Optimal management of HBV infection during pregnancy

Authors

  • Teerha Piratvisuth

    Corresponding author
    • Department of Medicine, NKC Institute of Gastroenterology & Hepatology, Prince of Songkla University, Hat Yai, Thailand
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Correspondence

Teerha Piratvisuth, NKC Institute of Gastroenterology & Hepatology, Songklanagarind Hospital, Hat Yai 90110, Thailand

Tel: + 66 74 451966

Fax: + 66 74 429 436

e-mail: teerha.p@psu.ac.th

Abstract

Chronic hepatitis B virus (HBV) infection in pregnancy presents a unique and important challenge. Over 50% of chronic HBV carriers in endemic areas acquire infection vertically from their mothers. More importantly, over 90% of perinatally acquired infections progress to chronic HBV infection. Thus, management of chronic HBV during pregnancy and strategies to prevent mother-to-child transmission is an important step in eradicating or reducing the global burden of chronic hepatitis B. In addition, chronic HBV infection in pregnancy presents a unique clinical challenge because of the complex relationship between the physiological changes of pregnancy and the pathophysiological response to HBV. This review will present the current knowledge and a practical approach to management of HBV in pregnancy.

Abbreviations
HBV

hepatitis B virus

HBIG

hepatitis B immunoglobulin

MTCT

mother to child transmission

Chronic hepatitis B virus (HBV) infection in pregnancy is an important global health problem. Over 50% of the 350 million chronic hepatitis B carriers acquire their infection perinatally [1, 2]. Without immunoprophylaxis, infants born to HBeAg-positive mothers have a 40–90% risk of vertical transmission [3]. The risk of progression to chronic HBV infection is inversely proportional to the age at infection. Between 85 and 95% of infected infants develop chronic infection, whereas less than 5% of those who acquire infection during adulthood develop chronic infection [3-6]. Women of childbearing age with chronic HBV infection remain an important source of HBV transmission. Thus, the management of chronic HBV infection during pregnancy is an important opportunity to interrupt the perinatal transmission of HBV.

Because of the complex relationship between the physiological changes of pregnancy and the host immunological response to HBV, chronic HBV infection in pregnancy is a unique challenge [7]. This review will provide an optimal approach to a number of issues of HBV management in pregnancy, including the prevention of perinatal transmission and the treatment of chronic hepatitis B in pregnancy.

Influence of hepatitis B virus infection on pregnancy

Hepatitis B virus infection does not significantly influence fertility or conception unless the patient has cirrhosis or liver failure [8]. Moreover, HBV infection during pregnancy does not increase maternal or fetal morbidity and mortality. A study comparing 824 HBsAg-positive mothers to 6281 HBsAg negative but otherwise similar control mothers, found no difference in preterm delivery, birth weight, neonanatal jaundice, congenital anomalies or perinatal mortality [9]. However, a recent case-control study showed that HBsAg-carrier mothers had an increased risk of gestational diabetes mellitus, antepartum haemorrhage and threatened preterm labour [10]. This may be because a proportion of mothers with HBV-related active disease were included in the study. Chronic hepatitis B is associated with increased levels of proinflammatory cytokines [11, 12]. These systemic inflammatory responses may account for the adverse outcomes of pregnancy [13].

Pregnant women with cirrhosis have an increased risk of developing significant perinatal complications and having poor pregnancy outcomes [14]. Pregnant women with cirrhosis have a higher spontaneous abortion rate, 30– 40% compared to 15– 20% in the general population [8, 15]. Pregnant women with cirrhosis also have higher rates of maternal complications, including gestational hypertension, placental abruption and peripartum haemorrhage compared to age-matched controls [16]. Hepatic decompensation has been reported in 15% of mothers with liver disease [16].

Effects of pregnancy on hepatitis B virus-related liver disease

There is usually no worsening of liver disease during pregnancy. However, cholestasis, a chronic hepatitis B flare and liver failure have been rarely reported during pregnancy [14, 17, 18]. A normal pregnancy is associated with high levels of adrenal corticosteroids and oestrogen hormones resulting in increased HBV viraemia [7]. These hormonal and cytokine changes can lead to minimal fluctuations in liver function tests. Serum alanine aminotransferase (ALT) tends to increase in late pregnancy and the postpartum period [19]. Peripartum hepatitis flares leading to hepatic decompensation have been reported [17].

