Background Autoimmune conditions are common in women of reproductive age. They are associated with increased risk of adverse pregnancy outcomes; whether this is causal is unclear. Our aim was to explore the effects of autoimmune condition liability on pregnancy outcomes.

Methods We conducted two-sample Mendelian randomization (MR) to estimate effects of liability to ten autoimmune conditions on nine primary and seven secondary pregnancy outcomes. We used data from the MR-PREG collaboration including up to 934,566 pregnancies. Main analyses used the inverse variance weighted method; sensitivity analyses were used to explore bias due to pleiotropic variants and fetal genetics.

Findings We found evidence for 14 effects of autoimmune condition liability on primary pregnancy outcomes that were robust across sensitivity analyses. Higher liability to Hashimoto’s thyroiditis was protective against large for gestational age and increased risks of hypertensive disorders of pregnancy (HDP), preterm birth (PTB), and neonatal intensive care unit (NICU) admission. For instance, risk of PTB increased by 6% (OR=1.06 (95%CI: 1.02, 1.11)) per doubling in log odds of Hashimoto’s thyroiditis. Liability to type 1 diabetes increased risks of HDP and NICU admission, as well as gestational diabetes mellitus (GDM) and stillbirth.

Liability to rheumatoid arthritis increased risks of NICU admission, HDP, and GDM. Higher ankylosing spondylitis liability reduced risks of HDP and increased risks of low Apgar score, while systemic lupus erythematosus liability increased risks of PTB only. For multiple sclerosis, systemic sclerosis, coeliac disease, inflammatory bowel disease, and psoriasis, we did not detect any robust effects of increased liability.

Interpretation We observed higher liability to Hashimoto’s thyroiditis, type 1 diabetes, and rheumatic conditions cause increased risks of adverse pregnancy outcomes, suggesting the need for enhanced antenatal monitoring of women with these conditions.

Funding Wellcome Trust, UK Medical Research Council

The authors have declared no competing interest.

This study is supported by the UK Medical Research Council and University of Bristol via the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00032/5). EA is supported by a Wellcome Trust PhD studentship (217065/Z/19/Z). DAL's contribution to this research is supported by the British Heart Foundation (AA/18/1/34219). MCM works at a unit that is supported by the Research Council of Norway (Centers of Excellence funding scheme; project No 262700). AGS, GC and DAL are supported by European Union's Horizon Europe Research and Innovation Programme under grant agreement no 101137146. UK participants in Horizon Europe Project STAGE are supported by UKRI grant numbers 10112787 (Beta Technology), 10099041 (University of Bristol) and 10109957 (Imperial College London). QY is also supported by the Noncommunicable Chronic Disease-National Science and Technology Major Project (2024ZD0531500, 2024ZD0531502, 2024ZD0531504). All cohort-specific funding is outlined in Supplementary material. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this paper are those of the authors and not necessarily any of the funders.

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Avon Longitudinal Study of Parents and Children (ALSPAC) Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Ethical approval was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Informed consent for the use of data collected via questionnaires and clinics was obtained from participants following the recommendations of the ALSPAC Ethics and Law Committee at the time (details and reference numbers of all ethics approvals can be found at http://www.bristol.ac.uk/medialibrary/sites/alspac/documents/governance/Research%20Ethics%20Committee%20approval%20references.pdf). Born in Bradford (BiB) Ethical approval for the study was granted by the Bradford National Health Service Research Ethics Committee (ref 06/Q1202/48), and all participants gave written informed consent. The ALL IN sub-study had ethical approval from the London School of Hygiene & Tropical Medicine ethics committee (ref: 5320) and the Bradford Research Ethics committee (ref: 08/H1302/21). Parents (usually the mother) gave informed, written consent to take part in the study. Norwegian Mother, Father and Child Cohort Study (MoBa) The current study is based on version 12 of the quality-assured data files released for research in 2019. The establishment of MoBa and initial data collection was based on a license from the Norwegian Data Protection Agency and approval from The Regional Committees for Medical and Health Research Ethics. The MoBa cohort is currently regulated by the Norwegian Health Registry Act. The current study was approved by The Regional Committees for Medical and Health Research Ethics of South/East Norway (ref 2018/1256). UK Biobank (UKB) The UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval. This RTB approval was granted initially in 2011 (11/NW/0382) and it is renewed on a 5-yearly cycle, with the latest one successfully renewed in 2021 (21/NW/0157).

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