The objective of the study was to explore the impact of paternal age on the risk of congenital anomalies and birth outcomes in infants born in the USA between 2016 and 2021. This retrospective cohort study used data from the National Vital Statistics System (NVSS) database, a data set containing information on live birth in the USA between 2016 and 2021. Newborns were divided into four groups based on their paternal age (< 25, 25–34, 35–44, and > 44 years) and using the 25–34 age group as a reference. The primary outcomes were congenital anomalies involving structural anomalies and chromosome anomalies. Secondary outcomes were preterm birth, low birth weight, severe neonatal perinatal asphyxia, and admission to neonatal intensive care units (NICU). A multivariable logistic regression model was used to analyze the association between paternal age and outcomes. Overall, 17,764,695 live births were included in the final analyses. After adjusting confounding factors, advanced paternal age > 44 years was associated with increased odds of congenital anomalies (adjusted odds ratio (aOR) = 1.17, 95%CI 1.12–1.21) compared with the 25–34 age group, mainly for the chromosomal anomalies (aOR = 1.59, 95%CI 1.40–1.78) but not the structure anomalies (aOR = 1.03, 95%CI 0.97–1.09). The risk of preterm delivery, low birth weight, and NICU hospitalization in their infants was increased by advanced parental age as well.
Conclusion: Advanced paternal age increases the risk of congenital anomalies, especially chromosomal anomalies in their offspring, implying prenatal genetic counseling is required.
What is Known:
• There's a rising trend of advanced paternal age, which is associated with an increased likelihood of premature birth and low birth weight in their offspring. However, the exploration between paternal age and congenital abnormalities in offspring was limited and contradictory.
What is New:
• Infants with a paternal age > 44 years were more likely to be born with congenital anomalies, especially chromosomal anomalies.
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The data that support the findings of this study are available from the National Vital Statistics System at https://www.cdc.gov/nchs/data_access/vitalstatsonline.htm.
Adjusted odds ratio
Body mass index
Neonatal intensive care unit
National Vital Statistics System
Matthews TJ, Hamilton BE (2009) Delayed childbearing: more women are having their first child later in life. NCHS Data Brief:1–8
Sharma R, Agarwal A, Rohra VK, Assidi M, Abu-Elmagd M, Turki RF (2015) Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. Reprod Biol Endocrinol 13:35. https://doi.org/10.1186/s12958-015-0028-x
Waldenström U, Cnattingius S, Vixner L, Norman M (2017) Advanced maternal age increases the risk of very preterm birth, irrespective of parity: a population-based register study. BJOG 124:1235–1244. https://doi.org/10.1111/1471-0528.14368
Favilli A, Pericoli S, Acanfora MM, Bini V, Di Renzo GC, Gerli S (2012) Pregnancy outcome in women aged 40 years or more. J Matern Fetal Neonatal Med 25:1260–1263. https://doi.org/10.3109/14767058.2011.643327
Zhang H, Wang W (2022) Risk factors and adverse pregnancy outcomes in older pregnant women with hypertensive disorders of pregnancy. J Obstet Gynaecol Res. https://doi.org/10.1111/jog.15295
Morris G, Mavrelos D, Odia R, Vinals Gonzalez X, Cawood S, Yasmin E, Saab W, Serhal P, Seshadri S (2021) Paternal age over 50 years decreases assisted reproductive technology (ART) success: a single UK center retrospective analysis. Acta Obstet Gynecol Scand 100:1858–1867. https://doi.org/10.1111/aogs.14221
Wood KA, Goriely A (2022) The impact of paternal age on new mutations and disease in the next generation. Fertil Steril. https://doi.org/10.1016/j.fertnstert.2022.10.017
Niederberger C (2018) Re: The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015. J Urol 199:1099. https://doi.org/10.1016/j.juro.2018.02.040
Chan PTK, Robaire B (2022) Advanced paternal age and future generations. Front Endocrinol (Lausanne) 13:897101. https://doi.org/10.3389/fendo.2022.897101
Weiser M, Fenchel D, Frenkel O, Fruchter E, Burshtein S, Yehuda AB, Yoffe R, Bergman-Levi T, Reichenberg A, Davidson M, Sandin S (2020) Understanding the association between advanced paternal age and schizophrenia and bipolar disorder. Psychol Med 50:431–437. https://doi.org/10.1017/s0033291719000242
Lyall K, Song L, Botteron K, Croen LA, Dager SR, Fallin MD, Hazlett HC, Kauffman E, Landa R, Ladd-Acosta C, Messinger DS, Ozonoff S, Pandey J, Piven J, Schmidt RJ, Schultz RT, Stone WL, Newschaffer CJ, Volk HE (2020) The association between parental age and autism-related outcomes in children at high familial risk for autism. Autism Res 13:998–1010. https://doi.org/10.1002/aur.2303
Whitley E, Deary IJ, Der G, Batty GD, Benzeval M (2012) Paternal age in relation to offspring intelligence in the West of Scotland Twenty-07 prospective cohort study. PLoS One 7:e52112. https://doi.org/10.1371/journal.pone.0052112
