Parental infertility and offspring cardiometabolic trajectories up to 25 years: a pooled analysis of three European cohorts

Objective To assess whether parental infertility is associated with differences in cardiometabolic trajectories in offspring from childhood to 25 years of age. Design Pooled analysis of three European pregnancy cohort studies. Subjects Up to 14,609 singletons from three pregnancy cohorts (the UK Avon Longitudinal Study of Parents and Children, the Portuguese Geraçao 21, and the Amsterdam Born Children and their Development study). Exposure Parental infertility defined as time-to-pregnancy ≥12 months. Main Outcome Measures Trajectories of body mass index (BMI), waist circumference, systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and glucose from childhood to 25 years of age were compared in offspring of couples with and without infertility. Trajectories were modelled using mixed-effects models with natural cubic splines adjusting for cohort, sex of the offspring, and maternal factors (age, body mass index, smoking, educational level, parity, and ethnicity). Predicted levels of cardiometabolic traits up to 25 years of age were compared by parental infertility. Results Offspring of couples with infertility had increasingly higher BMI (difference in mean predicted levels by age 25: +1.09 kg/m2, 95% confidence interval [0.68 to 1.50]) and suggestively higher DBP at age 25 (+1.21 mmHg [0.00 to 2.43]). Their LDL-C tended to be higher, and their HDL-C values tended to be lower over time (age 25, LDL-C: +4.07% [-0.79 to 8.93]; HDL-C: −2.78% [-6.99 to 1.43]). At middle-late adolescence, offspring of couples with infertility had higher waist circumference (age 17: +1.05 cm [0.11 to 1.99]) and SBP (age 17: +0.93 mmHg [0.044 to 1.81]), but these differences attenuated at later ages. No clear inter-group differences in triglyceride and glucose trajectories were observed. Further adjustment for paternal age, body mass index, smoking, and educational level, and both parent’s history of diabetes and hypertension in the cohort with this information available (Avon Longitudinal Study of Parents and Children) did not attenuate inter-group differences. Conclusion Offspring of couples with infertility have increasingly higher BMI over the years, suggestively higher blood pressure levels, and tend to have greater values of LDL-C and lower values of HDL-C with age. ### Competing Interest Statement T.G.M.V. received grants from the Amsterdam Academic Medical Centre, Amsterdam Public Health Services, and Dutch Organization for Health Research and Development during the study. D.A.L. received support from the UK Medical Research Council, National Institute of Health Research, European Research Council and British Heart Foundation during the course of this study. M.C.M. received grants from the European Research Council during the study. The rest of the authors declare that no competing interests exist. ### Funding Statement This project received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement number 947684). It received additional support from other European Research Council projects (grant agreements 101021566, 874739, and 733206). This work was also partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700, and the project "Women's fertility - an essential component of health and well-being", number 320656, and the British Heart Foundation (CH/F/20/90003 and AA/18/1/34219). ALSPAC core funding is provided by the UK Medical Research Council and Wellcome Trust (217065/Z/19/Z) and the University of Bristol. A comprehensive list of grants funding is available on the ALSPAC website (). G21 core funding was provided by Programa Operacional de Saude "Saude XXI", Quadro Comunitario de Apoio III, Administracao Regional de Saude Norte (Regional Department of Ministry of Health) and Foundation for Science and Technology (UIDB/04750/2020, Unidade de Investigacao em Epidemiologia, Instituto de Saude Publica da Universidade do Porto). ABCD core funding is provided by the Amsterdam Academic Medical Centre, the Amsterdam Public Health Services, and the Dutch Organization for Health Research and Development (ZonMw). A.E., A.F. and D.A.L. work in, or are affiliated to, a unit that is supported by the University of Bristol and UK Medical Research Council (MC\_UU\_00032/05). The funders had no role in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. ### 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: All cohorts comply with the Declaration of Helsinki for Medical Research involving Human Subjects. In all three studies informed written consent for the collection and use of data was provided by parents up to offspring age 16, 12, and 13 (in ALSPAC, G21, and ABCD, respectively) and thereafter by the offspring in ALSPAC. in ALSPAC, ethical approval is provided by the ALSPAC Ethics and Law Committee and UK Research Ethics Committees (), consent for biological samples was collected following the Human Tissue Act (2004), and informed consent for the use of data collected via questionnaires and clinics was obtained following the recommendations of the ALSPAC Ethics and Law Committee at the time. In G21, ethical approval is provided by the Ethics Committee of Hospital de Sao Joao and the Institute of Public Health of the University of Porto. In ABCD, it is provided by the Netherlands Central Committee on Research involving Human Subjects, the Medical Ethical Committees of the participating hospitals, and the Registration Committee of the Municipality of Amsterdam. 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 Consent given by the participants does not allow individual level participant data to be presented in repositories or journals. Data used in this study is available to bone fide researchers upon request to each cohort (ALSPAC: application to the ALSPAC Executive Committee through ; G21: application to Dr. Henrique Barros, henrique.barros{at}ispup.up.pt; ABCD: application according to the guidelines in the ABCD website [], directed to abcd{at}amsterdamumc.nl). Please contact Prof. Deborah A. Lawlor (d.a.lawlor{at}bristol.ac.uk) and Dr. Ahmed Elhakeem (a.elhakeem{at}bristol.ac.uk) if you have relevant data and would like to join the A.R.T-HEALTH partnership () and contribute to future collaborations.