Best Practice & Research Clinical Obstetrics and Gynaecology 68 (2020) 54e65

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Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Hepatitis Bdmanagement of acute infection and

active inflammation in pregnancyda
hepatologist's perspective
Grace Lai-Hung Wong a, *, Wan-Hsin Wen b, Calvin Q. Pan c
a
The Chinese University of Hong Kong, Hong Kong SAR, China
b
Fu-Jen Catholic University and Cardinal Tien Hospital, New Taipei City, Taiwan
c
New York University, New York City, United States

a b s t r a c t
Keywords:
Acute hepatitis Women at childbearing age and pregnant ladies living in the areas
Chronic hepatitis of high or intermediate prevalence of hepatitis B virus (HBV)
Hepatitis B virus remain at risk of getting the infection and passing the infections to
Mother-to-child transmission their offspring via mother-to-child transmission (MTCT) of HBV.
Pregnancy HBV infection may affect the mothers by active hepatitis, very
Tenofovir disoproxil fumarate
occasionally liver cirrhosis and rarely fulminant hepatitis and liver
failure. The virus may be transmitted to the babies despite
immunoprophylaxis in the setting of very high maternal viral load.
Tenofovir disoproxil fumarate (TDF) has been shown to be effica-
cious to reduce MTCT of HBV, which contributes to the elimination
of chronic HBV infection by 2030, the goal set by World Health
Organization.
© 2020 Published by Elsevier Ltd.

Introduction

Hepatitis B virus (HBV) infection is a significant public health problem worldwide and a major
cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). HBV infection occurs
worldwide; the areas of highest prevalence are China, Southeast Asia, sub-Saharan Africa, and Alaska
[1]. Almost 50% of the world's population live in these regions, where the prevalence of hepatitis B

* Corresponding author. Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital, Shatin, Hong Kong.
E-mail address: wonglaihung@cuhk.edu.hk (G.L.-H. Wong).

https://doi.org/10.1016/j.bpobgyn.2020.03.014
1521-6934/© 2020 Published by Elsevier Ltd.
 G.L.-H. Wong et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 68 (2020) 54e65 55

surface antigen (HBsAg), a serological marker of chronic infection, can exceed 8% in some areas [2].
Another 40% of the world's population live in areas with intermediate prevalence (3%e5%), such as
Japan and India. In low-prevalence areas, such as the United States, Western Europe, and Australia,
the rate of HBsAg positivity is 0.1%e2%. In endemic areas, most infections occur in children, whereas
in areas of low seroprevalence, most infections occur in adults [3]. World Health Organization (WHO)
published the first global health sector strategy on viral hepatitis in June 2016, a strategy that con-
tributes to the proposed targets for the reduction of chronic viral hepatitis incidence and mortality of
80% and 65%, respectively, by 2030 [4].
With this background, women at childbearing age and pregnant ladies living in the areas of high
or intermediate prevalence would be at risk of getting the infection. Fortunately, since the
implementation of universal vaccination in 1980s, together with public health measures to educate
the general public on transmission risks, the number of cases of acute HBV infection has declined
substantially in recent years [2]. The incidence of acute HBV infection has declined dramatically in
the United States from 11.5 cases per 100,000 population in 1985 to 1.5 per 100,000 population in
2007 [5]. This decline has been attributed to the implementation of the universal vaccination
program.
Acute HBV infection during pregnancy was previously a common reason for abnormal maternal
liver transaminase; in recent years, vaccination programs have significantly reduced this risk [6]. If
acute HBV infection occurs, the likelihood of transmission to the infant is dependent on the timing of
the infection, which is highest when mothers acquire HBV in the third trimester. It is recommended
that all pregnant women undergo screening for HBV by checking the HBsAg, which is now part of the
routine antenatal checkup. Women who report never receiving HBV vaccination may be tested for
hepatitis B surface antibody (anti-HBs); if negative, women who are neither HBsAg carriers nor have
the immunity should receive HBV vaccination [7]. This is especially important for those women at high
risk for acquisition of HBV [8]. For women with no previous HBV immunization and no evidence of
prior infection, an HBV vaccination series should be initiated. A proposed accelerated protocol should
establish a high level of immunity early in the pregnancy [9]. All women with negative HBsAg, and who
qualify as having a high-risk lifestyle, should be retested for HBsAg at 28 weeks and again at time of
delivery admission [10].
Acute HBV infection and active inflammation would not only affect mothers' health and hence fetal
outcomes; but it also increases the risk of mother-to-child transmission (MTCT) of HBV, a major route
of transmission in the regions of high HBV prevalence, if the acute infection occurs later in gestation.
Recent clinical studies demonstrated the beneficial effect of antiviral therapy with tenofovir disoproxil
fumarate (TDF) for highly viremic HBsAg-positive mothers (HBV DNA >200,000 IU/mL) can signifi-
cantly reduce MTCT, which is recommended in the third trimester from 28 weeks of gestation onward.
TDF may be discontinued within a few weeks postpartum if the mothers do not have treatment
indication otherwise. The current review summarizes the latest evidence of various aspects about the
management of acute infection and active inflammation in pregnancy from a hepatologist's
perspective.

