Interaction between placental efflux transporters and use of antiseizure or antidepressant drugs during pregnancy on birth weight in the Norwegian Mother, Father and Child Cohort Study

Background Intrauterine exposure to antiseizure and antidepressant drugs is associated with adverse pregnancy outcomes, including low birth weight. Gene variants in placental efflux transporter genes may alter foetal exposure to these drugs. Methods We investigated whether genetic variants in placental efflux transporters modified the impact of maternal antiseizure and antidepressant drug use on offspring birth weight, using data from the Norwegian Mother, Father and Child Cohort Study and the Medical Birth Registry of Norway (69,828 offspring with their genotype data, 81,189 with maternal genotype data). We systematically searched for gene variants in placental efflux transporters influencing drug exposure [MDR1- ABCB1 (7 alleles), MRP1- ABCC1 (2), MRP2-ABCC2 (3) and, BCRP- ABCG2 (2)] and calculated genetic scores (sum of alleles potentially related to low transporter activity). We assessed the interaction between prenatal drug use and genetic scores on birth weight. Findings Prenatal antiseizure medication exposure was associated with lower birth weight (-95.5 grams, 95% CI -190 to -0.78). This relationship depended on the offspring’s MRP2- ABCC2 genetic score. Birth weight differences between exposed vs. unexposed were 70.3 g (95% CI -494 to 634) in the lowest genetic score category and -306 g (95% CI -361 to -31.8) in the highest (interaction p -value = 0.019; main variant: rs3740066). The antiseizure medication-lower birth weight association also depended on the maternal MDR1- ABCB1 genetic score. Birth weight differences between exposed vs. unexposed were -66.8 g (95% CI -225 to 91.2) in the lowest genetic score category and -317 g (95% CI -517 to -117) in the highest (interaction p -value = 0.037; main variants: rs10248420 and rs2235015). Prenatal antidepressant exposure was associated with low birth weight, but no gene-drug interactions were observed. Conclusions MRP2- ABCC2 and MDR1- ABCB1 variants may influence prenatal antiseizure medication’s impact on neonatal birth weight. What is already known on this topic What this study adds ### Competing Interest Statement O.A.A. is a consultant for cortechs.ai and has received speaker's honorarium from Janssen, Lundbeck, and Sunovion unrelated to the current work. The rest of the authors declare that no competing interests exist. ### Funding Statement The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). This work was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700 and 223273, and the project Women's fertility an essential component of health and well-being, number 320656, and co-funded by the European Research Council (grant agreement No 101071773). M.H.H. was supported by the fellowship: Estancias de movilidad Jose Castillejo dentro del Programa Estatal de Promocion del Talento y su empleabilidad, en el marco del Plan Estatal de lnvestigacion Cientifica y Tecnica y de lnnovacion 2017-2020, from the Spanish government. P.R.N. was supported by the European Research Council (grant agreement No 293574), the Novo Nordic Foundation (#NNF19OC0054741) and the Trond Mohn Foundation (PRECISE-DIA). E.C. and A.Havdahl were supported by the Research Council of Norway (274611) and the South-Eastern Norway Regional Health Authority (project numbers 2020022, 2021045). O.A.A. was supported by the European Research Council (grant agreement No 964874) and the Research Council of Norway (300309, 273291). The funders had no role in the study design; the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Views and opinions expressed in this paper are those of the authors only and do not necessarily reflect those of the funders. Neither the European Union nor the granting authority can be held responsible for them. ### 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 MoBa study is conducted according to the Declaration of Helsinki for medical research involving human subjects. The establishment of MoBa and initial data collection was based on a license from the Norwegian Data Protection Agency. It is now based on regulations related to the Norwegian Health Registry Act. Participants provided written informed consent before joining the cohort. This project was approved by the Regional Committee for Medical and Health Research Ethics of South/East Norway (reference: 2017/1362). 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