Journal Article Annotations
2017, 3rd Quarter

Women’s Mental Health

Annotations by Tareq Yaqub, MD, and Priyanka Amin, MD
of the APM Women’s Health SIG
October 2017

Association of antidepressant medication use during pregnancy with intellectual disability in offspring
Association of panic disorder, generalized anxiety disorder, and benzodiazepine treatment during pregnancy with risk of adverse birth outcomes

PUBLICATION #1 — Women’s Mental Health

Association of antidepressant medication use during pregnancy with intellectual disability in offspring

Viktorin A, Uher R, Kolevzon A, Reichenberg A, Levine SZ, Sandin S

JAMA Psychiatry 2017; 74(10):1031-1038

Importance: Maternal antidepressant medication use during pregnancy has previously been associated with adverse outcomes in offspring, but to our knowledge, the association with intellectual disability (ID) has not been investigated.

Objectives: To examine the association of maternal antidepressant medication use during pregnancy with ID in offspring and investigate the importance of parental mental illness for such an association.

Design, Setting, and Participants: A population-based cohort study of 179 007 children born from January 1, 2006, through December 31, 2007, with complete parental information from national registers who were followed up from birth throughout 2014.

Main Outcomes and Measures: We estimated relative risks (RRs) and 95% CIs of ID in children exposed during pregnancy to any antidepressant medication or specifically to selective serotonin reuptake inhibitor (SSRI) antidepressants, all other non-SSRI antidepressants, or other non-antidepressant psychotropic medications. Analyses were adjusted for potential confounders. In addition to full population analyses, we used a subsample to compare mothers who used antidepressants during pregnancy with mothers who had at least one diagnosis of depression or anxiety before childbirth but did not use antidepressants during pregnancy.

Results: Of the 179 007 children included in the study (mean [SD] age at end of follow-up, 7.9 [0.6] years; 92 133 [51.5%] male and 86 874 [48.5%] female), ID was diagnosed in 37 children (0.9%) exposed to antidepressants and in 819 children (0.5%) unexposed to antidepressants. With adjustment for potential confounders, the RR of ID after antidepressant exposure was estimated at 1.33 (95% CI, 0.90-1.98) in the full population sample and 1.64 (95% CI, 0.95-2.83) in the subsample of women with depression. Results from analyses of SSRI antidepressants, non-SSRI antidepressants, and non-antidepressant psychotropic medications and analyses in the clinically relevant subsample did not deviate from the full-sample results.

Conclusions and Relevance: The unadjusted RR of ID was increased in offspring born to mothers treated with antidepressants during pregnancy. After adjustment for confounding factors, however, the current study did not find evidence of an association between ID and maternal antidepressant medication use during pregnancy. Instead, the association may be attributable to a mechanism integral to other factors, such as parental age and mother’s psychiatric disorder.

On PubMed: JAMA Psychiatry 2017; 74(10):1031-1038

Annotation

The finding: After implementing a four-step covariate model to control for confounders, there was no statistically significant increase in risk of offspring intellectual disability in women taking antidepressant medications during pregnancy. Therefore, previous associations made could be attributable to other confounding factors.

Strength and weaknesses: The study included a rigorous analysis of confounders (a four-step covariate analysis) in a large starting population of nearly 180,000 patients. It included an analysis of the RR (relative risk) at each step. The participants were selected from one national healthcare database (Sweden) which made follow-up relatively simple and accurate. The study was selective in who to include in the experiment group: 2 antidepressant dispensations were required to be included in the experiment group; this was done to suggest that women included were adhering to their medications. The study also included a clinical subsample of women who carried diagnoses of depression/anxiety but did not receive anti-depressants during pregnancy as one of the control groups to further adjust for underlying mental illness as a confounder.

The study did contain some limitations. It did not include information on the severity of the depression in the patients. The design also did not allow for a way to prove patient adherence. There was no exploration of dose-dependent effects of medications. In fact, no dosages were provided in the study. The supplemental information did not seem to include information on how the psychotropic medications were classified. Finally, the experimental group population could have been larger as mental illness diagnoses made in primary care specialties were not included if there was no specialty follow-up.

Relevance: Given this information, women with underlying depression/anxiety should not be deterred from continuing or starting antidepressant therapy while pregnant if they have concerns about teratogenic neurocognitive effects in the offspring. There does not appear to be an association between maternal anti-depressant use and intellectual disability in the offspring.

PUBLICATION #2 — Women’s Mental Health

Association of panic disorder, generalized anxiety disorder, and benzodiazepine treatment during pregnancy with risk of adverse birth outcomes

Yonkers KA, Gilstad-Hayden K, Forray A, Lipkind HS

JAMA Psychiatry 2017 Sep 13 (Epub ahead of print)

Importance: Registry data show that maternal panic disorder, or anxiety disorders in general, increase the risk for adverse pregnancy outcomes. However, diagnoses from registries may be imprecise and may not consider potential confounding factors, such as treatment with medication and maternal substance use.

Objective: To determine whether panic disorder or generalized anxiety disorder (GAD) in pregnancy, or medications used to treat these conditions, are associated with adverse maternal or neonatal pregnancy outcomes.

