Maternal, Fetal, and Child Outcomes of Mental Health Treatments in Women: A Systematic Review of Perinatal Pharmacologic Interventions

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.

Maternal, Fetal, and Child Outcomes of Mental Health Treatments in Women: A Meta‐Analysis of Pharmacotherapy

“…This review followed an a priori protocol ( 11 ) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) ( 12 ) statement. None of the authors reported financial conflicts of interest.…”

Treatment and Management of Mental Health Conditions During Pregnancy and Postpartum

“…Perinatal anxiety disorders may be more common than perinatal depression and are associated with adverse perinatal outcomes ( 1). Yet a recent systematic review identified no effectiveness or comparative effectiveness evidence to inform the treatment of perinatal anxiety disorders (52). Rather, as with antenatal depression, extrapolation of treatment from the general population is required.…”

“…Compared with continued use of mood-stabilizing medication for bipolar disorder, two cohort studies found that discontinuing use of medications during pregnancy is associated with an increased risk of recurrence (adjusted hazard ratio 2.2, 95% CI 1.2–4.2) and reduced time to recurrence of mood disorders (2 weeks vs 28 weeks; adjusted hazard ratio 12.1, 95% CI 1.6–91) (52). Although pharmacotherapy represents an exposure, for most individuals and most medications, the risk of this exposure is lower than the risks associated with symptom exacerbation or relapse.ACOG recommends against valproate as a first-line treatment for bipolar disorder.…”

Inclusion of Nonrandomized Studies of Interventions in Systematic Reviews of Intervention Effectiveness: An Update

“…48 For example, in NRSIs of mental health treatments in pregnancy, women with greater symptom severity may be more likely to be treated with psychotropic medications and may also be more likely to experience adverse pregnancy outcomes (e.g., low infant birthweight or premature delivery) from the underlying condition (e.g., depression). 49 In this example, the effect of the intervention on pregnancy outcomes is confounded by the underlying severity of the condition.…”