Associations of insomnia on pregnancy and perinatal outcomes: Findings from Mendelian randomization and conventional observational studies in up to 356,069 women

Abstract

Background: Insomnia is common and associated with adverse pregnancy and perinatal outcomes in observational studies. Our aim was to test whether insomnia causes stillbirth, miscarriage, gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth, or low/high offspring birthweight (LBW/HBW). Methods and Findings: We used two-sample Mendelian randomization (MR) with 81 single nucleotide polymorphisms instrumenting for a lifelong predisposition to insomnia. We used data (N=356,069) from the UK Biobank, FinnGen, and three European birth cohorts (Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford, and Norwegian Mother, Father and Child Cohort Study). Main MR analyses used inverse variance weighting (IVW), with weighted median and MR-Egger as sensitivity analyses. We compared MR estimates with multivariable regression of insomnia in pregnancy on outcomes in ALSPAC (N=11,745). IVW showed evidence of an effect of genetic susceptibility to insomnia on miscarriage (odds ratio (OR): 1.60, 95% confidence interval (CI): 1.18, 2.17), perinatal depression (OR 3.56, 95% CI: 1.49, 8.54) and LBW (OR 3.17, 95% CI: 1.69, 5.96). For other outcomes IVW indicated potentially clinically important adverse effects of insomnia (OR range 1.20 to 2.43), but CIs were wide and included the null. Weighted median and MR Egger results were directionally consistent, except for MR-Egger for gestational diabetes, perinatal depression, and preterm birth. Multivariable regression showed associations of insomnia at 18 weeks of gestation with miscarriage (OR 1.30, 95% CI: 1.12, 1.51), stillbirth (OR 2.10, 95% CI: 1.20, 3.69), and perinatal depression (OR 2.96, 95% CI: 2.42, 3.63), but not with LBW (OR 0.92, 95% CI: 0.69, 1.24). Key limitations are potential horizontal pleiotropy and low statistical power in MR, and residual confounding in multivariable regression. Conclusions: There is evidence of causal effects of insomnia on miscarriage, perinatal depression, and LBW. We highlight the need for larger studies with genomic data and pregnancy outcomes.