Impact of HBV infection on pregnant women

Impact on mothers

In general, acute HBV is uncommon in the era of universal HBV vaccination. Yet the recent opioid
epidemic has brought with it a resurgence of acute HBV infection in pregnant women, with approxi-
mately 1000 new cases of chronic HBV infection in infants born of HBV-infected mothers identified
annually in the United States [11]. For diagnosis of acute HBV infection, HBV IgM anti-core antibody
(anti-HBc) must be obtained; if positive in persons with no known chronic HBV infection, acute HBV
infection is confirmed (Table 1). As pregnant women who become acutely infected with HBV may be
more likely to develop chronic HBV infection due to the immunologic changes that occur during
pregnancy (see below) [12].
56 G.L.-H. Wong et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 68 (2020) 54e65

Table 1
Interpretation of HBV serology.

HBsAg Ant-HBs Anti-HBc IgG Anti-HBc IgM HBeAg Anti-HBe

No immunity, susceptible Negative Negative Negative Negative Negative Negative

Immunity due to HBV vaccination Negative Positive Negative Negative Negative Negative
Resolved HBV infection Negative Positive Positive Negative Negative Positive
Chronically infected Positive Negative Positive Negative Positive/Negative Negative/Positive
Chronically infected, highly viremic Positive Negative Positive Negative Positive Negative
Acutely infected Positive Negative Positive Positive Positive Negative

HBsAg ¼ hepatitis B surface antigen; HBcAb ¼ hepatitis B core antibody; HBeAg ¼ hepatitis B e antigen; HBeAb ¼ hepatitis B e
antibody; HBsAb ¼ hepatitis B surface antibody; HBcAb ¼ hepatitis B core antibody (IgM and IgG).

