Associations between Advanced Paternal Age and Adverse Reproductive Outcomes in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b)

Abstract

Objective

The association between paternal age and adverse pregnancy outcomes (APOs) has not been well studied. We sought to determine whether advanced paternal age (APA) is associated with adverse maternal or neonatal outcomes.

Study Design

Secondary analysis of 8,863 pregnancies from the Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-Be (nuMoM2b) prospective cohort in which both maternal and paternal age at conception were known. APA was defined as age ≥ 40 years and AMA was defined as age ≥ 35 years. Composite maternal and fetal/neonatal APO outcomes were adjudicated by experts using previously defined methods. Univariable and multivariable logistic regression models were used to estimate the associations between APA, AMA, and their combination (AMA and APA), with the outcomes of interest (APO, fetal/neonatal, and combined APO or fetal/neonatal outcomes). Multivariable analyses were adjusted for covariates identified a priori: self-reported race and ethnicity, education, body mass index, maternal medical conditions, assisted reproductive technology (ART), and maternal age in APA only models.

Results

APA in isolation was not significantly associated with maternal or fetal/neonatal adverse outcomes (adjusted odds ratio [aOR] = 1.08, 95% confidence interval [CI]: 0.89 – 1.32). In contrast, AMA pregnancies and pregnancies in which both parents were of advanced age were associated with significantly increased risk of maternal or fetal/neonatal adverse outcome (aOR = 1.37, 95% CI: 1.17 – 1.59, p < 0.001 and aOR = 1.60, 95% CI: 1.25 – 2.05, p < 0.001), respectively. Findings were similar when individuals who used assisted reproductive technology (ART) were excluded from analyses.

Conclusion

In our study of nulliparous birthing people, in contrast to AMA pregnancies, APA alone was not significantly associated with a heightened risk of maternal or fetal/neonatal APOs. However, pregnancies from both AMA and APA individuals demonstrated a trend toward a higher risk of APOs compared with AMA pregnancies. Further research is needed to delineate the mechanism driving this finding.

Key Points

• There is an established association between older maternal age and increased risk of adverse pregnancy outcomes. Determining the influence of paternal age on pregnancy outcomes is of equal importance.

• Prior data are inconclusive on the association of APA and rates of miscarriage, fertilization rates, and aneuploidy, and to our knowledge, the associations with adverse pregnancy outcomes have not been previously examined.

• This study examines if APA (paternal age ≥ 40 years) is an independent risk factor for adverse pregnancy outcomes in a cohort of nulliparous birthing people.

Keywords

advanced paternal age - adverse pregnancy outcomes - advanced maternal age - neonatal outcomes

Publication History

Received: 18 November 2024

Accepted: 23 December 2024

Article published online:
30 January 2025

• References

• 1 Osterman MJK, Hamilton BE, Martin JA, Driscoll AK, Valenzuela CP. . Births: Final data for 2021. National Vital Statistics Reports; vol 72, no 1. Hyattsville, MD: National Center for Health Statistics. 2023 (e-pb ahead of print). doi: https://dx.doi.org/10.15620/cdc:122047
• 2 Toriello HV, Meck JM. Professional Practice and Guidelines Committee. Statement on guidance for genetic counseling in advanced paternal age. Genet Med 2008; 10 (06) 457-460
• 3 Heffner LJ. Advanced maternal age–how old is too old?. N Engl J Med 2004; 351 (19) 1927-1929
• 4 du Fossé NA, van der Hoorn MP, van Lith JMM, le Cessie S, Lashley EELO. Advanced paternal age is associated with an increased risk of spontaneous miscarriage: a systematic review and meta-analysis. Hum Reprod Update 2020; 26 (05) 650-669
• 5 Frattarelli JL, Miller KA, Miller BT, Elkind-Hirsch K, Scott Jr RT. Male age negatively impacts embryo development and reproductive outcome in donor oocyte assisted reproductive technology cycles. Fertil Steril 2008; 90 (01) 97-103
• 6 Luna M, Finkler E, Barritt J. et al. Paternal age and assisted reproductive technology outcome in ovum recipients. Fertil Steril 2009; 92 (05) 1772-1775
• 7 Klonoff-Cohen HS, Natarajan L. The effect of advancing paternal age on pregnancy and live birth rates in couples undergoing in vitro fertilization or gamete intrafallopian transfer. Am J Obstet Gynecol 2004; 191 (02) 507-514
• 8 Sagi-Dain L, Sagi S, Dirnfeld M. Effect of paternal age on reproductive outcomes in oocyte donation model: a systematic review. Fertil Steril 2015; 104 (04) 857-865.e1
• 9 Hanson BM, Kim JG, Osman EK. et al. Impact of paternal age on embryology and pregnancy outcomes in the setting of a euploid single-embryo transfer with ejaculated sperm: retrospective cohort study. F S Rep 2020; 1 (02) 99-105
• 10 Lucas JN, Deng W, Moore D. et al. Background ionizing radiation plays a minor role in the production of chromosome translocations in a control population. Int J Radiat Biol 1999; 75 (07) 819-827
• 11 Frenck Jr RW, Blackburn EH, Shannon KM. The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci U S A 1998; 95 (10) 5607-5610
• 12 Haas DM, Parker CB, Wing DA. et al; NuMoM2b study. A description of the methods of the Nulliparous Pregnancy Outcomes study: monitoring mothers-to-be (nuMoM2b). Am J Obstet Gynecol 2015; 212 (04) 539.e1-539.e24
• 13 Alio AP, Salihu HM, McIntosh C. et al. The effect of paternal age on fetal birth outcomes. Am J Mens Health 2012; 6 (05) 427-435
• 14 Olshan AF, Ananth CV, Savitz DA. Intrauterine growth retardation as an endpoint in mutation epidemiology: an evaluation based on paternal age. Mutat Res 1995; 344 (1–2): 89-94
• 15 Basso O, Wilcox AJ. Paternal age and delivery before 32 weeks. Epidemiology 2006; 17 (04) 475-478
• 16 Abel EL, Kruger M, Burd L. Effects of maternal and paternal age on Caucasian and Native American preterm births and birth weights. Am J Perinatol 2002; 19 (01) 49-54
• 17 Cincotta RB, Brennecke SP. Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas. Int J Gynaecol Obstet 1998; 60 (01) 23-27
• 18 Mogren I, Högberg U, Winkvist A, Stenlund H. Familial occurrence of preeclampsia. Epidemiology 1999; 10 (05) 518-522
• 19 Esplin MS, Fausett MB, Fraser A. et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 2001; 344 (12) 867-872