Cohort Profile: The Mendelian Randomization in Pregnancy (MR-PREG) collaboration - Improving evidence for prevention and treatment of adverse pregnancy and perinatal outcomes

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. A better understanding of the causes of APPOs is essential to inform lifestyle and pharmaceutical interventions for their prevention and management. Given the difficulty of undertaking randomised controlled trials in pregnant women, triangulating evidence from across methods with different sources of bias may improve causal inference for APPOs. The purpose of the Mendelian Randomization in Pregnancy (MR-PREG) collaboration is to support such triangulation using genetic (e.g., Mendelian randomization [MR]) and non-genetic (e.g., partner negative controls) approaches to investigate the 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, as well as summary data from FinnGen and publicly available genome-wide association studies (GWAS). Data have been harmonised across studies and currently include information on up to 35 APPOs in up to 714,899 women.

Findings to date:
The main aims of MR-PREG are to strengthen the evidence base for 1) prevention, by advancing understanding of maternal lifestyle factors on APPOs, 2) the role of pre-conceptional health, by improving understanding of the effect of maternal pre-existing conditions on APPOs, and 3) treatments, by evaluating the efficacy and safety of existing medications used for pre-existing conditions, and by identifying and testing novel or repurposed therapies for APPOs. To date, our published work has mainly addressed aims 1 and 3. Examples include triangulation of evidence from MR, conventional multivariable regression and paternal negative control, showing that higher maternal body mass index increases the risk of multiple APPOs, as well as the identification of maternal circulating metabolites and proteins that may influence birthweight.

Future Plans:
Future priorities include increasing diversity within the MR-PREG collaboration by expanding representation of participants from non-European ancestries. We are also integrating molecular data, including circulating protein levels and placental transcriptomics, to better characterise the molecular mechanisms underlying APPOs. Additionally, we are using whole-exome and whole-genome sequencing to identify novel causal genes and to inform the prioritisation of candidate therapeutic targets for APPOs.

Strengths and Limitations:
•We have curated data on 35 APPOs and harmonized data across multiple studies to support large-scale investigations of causes of APPOs.
•The breadth and nature of the data support triangulation of evidence from a range of genetic and non-genetic methods, each with distinct sources of bias, to identify causes of APPOs.
•Over the coming year, we will further enhance the data to enable identification of molecular mechanisms underlying APPOs.
•MR-PREG has limited power to detect causal effects for rarer APPOs, such as congenital anomalies and low Apgar scores at 5 minutes, particularly when using genetic methods. Future work will incorporate larger samples and rare genetic variant data.
•Participants are predominantly of European ancestry; future efforts will focus on increasing ancestral diversity within the data.