It is said that the hepatitis B virus (HBV) is not teratogenic because it does not cross the placenta early in pregnancy, during the organogenesis of the embryo. This assertion is contested by Chinese researchers who have demonstrated associations between maternal HBV infection before conception and congenital fetal heart defects (1). At the same time, adverse pregnancy outcomes associated with paternal HBV infection before conception have also been reported. The researchers’ working hypothesis is that the DNA of the virus is integrated into the genome of the oocytes or sperm, or that the sperm of the procreator is defective. A retrospective epidemiological study carried out by the same team shows a link between pre-conception HBV infection of fathers and heart malformations in children (2).
A retrospective cohort study in mainland China
This study included data from more than 3 million couples who conceived a singleton child within a year of a planned pregnancy consultation, which consisted of HBV-uninfected women (susceptible or vaccinated) and men. infected or not with HBV, and matched with a propensity score, in the ratio of 1:4 (1 infected man vs 4 uninfected men). The occurrence of six cardiac malformations affecting their descendants was recorded: ventricular septal defect, atrial septal defect, atrioventricular canal, tetralogy of Fallot, pulmonary stenosis, transposition of the great vessels.
According to hepatitis B serologies, approximately 611,000 men were infected before conception, including 38.4% previously (presence of antibodies, but not antigens) and 61.6% recently (presence of a HBs antigen).
40% increase in risk, regardless of maternal vaccination
The prevalence of cardiac malformations is low: 0.025% in the offspring of all fathers, and 0.023%, 0.036%, and 0.028% in those of uninfected, formerly infected, and recently infected fathers, respectively.
Compared to uninfected fathers, the risk of heart malformation is significantly increased in the offspring of formerly infected fathers (Adjusted Relative Risk RRa: 1.40; [Intervalle de Confiance de 95 % : 1,11 à 1,76]), but not in that of recently infected fathers (RRa: 1.10 [0,89 à 1,36]).
Compared to “negative” couples (father not infected before conception, receptive mother), the risk of heart malformation is increased in the offspring of couples combining a formerly infected father and a receptive mother (RRa = 1.49 [1,10 à 2,03]) or vaccinated (RRa: 1.49 [1,07 à 2,09]), and in that of couples combining a recently infected father and a vaccinated mother (RRa: 1.38 [1,05 à 1,82]). There is no interaction between the mother’s immune status and the father’s infection.
The authors conclude that HBV infection of the father, prior to pregnancy, increases the risk of cardiac malformation in the fetus, to a certain extent when it is old, and that immunization of the mother by vaccination does not does not mitigate father-related risk. It is therefore justified to determine the HBV status of both partners before pregnancy and to provide them with personalized advice on screening and prevention of HBV infection.
However, it seems difficult to believe in the teratogenic effect of HBV transmitted by the father’s gametes on the results of this single study. Significant associations may not be true or clinically relevant. And furthermore, the Relative Risks reported are probably erroneous because they are calculated from low, underestimated prevalences. Usually the prevalence of heart defects is much higher than 0.025%, i.e. at 2.5 cases per 10,000 singletons…
