Later Fatherhood May Up Risk for Adverse Perinatal Outcomes

Diana Phillips

October 31, 2018

Babies born to older fathers are at increased risk for multiple adverse birth outcomes, and their mothers are more likely to develop gestational diabetes, a study has shown.

Yash S. Khandwala, MD, of the Department of Urology at Stanford Medicine, California, and colleagues published findings from a retrospective analysis of more than 40 million live births online October 31 in BMJ.

Older paternal age was associated with an increased likelihood of preterm birth, low birth weight, neonatal morbidity, and low Apgar scores in offspring and gestational diabetes. The findings are consistent with those of recent studies suggesting that age-related changes to sperm DNA may negatively influence placental and embryonic growth, the authors write.

Using data from the National Vital Statistics System, the investigators analyzed a total of 40,529,905 reported live births between 2007 and 2016 in the United States to examine the association between paternal age and maternal and neonatal health. They categorized paternal age into 10-year intervals: <25 years, 25-34 years, 35-44 years, 45-54 years, and ≥55 years.

The primary outcomes of interest were the perinatal risks to offspring, as indicated through rates of premature birth (gestational age fewer than 37 weeks), low birth weight (lower than 2500 g), low 5-minute APGAR score (less than 8), assisted ventilation at birth, admission to the neonatal intensive care unit, need for postpartum antibiotics, and seizures; and prenatal maternal risks, including gestational diabetes, preeclampsia, and eclampsia.

During the study, the mean age of fathers increased from 30.0 years to 31.2 years. After adjustment for maternal age, race, education, smoking status, and number of prenatal visits, offspring born to fathers older than 45 years compared with those born to younger fathers had gestational ages that were on average 0.12 weeks lower (99% confidence interval [CI], −0.13 to −0.11 weeks), and there was a 14% higher risk of having a premature birth (adjusted odds ratio [AOR], 1.14; 99% CI, 1.13 - 1.15).

Additionally, babies of 45- to 54-year-old fathers were 20.2 g lighter (99% CI, −22.5 to −18.0) and had a 14% greater risk for low birth weight than infants born to younger fathers (AOR, 1.14; 99% CI, 1.12 - 1.15).

The offspring of fathers aged 55 years or older were more likely to have low APGAR scores (AOR, 1.14; 99% CI, 1.08 - 1.20), and they had a significantly higher risk of requiring assisted ventilation (AOR, 1.10; 99% CI, 1.04 - 1.16) and of being admitted to the neonatal intensive care unit (AOR, 1.28; 99% CI, 1.24 - 1.33).

With respect to maternal pregnancy-related outcomes, the adjusted odds of maternal gestational diabetes was 28% greater in pregnancies with fathers aged 45 to 54 years (AOR, 1.28; 99% CI, 1.27 - 1.30). No significant association was found between paternal age and risk for preeclampsia or eclampsia. After stratification for maternal age, increasing paternal age remained significantly associated with perinatal outcomes across all stratums, the authors write.

The investigators also estimated the population attributable risk of advanced paternal age and determined that during the past decade, the increase in the number of fathers older than 45 years may have contributed 13.2% of premature births, 14.5% of low-birth-weight infants, 15.1% of admissions to a neonatal intensive care unit, and 18.2% of gestational diabetes diagnoses.

The authors stress, however, that the population-level impact of these associations is uncertain, given the modest prevalence of advanced paternal age (2.7% of the fathers included in the analysis were 45 to 54 years old, and 0.3% were aged 55 years or older) and the low absolute and relative risks.

Hilary K. Brown, PhD, assistant professor in the Interdisciplinary Center for Health and Society at the University of Toronto Scarborough, Ontario, Canada, echoes that point in an accompanying editorial. "[T]he relative and absolute risks of adverse perinatal outcomes associated with advanced paternal age were low," she writes. "None of the odds ratios exceeded 1.5, and infants of fathers aged 45 or older were delivered only 0.12 weeks earlier and were only 20.2 g lighter than those of infants of younger fathers."

Other limitations, Brown notes, include the difficulty of controlling for the contributing effect of maternal age. "[A]lthough women tend to be younger than their male partners, maternal and paternal age are correlated, making it difficult to disentangle their effects," she explains.

Preconception Health Important for Fathers Too

Brown suggests that age-related changes to sperm DNA is but one of multiple explanations for the observed associations. "Studies have shown that advanced paternal age is associated with negative health behaviours such as smoking and frequent alcohol consumption, obesity, chronic disease, mental illness, and subfertility," she writes. "These factors have also been linked to adverse perinatal outcomes. Therefore, although the observed association between paternal age and adverse perinatal outcomes could be real, it might not be causal."

The findings do contribute to a better understanding of the role of paternal age in perinatal health, and they underline the importance of including men in preconception healthcare, Brown states. "Until recently, preconception health has been a topic aimed primarily at women. With the growing understanding of the importance of contributions by men to perinatal health, however, preconception health is increasingly being defined as the health of all people of reproductive age, regardless of sex."

The authors agree. "This study evaluated potential fetal-maternal risks associated with advanced paternal age. As more than 12% of births to fathers aged 45 years or older with adverse outcomes might have been prevented were the father younger, the importance of these data are most relevant to parents planning their reproductive future," they write. They also suggest the potential importance of altering preconception counseling guidelines "to incorporate the possibility that delaying parenthood for fathers might not be as inconsequential as previously understood."

Although they acknowledge that the absolute risk of advancing paternal age on adverse perinatal outcomes is modest, "our findings emphasize the need to further investigate the public health implications of increasing paternal age within the US and other countries," the researchers write.

The authors and Dr Brown have disclosed no relevant financial relationships.

BMJ. Published online October 31, 2018.

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