The clinical picture of acute HBV infection in pregnant women is not distinguishable from that in the
general population [13]. There is no difference with regard to mortality and incidence of fulminant
hepatitis between pregnant ladies and non-gravid women [14]. Acute HBV infection is commonly
managed with supportive care, and antiviral therapy has not been shown to have an impact on the
course of the disease [15]. Patients should be monitored closely with liver biochemistries and pro-
thrombin time. They should be evaluated for mental status changes that could signal the development
of a fulminant hepatitis, which would warrant urgent referral for liver transplantation [16]. Luckily,
pregnant women are less prone to develop fulminant hepatitis due to the immune modulation of
pregnancy. Indications or criteria for liver transplantation in pregnancy are generally similar to those in
non-pregnant patients. The gestation at diagnosis mainly affect the timing of delivery; delivery be
expedited whenever possible before liver transplantation. Depending on the age of gestation and the
viability of the fetus, continuation or termination of the pregnancy must be tactfully discussed with the
patient.
Development of an acute HBV infection during pregnancy has been associated with gestational
diabetes, increased postpartum hemorrhage, preterm delivery, and low birth weights [17e19]. Hence,
we recommend to check clotting profile for once at least during acute HBV infection, and to be repeated
if there is coagulopathy to start with, or hepatitis is getting worse. Vitamin K should be given if in-
ternational normalized ratio (INR) > 1.5, while fresh frozen plasma is reserved for patients who have
clinical bleeding or before invasive procedures (including delivery). Short-term use (7 days or shorter)
of corticosteroid in case of preterm labor/delivery, irrespective of the dosage is generally very safe; yet
if prolonged corticosteroid is anticipated, TDF would prevent HBV reactivation in the pregnant women.
The risk of MTCT of HBV is dependent on the timing of the exposure and highest in the third trimester
of pregnancy. Although there is a 10% likelihood of transmission to the newborn if maternal infection
occurs in the first trimester, the risk of HBV transmission is as high as 60% if exposure occurs in the third
trimester [20].
In HBV-infected pregnant women with advanced fibrosis, initiation and/or continuation of antiviral
therapy is mandatory to prevent episodes of acute exacerbation of HBV and/or decompensated liver
disease [10]. Pregnancy in patients with cirrhosis occurs rarely as advanced liver disease frequently
occurs later in life, more often after the end of reproductive years. Pregnant women with compensated
cirrhosis there may not be significant increased risks; however, for those women with decompensated
HBV cirrhosis, unique risks exist throughout their pregnancy and include higher rates of spontaneous
abortion, fetal prematurity, life-threatening variceal bleeding, liver failure and decompensation, and
postpartum hemorrhage [21]. In addition, the course of HCC develop during pregnancy is much more
aggressive, with poor outcomes likely [22].

Impact on fetus

HBV-infected mothers transmit the virus to their children. Maternal transmission leads to more
severe morbidity and mortality than horizontal transmission because chronic infection, which lasts for
decades, develops in ~95% of those who acquire HBV in neonatal period [23]. Most maternal trans-
mission occurs during labor and delivery when the infant encounters infected maternal secretions and
 G.L.-H. Wong et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 68 (2020) 54e65 57

