Purpose Adverse pregnancy and perinatal outcomes (APPOs), including pre-term birth, pre-eclampsia, and gestational diabetes, can result in maternal and neonatal morbidity and mortality, parental anxiety, and increased health care costs. Better understanding of causes of APPOs is essential to inform lifestyle and pharmaceutical interventions for their prevention and management. Given the difficulty of undertaking randomised control trials in pregnant women, triangulating evidence from across different methods with different sources of bias could improve our understanding of the causes of APPOs. The purpose of the Mendelian Randomization in Pregnancy (MR-PREG) collaboration is to support triangulation of evidence from genetic (e.g., Mendelian randomization [MR]) and non-genetic (e.g., partner negative controls) methods to explore causal effects of maternal exposures on a comprehensive set of APPOs

Participants The MR-PREG collaboration includes individual participant data from three birth cohorts (two from the UK and one from Norway) and UK Biobank, and summary data from FinnGen and publicly available genome wide association studies (GWAS). We have harmonised data across studies so that currently includes exposures on up to 34 APPOs in up to 678,001 women.

Findings to date The main aims of MR-PREG are to improve the evidence base for 1) prevention, by advancing our understanding of maternal modifiable causes of APPOs, 2) better understanding of the effect of pre-existing conditions on APPOs, and 3) treatment, by advancing our knowledge of the efficacy and safety of existing medications that women may require for pre-existing conditions, and identifying and testing the efficacy and safety of novel medications, and those that might be repurposed to effectively and safely treat APPOs. To date, our published research mainly addresses aims 1 and 3; some examples include triangulation of evidence from MR, conventional multivariable regression and a paternal negative control, showing that higher maternal body mass index increases the risk of many APPOs, and identification of maternal circulating metabolites and proteins that may influence birthweight.

Future Plans Our future priorities include increasing diversity in the MR-PREG collaboration by expanding participant representation from non-European ancestries. We are also integrating molecular data, such as circulating protein levels and placental transcriptomics, to better understand the molecular mechanisms underlying APPOs. Additionally, we are using exome and whole-genome sequencing to identify novel causal genes for APPOs and advance our knowledge on candidate targets for APPOs.

Strengths and limitations

We have curated data for 34 APPOs and harmonized data across multiple studies to support large-scale investigations of causes of APPOs.

The scope and type of the data supports triangulation of evidence from a range of genetic and non-genetic methods, with different unrelated sources of bias, to identify causes of APPOs.

Over the coming year we will enhance the data to enable identification of molecular mechanism underlying APPOs.

MR-PREG has limited power to detect causal effects on rarer APPOs, such as congenital anomalies and low Apgar scores at 5 minutes, particularly when using genetic methods. Future work will include larger samples and rare genetic variant data.

Participants are mostly of European ancestry; future efforts will be focussed on diversifying the ancestry representation in the data.

The authors have declared no competing interest.

All cohort specific funding information is detailed in the Supplementary text. This publication is the work of the authors, who will serve as guarantors for the contents of this paper. DAL, MCB, GC, AGS, TB, QY, AT, HC, EA, PH, and NM work in a unit supported by the University of Bristol and UK Medical Research Council (MC_UU_00032/5) and the British Heart Foundation (AA/18/1/34219). AGS is supported by the European Union's Horizon 2020 research and innovation programme (grant agreement No 874739, LongITools). AGS, GC and DAL are supported by the European Union's Horizon Europe Research and Innovation Programme (grant agreement No 101137146, STAGE, via UKRI grant number 10099041). EA is supported by a Wellcome Trust PhD studentship (228276/Z/23/Z). MCM is supported by the Research Council of Norway through its Centres of Excellence funding scheme (project No 262700) and the European Research Council under the European Union's Horizon 2020 research and innovation program (ERC Starting Grant, INFERTILITY grant agreement No 947684).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

ALSPAC: The Avon Longitudinal Study of Parents and Children Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Full details of the ALSPAC consent procedures are available on the study website (http://www.bristol.ac.uk/alspac/researchers/research-ethics/http://www.bristol.ac.uk/alspac/researchers/research-ethics/). BiB: Born in Bradford Ethical approval for the study was granted by the Bradford National Health Service Research Ethics Committee (ref 06/Q1202/48). The study website provides further cohort details and an overview of available data (https://borninbradford.nhs.uk/). MoBa: The Norwegian Mother, Father and Child Cohort Study 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. Ethical approval for our study was obtained from The Regional Committees for Medical and Health Research Ethics (ref 2018/1256). UKB: UK Biobank Ethical approval for UKB was obtained from the Northwest Multi-Centre Research Ethics Committee (MREC), and MR-PREG collaboration studies are linked to UKB application number 23938. FinnGen The Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District has approved the FinnGen consortium (Nr HUS/990/2017). More information about FinnGen can be found on the website https://www.finngen.fi/en. The metadata from FinnGen used by the MR-PREG collaboration is publicly available at https://www.finngen.fi/en/access_results.

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