Zulresso is approved through a Risk Evaluation and Mitigation Strategy–restricted program and, per that protocol, needs to be administered by a health care provider in a recognized health care setting intravenously over 2.5 days (60 hours). Because of concerns regarding increased sedation, continuous pulse oximetry is required, and this is outlined in a boxed warning in the prescribing information. Zulresso has been classified by the Drug Enforcement Administration (DEA) as a Schedule IV injection and is subject to the prescribing regulations for a controlled substance.
Since Zulresso’s approval, my colleagues and I at the Center for Women’s Mental Health have received numerous queries from patients and colleagues about our clinical impression of this new molecule with a different mechanism of action – a welcome addition to the antidepressant pharmacopeia. The question posed to us essentially is: Where does brexanolone fit into our algorithm for treating women who suffer from postpartum depression? And frequently, the follow-up query is: Because subjects in the clinical trials for this medication included women who had onset of depression either late in pregnancy or during the postpartum period, how specific is brexanolone with respect to being a targeted therapy for postpartum depression, compared with depression encountered in other clinical settings.
What clearly can be stated is that Zulresso has a rapid onset of action and was demonstrated across clinical trials to have sustained benefit up to 30 days after IV administration. The question is whether patients have sustained benefit after 30 days or if this is a medicine to be considered as a “bridge” to other treatment. Data answering that critical clinical question are unavailable at this time. From a clinical standpoint, do patients receive this treatment and get sent home on antidepressants, as we would for patients who receive ECT, often discharging them with prophylactic antidepressants to sustain the benefit of the treatment? Or do patients receive this new medicine with the clinician providing close follow-up, assuming a wait-and-see approach? Because data informing the answer to that question are not available, this decision will be made empirically, frequently factoring in the patient’s past clinical history where presumably more liberal use of antidepressant immediately after the administration of Zulresso will be pursued in those with histories of highly recurrent major depression.
So where might this new medicine fit into the treatment of postpartum depression of moderate severity, or modest to moderate severity? It should be kept in mind that for patients with mild to moderate postpartum depression, there are data supporting the efficacy of cognitive-behavioral therapy (CBT). CBT frequently is pursued with concurrent mobilization of substantial social support with good outcomes. In patients with more severe postpartum depression, there are data supporting the use of antidepressants, and in these patients as well, use of established support from the ever-growing network of community-based support groups and services can be particularly helpful. It is unlikely that Zulresso will be a first-line medication for the treatment of postpartum depression, but it may be particularly appropriate for patients with severe illness who have not responded to other interventions.
Other practical considerations regarding use of Zulresso include the requirement that the medicine be administered in hospitals that have established clinical infrastructure to accommodate this particular population of patients and where pharmacists and other relevant parties in hospitals have accepted the medicine into its drug formulary. While coverage by various insurance policies may vary, the cost of this new medication is substantial, between $24,000 and $34,000 per treatment, according to reports.
Where Zulresso fits into the pharmacopeia for treating postpartum depression may fall well beyond the issues of efficacy. Given all of the attention to this first-in-class medicine, Zulresso has reinforced the growing interest in the substantial prevalence and the morbidity associated with postpartum depression. It is hard to imagine Zulresso being used in cases of more mild to moderate depression, in which there is nonemergent opportunity to pursue options that do not require a new mom to absent herself from homelife with a newborn. However, in picking cases of severe new onset or recurrence of depression in postpartum women, the rapid onset of benefit that was noted within days could be an extraordinary relief and be the beginning of a road to wellness for some women.
Ultimately, the collaboration of patients with their doctors, the realities of cost, and the acceptability of use in various clinical settings will determine how Zulresso is incorporated into seeking treatment to mitigate the suffering associated with postpartum depression. We at the Center for Women’s Mental Health are interested in user experience with respect to this medicine and welcome comments from both patients and their doctors at [email protected].