blood. Timely immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and vaccine after birth
prevents ~90% of mother-to-infant transmission [24,25]. However, despite immunoprophylaxis, a small
proportion of infants are still infected. The causes of immunoprophylactic failure include: (i) intra-
uterine infection, which cannot be prevented by immunoprophylaxis after birth; (ii) breakthrough
infection occurring at perinatal period (i.e. HBV infection despite immunoprophylaxis as the maternal
viral load was too high); and rarely, (iii) postnatal infection, occurring in a small number of children
who have inadequate antibody response to neonatal immunoprophylaxis [26,27].
The most important risk factor for HBV transmission is maternal viral load [27]. With appropriate
immunization by HBIG and vaccine, the rate of mother-to-infant transmission decreased from 80e90%
to 5e10% in infants born to mothers with positive hepatitis B e antigen (HBeAg), which indicates high
viral load [27e29]. To further reduce transmission, the latest professional organization guidelines
recommend highly viremic pregnant women with stable HBV disease activity to receive short-term
antiviral therapy starting in the second or third trimester, ranging from 24 to 32 weeks of gestation
[10,30,31]. The eligibility criterion of maternal viral load for antiviral therapy ranges from 200,000 IU/
mL [10,30] to 6e7 log10 IU/ml [31]. The nucleos(t)ide analogs that have been used in HBV-infected
pregnant women to prevent transmission include lamivudine, telbivudine, and TDF, which is
preferred owing to its efficacy and safety [32]. For mothers who have no other indications for
continuing antiviral therapy, the nucleos(t)ide analogs used to prevent transmission is suggested to
stop at delivery or within 12 weeks postpartum [10,30,31]. Clinical trials of antiviral therapy during late
pregnancy in highly viremic mothers showed that the rate of mother-to-infant transmission, assessed
by infant's HBsAg seropositivity at 6e9 months of age, was significantly lower in TDF group than that in
control group (0%e2% vs 7%e20%) [26,33,34].
Procedures or conditions related to maternalefetal hemorrhage, such as threatened preterm labor,
chorionic villus sampling, amniocentesis, and emergent cesarean delivery, have been reported to in-
crease the risk of mother-to-infant transmission [35,36], especially in those mothers with high viral
load [37,38]. When invasive procedures during pregnancy are indicated in mothers with HBV DNA >7
log10 IU/ml, the risk mother-to-infant transmission should be notified and non-invasive procedures
should be considered to minimize the risk of transmission [39,40]. Elective cesarean delivery may have
a potential role to reduce transmission in highly viremic mothers [37]. However, elective cesarean
delivery is not recommended solely for HBV prevention, according to the practice guidelines from
leading professional organizations [10,39,40].
The safety of mothers and children with exposure to antiviral therapy during pregnancy is an
important issue. Most studies of antiviral therapy during pregnancy to prevent mother-to-infant HBV
transmission reported short-term outcomes no longer than 1 year after delivery. A systematic review
and meta-analysis of antiviral therapy in pregnant HBV-infected women concluded that the use of
lamivudine, telbivudine, and TDF is safe in pregnancy with no increased adverse maternal complica-
tions, such as postpartum hemorrhage, cesarean section, and elevated creatinine kinase rates, and with
no increased adverse fetal outcomes, such as congenital malformation and prematurity rates [32]. Data
from HBV-infected adults showed that decreases in bone mineral density and renal function impair-
ment could occur after long-term use of TDF [41,42]. A newly published long-term follow-up study
demonstrated that children of HBV-infected mothers with and without TDF treatment during late
pregnancy had comparable growth, renal function, and bone development up to 6e7 years after de-
livery [43].
In addition to mother-to-infant transmission, some studies reported associations between maternal
HBV infection and adverse neonatal outcomes, such as preterm birth and small for gestational age
[44,45]. Other studies had inconsistent results [46,47]. A meta-analysis including 22 studies with over 6
million pregnant women showed that chronic HBV infection was significantly associated with a 16%
increase in the risk of preterm birth, although substantial heterogeneity was found among the studies
included [48].

Impact of pregnancy on HBV infection

Pregnancy results in many physiologic changes, has multi-organ effects, and is an immune-tolerant
state. It is associated with significant hormonal changes, including an increase in estrogen,
58 G.L.-H. Wong et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 68 (2020) 54e65

progesterone, and adrenocorticoids [49]. During pregnancy, the maternal immune system adapts to
tolerate external antigens and allow for the development of the semi-allogenic fetus [50]. Overall, pro-
inflammatory processes decrease, whereas anti-inflammatory processes increase during pregnancy
[51]. These changes are required for proper implantation and growth of the placenta, allow for the
development of maternalefetal interface, and help avoid rejection of the developing fetus. The natural
course of HBV infection, however, may be impacted due to these immunologic changes.
HBV DNA flares were observed in 9% of the patients during pregnancy and 4% during postpartum.
Hepatitis flares (raised transaminases) were observed in 6% during pregnancy and 10% within the first
3 months of delivery. Hepatitis flares were generally asymptomatic, but rarely patient may develop
hepatic decompensation associated with the flare. It is generally reported that alanine aminotrans-
ferase (ALT) levels increase during late third trimester or early postpartum [21]. About 50% of ALT flares
were observed during the second trimester or earlier. Clinical parameters such as HBV DNA, ALT, age,
HBeAg positivity, gravida, and parity were not identified as predictors of hepatitis flares in both uni-
variate and multivariate analyses [52].
Despite the fact that more than 95% of adult-acquired acute HBV infection will not turn into chronic
infection [53], it may be different if the acute HBV infection happens during pregnancy. The increase in
steroid hormones seen early in pregnancy results in depressed cell-mediated immunity. Animal studies
have demonstrated that estrogen and progesterone have a detrimental effect on T-cell development,
both in number and activity [12]. This may explain why loss of HBsAg in pregnant women acutely
infected with HBV is less likely than that observed in non-pregnant women. Pregnancy is a risk factor
for the development of chronic HBV infection if an acute exposure to HBV occurs [14].
HBsAg-positive pregnant women, including both treated and untreated, should be monitored for at
least 6 months postpartum for hepatitis flares and seroconversion [52,54]. The American Association
for the Study of Liver Diseases (AASLD) suggests that HBV-infected pregnant patients with cirrhosis
should be managed in a tertiary care center where high-risk obstetric services are readily available.

