ABSTRACT Decisions about using antidepressants to treat major depressive disorder during pregnancy are complex. A potential adverse effect is persistent pulmonary hypertension of the newborn (PPHN), with an estimated baseline prevalence of 1.9 of 1000 live births. Symptoms can range from mild respiratory distress to hypoxia. Although a potential association between maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and PPHN was noted in 2006, subsequent published evidence is contradictory. This systematic review and meta-analysis was undertaken to determine whether a relationship exists between prenatal exposure to antidepressants and PPHN, with consideration of known risk factors. The literature search included EMBASE, MEDLINE, PsycINFO, and CINAHL through December 2012. Cohort and case-control English-language studies were eligible if they reported on PPHN after any exposure to antidepressants, had a comparison group of unexposed pregnant women for the antidepressant under analysis, and included or had data to calculate an effect size. Because PPHN is rare, adjusted or unadjusted odds ratios (ORs), prevalence, or relative risks were included in the analyses as estimates of ORs. Of 738 articles assessed, 5 cohort and 2 case-control studies were included in the final quantitative analysis; 3 reported data on exposure to SSRIs in early pregnancy, 2 reported on exposure at any time in pregnancy, 2 reported on exposure for most or all of pregnancy, and 5 reported on exposure in late pregnancy. For studies examining exposure to SSRIs in early pregnancy, the pooled OR was 1.23 (95% confidence interval [CI], 0.58–2.60), and significant study heterogeneity was found. The pooled OR for exposure to SSRIs at any time was 1.55 (95% CI, 0.79–3.04). The pooled OR with exposure during “most or all of pregnancy” was significant at 3.33 (95% CI, 1.58–7.02). The pooled OR for exposure in late pregnancy was significant at 2.50 (95% CI, 1.32–4.73). The absolute risk difference for developing PPHN after exposure to SSRIs in late pregnancy was 2.9 to 3.5 of 1000 infants; 286 to 351 women would need to be treated with an SSRI in late pregnancy to result in a mean of 1 additional case of PPHN. These results suggest that the risk for PPHN is increased with exposure to SSRIs in late pregnancy. Study design, congenital malformations, or meconium aspiration were not significant effect modifiers; cesarean delivery, maternal obesity, and preterm delivery could not be assessed as possible moderating effects. Depression during pregnancy must not be left untreated, and the parturient and her family must be advised of the risks for exposing the fetus to antidepressant drugs weighed against the risks for severe maternal depression. To avoid delays in diagnosis and treatment of PPHN, neonatologists must be made aware of the mother’s exposure to SSRIs.