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

BackgroundInsomnia 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 FindingsWe 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. ConclusionsThere 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. Author summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIInsomnia in pregnancy was associated with higher risks of adverse pregnancy and perinatal outcomes in observational studies. C_LIO_LIIt is currently no clear whether insomnia causes adverse pregnancy and perinatal outcomes or whether the unfavourable associations are explained by confounding. C_LIO_LINo Mendelian randomization has been conducted to explore the association of insomnia with adverse pregnancy and perinatal outcomes. C_LI What did the researchers do and find?O_LIWe used data on up to 356,069 women from UK Biobank, FinnGen and three birth cohorts, and assessed whether genetic susceptibility to insomnia was associated with stillbirth, miscarriage, gestational diabetes, hypertensive disorders of pregnancy, perinatal depression, preterm birth, low offspring birthweight, and high offspring birthweight in two-sample Mendelian randomization. C_LIO_LITo triangulate with our Mendelian randomization estimates, we conducted multivariable regression in 11,745 women from the Avon Longitudinal Study of Parents and Children, where insomnia was measured in pregnancy. C_LIO_LIWe found consistent evidence from Mendelian randomization and multivariable regression that insomnia was associated with higher risks miscarriage and perinatal depression, and Mendelian randomization also suggested an unfavourable effect on low offspring birthweight. C_LI What do these findings mean?O_LIInterventions to improve healthy sleep in women of reproductive age might be beneficial to a healthy pregnancy. C_LI