Treatment for HBV infection

Acute HBV infection in pregnancy

In adult patients, it is estimated that acute hepatitis B infection occurs in 1.5 cases per 100,000 in the
US general population [55]. However, the incidence could be underestimated if asymptomatic in-
fections were not taken into account as well. Although the incidence was reported higher among
persons aged 25e44 years (2.9 cases per 100,000 populations), the male-to-female ratio of cases
remained stable (1.5e1.8) in the last two decades [55]. The majority of adult patients acquired their
infection through high-risk behaviors, such as intravenous use of recreational drugs or unprotected
sexual intercourse. For a woman who is negative for both HBsAg and anti-HBs while her partner is
HBsAg-positive, we recommend to use condom whenever they have intercourse. In addition, patients
with the history of alcohol abuse, multiple sex partners, sexual contact with a hepatitis B patient,
history of surgery, and infection with HIV or HCV are considered at risk for acute hepatitis B infection
[55,56]. After exposure to HBV, the incubation period of acute hepatitis B is approximately 4e16 weeks.
Clinical features of acute HBV range from subclinical or anicteric hepatitis (70%), to icteric hepatitis, and
rarely, fulminant hepatitis (<1.5% of patients with acute HBV) [55,57,58]. Among those with icteric
hepatitis, typical presentations include the following non-specific symptoms: fatigue, arthralgia,
change in skin or urine/stool color, poor appetite, nausea, vomiting, and right upper quadrant
discomfort or pain; followed with physical findings of jaundice, rash, rheumatoid-like polyarthritis,
and abnormal liver function tests [59].
The incidence of acute hepatitis B in pregnant mothers is unknown due to the regional difference
and few data exist on this sub-population. Although the natural history and clinical presentations of
acute HBV in pregnant mothers may differ from that of non-pregnant women, there were no significant
differences in mortality and occurrence of fulminant hepatitis between the two groups [14]. During
pregnancy, several studies have suggested that maternal T-cell-mediated immunity is down-regulated
 G.L.-H. Wong et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 68 (2020) 54e65 59

