By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
SYNOPSIS: A new study suggests that both women and men who have had hepatitis B infection prior to conceiving offspring are more likely to give birth to children with congenital heart disease.
SOURCE: Wu H, Yang Y, Jia J, et al. Maternal preconception hepatitis B virus infection and risk of congenital heart diseases in offspring among Chinese women aged 20 to 49 years. JAMA Pediatr 2023;177:498-505.
Congenital heart disease can result from various combinations of environmental and genetic factors. Infections by viruses such as rubella and cytomegalovirus during early pregnancy, for instance, are known to be associated with cardiovascular malformation in newborns. However, a causative role of hepatitis B infection in causing fetal cardiac malformations during the initial months of pregnancy is suspected but incompletely proven. The impact of preconception hepatitis B on subsequent offspring is even less understood.
China is endemic for hepatitis B, with various studies showing 3% to 10% of women of childbearing age being affected. Wu and colleagues postulated that hepatitis B infection prior to pregnancy might affect developing fetuses, either by transmission of hepatitis B virus across the placenta or by hepatitis B virus deoxyribonucleic acid (DNA) having been incorporated into oocytes’ genomes or by altering sperm function. Thus, they investigated preconception hepatitis B infection status with subsequent risks for having children with congenital heart disease.
Wu and colleagues used retrospective data from a free Chinese health service, National Free Preconceptions Checkups Project, which provided care for women expecting to conceive. Data were available from 7,398,885 women aged 20 to 49 (median 28) years during 2013 to 2019 who conceived within a year of enrollment and went on to have singleton pregnancies. More than half of women had not previously been pregnant prior to entry into the study. Blood was tested for hepatitis B markers, including hepatitis B surface antibody, hepatitis B surface antigen, hepatitis B core antibody, hepatitis B envelope antibody, and hepatitis B envelope antigen. Based on blood test results, study participants were categorized as uninfected, previously infected, or newly infected. (Male partners were similarly tested and categorized.) Birth defect registration cards were used to identify newborns with congenital heart diseases, including septal defects, patent ductus arteriosus, tetralogy of Fallot, pulmonary atresia, and transposition of the great arteries. Factors including age, ethnicity, tobacco exposure, alcohol exposure, medication use, illnesses, and family history of congenital heart disease were noted.
From the total 7,398,885 women in the study, 1,822 offspring had congenital heart disease. Of previously hepatitis B-uninfected women and of women newly infected with hepatitis B, 0.03% had offspring with congenital heart disease; of women with laboratory evidence of previous preconception hepatitis B infection, 0.04% had children with congenital heart disease (P = 0.007). Adjusting statistically for relevant risk factors, women with previous hepatitis B infection were 23% more likely to have a child with congenital heart disease than were previously uninfected women. Among previously uninfected women, having a partner with previous hepatitis B infection raised the risk of having a child with congenital heart disease by 51%; paternal status did not alter the risk of congenital heart disease in offspring of women with past or recent hepatitis B infection.
In female mice, hepatitis B infection leads to incorporation of hepatitis B DNA into oocytes. Males with hepatitis B infection have been shown to have sperm dysfunction. Wu and colleagues suggested that further studies could evaluate whether effects of initial hepatitis B infection could increase the risk of subsequently producing offspring with congenital heart disease through alterations in maternal genes or paternal gamete function. The authors also suggested that prior maternal hepatitis B infection might lead to subsequent epigenetic changes that increase the risk of cardiac malformations in offspring.
COMMENTARY
Wu and colleagues used a huge database to identify a statistically significant association between pre-conception hepatitis B infection and subsequent offspring with congenital heart disease. Is the association clinically significant? To the one of 10,000 families affected, the difference would be clinically and personally significant; in a huge population area like China, that would add up to many affected individuals.
While the association between preconception hepatitis B infection and subsequent congenital heart disease has now been demonstrated, is causality proven? Certainly not! The use of “big data” is helpful in studying relatively rare conditions, but the use of “big data” is not always associated with accurate granular analysis. The authors acknowledged that while they evaluated whether or not the mothers were exposed to medication prior to conception, they did not document just what medications might have been used during pregnancy; it is entirely possible that other teratogenic exposures were not recorded in this study.
In addition, while the investigators adjusted statistically for the risk of preconceptual diabetes, they were not able to evaluate the risks of gestational diabetes on pregnancy outcomes. Further studies will be needed to better determine whether the link between pre-conception hepatitis B and congenital heart disease holds up statistically when additional potentially confounding factors also are studied. It also is possible that hepatitis B and other risk factors might not uniformly apply to each sort of congenital heart disease; the contributing etiologic factors for tetralogy of Fallot, for instance, likely are different than those factors relevant to the development of atrial septal defects.
Almost all (190) countries now have national programs for hepatitis B vaccination of infants.1 Globally, however, the World Health Organization reports that only about 42% of children have been appropriately vaccinated against hepatitis B. Vaccination coverage was even lower two decades ago when women currently becoming pregnant were at the age for childhood vaccination. Thus, many people still are growing up with the risk of becoming infected by hepatitis B and then of subsequently passing the results of that infection on to their own children who might be at increased risk of congenital heart disease.
REFERENCE
- World Health Organization. Immunization coverage. Updated July 14, 2022. https://www.who.int/news-room/fact-sheets/detail/immunization-coverage
