Professor and Chair, Department of Obstetrics and Gynecology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo
Dr. Rebar reports no financial relationships to this field of study.
SYNOPSIS: Fathering infants at or after age 45 years is associated with negative effects on both the mothers and the resulting offspring.
SOURCE: Khandwala YS, Baker VL, Shaw GM, et al. Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: Population based cohort study. BMJ 2018;363:k4372. doi: 10.1136/bmj.k4372.
To assess the effect of paternal age on maternal and perinatal outcomes, investigators conducted a retrospective cohort analysis of all live births between 2007 and 2016 within the United States as published by 30.0 years to 31.2 years. After adjustment for a variety of factors, including maternal age, race, education, smoking status, and number of prenatal visits, births related to the oldest fathers were associated with worse outcomes. Children born to fathers older than 45 years of age had a 14% higher chance of preterm birth (< 37 weeks) compared with fathers between 25 and 34 years of age (adjusted odds ratio [aOR], 1.14; 99% confidence interval [CI], 1.13-1.15). Children born to fathers 45 to 54 years of age had a 14% higher risk of low birth weight (< 2,500 g) than children born to younger fathers (aOR, 1.14; 99% CI, 1.12-1.15). Fathers older than 45 years of age had 28% increased odds of a pregnancy complicated by gestational diabetes compared with fathers aged 25 to 34 years (aOR 1.28; 99% CI, 1.27-1.30). After stratification by maternal age, increasing paternal age remained significantly associated with perinatal outcomes. In addition, the findings were similar when the analysis was limited to first births for mothers.
Although the authors of this extraordinarily large and robust study documented only a modest effect of advanced paternal age (> 45 years) on perinatal outcomes, the effect is of great significance because the percentage of all U.S. births to fathers older than 40 years of age has doubled to approximately 9% since the 1970s.1 Khandwala et al estimated the population-attributable risk of advanced paternal age by recalculating the distribution of paternal age groups for a postulated scenario in which all fathers were younger than 45 years of age. During the past 10 years, 13.2% (95% CI, 12.5-13.9%) of premature births and 14.5% (95% CI, 13.6-15.4%) of low birth weight infants with older fathers can be attributed to the increase in fathers older than 45 years of age. In addition, 15.1% (95% CI, 14.2-15.9%) of neonatal intensive care unit admissions and 18.2% (95% CI, 17.5-18.9%) of gestational diabetes diagnoses were attributable to the increase in older fathers.
In contrast to older mothers, it has been difficult to estimate any effect of advanced paternal age on offspring. Gradually, it has become recognized that the offspring of fathers with advanced paternal age (defined in most reports as older than 50 years of age) have increased rates of genetic abnormalities, cancer, autism, and other psychiatric disorders.2,3 Still, any reported changes develop gradually without any specific age cutoff.
In women, regardless of their age, 23 cell divisions are required to form mature egg cells from oogonia. In men, about 30 spermatogonial cell divisions occur before puberty.3 After puberty, spermatogonial cells divide about 23 times per year. For example, sperm produced by a 70-year-old male will have formed after perhaps 1,300 spermatogonial mitotic divisions. Thus, it is not difficult to deduce that advanced paternal age may lead to an increased number of de novo mutations.