to allow for the tolerance of the genetically different fetus and accommodate the intra-uterus fetal
development [14,60]. Compared with non-pregnant women after acute HBV infection, pregnant
mothers had a significantly lower frequency of fever (febrile hypo-responsiveness phenomenon) due
to the hormone-driven, gestational immune attenuation [61]. Han et al. compared clinical features of
acute HBV infection between 22 pregnant mothers and those of non-pregnant women. They observed
that pregnant mothers had significantly lower ALT (p ¼ 0.015) and GGT levels (p < 0.001), but higher
HBsAg titers (51.7% vs 77.3%, p ¼ 0.03) with lower HBsAg seroconversion rate (40.9% vs 67.8%, p ¼ 0.02)
during acute HBV infection. Also, the mother had higher rates of becoming chronic HBV carriers than
non-pregnant women (18.2% vs 4.6%, p ¼ 0.03) after 7-month follow-ups. These findings further
highlight the suboptimal immune response to HBV infection during pregnancy and subsequent
persistent infection.
Pregnant mothers with symptoms and jaundice from acute hepatitis B should be differentiated from
those who developed gallbladder disease, acute hepatitis A, acute fatty liver of pregnancy, pre-
eclampsia or eclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets
count syndrome). In countries with intermediate and high prevalence of chronic hepatitis B, the acute
reactivation or exacerbation of chronic hepatitis B should also be considered because this may account
for 27e70% of presumed acute hepatitis B in some studies [62,63]. Although clinical and biochemical
features do not help in differentiating the two, the quantitative serum HBV DNA levels and IgM anti-
HBc titers at initial presentation can differentiate patients with a true onset of acute hepatitis B from
patients with the first episode of symptomatic exacerbation of chronic hepatitis B. Extremely high
levels of viremia and anti-HBc IgM (>1:1000) titer are suggestive of an acute HBV infection [62,64].
The resolution of acute hepatitis B involves a complex interplay of innate and HBV-specific adaptive
immune responses from cellular and humoral immunity. In a study by Whalley et al., after a peak viral
load of serum HBV DNA levels nearly 10  log10 copies/ml is attained, the spontaneous clearance of
HBV DNA follows a two- or three-phase decay pattern with an initial rapid decline characterized by a
mean half-life of 3.7 ± 1.2 days [65]. When the diagnosis of acute hepatitis B is confirmed, patients with
mild disease can be monitored in the outpatient setting, as most patients with icteric acute HBV resolve
spontaneously. However, patients should be hospitalized with fetal monitoring if they have dehy-
dration, severe nutritional aberrations, coagulopathy, marked jaundice (serum bilirubin >10.0 mg/dL),
encephalopathy, or renal failure [57,66]. The treatment of acute hepatitis B during pregnancy is largely
supportive for both pregnant mother and fetus and an oral anti-HBV agent is not necessary [66].
The use of an oral anti-HBV agent may be indicated in certain subgroups of patients (Table 2). The
indications include severe diseases such as fulminant hepatitis or evidence of hepatic decompensation,
the protracted course with persistent symptoms or marked jaundice, and the status of immunocom-
promised. HBV DNA level does not always go along with hepatitis activity, in particulars in women in
“immune-tolerant phase,” or now called HBeAg-positive chronic infection phase. If there is active
hepatitis (ALT above two times of upper limit of normal (ULN) and serum HBV DNA above 2000 IU/mL),
TDF should be started irrespective to HBV DNA > 200,000 IU/mL or not. As aforementioned in the
introduction section, acute HBV infection during pregnancy may increase the frequency of MTCT of
hepatitis B. It has been reported the MTCT rates are 10% and 89e90% if acute HBV infection occurs in the
first and the third trimesters, respectively [67]. In the authors’ opinion, it is a reasonable approach to
treat mothers who present with acute HBV infection during the third trimester to reduce the level of
viremia. The recommendation of therapy and treatment duration is also presented in Table 2. Antiviral
treatment is generally not recommended in acute hepatitis B as it does not alter the clinical outcomes;
yet it can also be considered in earlier stages of pregnancy with the hope to reduce pregnancy com-
plications, even though no strong evidence in this regards.

Acute exacerbation of chronic HBV infection

Acute exacerbation of chronic HBV infection is referred to as the acute worsening of hepatic necro-
inflammation with or without impairments of hepatic synthetic functions. Such events are usually
presented with significant elevation of ALT with or without the elevation of total bilirubin and decrease
of albumin levels, as well as prolonged prothrombin time. Rarely, patients with acute exacerbation of
chronic HBV infection may progress to acute or chronic liver failures with poor outcomes. Most clinical
60 G.L.-H. Wong et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 68 (2020) 54e65

Table 2
Treatment Indications with antiviral therapy for HBV during pregnancy.

