Adverse obstetric and neonatal outcomes associated with maternal schizophrenia-spectrum disorders and prenatal antipsychotic use: a meta-analysis of 37,214,330 pregnancy deliveries and propensity-score weighted population-based cohort study assessing confounder dependency of risk estimates

Studies demonstrated increased obstetric and neonatal complications in women with schizophrenia-spectrum disorder (SSD), but most inadequately addressed confounders and rarely considered antipsychotic effects. We conducted a meta-analysis and a population-based cohort study evaluating associations of adverse obstetric/neonatal outcomes with SSD and prenatal antipsychotic use. In the meta-analysis, we searched four databases from inception to October-31-2023 and generated pooled risk estimates using random-effect models. In the cohort study, we identified women aged 15-50 years with SSD-diagnosis from electronic-heath-record database of public healthcare-services who delivered first/singleton children between 2003 and 2018 in Hong Kong. Propensity-score weighted regression-analyses incorporating important confounders including maternal pre-existing and gestational morbidities, substance/alcohol abuse, and psychotropic use, were performed to assess risk of adverse obstetric/neonatal outcomes in SSD-women versus non-SSD-women, and subsequently treated-SSD and untreated-SSD subgroups to disentangle effects of SSD from antipsychotic exposure. The meta-analysis (studies = 18, women = 37,214,330, including 42,926 SSD-women) found significant associations of SSD with 12 of 17 analyzed negative obstetric/neonatal outcomes (with pooled relative risk ranged:1.12-2.10), including placental complications, induced labor, Caesarean delivery, fetal distress, stillbirth, preterm birth, small-for-gestational-age, low birth weight, low APGAR scores, neonatal and post-neonatal deaths. However, the cohort study (466,358 women, including 804 SSD-women) revealed that elevated risk of most study outcomes in unadjusted-models were markedly-attenuated or became non-significant in propensity-score weighted adjusted-models, except index-delivery hospitalization ≥7 days (odds ratio [OR] = 1.76 [95% CI = 1.33-2.34]), preterm birth (OR = 1.48 [95% CI = 1.09-2.00]) and neonatal special-care admission (OR = 1.65 [95% CI = 1.35-2.01]). Apart from higher neonatal special-care admission in treated-SSD than untreated-SSD women (OR = 1.75 [95% CI = 1.23-2.52]), no significant between-group differences emerged in other outcomes. In sum, elevated risk of most obstetric/neonatal complications reported in SSD-women might largely be explained by maternal physical comorbidities, substance/alcohol use disorders and other confounders. Interventions targeting modifiable maternal risk factors should be incorporated in prenatal care for SSD-women to minimize avoidable adverse outcomes.