While numerous published studies have investigated the impact of treatments for major depressive disorder (MDD) in pregnancy on maternal and neonatal outcomes, few studies have examined the perinatal effects of anxiety disorders such as generalized anxiety disorder (GAD) and panic disorder (PD). Despite the comorbidity of the two types of psychiatric disorders in women of reproductive age and shared risk factors, their clinical distinction and subsequent treatment is important. To address this deficit in the literature, a group at the Yale University School of Medicine organized the Yale Blue and Pink study to examine the prevalence and course of generalized anxiety disorder (GAD) in a prospectively ascertained population of pregnant women.

The study gathered longitudinal, prospective data between July 2005 and July 2009 across 137 obstetric practices in Connecticut and Massachusetts. Women were screened for a history of MDD, post-traumatic stress disorder, or antidepressant use.  Those who screened positive for one of these qualifiers were included, as well as some randomly-selected controls. Participation in the study included an in-person structured interview and EPDS administration prior to gestational week 17 and two follow-up telephone interviews at week 28 weeks of gestation  (±2 weeks) and 8 weeks postpartum (±4 weeks) with trained interviewers. The study design and the use of structured interviews allowed for the capture of longitudinal data and thorough analysis of psychiatric history and confounding factors, such as illicit substance use. This is a clear strength, particularly when compared to previous studies that utilize registry data, which encompass a large number of participants but frequently provide incomplete capture of maternal diagnosis, severity of illness, and potential confounding factors.

The purpose of this analysis was to determine if there is an association between maternal anxiety disorders and certain maternal and fetal outcomes.  The main outcomes the researchers tracked were (1) hypertensive diseases of pregnancy (gestational hypertension or preeclampsia), (2) cesarean delivery, (3) preterm delivery, (4) low infant birth weight, (5) minor neonatal respiratory interventions, and (6) neonatal ventilatory support.

A total of  2654 women (mean age= 31 [SD=5.7], 73.7% non-Hispanic white) completed the study. Using the World Mental Health Composite International Diagnostic Interview,  98 (3.7%) participants were diagnosed with PD and 252 (9.5%) were diagnosed with GAD. The diagnosis of GAD was made based on a required symptomatic period of 1 month of illness, as opposed to the DSM-IV-required six month period due to the short interval of study follow-up. In pregnancy,  67 participants were treated with a benzodiazepines (n=56 in the first trimester, n=15 in the second trimester, n=11 in the third trimester) and 293 were treated with a selective serotonin reuptake inhibitor (SSRI; 257 in the first trimester, 157 in the second trimester, 147 in the third trimester).

Importantly, there were no significant associations in adjusted models between PD or GAD and the maternal and neonatal outcomes of interest. Furthermore, the comorbidity for either of these disorders with a major depressive episode did not increase the risk of complications.

Use of benzodiazepines in pregnancy, independent of PD, GAD, and SSRI use, resulted in an associated risk of cesarean delivery (odds ratio [OR] 2.45; 95% CI, 1.36-4.40), neonatal ventilatory support (OR, 2.85; 95% CI, 1.17-6.94), and low birth weight at delivery (OR, 3.41; 95% CI, 1.61-7.26). However, in post hoc regression analysis, when the last outcome was instead defined as “delivery of small for gestational age infant,” this association with benzodiazepines was not significant (OR, 0.85; 95% CI, 0.35-2.10). This could possibly be explained by an additional finding that exposure to benzodiazepines shortened gestational duration by an average of 3.6 days.

Independent of PD, GAD, and benzodiazepine use, use of SSRIs in pregnancy was associated with preterm birth (OR, 1.56; 95% CI, 1.02-2.38), minor neonatal respiratory interventions (OR, 1.81; 95% CI, 1.39-2.37), and hypertensive diseases of pregnancy (OR, 2.82; 95% CI, 1.58-5.04). Women who took SSRIs in pregnancy delivered on average 1.8 days sooner than the women who did not take SSRIs.  The mean EPDS score was not higher for women treated with SSRIs in pregnancy than those who were not and a sensitivity analysis showed that the EPDS anxiety subscale did not change the significance of the findings. This suggests that illness severity did not confound associations with SSRI exposure, which is a common shortcoming of larger registry studies based on electronic medical records.  However, in this type of naturalistic study,  it is possible that there are differences between women who choose to use medications during pregnancy and those who choose to avoid them and that these factors may contribute to the observed differences in outcomes.

To summarize, PD and GAD did not contribute to adverse pregnancy complications; however, the use of benzodiazepines or SSRIs in pregnancy slightly reduced the gestational period by 3.6 or 1.8 days, respectively.  Primary author, Dr. Kimberly Yonkers summarized these findings in an NPR interview by saying “it should be reassuring that we’re not seeing a huge magnitude of an effect [in these results.]”  Overall, these results can assuage women who have been diagnosed with PD and/or GAD and struggling to make decision regarding the use of medications during pregnancy with their provider.

Lauren Claypoole, BA


Association of Panic Disorder, Generalized Anxiety Disorder, and Benzodiazepine Treatment During Pregnancy With Risk of Adverse Birth Outcomes. KA Yonkers, K Gilstad-Hayden, A Forray, HS Lipkind. JAMA Psychiatry. 2017 Sep 13.

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