Higher maternal adiposity reduces offspring birth weight if associated with a metabolically favourable profile

Aims/Hypothesis Higher maternal BMI during pregnancy results in higher offspring birth weight, but it is not known whether this is solely the result of adverse metabolic consequences of higher maternal adiposity, such as maternal insulin resistance and fetal exposure to higher glucose levels, or whether there is any effect of raised adiposity through non-metabolic (e.g. mechanical) factors. We aimed to use genetic variants known to predispose to higher adiposity coupled with a favourable metabolic profile, in a Mendelian Randomisation (MR) study comparing the effect of maternal “metabolically favourable adiposity” on offspring birth weight with the effect of maternal general adiposity (as indexed by BMI). Methods To test the causal effects of maternal metabolically favourable adiposity or general adiposity on offspring birth weight, we performed two sample MR. We used variants identified in large genetic association studies as associated with either higher adiposity and a favourable metabolic profile, or higher BMI (N = 442,278 and N = 322,154 for metabolically favourable adiposity and BMI, respectively). We then used data from the same variants in a large genetic study of maternal genotype and offspring birth weight independent of fetal genetic effects (N = 406,063 with maternal and/or fetal genotype effect estimates). We used several sensitivity analyses to test the reliability of the results. As secondary analyses, we used data from four cohorts (total N = 9,323 mother-child pairs) to test the effects of maternal metabolically favourable adiposity or BMI on maternal gestational glucose, anthropometric components of birth weight and cord-blood biomarkers. Results Higher maternal adiposity with a favourable metabolic profile was associated with lower offspring birth weight (−94 (95% CI: −150 to −38) grams per 1 SD (6.5%) higher maternal metabolically favourable adiposity). By contrast, higher maternal BMI was associated with higher offspring birth weight (35 (95% CI: 16 to 53) grams per 1 SD (4 kg/m2) higher maternal BMI). Sensitivity analyses were broadly consistent with the main results. There was evidence of outlier SNPs for both exposures and their removal slightly strengthened the metabolically favourable adiposity estimate and made no difference to the BMI estimate. Our secondary analyses found evidence to suggest that maternal metabolically favourable adiposity decreases pregnancy fasting glucose levels whilst maternal BMI increases them. The effects on neonatal anthropometric traits were consistent with the overall effect on birth weight, but the smaller sample sizes for these analyses meant the effects were imprecisely estimated. We also found evidence to suggest that maternal metabolically favourable adiposity decreases cord-blood leptin whilst maternal BMI increases it. Conclusions/Interpretation Our results show that higher adiposity in mothers does not necessarily lead to higher offspring birth weight. Higher maternal adiposity can lead to lower offspring birth weight if accompanied by a favourable metabolic profile. What is already known about this subject? What is the key question? What are the new findings? How might this impact on clinical practice in the foreseeable future? ### Competing Interest Statement DAL has received support from Medtronic LTD and Roche Diagnostics for biomarker research that is not related to the study presented in this paper. The other authors report no conflicts. ### Funding Statement This study was supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 669545, the British Heart Foundation (CS/16/4/32482 and AA/18/7/34219) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. Core funding for ALSPAC is provided by the UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol. Genotyping of the ALSPAC maternal samples was funded by the Wellcome Trust (WT088806) and the offspring samples were genotyped by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Born in Bradford (BiB) data used in this research was funded by the Wellcome Trust (WT101597MA) a joint grant from the UK Medical Research Council (MRC) and UK Economic and Social Science Research Council (ESRC) (MR/N024397/1) and the National Institute for Health Research (NIHR) under its Collaboration for Applied Health Research and Care (CLAHRC) for Yorkshire and Humber and the Clinical Research Network (CRN). The Exeter Family Study of Childhood Health (EFSOCH) was supported by South West NHS Research and Development, Exeter NHS Research and Development, the Darlington Trust and the Peninsula National Institute of Health Research (NIHR) Clinical Research Facility at the University of Exeter. Genotyping of the EFSOCH study samples was funded by Wellcome Trust and Royal Society grant 104150/Z/14/Z. WDT is supported by the GW4 BIOMED DTP awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the UK Medical Research Council (MRC). M-CB is supported by a UK MRC Skills Development Fellowship (MR/P014054/1). RMF and RNB are funded by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (104150/Z/14/Z). M-CB, RMF and DAL work in / are affiliated with a unit that is supported by the University of Bristol and UK Medical Research Council (MC\_UU\_00011/6). DAL is a NIHR Senior Investigator (NF-0616-10102). ATH is supported by a NIHR Senior Investigator award and also a Wellcome Trust Senior Investigator award (098395/Z/12/Z). The funders had no role in the design of the study, the collection, analysis, or interpretation of the data; the writing of the manuscript, or the decision to submit the manuscript for publication. The views expressed in this paper are those of the authors and not necessarily those of any funder. ### 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: UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC), which covers the UK. UK Biobank's research ethics committee and Human Tissue Authority research tissue bank approvals mean that researchers wishing to use the resource do not need separate ethics approval. For ALSPAC, informed consent for the use of questionnaires and clinics was obtained from the participants following the recommendations of the ALSPAC Ethics and Law Committee at the time. For BiB, ethics approval was obtained for the main platform study and all of the individual sub-studies from the Bradford Research Ethics Committee. For EFSOCH, all mothers and fathers gave informed consent and ethical approval was obtained from the local review committee. For HAPO, the protocol was approved by the institutional review board at each field centre. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Our study uses two-sample Mendelian randomization (MR). We used both published summary results (i.e. taking results from published research papers and websites) and individual participant cohort data as follows: Journal published and website summary data were used for sample one of the two sample Mendelian randomization (published GWAS of BMI and body fat percentage). The references to those published data sources are provided in the main paper. The data for the GWAS of BMI is available here. https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT\_consortium\_data_files The data for the GWAS of body fat percentage is available here. https://walker05.u.hpc.mssm.edu We used individual participant data for the second MR sample and for undertaking sensitivity analyse from the UKB, ALSPAC, BiB, EFSOCH and HAPO cohorts. The data in UKB, ALSPAC and BiB are fully available, via managed systems, to any researchers. The managed system for both studies is a requirement of the study funders but access is not restricted on the basis of overlap with other applications to use the data or on the basis of peer review of the proposed science. Researchers have to pay for a dataset to be prepared for them. UKB. Full information on how to access these data can be found here - https://www.ukbiobank.ac.uk/using-the-resource/ ALSPAC. The ALSPAC data management plan (http://www.bristol.ac.uk/alspac/researchers/data-access/documents/alspac-data-management-plan.pdf) describes in detail the policy regarding data sharing, which is through a system of managed open access. The steps below highlight how to apply for access to the data included in this paper and all other ALSPAC data. 1. Please read the ALSPAC access policy (PDF, 627kB) which describes the process of accessing the data and samples in detail, and outlines the costs associated with doing so. 2. You may also find it useful to browse the fully searchable ALSPAC research proposals database, which lists all research projects that have been approved since April 2011. 3. Please submit your research proposal for consideration by the ALSPAC Executive Committee. You will receive a response within 10 working days to advise you whether your proposal has been approved. If you have any questions about accessing data, please email alspac-data{at}bristol.ac.uk. BiB. Full information on how to access these data can be found here - https://borninbradford.nhs.uk/research/how-to-access-data/ EFSOCH. Requests for access to the original EFSOCH dataset should be made in writing in the first instance to the EFSOCH data team via the Exeter Clinical Research Facility crf{at}exeter.ac.uk. [https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT\_consortium\_data_files][1] [1]: https://portals.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium_data_files