McDonald EJ, De Jesus O (2022) Achondroplasia. StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC., Treasure Island (FL)
Khandwala YS, Baker VL, Shaw GM, Stevenson DK, Lu Y, Eisenberg ML (2018) Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study. BMJ 363:k4372. https://doi.org/10.1136/bmj.k4372
Hamilton BE, Martin JA, Osterman MJ, Curtin SC, Matthews TJ (2015) Births: final data for 2014. Natl Vital Stat Rep 64:1–64
Saccone G, Berghella V (2016) Antenatal corticosteroids for maturity of term or near term fetuses: systematic review and meta-analysis of randomized controlled trials. BMJ 355:i5044. https://doi.org/10.1136/bmj.i5044
Urhoj SK, Raaschou-Nielsen O, Hansen AV, Mortensen LH, Andersen PK, Nybo Andersen AM (2017) Advanced paternal age and childhood cancer in offspring: a nationwide register-based cohort study. Int J Cancer 140:2461–2472. https://doi.org/10.1002/ijc.30677
Sun Y, Li X, Jiang W, Fan Y, Ouyang Q, Shao W, Alolga RN, Ge Y, Ma G (2020) Advanced paternal age and risk of cancer in offspring. Aging (Albany NY) 13:3712–3725. https://doi.org/10.18632/aging.202333
Hurley EG, DeFranco EA (2017) Influence of paternal age on perinatal outcomes. Am J Obstet Gynecol 217:566 e561–566 e566. https://doi.org/10.1016/j.ajog.2017.07.034
du Fosse NA, van der Hoorn MP, van Lith JMM, le Cessie S, Lashley E (2020) Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis. Hum Reprod Update 26:650–669. https://doi.org/10.1093/humupd/dmaa010
Yang Q, Wen SW, Leader A, Chen XK, Lipson J, Walker M (2007) Paternal age and birth defects: how strong is the association? Hum Reprod 22:696–701. https://doi.org/10.1093/humrep/del453
Heron M (2019) Deaths: leading causes for 2017. Natl Vital Stat Rep 68:1–77
Green RF, Devine O, Crider KS, Olney RS, Archer N, Olshan AF, Shapira SK (2010) Association of paternal age and risk for major congenital anomalies from the National Birth Defects Prevention Study, 1997 to 2004. Ann Epidemiol 20:241–249. https://doi.org/10.1016/j.annepidem.2009.10.009
Fang Y, Wang Y, Peng M, Xu J, Fan Z, Liu C, Zhao K, Zhang H (2020) Effect of paternal age on offspring birth defects: a systematic review and meta-analysis. Aging (Albany NY) 12:25373–25394. https://doi.org/10.18632/aging.104141
Su XJ, Yuan W, Huang GY, Olsen J, Li J (2015) Paternal age and offspring congenital heart defects: a national cohort study. PLoS One 10:e0121030. https://doi.org/10.1371/journal.pone.0121030
Wang R, Shi Q, Jia B, Zhang W, Zhang H, Shan Y, Qiao L, Chen G, Chen C (2022) Association of preterm singleton birth with fertility treatment in the US. JAMA Netw Open 5:e2147782. https://doi.org/10.1001/jamanetworkopen.2021.47782
Sloter E, Nath J, Eskenazi B, Wyrobek AJ (2004) Effects of male age on the frequencies of germinal and heritable chromosomal abnormalities in humans and rodents. Fertil Steril 81:925–943. https://doi.org/10.1016/j.fertnstert.2003.07.043
Hack M, Klein NK, Taylor HG (1995) Long-term developmental outcomes of low birth weight infants. Future Child 5:176–196
Mao Y, Zhang C, Wang Y, Meng Y, Chen L, Dennis CL, Sheng J, Wu Y, Huang H (2021) Association between paternal age and birth weight in preterm and full-term birth: a retrospective study. Front Endocrinol (Lausanne) 12:706369. https://doi.org/10.3389/fendo.2021.706369
Sun Y, Vestergaard M, Zhu JL, Madsen KM, Olsen J (2006) Paternal age and Apgar scores of newborn infants. Epidemiology 17:473–474. https://doi.org/10.1097/01.ede.0000220690.43455.22
Yatsenko AN, Turek PJ (2018) Reproductive genetics and the aging male. J Assist Reprod Genet 35:933–941. https://doi.org/10.1007/s10815-018-1148-y
Stabile LA, Mendes CM, Goissis MD, Sousa RGB, Nichi M, Visintin JA, Hamilton T, Assumpcao M (2022) Paternal age impairs in vitro embryo and in vivo fetal development in murine. Sci Rep 12:13031. https://doi.org/10.1038/s41598-022-16469-9
Grégoire MC, Massonneau J, Simard O, Gouraud A, Brazeau MA, Arguin M, Leduc F, Boissonneault G (2013) Male-driven de novo mutations in haploid germ cells. Mol Hum Reprod 19:495–499. https://doi.org/10.1093/molehr/gat022
Lowe X, Eskenazi B, Nelson DO, Kidd S, Alme A, Wyrobek AJ (2001) Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. Am J Hum Genet 69:1046–1054. https://doi.org/10.1086/323763
Witt E, Langer CB, Svetec N, Zhao L (2023) Transcriptional and mutational signatures of the Drosophila ageing germline. Nat Ecol Evol 7:440–449. https://doi.org/10.1038/s41559-022-01958-x
Since the data used in the study was publicly available and the study involved no human subjects, the Children’s Hospital of Fudan University Institutional Review Board waived the informed consent requirement.
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Bu, X., Ye, W. & Zhou, J. Paternal age, risk of congenital anomalies, and birth outcomes: a population-based cohort study. Eur J Pediatr 182, 3519–3526 (2023). https://doi.org/10.1007/s00431-023-05025-w