Design, Setting, and Participants: This cohort study conducted between July 1, 2005, and July 14, 2009, recruited women at 137 obstetric practices in Connecticut and Massachusetts before 17 weeks of pregnancy and reassessed them at 28 (±4) weeks of pregnancy and 8 (±4) weeks postpartum. Psychiatric diagnoses were determined by answers to the World Mental Health Composite International Diagnostic Interview. Assessments also gathered information on treatment with medications and confounding factors, such as substance use, previous adverse birth outcomes, and demographic factors.

Exposure: Panic disorder, GAD, or use of benzodiazepines or serotonin reuptake inhibitors.

Main Outcomes and Measures: Among mothers: preterm birth, cesarean delivery, and hypertensive diseases of pregnancy. Among neonates: low birth weight, use of minor respiratory interventions, and use of ventilatory support.

Results: Of the 2654 women in the final analysis (mean [SD] age, 31.0 [5.7] years), most were non-Hispanic white (1957 [73.7%]), 98 had panic disorder, 252 had GAD, 67 were treated with a benzodiazepine, and 293 were treated with a serotonin reuptake inhibitor during pregnancy. In adjusted models, neither panic disorder nor GAD was associated with maternal or neonatal complications of interest. Most medication exposures occurred early in pregnancy. Maternal benzodiazepine use was associated with cesarean delivery (odds ratio [OR], 2.45; 95% CI, 1.36-4.40), low birth weight (OR, 3.41; 95% CI, 1.61-7.26), and use of ventilatory support for the newborn (OR, 2.85; 95% CI, 1.2-6.9). Maternal serotonin reuptake inhibitor use was associated with hypertensive diseases of pregnancy (OR, 2.82; 95% CI, 1.58-5.04), preterm birth (OR, 1.56; 95% CI, 1.02-2.38), and use of minor respiratory interventions (OR, 1.81; 95% CI, 1.39-2.37). With maternal benzodiazepine treatment, rates of ventilatory support increased by 61 of 1000 neonates and duration of gestation was shortened by 3.6 days; with maternal serotonin reuptake inhibitor use, gestation was shortened by 1.8 days, 152 of 1000 additional newborns required minor respiratory interventions, and 53 of 1000 additional women experienced hypertensive diseases of pregnancy.

Conclusions and Relevance: Panic disorder and GAD do not contribute to adverse pregnancy complications. Women may require treatment with medications during pregnancy, which can shorten the duration of gestation slightly. Maternal treatment with a serotonin reuptake inhibitor is also associated with hypertensive disease of pregnancy and cesarean delivery.

On PubMed: JAMA Psychiatry 2017 Sep 13 [Epub ahead of print]

Annotation

The finding: Panic disorder (PD) and generalized anxiety disorder (GAD) did not increase risk of maternal outcomes during delivery (including hypertensive disease in pregnancy, cesarean delivery, and preterm birth) nor increase risk of neonatal outcomes (including low birth weight, neonatal ventilatory support, or minor respiratory intervention) in models adjusted for substance use, age, body mass index, prior preterm birth, race/ethnicity, and maternal education. Mothers are more likely to require a cesarean delivery when taking benzodiazepines (OR 2.45, 95% CI 1.36-4.40, or an additional 200 cesarean deliveries per 1000 births).

Maternal benzodiazepine use was also linked to an increased risk of neonatal low birth weight (OR 3.41, 95% CI 1.61-7.26, or an additional 117 newborns per 1000 births) and increased risk of the newborn requiring ventilatory support (OR 2.85, 95% CI 1.17-6.94). Women were more likely to develop a hypertensive disease in pregnancy when taking a serotonin reuptake inhibitor (SRI) (OR 2.82, 95% CI 1.58-5.04). Maternal SRI use is associated with an increased risk of the newborn requiring minor respiratory support (OR 1.81, 95% CI 1.39-2.37). Gestation age shortens modestly with both benzodiazepines and SRIs, by 3.6 days and 1.8 days, respectively.

Strength and weaknesses: A major strength of the research is that data analysis accounted for multiple confounders that have impacts on maternal and fetal/neonatal outcomes. Also, data were collected prospectively over pregnancy and had a large sample size of over 2500 women. Another strength is that a structured, validated interview was used to make the diagnosis of GAD or PD.

A limitation of the study is that the authors modified the GAD diagnostic criteria to require only one month of symptoms instead of six months. It is possible that there may have been maternal or neonatal outcomes associated with an increased duration of symptoms. Similarly, PD was excluded in individuals with another health condition that could mimic PD symptoms, such as asthma, which likely excluded individuals who have PD given the comorbidity of these conditions. Additionally, confounders were self-reported, and women may not have chosen to disclose substance use, including benzodiazepine abuse.

Relevance: This study is one of the first to examine the impact of GAD, PD, SRIs, and benzodiazepines on maternal and fetal outcomes, controlling carefully for confounders. The outcomes of the study are helpful to discuss when having a risk-benefit conversation with a pregnant patient with GAD or PD when thinking about medication options, such as SRIs or benzodiazepines.