Background: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. Methods: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (up to N = 805) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (up to N = 4475). The analysis was performed in pre-pregnancy smokers only, due to the specific role of the genetic instrument SNP rs1051730 (CHRNA5-CHRNA3-CHRNB4) in affecting smoking cessation but not initiation. Results: Fixed effect meta-analysis showed a 175 g [95%CI: 16, 334] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal estimate was a 12 g [95%CI: 2,22] higher placental weight per cigarette per day. Results were similar when the smoking exposures were measured at the end of pregnancy. Using the residuals of birth weight regressed on placental weight as the outcome, we showed weak evidence of lower offspring birth weight relative to the placental weight for continuing smoking. Conclusion: Our results suggest that continued smoking during pregnancy causes higher placental weights.

The authors have declared no competing interest.

The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and A.J. and R.M.F. will serve as guarantors for the contents of this paper. Genotyping of the ALSPAC maternal samples were funded by the Wellcome Trust (WT088806). Specific funds for recent detailed data collection on the mothers were obtained from the US National Institutes of Health (R01 DK077659) and Wellcome Trust (WT087997MA) for completion of selected items of obstetric data extraction, including placental weights. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). A.J. received funding for her PhD studentship from the Faculty of Health and Life Sciences at the University of Exeter P.R.N. was supported by grants from the European Research Council (AdG #293574), Trond Mohn Foundation (Mohn Center for Diabetes Precision Medicine), the Research Council of Norway (#240413), the Western Norway Regional Health Authority (Strategic Fund), the Novo Nordisk Foundation (#NNF54741). K.T.A. gratefully acknowledges the financial support of the EPSRC via grant EP/T017856/1. S.J. was supported by Helse Vest's Open Research Grant (grants #912250 and F-12144), the Novo Nordisk Foundation (NNF20OC0063872) and the Research Council of Norway (grant #315599). M.V. acknowledges the support of the Research Council of Norway (project #301178) R.M.F. is supported by a Wellcome Senior Research Fellowship (WT220390). This project utilised high-performance computing funded by the UK Medical Research Council (MRC) Clinical Research Infrastructure Initiative (award number MR/M008924/1). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. This research was funded in part, by the Wellcome Trust (Grant number: WT220390). 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.

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The establishment of MoBa and initial data collection was based on a licence 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 (no. 2012/67). Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. 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.

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