Discussion

In the current study, maternal HBV/HCV was associated with a significantly increased risk for offspring neurological-related hospitalisations, mainly for movement disorders (tremor, chorea and other extrapyramidal movement disorders) and developmental disorders (mild cognitive impairment, unspecified mental retardation and unspecified delay in development; Supplement A). To the best of our knowledge, this association has not yet been described. Maternal HBV/HCV was previously found to be associated also with offspring endocrine, respiratory and infectious morbidity.^{Reference Govrin-Yehudain, Wainstock, Abu-Freha and Sheiner13–Reference Abu Freha, Wainstock, Poupko, Yonat Shemer, Sergienko and Sheiner15} Thus, offspring of mothers having a chronic infectious disease (HBV/HCV) are prone to higher risk of non-communicable diseases, confirming again the concept of fetal origin of lifespan diseases. Because HBV/HCV mothers had higher premature birth rates, one may speculate that this may explain higher rates of neurological hospitalisations in offspring. However, this association remained significant even after adjusting for mode and week and of delivery as well as maternal complications (Table 3).

Several theories may explain these findings, including the microbiome theory, which suggest that HBV alters the normal gut microbiota.^{Reference Wei, Yan and Zou16,Reference Zhang, Lun and Tsui17} Immune alterations, such as viral infections during pregnancy, have been shown to alter maternal intestinal microbiome, resulting in potentially long-lasting consequences for offspring.^{Reference Zhang, Lun and Tsui17} Moreover, among patients with chronic HBV infection, the composition of gastrointestinal fungi has been found to be positively correlated with disease progression.^{Reference Chen, Chen and Guo18} Alterations in maternal microbiota have been found to affect various offspring health conditions, such as fetal microbiome,^{Reference Bhagavata Srinivasan, Raipuria, Bahari, Kaakoush and Morris19} glucose and lipid metabolism.^{Reference Zhou, Xiao and Zhang20} In animal models, an aberrant maternal microbiome has been shown to affect fetal brain development, and neurodevelopmental disorders have been suggested to determine life-long neurological outcomes.^{Reference Degroote, Hunting, Baccarelli and Takser21,Reference Hsiao, McBride and Hsien22} Moreover, HBV/HCV women had a higher rate of caesarean delivery, which was shown to alter fetal microbiome as compared to vaginal deliveries.^{Reference Salas Garcia, Yee, Gilbert and Dsouza23,Reference Shao, Forster and Tsaliki24} Thus, maternal microbiome changes in chronic HBV/HCV carriers contribute, at least in part, to the higher incidence of neurological diseases in offspring.

The association between maternal HBV/HCV and neurological disorders in offspring may also be explained by the immune theory. Several animal studies have shown that alteration in maternal immune response following viral infections results in increased incidence of various developmental, neurological and psychiatric disorders.^{Reference Shi, Tu and Patterson25–Reference Armario, Hernandez, Bluethmann and Hidalgo28} Injecting pregnant rodents with bacterial lipopolysaccharide, which induces strong innate immune responses in the absence of infection, results in behavioural and histological abnormalities in adult offspring similar to those observed in offspring of infected mothers.^{Reference Shi, Tu and Patterson25} Other studies in animal models have shown that alterations in maternal immune response result in increased incidence of various developmental, neurological and psychiatric disorders.^{Reference Patterson26,Reference Patterson27}

HBV and HCV have been found to trigger epigenetic changes in hepatitis carriers,^{Reference Vivekanandan, Daniel, Kannangai, Martinez-Murillo and Torbenson29–Reference Hong, Kim and Guo31}which may also explain the present findings. Cheng et al. found altered DNA methylation status in offspring of mothers with HBV compared to offspring of non-infected mothers, and these authors concluded that prenatal HBV exposure, even without malformations or premature birth, may alter the epigenome profile in newborns.^{Reference Cheng, Zhao and Huang32}

Our study has several strengths. This is a long follow-up study on a large cohort of a single tertiary hospital in this region. Thus, offspring born in this centre are admitted to the same hospital, which enables accessibility to data regarding offspring hospitalisation events.

Our study has several limitations. The study data were obtained from hospital admission charts; therefore, we expect an underestimation of the outcome because only the more severe cases of neurological morbidities are hospitalised. This misclassification, however, would most likely be non-differential and occur independently of maternal HBV/HCV status, and it would shift our findings towards the null hypothesis. In addition, data on antiviral treatment of HBV/HCV mothers were unavailable, but most parturients do not require therapy. Antiviral therapies are listed as category B or C under the FDA pregnancy categories.^{Reference Wong, Seto, Wong, Yuen and Chan33,Reference Bzowej34} Therefore, it is unlikely that maternal antiviral treatment accounted for our findings.

Studies should further investigate whether changes in the microbiome of HBV/HCV mothers, immune system modulation or epigenetic changes lead to increased susceptibility to neurological hospitalisations as found in the current study. Future studies should also include data on antiviral treatments and consider their effect on offspring health.