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. This center was an investigator site for one of the studies supported by Sage Therapeutics, the manufacturer of Zulresso. Dr. Cohen is also the Edmund and Carroll Carpenter professor of psychiatry at Harvard Medical School, also in Boston. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Oral drug for postpartum depression aces phase 3 trial
COPENHAGEN – A first-in-class, once-daily, orally administered neuroactive steroid known for now as SAGE-217 aced all of its primary and secondary outcomes for the treatment of postpartum depression in the phase 3, randomized, double-blind, placebo-controlled ROBIN study, Eduard Vieta, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“I think this changes the paradigm in the treatment of postpartum depression,” declared Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Like brexanolone (Zulresso), an intravenous formulation of allopregnanolone approved by the Food and Drug Administration in March 2019 as the first-ever drug specifically targeting postpartum depression, SAGE-217 is a positive allosteric modifier of synaptic and extrasynaptic GABA-A receptors. That differentiates the two drugs from benzodiazepines, which target only synaptic receptors. Both brexanolone and SAGE-217 are drugs developed by Sage Therapeutics. But SAGE-217, an investigational agent, is vastly more convenient to use than brexanolone since, as an oral drug, it doesn’t require hospitalization for intravenous administration.
Dr. Vieta ticked off five reasons why he considers SAGE-217 a game changer in the treatment of postpartum depression: “It’s an amazingly effective compound, with an effect size that’s bigger than we usually see with antidepressants. It has an early onset of action, similar to what we see with glutaminergic agents, although with an opposite mechanism: enhancing GABA rather than opposing glutamate. It has excellent tolerability, similar to placebo. It’s made to be used orally, a major advantage over other drugs that are available or close to becoming available, which have to be given IV. And last but not least, a patient will get it for only 2 weeks. The treatment can be stopped after 2 weeks, and there is long-term improvement.”
The ROBIN trial included 151 patients with postpartum depression as defined by a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 26 who were randomized double-blind to 14 days of SAGE-217 at 30 mg once daily or to placebo. The primary endpoint was the change in HAM-D scores between baseline and day 15. The key finding was that the SAGE-217 group averaged a 17.8-point reduction, significantly greater than the 13.6-point improvement with placebo. This advantage was maintained at assessment on day 45 – a full month after treatment stopped – with a 24.8-point improvement over baseline in the SAGE-217 recipients, compared with a 19-point reduction in controls. The advantage favoring SAGE-217 was significant as early as day 3, the first assessment, at which point the average improvement in HAM-D was 12.5 points, compared with 9.8 points in controls.
Other secondary endpoints included change from baseline to day 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS): a 22.8-point improvement in the SAGE-217 group, significantly greater than the 17.6-point improvement in the placebo arm. The same pattern was evident at day 45, with reductions in MADRS of 24.8 and 19 points, respectively, in the SAGE-217 and placebo groups.
Another key prespecified secondary endpoint was change in scores on the Hamilton Rating Scale for Anxiety through day 15. There was a mean 16.6-point drop in the active treatment arm, compared with a 12.7-point improvement with placebo, again a statistically significant and clinically meaningful between-group difference. This is an important endpoint because comorbid anxiety is common in the setting of postpartum depression, the psychiatrist continued.
The SAGE-217 group also demonstrated significantly higher rates of HAM-D response as defined by a 50% or greater reduction in total score at day 15, as well as in HAM-D remission, which entails having a score of 7 or less.
Treatment-emergent adverse events in the SAGE-217 and placebo arms were similar in frequency and type. The most common adverse events associated with SAGE-217 – all occurring in single-digit frequencies – were sleepiness, headache, dizziness, upper respiratory infections, and diarrhea. There was no signal of increased suicidal thoughts or behavior as assessed using the Columbia Suicide Severity Rating Scale.
SAGE-217 also is the focus of an ongoing pivotal phase 3 trial in patients with major depression. In addition, the drug is under study for bipolar depression, major depressive disorder with comorbid insomnia, and generalized anxiety disorder.
Dr. Vieta reported serving on advisory boards for Sage Therapeutics, the study sponsor, as well as for two dozen other pharmaceutical companies. He receives research funding from the Spanish Ministry of Science and Education, the Stanley Medical Research Institute, and more than a dozen pharmaceutical companies.