Risk of perinatal transmission of hepatitis B virus

Vertical transmission of HBV infection is the main source of chronic infection in endemic areas. As many as 90% of infants who acquire HBV infection from their mothers fail to clear the infection and develop chronic infection [14]. Risk factors for mother to child transmission (MTCT) include both viral and host or maternal factors. In the clinical setting, HBeAg is used as an index for active viral replication and infectivity. Maternal HBeAg may be filtered through the placenta [20, 21]. Although HBeAg is detected in up to 70% of neonates, only 10% of these infants are actually infected at birth [22]. Without HBV viraemia, most of these infants will clear HBeAg by 6 months of age [22]. In the absence of immunoprophylaxis, the risk of MTCT of HBV infection is as high as 70–90% in infants born to HBeAg-positive mothers, and 10–40% for infants born to HBeAg-negative mothers [14, 23]. Serum HBV DNA levels are the most important independent risk factor for MTCT [24-28]. Results of studies on the effect of HBV genotype in MTCT have been conflicting and are still inconclusive [29-31].

Maternal factors are mainly related to the placenta. Prolonged uterine contractions during normal labour or threatened preterm labour may disrupt the placenta or result in transplacental leakage leading to maternal-fetal microtransfusions, thus increases the risk of MTCT [25, 28]. A first stage of labour of more than 9 h is associated with HBsAg positivity in cord blood [28]. Mothers with a prior infant who failed immunoprophylaxis have a higher risk of transmitting HBV to their infants in subsequent pregnancies [32].

Mode of mother to child hepatitis B virus transmission

Intrauterine transmission

Hepatitis B virus can reach the fetus through the placental barrier; however, the impact of this mode of vertical transmission is not clear. Detection of HBsAg in cord or peripheral blood of newborns has been reported in 37% of those born to HBsAg-positive mothers [33]. However, HBsAg positivity at birth did not predict subsequent HBV infection at 18 weeks or at 2 years of age [33]. A Chinese study found that only 3.7% of babies tested HBsAg-positive at birth from intrauterine infection [25]. Thus, intrauterine transmission is not the predominant mode of MTCT [14, 43]. However, intrauterine transmission cannot be prevented by HBV vaccine or HBIG given at birth, which is one important reason for the failure of immunoprophylaxis [35]. HBV infection is transmitted to the placenta by a hematogenous route, then HBV spread in placental cells is cell-to-cell [35, 36]. Increased uterine contractions during a threatened abortion or threatened preterm labour can cause partial leakage of maternal blood into fetal circulation leading to HBV infection to the fetus [37-39].

Transmission during delivery

Transmission during delivery is the most frequent route of MTCT of HBV. Thus, the neonatal administration of HBIG and HBV vaccination can prevent HBV infection in more than 85% of the infants born to HBsAg-positive mothers [40]. The mechanisms of HBV transmission may include micro-transfusion of mother's blood to the fetus during contractions, infection after the rupture of membranes and direct contact of the infant's mucosal membrane with the infected secretions or blood from the maternal genital tract [41]. HBsAg is detected in 95% of the gastric fluids of infants born to HBV–infected mothers [34].

Post-partum transmission

A total of 34% of infants born to HBeAg-positive mothers who are not infected at birth will acquire HBV infection in the next 6 months [14]. Hepatitis B virus transmission in the post-partum period may be a result of close contact between the mother and baby [40, 42]. Breastfeeding is a major concern for transmission either through ingestion of HBV or by contact with skin lesions on the mother's breast milk samples [28, 43, 44]. However, several studies have shown that breastfeeding carried no additional risk of HBV transmission [45-48].

Strategies to prevent MTCT HBV transmission

Antepartum

Hepatitis B immunoglobulin (HBIG) injection

Previous studies have shown that HBIG given at the antepartum stage could induce a > 2 log10 decline in maternal HBV DNA with a modest reduction in MTCT rates [49-51]. However, a recent large controlled study showed that antepartum HBIG was not effective in preventing MTCT [52]. Therefore, this strategy is not currently recommended.