Hepatitis B Disease Phase Indications for Antiviral Therapy Agents of choice Therapy Duration

Acute hepatitis B
Acute execration of CHB
CHB with cirrhosis
CHB with high risk
for MTCT
1) Pre-existing other liver diseases, TDFa Four weeks or longer, based on
2) Fulminant hepatitis or the individual patient's clinical
encephalopathy; improvement
3) Co-infection with hepatitis C or D
virus;
4) INR >1.6, especially if it is
increasing;
5) Protracted course such as
persistent symptoms or marked
jaundice (bilirubin>10 mg/dL) for
more than 4 weeks after the
presentation;
6) Immunocompromised (HIV or
hemodialysis or diabetic
individuals);
7) Acute HBV during the third
trimester (endorsed by authors for
the reduction of MTCT).
ALT >5 ULN, or any levels of TDFa Entire pregnancy
elevation associated with
impairment of synthetic function,
or any levels of ALT elevation
associated with changes in one of
the following parameters: elevation
of total bilirubin, a decrease of
albumin levels, or prolonged
prothrombin time.
Stage III or IV on previous liver TDF Entire pregnancy
biopsy, or severe fibrosis on non-
invasive assessment, or clinical
cirrhosis.
Maternal HBV DNA levels >200,000 TDF is preferred, Third trimester
IU/mL at the second trimester, or LDT or LAM as the
HBsAg levels >4 log10 IU/mL. second line

CHB ¼ chronic hepatitis B; INR ¼ international normalized ratio; MTCT ¼ mother-to-child transmission; TDF ¼ tenofovir dis-
oproxil fumarate; LDT ¼ telbivudine; LAM ¼ lamivudine.
a
Based on the currently available data on the antiviral efficacy and safety during pregnancy, the authors recommend the use
of TDF as the preferred antiviral for acute hepatitis B or acute exacerbation of chronic HBV infection during pregnancy and
telbivudine or lamivudine as the second-line treatment (not recommended for any patients who had received these nucleosides
previously and have developed drug resistance).

studies define the exacerbation of hepatitis B based on the elevation levels of ALT [34,62,68,69]. Severe
exacerbation was defined as an ALT level that was 5.1e10 times above the ULN, and a serious exac-
erbation as a level of ALT that was more than 10 times the ULN, or any levels of ALT elevation associated
with changes in one of the following parameters: elevation of total bilirubin, a decrease of albumin
levels, or prolonged prothrombin time [34,68,69]. In addition to the acute exacerbation, mothers who
have advanced stages of liver disease due to hepatitis B infection should also be closely monitored and
treated with antiviral therapy [10,70,71].
To assess the liver disease stage in chronic HBV infection patients, it is necessary to combine clinical
findings with non-invasive serum tests or transient elastography (Fibroscan®) for the staging fibrosis
because liver biopsy is not feasible [67]. On the manufacturer website, it mentions that Fibroscan is
contraindicated on pregnant women under the section Examination contraindications [FOR USA ONLY].
Yet this tool has been used in a handful of clinical studies, including a recent longitudinal cohort study
with Fibroscan performed at different stages (weeks 18e20, 26e28, and 36e38) of pregnancy [72]. In
case of any concern about the safety of Fibroscan examination during pregnancy, the pregnant women
may opt for serum tests instead. However, the patient's ALT levels may have effects on the results of
 G.L.-H. Wong et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 68 (2020) 54e65 61

