Autoimmune diseases and risk of adverse pregnancy outcomes: a population-based cohort study of five million pregnancies in the UK

BACKGROUND: With an increasing trend in the prevalence of maternal autoimmune diseases in pregnancy, there is need for evidence on the association between autoimmune diseases and pregnancy outcomes. METHODS: This population-based cohort study used data on pregnancies from primary care practices that contributed to the UK Clinical Practice Research Datalink (CPRD) database (Gold and Aurum) between 2000 and 2022, linked to Hospital Episode Statistics (HES). Modified Poisson regression with robust standard errors estimated adjusted relative risks (aRR) and 95% confidence intervals (95% CI) assessing the association between 17 autoimmune diseases and 12 pregnancy outcomes, selected following literature review and expert consultation. Models were adjusted for demographic and comorbidity variables. Findings were evaluated using the Benjamini-Yekutieli procedure to control for multiple testing across autoimmune disease-outcome associations. RESULTS: A total of 5,239,383 pregnancies from the CPRD pregnancy register and 2,485,366 births recorded in HES maternity data met the eligibility criteria. Women with autoimmune diseases had an increased risk across all pregnancy outcomes examined. Among antenatal outcomes, markedly elevated risks were observed for hyperemesis gravidarum in Addison's disease (aRR 3.72, 95% CI 2.48-5.59), miscarriage in Sjögren's syndrome (1.66, 1.02-2.70), gestational hypertension in type 1 diabetes mellitus (T1DM; 2.95, 2.77-3.15), pre-eclampsia/eclampsia in T1DM (3.56, 3.32-3.82), and gestational diabetes mellitus in Graves' disease (1.37, 1.21-1.54). For obstetric outcomes, increased risks were observed for caesarean birth in inflammatory bowel disease (IBD; 1.27, 1.22-1.31), small for gestational age in systemic lupus erythematosus (SLE; 2.45, 1.65-3.62), preterm birth in rheumatoid arthritis (1.53, 1.33-1.76), and stillbirth in SLE (1.82, 1.12-1.84). Perinatal mental health outcomes were more common across several autoimmune diseases, with particularly high risks in myasthenia gravis (anxiety 3.05, 1.89-4.92; depression 1.77, 1.37-2.28), SLE (anxiety 2.11, 1.67-2.67; depression 1.36, 1.22-1.53), and multiple sclerosis (anxiety 1.76, 1.38-2.23; depression 1.94, 1.77-2.12). Inverse associations were observed for hyperemesis gravidarum in systemic sclerosis, SLE, and myasthenia gravis, and for hypertensive disorders of pregnancy in multiple sclerosis. After Benjamini-Yekutieli correction for multiple testing, the number of statistically significant associations was reduced, with a core set of robust associations persisting across selected autoimmune diseases particularly, T1DM, SLE, Graves' disease, IBD and key pregnancy outcomes. CONCLUSIONS: Autoimmune diseases were associated with increased risks across a wide range of adverse pregnancy outcomes, with marked heterogeneity between individual conditions. This study provides adjusted relative risks across multiple domains of pregnancy outcomes including antenatal (e.g. miscarriage, hyperemesis gravidarum, gestational hypertension, pre-eclampsia, gestational diabetes), obstetric (e.g. preterm birth, caesarean birth, small for gestational age, stillbirth), and perinatal mental health outcomes (anxiety and depression), for both common and less frequently studied autoimmune diseases. The findings highlight the importance of disease-specific evaluation of pregnancy risks.