Dad’s preconception HBV infection tied to baby’s heart defects

A preconception history of hepatitis B virus (HBV) infection among fathers carries an increased risk of congenital heart disease (CHD) in offspring, as shown in a study.

In a large retrospective cohort from the Chinese National Free Preconception Checkup Project (NFPCP), the prevalence rate of CHDs in offspring was higher among couples with husbands who had previous HBV infection than among couples with uninfected husbands or husbands with new HBV infection (0.036 percent vs 0.023 percent and 0.028 percent, respectively). [JAMA Pediatr 2024;doi:10.1001/jamapediatrics.2024.2680]

Logistic regression analysis showed that compared with no paternal HBV infection, previous paternal HBV infection was independently associated with a 40-percent higher risk of CHDs in offspring (adjusted relative risk [ARR], 1.40, 95 percent confidence interval [CI], 1.11–1.76). No risk increase was observed with new paternal HBV infection (ARR, 1.10, 95 percent CI, 0.89–1.36).

There are two possible explanations for the lack of association between new paternal infection and CHD risk, according to the investigators. “One is that couples with new paternal HBV infection detected and identified in the prepregnancy examination were probably advised to delay conception plans. The other is that early abortion or miscarriage was more likely to occur among couples with husbands who had new HBV infection. [Arch Gynecol Obstet 2017;295:253-257; Eur J Obstet Gynecol Reprod Biol 2014;172:10-14]

“Both of the said situations may result in an underestimation of the association of paternal HBV infection with risk of CHDs because we had little chance to observe CHD events, which are mostly detected and diagnosed in late pregnancy or after birth,” they continued.

Also of note is that maternal immunity against HBV may not be able to mitigate the teratogenic associations of paternal HBV infection with risk of CHDs in offspring, the investigators pointed out.

In the combined analysis of paternal HBV infection status and maternal HBV immune status, the risk of CHD in offspring was elevated among couples with previously infected husbands and immune wives (ARR, 1.49, 95 percent CI, 1.07–2.09), those with previously infected husbands and susceptible wives (ARR, 1.49, 95 percent CI, 1.10–2.03), and those with newly infected husbands and immune wives (ARR, 1.38, 95 percent CI, 1.05–1.82). No risk increase was seen among couples with newly infected husbands and susceptible wives (ARR, 0.99, 95 percent CI, 0.72–1.36).

“Consequently, it is essential to consider paternal HBV infection status prior to pregnancy regardless of maternal viral immunity,” the investigators said.

The exact mechanisms underlying CHDs, the most common birth defect in China, remain unclear. But existing literature links paternal risk factors—such as paternal age, smoking, and alcohol consumption—to the risk of CHD in offspring by way of potentially reducing semen quality, inducing mutations in sperm DNA, or disrupting the epigenetic programming that occurs during sperm development. Several studies suggest that a similar pathway might exist between a father’s HBV and the sperm. [Hum Reprod 2020;35:2113-2113; Birth Defects Res 2020;112:1273-1286; Clin Cardiol 2019;42:684-691; Hum Reprod 2024;39:43-52]

“These findings provide important evidence for studying paternal HBV infection as a factor associated with CHDs in offspring,” the investigators said. “Personalized reproductive guidance regarding undergoing HBV screening and staying free of HBV infection should be provided for both wives and husbands, which might be helpful for the reduction of congenital malformation risk and improvement of neonatal outcomes.”

The analysis included 3,047,924 propensity score-matched couples. Of these, 2,436,946 had husbands without preconception HBV infection, 234,757 had husbands with preconception HBV infection, and 376,221 had husbands with new HBV infection. The median age of the husbands was 27 years.