Antiviral therapy in pregnancy

Early studies by Beasley et al. have shown that HBIG administration to newborns could reduce the rate of HBV transmission from >90% in HBeAg-positive mothers to approximately 26% [53, 54]. When combined with the HBV vaccine, the rates of transmission fell to 3–7% [55, 56]. However, unsuccessful immunoprophylaxis leading to MTCT has been reported in 8– 32% of infants born to HBeAg-positive mothers with high HBV DNA levels [24, 57]. A serum HBV DNA > 8 log10 copies/ml was considered to be the level of viraemia resulting in unsuccessful immunoprophylaxis [24, 30]. A recent study showed that all cases of unsuccessful immunoprophylaxis were born to mothers with HBV DNA levels ≥ 6 log10 copies/ml [26]. Antiviral therapy has been studied to prevent MTCT of HBV in mothers with high serum HBV DNA levels. All current oral anti-HBV drugs are FDA pregnancy category C, except telbivudine and tenofovir disoproxil, which are pregnancy category B drugs (Table 1). In a pilot study, eight pregnant women with HBV DNA levels >10[9] copies/ml were given lamivudine at week 34 of gestation. All newborns received HBIG and a vaccine at birth. Only one infant acquired HBV infection compared to 7/25 (28%) in matched historical control mothers [58]. A randomized, double-blind placebo-controlled trial of lamivudine to prevent the transmission of HBV in highly viraemic HBeAg-positive mothers showed significantly lower rates of MTCT infection of 18% at 1 year old compared to 39% in placebo-treated mothers [57]. However, 13% of infants in the lamivudine group and 31% in the placebo group were lost to follow-up and the transmission rates were not significantly different when only those with complete data were evaluated (6% lamivudine vs 12% placebo, P = 0.37). Two recent meta-analyses showed that lamivudine treatment from 24 to 32 weeks of gestation until delivery and 1 month post-partum was safe and more effective than HBIG and a vaccine in preventing MTCT of HBV, but only if HBV DNA was < 6 log10 copies/ml [59, 60].

Table 1. FDA pregnancy categories for hepatitis B virus antiviral therapy
Pregnancy categoryFDA descriptionHBV therapy
  1. FDA, Food and Drug Administration.

AAdequate and well controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters) 
BAnimal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women or animal studies that have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimesterTelbivudine Tenofovir
CAnimal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well controlled studies in humans, but potential benefits might warrant use of the drug in pregnant women despite potential risksLamivudine Entecavir Adefovir
DThere is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits might warrant use of the drug in pregnant women despite potential risks 
XStudies in animals or humans have demonstrated fetal abnormalities, and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefitsInterferon

A small study of telbivudine in 31 HBeAg-positive Chinese pregnant women (treatment was begun between 28 and 32 weeks of gestation until 1 month post-partum), showed a significant reduction in HBV DNA from 7.38 log10 copies/ml at baseline to 4.08 log10 copies/ml prior to parturition [61]. All newborns received HBIG and vaccine at birth. None of the infants born to telbivudine-treated mothers acquired HBV infection compared to 13.3% of infants born to untreated controls. In a large prospective open label study in 229 mothers with HBV DNA levels >1.0 × 10 [7] copies/ml, telbivudine 600 mg was given daily from 20 to 32 weeks of gestation in 135 mothers, while 94 mothers served as controls [62]. Telbivudine treatment was stopped in mothers in the immunotolerant phase after 1 month post-partum, while the other mothers with elevated ALT at baseline continued to take telbivudine or another commercially available HBV therapy. All the infants were given HBIG and HBV vaccine within 12 h post-partum. Prior to delivery, all telbivudine-treated mothers had >3 log10 decline in HBV DNA levels, whereas the viral load in untreated mothers remained unchanged. At 7 months of age, the incidence of perinatal transmission was lower in the infants born to telbivudine-treated mothers and who completed follow-up than that in untreated controls (0% vs 8%; = 0.002). No serious adverse events were noted in telbivudine-treated mothers or their infants. In a recent meta-analysis of two randomized controlled trials and four non-randomized controlled trials with a total of 576 mothers [63], 306 mothers received telbivudine treatment and 270 served as controls. The study showed that telbivudine given in late pregnancy is effective in preventing or reducing perinatal HBV transmission with no significant adverse effects [63].

Because of its potency tenofovir is expected to be at least as effective as lamivudine and telbivudine in reducing the MTCT of HBV. Tenofovir has been used by pregnant women for HIV infection with no evidence of increased congenital malformations, renal impairment, abnormal bone metabolism or impaired growth in children exposed to tenofovir in utero [64]. In a recent small study in 11 highly viraemic HBAg-positive Asian women, tenofovir was given at a median gestational age of 29 weeks and the median duration of tenofovir use before delivery was 10 (7–12) weeks [65]. All infants were HBsAg negative 28–36 weeks after birth.

