Main Points

• Few studies have been conducted in pregnant and postpartum women on the benefits of pharmacotherapy; many studies report on harms but are of low quality.
• Brexanolone probably improves depressive symptoms; it may increase the risk of sedation or somnolence, leading to dose interruption or reduction.
• Sertraline may improve response, remission, and depression and anxiety symptoms.
• Mood stabilizers may reduce recurrence and increase time to recurrence.
• Although associations may exist between psychotropic medications and adverse events, causality cannot be inferred.
• First-trimester exposure to lithium is more likely to be associated with overall congenital and cardiac anomalies than first trimester exposure to lamotrigine, which can inform the decision to switch a medication in a successfully treated individual.
• We did not find eligible evidence on congenital anomalies for triazolam, alprazolam, valproate, carbamazepine, clonazepam, and topiramate, although evidence is available from studies of other populations ineligible for this review.
• The paucity of evidence does not mean that pharmacotherapy is not beneficial, nor that harms do not exist; rather, it underscores the absence of high-quality research.

Abstract

Background. Untreated maternal mental health disorders can have devastating sequelae for the mother and child. For women who are currently or planning to become pregnant or are breastfeeding, a critical question is whether the benefits of treating psychiatric illness with pharmacologic interventions outweigh the harms for mother and child.

Methods. We conducted a systematic review to assess the benefits and harms of pharmacologic interventions compared with placebo, no treatment, or other pharmacologic interventions for pregnant and postpartum women with mental health disorders. We searched four databases and other sources for evidence available from inception through June 5, 2020 and surveilled the literature through March 2, 2021; dually screened the results; and analyzed eligible studies. We included studies of pregnant, postpartum, or reproductive-age women with a new or preexisting diagnosis of a mental health disorder treated with pharmacotherapy; we excluded psychotherapy. Eligible comparators included women with the disorder but no pharmacotherapy or women who discontinued the pharmacotherapy before pregnancy.

Results. A total of 164 studies (168 articles) met eligibility criteria. Brexanolone for depression onset in the third trimester or in the postpartum period probably improves depressive symptoms at 30 days (least square mean difference in the Hamilton Rating Scale for Depression, -2.6; p=0.02; N=209) when compared with placebo. Sertraline for postpartum depression may improve response (calculated relative risk [RR], 2.24; 95% confidence interval [CI], 0.95 to 5.24; N=36), remission (calculated RR, 2.51; 95% CI, 0.94 to 6.70; N=36), and depressive symptoms (p-values ranging from 0.01 to 0.05) when compared with placebo. Discontinuing use of mood stabilizers during pregnancy may increase recurrence (adjusted hazard ratio [AHR], 2.2; 95% CI, 1.2 to 4.2; N=89) and reduce time to recurrence of mood disorders (2 vs. 28 weeks, AHR, 12.1; 95% CI, 1.6 to 91; N=26) for bipolar disorder when compared with continued use. Brexanolone for depression onset in the third trimester or in the postpartum period may increase the risk of sedation or somnolence, leading to dose interruption or reduction when compared with placebo (5% vs. 0%). More than 95 percent of studies reporting on harms were observational in design and unable to fully account for confounding. These studies suggested some associations between benzodiazepine exposure before conception and ectopic pregnancy; between specific antidepressants during pregnancy and adverse maternal outcomes such as postpartum hemorrhage, preeclampsia, and spontaneous abortion, and child outcomes such as respiratory issues, low Apgar scores, persistent pulmonary hypertension of the newborn, depression in children, and autism spectrum disorder; between quetiapine or olanzapine and gestational diabetes; and between benzodiazepine and neonatal intensive care admissions. Causality cannot be inferred from these studies. We found insufficient evidence on benefits and harms from comparative effectiveness studies, with one exception: one study suggested a higher risk of overall congenital anomalies (adjusted RR [ARR], 1.85; 95% CI, 1.23 to 2.78; N=2,608) and cardiac anomalies (ARR, 2.25; 95% CI, 1.17 to 4.34; N=2,608) for lithium compared with lamotrigine during first-trimester exposure.

Conclusions. Few studies have been conducted in pregnant and postpartum women on the benefits of pharmacotherapy; many studies report on harms but are of low quality. The limited evidence available is consistent with some benefit, and some studies suggested increased adverse events. However, because these studies could not rule out underlying disease severity as the cause of the association, the causal link between the exposure and adverse events is unclear. Patients and clinicians need to make an informed, collaborative decision on treatment choices.

Journal Citations

Viswanathan M, Middleton JC, Stuebe AM, et al. Maternal, fetal, and child outcomes of mental health treatments in women: a meta‐analysis of pharmacotherapy. Psychiatr Res Clin Pract. 2021;3:123–40. doi: 10.1176/appi.prcp.20210001.

Goulding AN, Metz TD, Middleton JC, et al. Pharmacologic treatment for perinatal mental health disorders. Obstet Gynecol. 2022 Jan 6. [Epub ahead of print.] doi: 10.1097/AOG.0000000000004638. PMID: 34991119.

Citation

Viswanathan M, Middleton JC, Stuebe A., Berkman N., Goulding AN, McLaurin-Jiang S, Dotson AB, Coker-Schwimmer M, Baker C, Voisin C, Bann C, Gaynes BN. Maternal, Fetal, and Child Outcomes of Mental Health Treatments in Women: A Systematic Review of Perinatal Pharmacologic Interventions. Comparative Effectiveness Review No. 236. (Prepared by the RTI International−University of North Carolina at Chapel Hill Evidence-based Practice Center under Contract No. 290-2015-00011-I.) AHRQ Publication No. 21-EHC001. Rockville, MD: Agency for Healthcare Research and Quality; April 2021. DOI: 10.23970/AHRQEPCCER236. Posted final reports are located on the Effective Health Care Program search page.