Effectiveness and safety of drugs in pregnancy: evidence from drug target Mendelian randomization

Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended foetal harm. We investigate genetically proxied intrauterine antihypertensive exposure on offspring outcomes, including gestational age and birthweight, using two-sample multivariable Mendelian randomization. Higher levels of maternal protein targets for calcium channel blockers increased gestational age by 3.99 days (95%CI: 0.02, 7.96) per 10mmHg decrease in SBP. Genetically proxied maternal protein targets for beta-adrenoceptor blocking drugs, vasodilator antihypertensive drugs on the KNCJ11 gene, potassium-sparing diuretics and aldosterone antagonists demonstrated little evidence of increased risk to offspring. Both parental genetic protein targets for vasodilator antihypertensive drugs demonstrated similar effects on birthweight, suggesting detrimental offspring effects due to genetic perturbation of these pathways is unlikely. Little evidence for increased risk of adverse offspring outcomes due to maternal antihypertensive drug target perturbation was found. Triangulation of these findings with existing evidence may guide physicians and mothers during pregnancy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Medical Research Council (MRC) and the University of Bristol MRC Integrative Epidemiology Unit (MC\_UU\_00011/1, MC\_UU\_00011/4). CJB is supported by a Wellcome Trust PhD studentship (218495/Z/19/Z). NMD is supported by the Research Council of Norway (295989). AH was supported by the RCN (#274611, #336085) and SENRHA (#2020022). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. No funding body has influenced data collection, analysis or interpretation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 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 Norwegian Health Registry Act currently regulates the MoBa cohort. The current study was approved by The Regional Committees for Medical and Health Research Ethics (2017/1702). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Information on how to access the MoBaPsychGen post-imputation QC data is available here: https://www.fhi.no/en/more/research-centres/psychgen/access-to-genetic-data-after-quality-control-by-the-mobapsychgen-pipeline-v/.