Safety data on HBV antivirals during pregnancy come from two major sources, the antiretroviral pregnancy registry (APR) [67] and the Development of AntiRetroviral Therapy Study (DART) [68]. There was no significant difference in the rate of adverse outcomes reported if an HBV antiviral drug was initially used in the first trimester (3.0 and 2.1%) compared to the second or third trimester (2.5 and 2.1%) of pregnancy. These rates compare favourably to the background 2.72% rate of defects in the general population reported by the CDC birth defect Surveillance System (Table 2). In one study, 42% of mothers who did not receive antiviral therapy during pregnancy had an ALT flare in the post-partum period compared to 62% in those who were treated and then discontinued therapy after delivery [7]. In two large telbivudine studies, none of the mothers who discontinued telbivudine 1 month post-partum had severe hepatitis (defined as serum ALT > 10 × ULN) [62].

Table 2. Antiretroviral pregnancy registry data
Proportion of defects reported with an exposure toEarliest trimester of exposure
First trimester birth defects/live birthsSecond/third trimester birth defects/live births
  1. Nus in pregnancy safety data.

Lamivudine122/3966 (3.1%)178/6427 (2.8%)
Tenofovir27/1219 (2.2%)15/714 (2.1%)
Telbivudine0/80/9
Adefovir dipivoxil0/430/0
Entecavir1/300/2
Any NRTI165/5582 (3.0%)216/7772 (2.5%)
Any NtRTI27/1262 (2.1%)15/712 (2.1%)

At the peripartum stage

Method of delivery

A study of 301 infants born to HBsAg-positive mothers showed no difference in the rates of HBsAg positivity at birth between the three different modes of delivery; 8.1% in spontaneous vaginal delivery, 7.7% invacuum extraction or forceps and 9.7% in Caesarean section [66]. The rates of chronic HBV infection were also similar for the different modes of delivery [66]. Significant evidence in a recent meta-analysis of four randomized trials with 789 mothers showed that elective Caesarean delivery effectively reduced the MTCT of HBV compared to vaginal delivery (transmission rates: 10.5% for elective Caesarean vs 28% for vaginal delivery) [41]. In a recent, large retrospective study of 569 HBeAg-positive mothers with HBV DNA > 6 log10 copies/ml, unsuccessful immunoprophylaxis was significantly reduced to 2.1% by elective Caesarean at 7–12 months after birth compared to 5.9% by vaginal delivery [68, 69]. Thus, elective Caesarean delivery plays a role in reducing MTCT of HBV in highly viraemic HBeAg-positive mothers.

At the post-partum stage

Most guidelines and WHO recommend that infants born to HBsAg-positive mothers receive both HBIG and the HBV vaccine within 12 h after birth [40]. This should be followed by at least two more doses of HBV vaccine within the first 6 months of life. Combining HBIG and at least 3 doses of HBV vaccine is more effective in reducing MTCT than HBIG or the HBV vaccine alone [56, 70]. After the vaccine protocol is completed, HBsAg and antiHBs should be tested by 9 months of age. HBsAg-negative infants with antiHBs levels >10 mIU/ml are protected and no further medical management is required.

Breastfeeding

With appropriate immunoprophylaxis, breastfeeding of infants by mothers with chronic HBV does not represent any additional risk of MTCT of HBV [45-48]. Hill et al. found a similar infection rate in breast-fed and formula-fed infants (0% vs 3%). A recent meta-analysis of 1624 infants confirmed that breastfeeding did not increase the risk of MTCT [71]. In addition, immunoglobulins and other proteins such as lactoferrin in the breast milk have antiviral properties [72]. Because of the many benefits of breastfeeding, WHO recommends breastfeeding even in infants of HBsAg-positive mothers in endemic areas where the HBV vaccination is not readily available [43, 73]. Breastfeeding is not recommended for mothers on antiviral therapy [74]. All antiviral drugs must be discontinued in the mother 1 month post-partum to limit exposure of the infant to these drugs through the breast milk. Mothers should be monitored with serial ALT and HBV DNA levels to detect hepatitis flares owing to treatment discontinuation, which may require treatment.

Conclusion

Hepatitis B in pregnancy is not only a unique challenge but also an important opportunity to prevent perinatal transmission of HBV. As maternal-fetal transmission is the major route of HBV transmission, strategies to reduce the global burden of disease must target this critical step in the propagation of HBV. The management of HBsAg-positive pregnant women and infants born to these mothers are summarized in the algorithm (Fig. 1). Early recognition of HBsAg-positive pregnancies followed by treatment with safe antiviral agents between the second and third trimester in highly viraemic mothers as well as proper immunoprophylaxis will reduce perinatal HBV infection, while minimizing the risk in infants.

Figure 1.

Algorithm for management of hepatitis B virus during pregnancy. * Individual consideration after a discussion on risk and benefits with mother.

Disclosure

The author has no disclosure.

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