Women’s health 2015: An update for the internist

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ABSTRACTThe field of women’s health is varied and dynamic. Major studies in 2014 and the first half of 2015 suggest that selective serotonin reuptake inhibitors are not strongly associated with congenital heart defects, that paroxetine 7.5 mg is effective for treating menopausal symptoms, and that women with heart failure may benefit more from cardiac resynchronization therapy than men.


  • Earlier trials had raised concerns about possible teratogenic effects of selective serotonin reuptake inhibitors, but more recent trials have found no strong association between these drugs and congenital heart defects, and no association with miscarriage or autism spectrum disorder, though there may be a risk of attention deficit hyperactivity disorder in offspring.
  • Paroxetine is approved for treating vasomotor symptoms of menopause, but in a lower dose (7.5 mg) than those used for depression and other psychiatric indications. Clinical trials have also shown good results with other antidepressants for treating hot flashes, but the drugs are not yet approved for this indication.
  • Women with heart failure and left bundle-branch block can decrease their risk of death with cardiac resynchronization therapy more than men with the same condition. Moreover, women may benefit from this therapy even if their QRS duration is somewhat shorter than the established cutoff, ie, if it is in the range of 130 to 149 ms.



Women's health encompasses a broad range of issues unique to the female patient, with a scope that has expanded beyond reproductive health. Providers who care for women must develop cross-disciplinary competencies and understand the complex role of sex and gender on disease expression and treatment outcomes. Staying current with the literature in this rapidly changing field can be challenging for the busy clinician.

This article reviews recent advances in the treatment of depression in pregnancy, nonhormonal therapies for menopausal symptoms, and heart failure therapy in women, highlighting notable studies published in 2014 and early 2015.


A 32-year-old woman with well-controlled but recurrent depression presents to the clinic for preconception counseling. Her depression has been successfully managed with a selective serotonin reuptake inhibitor (SSRI). She and her husband would like to try to conceive soon, but she is worried that continuing on her current SSRI may harm her baby. How should you advise her?

Concern for teratogenic effects of SSRIs

Depression is common during pregnancy: 11.8% to 13.5% of pregnant women report symptoms of depression,1 and 7.5% of pregnant women take an antidepressant.2

SSRI use during pregnancy has drawn attention due to mixed reports of teratogenic effects

SSRI use during pregnancy has drawn attention because of mixed reports of teratogenic effects on the newborn, such as omphalocele, congenital heart defects, and craniosynostosis.3 Previous observational studies have specifically linked paroxetine to small but significant increases in right ventricular outflow tract obstruction4,5 and have linked sertraline to ventricular septal defects.6

However, reports of associations of congenital malformations and SSRI use in pregnancy in observational studies have been questioned, with concern that these studies had low statistical power, self-reported data leading to recall bias, and limited assessment for confounding factors.3,7

Recent studies refute risk of cardiac malformations

Several newer studies have been published that further examine the association between SSRI use in pregnancy and congenital heart defects, and their findings suggest that once adjusted for confounding variables, SSRI use in pregnancy may not be associated with cardiac malformations.

Huybrechts et al,8 in a large study published in 2014, extracted data on 950,000 pregnant women from the Medicaid database over a 7-year period and examined it for SSRI use during the first 90 days of pregnancy. Though SSRI use was associated with cardiac malformations when unadjusted for confounding variables (unadjusted relative risk 1.25, 95% confidence interval [CI] 1.13–1.38), once the cohort was restricted to women with a diagnosis of only depression and was adjusted based on propensity scoring, the association was no longer statistically significant (adjusted relative risk 1.06, 95% CI 0.93–1.22).

Additionally, there was no association between sertraline and ventricular septal defects (63 cases in 14,040 women exposed to sertraline, adjusted relative risk 1.04, 95% CI 0.76–1.41), or between paroxetine and right ventricular outflow tract obstruction (93 cases in 11,126 women exposed to paroxetine, adjusted relative risk 1.07, 95% CI 0.59–1.93).8

Furu et al7 conducted a sibling-matched case-control comparison published in 2015, in which more than 2 million live births from five Nordic countries were examined in the full cohort study and 2,288 births in the sibling-matched case-control cohort. SSRI or venlafaxine use in the first 90 days of pregnancy was examined. There was a slightly higher rate of cardiac defects in infants born to SSRI or venlafaxine recipients in the cohort study (adjusted odds ratio 1.15, 95% CI 1.05–1.26). However, in the sibling-controlled analyses, neither an SSRI nor venlafaxine was associated with heart defects (adjusted odds ratio 0.92, 95% CI 0.72–1.17), leading the authors to conclude that there might be familial factors or other lifestyle factors that were not taken into consideration and that could have confounded the cohort results.

Bérard et al9 examined antidepressant use in the first trimester of pregnancy in a cohort of women in Canada and concluded that sertraline was associated with congenital atrial and ventricular defects (risk ratio 1.34; 95% CI 1.02–1.76).9 However, this association should be interpreted with caution, as the Canadian cohort was notably smaller than those in other studies we have discussed, with only 18,493 pregnancies in the total cohort, and this conclusion was drawn from 9 cases of ventricular or atrial septal defects in babies of 366 women exposed to sertraline.

Although at first glance SSRIs may appear to be associated with congenital heart defects, these recent studies are reassuring and suggest that the association may actually not be significant. As with any statistical analysis, thoughtful study design, adequate statistical power, and adjustment for confounding factors must be considered before drawing conclusions.

SSRIs, offspring psychiatric outcomes, and miscarriage rates

Clements et al10 studied a cohort extracted from Partners Healthcare consisting of newborns with autism spectrum disorder, newborns with attention-deficit hyperactivity disorder (ADHD), and healthy matched controls and found that SSRI use during pregnancy was not associated with offspring autism spectrum disorder (adjusted odds ratio 1.10, 95% CI 0.7–1.70). However, they did find an increased risk of ADHD with SSRI use during pregnancy (adjusted odds ratio 1.81, 95% CI 1.22–2.70).

Andersen et al11 examined more than 1 million pregnancies in Denmark and found no difference in risk of miscarriage between women who used an SSRI during pregnancy (adjusted hazard ratio 1.27) and women who discontinued their SSRI at least 3 months before pregnancy (adjusted hazard ratio 1.24, P = .47). The authors concluded that because of the similar rate of miscarriage in both groups, there was no association between SSRI use and miscarriage, and that the small increased risk of miscarriage in both groups could have been attributable to a confounding factor that was not measured.

Should our patient continue her SSRI through pregnancy?

Our patient has recurrent depression, and her risk of relapse with antidepressant cessation is high. Though previous, less well-done studies suggested a small risk of congenital heart defects, recent larger high-quality studies provide significant reassurance that SSRI use in pregnancy is not strongly associated with cardiac malformations. Recent studies also show no association with miscarriage or autism spectrum disorder, though there may be risk of offspring ADHD.

She can be counseled that she may continue on her SSRI during pregnancy and can be reassured that the risk to her baby is small compared with her risk of recurrent or postpartum depression.

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