Background Pregnancy with a male fetus carries a higher risk of term pre-eclampsia than pregnancy with a female fetus. Based on evidence that maternal blood pressure (BP) may be raised in pregnancies with Beckwith-Wiedemann syndrome (fetal overgrowth), a possible contributing factor to the association between male sex and term pre-eclampsia is that males grow faster, reaching ~130 g higher birth weight, on average, than females. The association between fetal sex and maternal BP in healthy pregnancies is not known. We hypothesized that male sex would be associated with higher maternal BP in healthy pregnancies, and that this association would be explained by birth weight differences between males and females. Methods and findings We tested the association between fetal sex and maternal systolic (SBP) and diastolic blood pressure (DBP), measured at ~28 weeks of gestation, in a meta-analysis of five different cohorts of mother-child pairs (n up to 109,842). Maternal BP was analyzed as both a continuous and dichotomized (high BP: yes or no) outcome. Linear regression models were constructed with and without adjustment for birth weight to assess whether any difference in maternal BP was explained by the difference in birth weight between male and female babies. Lastly, we constructed a fetal genetic score for birth weight using 186 own-birth-weight-associated single-nucleotide polymorphisms (SNPs) to test whether birth-weight-raising-alleles in the fetus were associated with maternal BP in pregnancy (n up to 32,232). Both maternal SBP and DBP were higher in pregnancy when carrying a male fetus compared to a female fetus (mean difference 0.35 mmHg [95%CI: 0.15-0.55] and 0.35 mmHg [95%CI: 0.21-0.49], for SBP and DBP, respectively). An independent effect of fetal sex remained when including birth weight but attenuated slightly (0.22 mmHg [95%CI: 0.02-0.42] and 0.31 mmHg [95%CI: 0.17-0.45], for SBP and DBP respectively). A positive effect estimate was found for odds of experiencing high maternal BP given pregnancy with a male fetus, but confidence intervals were wide (OR 1.05 [95%CI: 0.98-1.12]). No evidence for an association was found between a fetal birth weight genetic score and SBP or DBP when conditioned on maternal genotype. Conclusions We found strong evidence to support a small effect of male fetal sex on higher maternal BP in pregnancy and that larger fetal size at birth does not contribute to a substantial part of this association. Our findings do not indicate a difference in maternal BP that would warrant changes to routine monitoring in clinical practice but do suggest that male sex may be a contributing risk factor for BP-related complications.

The authors have declared no competing interest.

This work was supported by a PhD studentship granted to C.S.D. by the QUEX Institute, a collaborative program between the University of Exeter and the University of Queensland. R.M.F. and R.N.B. were supported by a Wellcome Senior Research Fellowship (WT220390). R.M.F. is also supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD101669. J.J. was supported by funding awarded to Bo Jacobsson by The Swedish Research Council, Stockholm, Sweden (2019-01004), and Agreement concerning research and education of doctors (ALFGBG-1005151), Sahlgrenska University Hospital, Sahlgrenska Academy, Gothenburg, Sweden. N.M.W. was supported by an Australian National Health and Medical Research Council (NHMRC) Investigator grant (APP2008723). D.M.E. is supported by an NHMRC Investigator grant (APP2017942). S.J. was supported by the Research Council of Norway (no. 315599)) and P.R.N. from the European Research Council (AdG SELECTionPREDISPOSED no. 293574), Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation TMS2022TMT01, the RCN #240413, the Novo Nordisk Foundation #NNF18OC0054741, the University of Bergen, and the Western Norway Regional Health Authority. Genotyping of the EFSOCH study samples was funded by the Wellcome Trust and Royal Society (grant 104150/Z/14/Z). 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 C.S.D. and R.M.F will serve as guarantors for the contents of this paper. A comprehensive list of grants funding (PDF, 330KB) is available on the ALSPAC website. This research was specifically funded by the Wellcome Trust (Grant ref: WT088806). HAPO was supported by grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Diabetes and Digestive and Kidney Diseases (R01-HD34242 and R01-HD34243); the National Center for Research Resources (M01-RR00048 and M01-RR00080); and the American Diabetes Association. Genotyping of the HAPO study samples was funded by Wellcome Trust and Royal Society grant 104150/Z/14/Z. BiB data used in this research were 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). We thank the Norwegian Institute of Public Health (NIPH) for generating high-quality genomic data. This research is part of the HARVEST collaboration, supported by the Research Council of Norway (#229624). We also thank the NORMENT Centre for providing genotype data, funded by the Research Council of Norway (#223273), South East Norway Versjon 6.9 3 Health Authorities and Stiftelsen Kristian Gerhard Jebsen. We further thank the Center for Diabetes Research, the University of Bergen for providing genotype data and performing quality control and imputation of the data funded by the ERC AdG project SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authorities. The authors would like to acknowledge the use of the University of Exeter High-Performance Computing facility in carrying out this work. We acknowledge use of high-performance computing (and/or long-read sequencing) funded by an MRC Clinical Research Infrastructure award (MRC Grant: MR/M008924/1).

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:

Ethical approval for the Exeter Family Study of Childhood Health was given by the North and East Devon (UK) Local Research Ethics Committee (approval number 1104), and informed consent was obtained from the parents of the newborns. 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. Consent for biological samples has been collected in accordance with the Human Tissue Act (2004). Study participants have the right to withdraw their consent for elements of the study or from the study entirely. Full details of the ALSPAC consent procedures are available on the study website (http://www.bristol.ac.uk/alspac/researchers/research-ethics/). Ethics approval was obtained for the main platform study and all of the individual sub-studies from the Bradford Research Ethics Committee. 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 administrative board of MoBa led by the Norwegian Institute of Public Health approved the study protocol and the current study was approved by the Regional Committees for Medical and Health Research Ethics (no. 2012/67).

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

Summary statistics from EFSOCH are available on request. Researchers interested in accessing the data are expected to send a reasonable request by sending an email to the Exeter Clinical Research Facility at crf@exeter.ac.uk. For access to the HAPO data used in this study, please contact Dr Rachel Freathy (r.freathy@exeter.ac.uk) and Prof. William Lowe Jr (wlowe@northwestern.edu). The website describing the study and other data available is https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000096.v4.p1 The ALSPAC data management plan describes in detail the policy regarding data sharing, which is through a system of managed open access. The data used in this study are linked to ALSPAC project number B3392. To request access to the data included in this paper and all other existing ALSPAC data: (i) Please read the ALSPAC access policy, which describes the process of accessing the data and samples in detail and outlines the costs associated with doing so, (ii) 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, and (iii) 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@bristol.ac.uk. Please note that the study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool: http://www.bristol.ac.uk/alspac/researchers/our-data/. Scientists are encouraged and able to use BiB data. Data requests are made to the BiB executive using the form available from the study website http://www.borninbradford.nhs.uk (please click on Science and Research to access the form). Guidance for researchers and collaborators, the study protocol and the data collection schedule are all available via the website. All requests are carefully considered and accepted where possible. Data from the Norwegian Mother, Father and Child Cohort Study and the Medical Birth Registry of Norway used in this study are managed by the Norwegian Institute of Public Health and are available to researchers through an application via https://helsedata.no. The consent given by the participants does not open for storage of data on an individual level in repositories or journals. Access to data sets requires approval from a Regional Committee for Medical and Health Research Ethics in Norway and an agreement with MoBa.

https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000096.v4.p1

http://www.bristol.ac.uk/alspac/researchers/our-data/

http://www.borninbradford.nhs.uk/

https://helsedata.no/