{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T19:51:05Z","timestamp":1775677865676,"version":"3.50.1"},"reference-count":81,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["101071773"],"award-info":[{"award-number":["101071773"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union or the European Research Council"},{"name":"Aarhus University and was supported by the Research Council of Norway"},{"name":"Centre of Excellence Funding Scheme","award":["262700"],"award-info":[{"award-number":["262700"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"Abstract<\/jats:title>\n \n STUDY QUESTION<\/jats:title>\n Is prenatal exposure to parental smoking associated with infertility in sons and daughters?<\/jats:p>\n <\/jats:sec>\n \n SUMMARY ANSWER<\/jats:title>\n The study does not provide robust evidence that prenatal smoking exposure increases the risk of infertility, defined as clinically diagnosed infertility or ART use, in adult sons and daughters.<\/jats:p>\n <\/jats:sec>\n \n WHAT IS KNOWN ALREADY<\/jats:title>\n Reproductive function is established early in fetal life and may be adversely affected by prenatal exposure to parental smoking.<\/jats:p>\n <\/jats:sec>\n \n STUDY DESIGN, SIZE, DURATION<\/jats:title>\n In this cohort study, we used data from the Danish birth cohort, Health Habits for Two, established in 1984\u20131987. In total, 11\u00a0980 (87% of eligible) women participated and gave birth to 11\u00a0144 liveborn, singleton sons and daughters.<\/jats:p>\n <\/jats:sec>\n \n PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n Adult sons and daughters born to mothers enrolled in the birth cohort constituted the study population and were aged 35\u201338\u2009years at follow-up. Around gestational week 36, mothers provided information on parental smoking. The primary exposure of interest was maternal smoking. Paternal smoking and combined parental smoking were also assessed to explore individual and potential synergistic effects. Infertility among offspring was defined as either an ICD-10 infertility diagnoses or use of ART, identified within two nationwide registers and considering their partners\u2019 records. Associations were examined using Cox regression models estimating crude and adjusted hazard ratios (HRs) for categories of prenatal smoking, with non-smoking as the reference, accounting for competing risks of infertility. Dose\u2013response associations were explored across categories of maternal and paternal smoking. The proportional hazards assumption was met only when stratifying analyses by age, using cutoffs of \u226426 and &gt;26\u2009years for sons, and \u226427 and &gt;27\u2009years for daughters. In a sensitivity analysis, follow-up was restricted to periods of registered partnership under the assumption that individuals in a relationship are more likely to be identified as infertile and vice versa. In a sub-analysis, analyses were stratified by offspring educational level to explore potential social gradients in being identified as infertile in medical records.<\/jats:p>\n <\/jats:sec>\n \n MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n Maternal smoking of &gt;9 cigarettes\/day tended to be associated with higher risk of infertility among sons \u226426\u2009years (HR 1.7 (95% CI: 0.8\u20133.5)) and daughters \u226427\u2009years (HR 1.2 (95% CI: 0.7\u20131.9)), both indicating suggestive dose\u2013response patterns with higher risk of infertility with increasing maternal smoking levels. No associations for sons &gt;26\u2009years or daughters &gt;27\u2009years were observed. Paternal smoking of &gt;10 cigarettes\/day tended to be associated with higher risk of infertility among sons &gt;26\u2009years (HR 1.3 (95% CI: 0.9\u20131.8)), indicating suggestive dose\u2013response patterns. No higher risk of infertility following paternal smoking was observed among sons \u226426\u2009years or daughters at any age. No synergistic effects of combined parental smoking were observed. When redefining the time at risk using the partnership model, we did not observe higher risks of infertility among maternally exposed sons and daughters. When stratifying the main analyses by the sons\u2019 and daughters\u2019 educational level, we observed tendencies of higher risks for infertility in some exposure groups among those with longer education. Overall, we found no robust evidence that prenatal exposure to parental smoking is associated with a higher risk of clinically recognized infertility in offspring.<\/jats:p>\n <\/jats:sec>\n \n LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n Parental smoking was self-reported by mothers late in pregnancy and might be subject to misclassification, most likely non-differential. Not all infertility cases may be captured in the registers as it requires pregnancy attempt and pursuing medical treatment. Most confidence intervals overlapped the null, indicating that the findings are also compatible with no association. Some analyses, particularly the stratified analyses, were limited by low statistical power.<\/jats:p>\n <\/jats:sec>\n \n WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n The observed diminishing effect estimates with increasing age for those exposed to maternal smoking may reflect growing influence from other dominant infertility risk factors. Results from analyses stratified by offspring educational level may be indicative of tendencies of greater awareness of fertility issues and higher health care-seeking among individuals from more advantaged socioeconomic backgrounds. A potential higher, although modest and uncertain, risk of infertility following prenatal smoking exposure cannot be excluded, supporting the current guidelines recommending smoking cessation prior to pregnancy.<\/jats:p>\n <\/jats:sec>\n \n STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n This study was funded by the European Union (ERC, BIOSFER, 101071773); expressed views and opinions are however those of the authors\u2019 only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. Additionally, this study received funding from Aarhus University and was supported by the Research Council of Norway, through its Centre of Excellence funding scheme (No. 262700). All authors have no conflicts or interests to declare.<\/jats:p>\n <\/jats:sec>\n \n TRIAL REGISTRATION NUMBER<\/jats:title>\n N\/A.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/humrep\/deag011","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T12:31:06Z","timestamp":1769430666000},"page":"595-605","source":"Crossref","is-referenced-by-count":0,"title":["Prenatal exposure to parental smoking and infertility in sons and daughters: a cohort study"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1136-7153","authenticated-orcid":false,"given":"M V","family":"Stokholm","sequence":"first","affiliation":[{"name":"Department of Public Health, Aarhus University , Aarhus C,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5533-8891","authenticated-orcid":false,"given":"A","family":"Ernst","sequence":"additional","affiliation":[{"name":"Department of Public 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