COPENHAGEN – A first-in-class, once-daily, orally administered neuroactive steroid known for now as SAGE-217 aced all of its primary and secondary outcomes for the treatment of postpartum depression in the phase 3, randomized, double-blind, placebo-controlled ROBIN study, Eduard Vieta, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“I think this changes the paradigm in the treatment of postpartum depression,” declared Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Like brexanolone (Zulresso), an intravenous formulation of allopregnanolone approved by the Food and Drug Administration in March 2019 as the first-ever drug specifically targeting postpartum depression, SAGE-217 is a positive allosteric modifier of synaptic and extrasynaptic GABA-A receptors. That differentiates the two drugs from benzodiazepines, which target only synaptic receptors. Both brexanolone and SAGE-217 are drugs developed by Sage Therapeutics. But SAGE-217, an investigational agent, is vastly more convenient to use than brexanolone since, as an oral drug, it doesn’t require hospitalization for intravenous administration.
Dr. Vieta ticked off five reasons why he considers SAGE-217 a game changer in the treatment of postpartum depression: “It’s an amazingly effective compound, with an effect size that’s bigger than we usually see with antidepressants. It has an early onset of action, similar to what we see with glutaminergic agents, although with an opposite mechanism: enhancing GABA rather than opposing glutamate. It has excellent tolerability, similar to placebo. It’s made to be used orally, a major advantage over other drugs that are available or close to becoming available, which have to be given IV. And last but not least, a patient will get it for only 2 weeks. The treatment can be stopped after 2 weeks, and there is long-term improvement.”
The ROBIN trial included 151 patients with postpartum depression as defined by a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 26 who were randomized double-blind to 14 days of SAGE-217 at 30 mg once daily or to placebo. The primary endpoint was the change in HAM-D scores between baseline and day 15. The key finding was that the SAGE-217 group averaged a 17.8-point reduction, significantly greater than the 13.6-point improvement with placebo. This advantage was maintained at assessment on day 45 – a full month after treatment stopped – with a 24.8-point improvement over baseline in the SAGE-217 recipients, compared with a 19-point reduction in controls. The advantage favoring SAGE-217 was significant as early as day 3, the first assessment, at which point the average improvement in HAM-D was 12.5 points, compared with 9.8 points in controls.
Other secondary endpoints included change from baseline to day 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS): a 22.8-point improvement in the SAGE-217 group, significantly greater than the 17.6-point improvement in the placebo arm. The same pattern was evident at day 45, with reductions in MADRS of 24.8 and 19 points, respectively, in the SAGE-217 and placebo groups.
Another key prespecified secondary endpoint was change in scores on the Hamilton Rating Scale for Anxiety through day 15. There was a mean 16.6-point drop in the active treatment arm, compared with a 12.7-point improvement with placebo, again a statistically significant and clinically meaningful between-group difference. This is an important endpoint because comorbid anxiety is common in the setting of postpartum depression, the psychiatrist continued.
The SAGE-217 group also demonstrated significantly higher rates of HAM-D response as defined by a 50% or greater reduction in total score at day 15, as well as in HAM-D remission, which entails having a score of 7 or less.
Treatment-emergent adverse events in the SAGE-217 and placebo arms were similar in frequency and type. The most common adverse events associated with SAGE-217 – all occurring in single-digit frequencies – were sleepiness, headache, dizziness, upper respiratory infections, and diarrhea. There was no signal of increased suicidal thoughts or behavior as assessed using the Columbia Suicide Severity Rating Scale.
SAGE-217 also is the focus of an ongoing pivotal phase 3 trial in patients with major depression. In addition, the drug is under study for bipolar depression, major depressive disorder with comorbid insomnia, and generalized anxiety disorder.
Dr. Vieta reported serving on advisory boards for Sage Therapeutics, the study sponsor, as well as for two dozen other pharmaceutical companies. He receives research funding from the Spanish Ministry of Science and Education, the Stanley Medical Research Institute, and more than a dozen pharmaceutical companies.
