How HBV impacts the health of pregnant subjects
The relationship between liver diseases and pregnancy is proteiform, and three categories of pathological conditions can be described: The ones representing underlying status, pre-existing to the moment of conception; the ones coincidental with maternity; and eventually, the ones specific of pregnancy (for example, pre-eclampsia). Viral hepatitis falls into the first two categories.
As far as acute hepatitis B is concerned, its occurrence during pregnancy is not associated with higher mortality, and the related clinical picture is not distinguishable from that in the general population. This notion was further confirmed by a case-control study run in China, comparing 22 pregnant patients and 87 matched non-gravid women, all suffering from acute hepatitis B: No difference with regard to mortality and incidence of fulminant hepatitis was detected. Of note, the HBsAg loss and seroconversion rates were lower in the first group, suggesting that pregnancy might act as a risk factor for chronicity.
An interesting and recent systematic review has assessed the impact of inactive HBV carriage on gravid women health, showing that this condition is not associated with complications in pregnancy, so this condition does not need any particular therapeutic measure. When it comes to chronic (active) HBV infection already established before conception, the immunological modifications that occur in pregnancy may raise the level of HBV viremia, whereas alanine aminotransferase (ALT) levels are normal or just above the upper limit of normal (ULN).
A more relevant exacerbation of chronic hepatitis might happen after delivery in a notable percentage of women (up to 45%), as observed in a small retrospective cohort involving 38 pregnancies in 31 subjects, in which the flare was defined as a three times increase in ALT levels within 6 mo post-partum. Authors suggested that this phenomenon, also found in the subgroup of women (8/13, 62%) who had undergone a course of lamivudine (LAM) during the third trimester, was attributable to the restoration after delivery of the immune system, whose functions were previously altered to prevent foetus rejection. The topic has been further elucidated by a subsequent prospective study recruiting 126 women: Post-partum flares, defined as ALT levels twice the ULN or the baseline, were described in 27 (25%) individuals, usually asymptomatic and with spontaneous resolution. At multivariate analysis, HBeAg positivity turned out to be the most relevant predictor of post-partum flares, although just barely not reaching the statistical significance (P = 0.051). Another study, a multicentre retrospective cohort involving 101 women and 113 pregnancies, did not identify clear risk factors for exacerbation of chronic hepatitis B after delivery.
With regard to maternal complications, chronic HBV infection does not seem a risk factor for many of them, as derived by research syntheses. A meta-analysis collecting data on 9088 placenta previa cases and 15571 placental abruption cases failed to demonstrate an association with HBV, implicated as a driver of an inflammation state able to induce dysfunction of trophoblasts: Odds ratio (OR) equal to 0.98 with 95%CI equal to 0.60-1.62 and OR = 1.42 with 95%CI: 0.93-2.15, respectively. A further meta-analysis involving 439514 subjects showed that HBV was not associated with increased risk of gestational diabetes mellitus (adjusted OR = 1.11, 95%CI: 0.96-1.28), a link suggested by the potential role played by the virus in inducing insulin resistance. Another research synthesis of observational studies did not detect a statistical significance between chronic HBV infection and preterm labour (OR = 1.12, 95%CI: 0.94-1.33). More recently, a meta-analysis including 11566 women has, quite surprisingly, highlighted a negative association between chronic HBV infection and preeclampsia (OR = 0.77, 95%CI: 0.65-0.90, P = 0.002): Actually, the protective effect, probably due to impaired immune response and/or increased immune-tolerance caused by the virus (preeclampsia is linked with exaggerated activation of immune system), was apparent only in an Asian population, as derived from the subgroup analysis.
Another aspect to be considered is how the most advanced stage of chronic liver disease, cirrhosis, impact the health of pregnant women, in the particular setting of HBV infection. Cirrhosis is, fortunately, an infrequent occurrence in pregnancy due to two factors: The development of end-stage liver disease requires time and more often takes place when women have gone beyond their reproductive age; moreover, hypothalamic-pituitary dysfunction related to cirrhosis may ensue in anovulation and amenorrhea. However, when present, cirrhosis is a relevant health issue for pregnant women. In a large population-based retrospective study in the United States on gravid women, comparing 339 cirrhotic cases with 6625 matched-controls, maternal mortality and complications of pregnancy (e.g., uterovaginal haemorrhage, pre-eclampsia, peri-partum infections) were higher among individuals suffering from liver disease: For example, the maternal death rate was 1.8% vs 0% (P < 0.0001). Mortality among cirrhotic pregnant women was higher in cases of viral aetiology (HBV as well as HCV). The high burden of liver cirrhosis in pregnancy has been confirmed in a more recent prospective study, matching 176 cirrhotic gravid women with 2179 pregnant non-cirrhotic women and 1034 cirrhotic but not pregnant female subjects. Maternal mortality rate was superior in the study group (7.8%) than in the first (0.2%) and second control group (2.5%; P = 0.001); variceal haemorrhage during vaginal delivery was the most frequent reason of maternal death. Indeed, the rupture of oesophageal varices represents probably the most important complications among the ones directly related to cirrhosis in pregnant women, especially in the advanced phase of pregnancy or during labour. An important predictor of liver-related complications during pregnancy is a model for end-stage liver disease (MELD) score ≥ 10.
Treatment criteria for acute and chronic hepatitis B in pregnancy
The paramount issue is which pregnant women with HBV infection should be treated.