In 2012, Kong et al reported on whole genome sequencing of parents and children from 78 Icelandic families.4 The researchers convincingly documented an association between paternal age at conception and the frequency of de novo mutations in offspring across the entire genome. This association was significant, especially for genes associated with autism spectrum disorders.4 As a result of this seminal study, it has become firmly established that advanced paternal age can contribute to birth defects associated with single gene mutations and chromosomal abnormalities. Both bipolar disorders and schizophrenia also have been linked to advanced paternal age.5,6
Achondroplasia, the most common cause of dwarfism, was the first genetic disorder thought to be influenced by paternal age.7 This autosomal dominant disorder now is known to be caused by mutations in the fibroblast growth factor 3 (FGFR3) gene.8 Similarly, mutations in the FGFR2 gene, which lead to autosomal dominant craniosynostotic disorders, also are associated with paternal age.9 Mutation in the RET gene, which leads to multiple endocrine neoplasia, is another example of a genetic disorder that almost exclusively has paternal origin associated with paternal age.3
With regard to chromosomal aberrations, researchers now recognize that the extra chromosome 21 is of paternal origin in approximately 10% of Down syndrome cases. Advanced paternal age significantly affects the incidence of Down syndrome when the female partner is older than 35 years of age.10 Furthermore, although controversial, it has been suggested that 50% of cases of Klinefelter syndrome with a 47,XXY karyotype are attributable to the male.11
Advanced paternal age also appears to have an association with malignant disease. In an extremely large cohort study from Northern Ireland, researchers found a small but significant increase in the risk of leukemia in children of fathers of advanced paternal age.12 A population-based cohort study from Sweden corroborated this increased risk of leukemia and also found an effect of paternal age on the incidence of central nervous system cancers.13 Even when controlling for maternal age, breast cancer also was associated with advanced paternal age, and the effect appeared to be stronger for breast cancer arising in premenopausal women.14
Thus, the Khandwala et al study adds to our knowledge about the effect of advanced paternal age on the offspring. The authors suggested that epigenetic changes in the sperm of older men may affect placental and embryonic growth and account for the preterm delivery, low birth weight, and low Apgar scores observed.15 Together with the genetic studies discussed, the current data indicate the need to counsel couples about the risks involved when the father is older. The risks not only are genetic but also involve other neonatal outcomes as well. Guidelines established by the American College of Genetics indicate that genetic testing for any pregnancy involving a man with advanced paternal age should be treated similarly to any other pregnancy.16
- Khandwala YS, Zhang CA, Lu Y, Eisenberg ML. The age of fathers in the USA is rising: An analysis of 168,867,480 births from 1972 to 2015. Hum Reprod 2017;32:2110-2116.
- Addai J, Smith RP, Coward RM, et al. The effects of advanced paternal age on fertility. Asian J Androl 2013;15:723-728.
- Ramasamy R, Chiba KI, Butler P, Lamb DJ. Male biological clock: A critical analysis of advanced paternal age. Fertil Steril 2015;103:1402-1406.
- Kong A, Frigge ML, Masson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 2012;488:471-475.
- Frans EM, Sandin S, Reichenberg A, et al. Advancing paternal age and bipolar disorder. Arch Gen Psychiatry 2008;65:1034-1040.
- Sipos A, Rasmussen F, Harrison G, et al. Paternal age and schizophrenia: A population based cohort study. BMJ 2004;329:1070.
- Penrose LS. Parental age and mutation. Lancet 1955;269:312-313.
- Wynn J, King TM, Gambello MJ, et al. Mortality in achondroplasia study: A 42-year follow-up. Am J Med Genet A 2007;143A:2502-2511.
- Wilkie AO, Slaney SF, Oldridge M, et al. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 1995;9:165-172.
- Zaragoza MV, Jacobs PA, James RS, et al. Nondisjunction of human acrocentric chromosomes: Studies of 432 trisomic fetuses and liveborns. Hum Genet 1994;94:411-417.
- Spano M, Bonde JP, Hjollund HI, et al. Sperm chromatin damage impairs human fertility. The Danish First Pregnancy Planner Study Team. Fertil Steril 2000;73:43-50.
- Murray L, McCarron P, Bailie K, et al. Association of early life factors and acute lymphoblastic leukaemia in childhood: Historical cohort study. Br J Cancer 2002;86:356-361.
- Yip BH, Pawitan Y, Czene K. Parental age and risk of childhood cancers: A population-based cohort study from Sweden. Epidemiology 1999;10:747-751.
- Choi JY, Lee KM, Park SK, et al. Association of paternal age at birth and the risk of breast cancer in offspring: A case control study. BMC Cancer 2005;5:143.
- Abbasi J. The paternal epigenome makes its mark. JAMA 2017;317:2049-2051.
- Torriello HV, Meck JM; Professional Practice and Guidelines Committee. Statement on guidance for genetic counseling in advanced paternal age. Genet Med 2008;10:457-460.