COPENHAGEN – A first-in-class, once-daily, orally administered neuroactive steroid known for now as SAGE-217 aced all of its primary and secondary outcomes for the treatment of postpartum depression in the phase 3, randomized, double-blind, placebo-controlled ROBIN study, Eduard Vieta, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“I think this changes the paradigm in the treatment of postpartum depression,” declared Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.
Like brexanolone (Zulresso), an intravenous formulation of allopregnanolone approved by the Food and Drug Administration in March 2019 as the first-ever drug specifically targeting postpartum depression, SAGE-217 is a positive allosteric modifier of synaptic and extrasynaptic GABA-A receptors. That differentiates the two drugs from benzodiazepines, which target only synaptic receptors. Both brexanolone and SAGE-217 are drugs developed by Sage Therapeutics. But SAGE-217, an investigational agent, is vastly more convenient to use than brexanolone since, as an oral drug, it doesn’t require hospitalization for intravenous administration.
Dr. Vieta ticked off five reasons why he considers SAGE-217 a game changer in the treatment of postpartum depression: “It’s an amazingly effective compound, with an effect size that’s bigger than we usually see with antidepressants. It has an early onset of action, similar to what we see with glutaminergic agents, although with an opposite mechanism: enhancing GABA rather than opposing glutamate. It has excellent tolerability, similar to placebo. It’s made to be used orally, a major advantage over other drugs that are available or close to becoming available, which have to be given IV. And last but not least, a patient will get it for only 2 weeks. The treatment can be stopped after 2 weeks, and there is long-term improvement.”
The ROBIN trial included 151 patients with postpartum depression as defined by a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 26 who were randomized double-blind to 14 days of SAGE-217 at 30 mg once daily or to placebo. The primary endpoint was the change in HAM-D scores between baseline and day 15. The key finding was that the SAGE-217 group averaged a 17.8-point reduction, significantly greater than the 13.6-point improvement with placebo. This advantage was maintained at assessment on day 45 – a full month after treatment stopped – with a 24.8-point improvement over baseline in the SAGE-217 recipients, compared with a 19-point reduction in controls. The advantage favoring SAGE-217 was significant as early as day 3, the first assessment, at which point the average improvement in HAM-D was 12.5 points, compared with 9.8 points in controls.
Other secondary endpoints included change from baseline to day 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS): a 22.8-point improvement in the SAGE-217 group, significantly greater than the 17.6-point improvement in the placebo arm. The same pattern was evident at day 45, with reductions in MADRS of 24.8 and 19 points, respectively, in the SAGE-217 and placebo groups.
Another key prespecified secondary endpoint was change in scores on the Hamilton Rating Scale for Anxiety through day 15. There was a mean 16.6-point drop in the active treatment arm, compared with a 12.7-point improvement with placebo, again a statistically significant and clinically meaningful between-group difference. This is an important endpoint because comorbid anxiety is common in the setting of postpartum depression, the psychiatrist continued.
The SAGE-217 group also demonstrated significantly higher rates of HAM-D response as defined by a 50% or greater reduction in total score at day 15, as well as in HAM-D remission, which entails having a score of 7 or less.
Treatment-emergent adverse events in the SAGE-217 and placebo arms were similar in frequency and type. The most common adverse events associated with SAGE-217 – all occurring in single-digit frequencies – were sleepiness, headache, dizziness, upper respiratory infections, and diarrhea. There was no signal of increased suicidal thoughts or behavior as assessed using the Columbia Suicide Severity Rating Scale.
SAGE-217 also is the focus of an ongoing pivotal phase 3 trial in patients with major depression. In addition, the drug is under study for bipolar depression, major depressive disorder with comorbid insomnia, and generalized anxiety disorder.
Dr. Vieta reported serving on advisory boards for Sage Therapeutics, the study sponsor, as well as for two dozen other pharmaceutical companies. He receives research funding from the Spanish Ministry of Science and Education, the Stanley Medical Research Institute, and more than a dozen pharmaceutical companies.
REPORTING FROM THE ECNP 2019