In the case of acute hepatitis B, the main goal of the treatment should be the prevention of acute liver failure. The quality of current evidence regarding pharmacological interventions in this setting is unfortunately very low. Nevertheless, antiviral therapy is rarely necessary, since the large majority of adult patients (> 95%) have a full and spontaneous recovery, and, as mentioned above, the clinical course of this entity does not differ between pregnant and non-pregnant women. The problem is the management of cases suffering from severe acute HBV infection. First, in case of serious hepatitis affecting gravid women, differential diagnosis is essential to rule out, for example, diseases unique to pregnancy, such as acute fatty liver of pregnancy (AFLP) as well as haemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, representing two hepatic emergencies in the third trimester. Once the viral aetiology is established, borrowing the recommendations applying to the general population, the treatment should rely on nucleos(t)ide analogue (NA) agents and the patients should be considered, as extrema ratio, for liver transplantation. Therapy with NAs can prevent acute liver failure and the related mortality, but needs to be started early in the course of severe acute hepatitis, otherwise the protective effect does not display. Due to the lack of high-quality data, there is high uncertainty regarding the best therapeutic options; recommendations for the general population support the use of tenofovir disoproxil fumarate (TDF), entecavir (ETV), and lamivudine (LAM). To date, there is no information about the use in severe acute hepatitis B of tenofovir alafenamide (TAF), the prodrug of tenofovir developed to ameliorate the safety and tolerability profile of TDF. Among the above-mentioned NAs, LAM and TDF are preferable in pregnancy, in particular the latter one, owing to its high resistance barrier that is fundamental in case of prolongation of therapy for chronicity. In extreme circumstances, liver transplantation might be a therapeutic option even during pregnancy if hepatic decompensation exceeds the point of no return: The difficulty of the task is doubled, as it involves two organisms (the mother and the foetus), but successful cases have been described, also related to fulminant hepatitis B.
At any rate, the management of severe acute hepatitis B in pregnancy needs more robust data to draw firm conclusions. Today, a case-by-case approach is needed. Chronic HBV infection is surely a more common scenario in pregnancy than fulminant hepatitis B. In the general population, according to the most authoritative guidelines endorsed by societies from all over the world, the main criteria for treatment are based on serum HBV DNA levels, serum ALT levels, and severity of liver disease[38,45,46]. Despite some discrepancies (for example, the locution “inactive carriers”, discouraged by Asian and European guidelines but kept in the American ones), there is a substantial consensus upon the following items, concerning situations wherein antiviral therapy is recommended: Cirrhosis; absence of cirrhosis, but viraemia > 20000 International Units (IU)/mL and ALT levels > 2 × ULN; no cirrhosis, viraemia > 2000 IU/mL, ALT 1-2 × ULN but at least moderate to severe inflammation on liver biopsy[38,45,46]. In the general population, there are two therapeutic options: Interferon-alfa (IFNα) and NAs. The rationale underpinning the choice of one strategy over another one is different. IFNα is administered to provide long-term immunological control through a finite duration treatment, attempting to achieve the so-called “functional cure” by HBsAg loss, but it is burdened by several side effects. NAs have a definitely better safety and tolerability profile, provide a very good virological control (persistent inhibition of HBV replication), but the duration of therapy is indefinite.
At any rate, in pregnant women, IFNα is contraindicated; therefore the therapeutic armamentarium is limited to NAs. Among this category, currently TDF (alternatively TAF) and ETV are considered the first-line drugs when starting a new therapy for chronic HBV infection, combining an excellent safety profile with a genetic barrier of resistance higher than earlier available agents, such as LAM and telbivudine (LdT)[38,45]. Nevertheless, according to the 5-class labelling used by the Food and Drug Administration (FDA) until 2015 as for safety in pregnancy, ETV has been classified as a “category C” agent, differently from LdT and TDF, labelled as “category B” drugs: That means the absence of teratogenic effects in animal studies. As a matter of fact, TDF is the drug of choice for pregnant females with chronic HBV infection requiring antiviral therapy (i.e., advanced fibrosis and cirrhosis), also in light of the huge amount of data from the setting of gravid women under treatment against the human immunodeficiency virus (HIV), in which TDF is administered safely in combination with other antiretroviral agents throughout the pregnancy, since the first trimester.
A delicate issue is how to handle cases of women who become pregnant when already on anti-HBV treatment. As a rule, appropriateness of therapy should be re-evaluated, striking a balance between benefits for the mother and the safety of the foetus. Whatever the diseases severity, IFNα must be immediately stopped; therapy with a NA can be continued in case of advanced fibrosis or cirrhosis, switching to TDF if therapy was started before conception with another drug (for instance, ETV). In case of mild disease (e.g., no advanced fibrosis, normal ALT levels, viraemia between 2000 UI/mL and 20000 IU/mL), discontinuation of therapy until delivery might be a viable option, as long as an adequate monitoring is carried out to re-start immediately treatment if necessary. Eventually, another matter of concern is the management of HBV resistance cases: In pregnant women there is limited experience, nonetheless, in gravid subjects experiencing treatment failure (HBV DNA rebound) under LAM or LdT, switching to TDF appears a safe and effective option. In Figure 2 the current knowledge regarding the treatment of HBV infection in pregnant women is summarized.
Figure 2 Treatment of acute and chronic hepatitis B in pregnancy.
The column marked by the red circle refers to interventions that are not allowed. The column marked by the yellow circle refers to interventions that are backed up by low-quality or conflicting evidence. The column marked by the green circle refers to the best practice according to current evidence. IFN: Interferon; NA: Nucleos(t)ide analogue; LAM: Lamivudine; TDF: Tenofovir disoproxil fumarate.