Fibroscan assessment of liver disease severity. Caution is advised on the interpretation of Fibroscan re-
sults when patients' ALT levels have already been elevated. Instead of using the diagnostic cutoff values of
>9 kPa for severe fibrosis in patients with normal ALT, the threshold of >12 kPa should be used for the
diagnosis of severe fibrosis in patients who have abnormal ALT levels elevated and up to 5 ULN [73].
Because the potential risks of disease progression, hepatic decompensation, and increased fetal
complications, antiviral therapy should be considered for the entire pregnancy in mothers with the
following conditions: 1) acute exacerbation of chronic HBV infection during pregnancy; 2) severe
fibrosis which is either determined by non-invasive tests (Fibroscan or serum markers) or stages of
IIIeIV fibrosis on previous liver biopsy report before pregnancy; and 3) clinical signs of cirrhosis. For
other mothers, the treatment for maternal disease may not be indicated even in the situation of mildly
elevated levels of ALT during pregnancy.
Current data support the safe use of TDF, lamivudine, and telbivudine during pregnancy as they are
all pregnancy category B agents and antiviral agents with significant amount of data in the Antire-
troviral Pregnancy Registry [10,30,71,74,75]. Entecavir and adefovir are not recommended for pregnant
mothers due to limited data on safety [70,71]. However, lamivudine and telbivudine are not considered
first-line agents for mothers due to the risk of developing antiviral resistance during pregnancy [10,30].
A meta-analysis by Brown et al. reported that when compared with lamivudine therapy, mothers who
received telbivudine had a higher frequency of HBV DNA levels below the low levels of quantitation and
normalized ALT levels [32]. However, Sheng et al. observed that telbivudine therapy during therapy did
not effectively reduce HBV DNA in 3% of pregnant mothers in the real-world setting, which is likely due
to resistance developed during the course of treatment [76]. In addition, the transient use of either
telbivudine or lamivudine during pregnancy could precipitate issues with resistance in the future.
Published guidelines and consensus recommend TDF as the first-line treatment during pregnancy
as it has great efficacy without any antiviral resistance [10,71,75,77]. Furthermore, TDF is effective even
in patients with lamivudine or telbivudine resistance [10,77]. Among mothers who have already
received antiviral treatment prior to pregnancy, it is recommended that they should continue on
antiviral treatment to prevent the exacerbation of chronic HBV infection during pregnancy [30]. In
addition, interrupting therapy can also trigger ALT flares from medication withdrawal [70]. For the
safety of the fetus, antiviral therapy should be switched to TDF treatment during pregnancy if other
agents were used [30]. During the treatment with antiviral therapy, patients should be monitored with
blood chemistry every 4e8 weeks and serum HBV DNA with serologic testing approximately every 12
weeks until delivery [75].

Impact of antiviral treatment on breastfeeding

Although HBsAg, HBeAg and HBV DNA are present in breast milk, transmission through breast-
feeding is unlikely, especially in infants who received HBIG and vaccine at birth [78]. No difference
exists in the infection rates between in breast-fed versus formula-fed infants of HBV-infected mothers
[79,80]. HBV-infected mothers are encouraged to breastfeed their infants after their infants received
adequate immunoprophylaxis [39,40].
Among the nucleos(t)ide analogs that have been used in HBV-infected mothers to prevent mother-to-
infant transmission, telbivudine has not been studied in nursing mothers so its effect on breastfeeding is
unknown [81]. The data regarding lamivudine and TDF use during lactation are mainly from HIV-infected
mothers. Lamivudine has not been studied in HIV-negative nursing mothers being treated for HBV
infection. Studies of HIV-infected mothers showed that although lamivudine was concentrated in breast
milk, its serum level in breast-fed infants was very low. It indicates that lamivudine is not very efficiently
absorbed through breast milk and the effect of lamivudine on breast-fed infants is small [82,83].
TDF has been used in HIV- or HBV-infected mothers to preventing MTCT and in HIV-negative
women for pre-exposure prophylaxis. TDF could be detected in the breast milk but the concentra-
tions were trivial [83,84]. Breastfed infants were exposed to only 0.5%e16% of the tenofovir dosage that
fetuses experienced via placental transfer, and 0.01%e0.04% of the recommended weight-adjusted
therapeutic dose [85]. Based on these evidences, current professional organization guidelines gener-
ally allow breastfeeding during maternal lamivudine and TDF therapy [10,30,40], although one
guideline cautions against it because of insufficient long-term safety data [31].
62 G.L.-H. Wong et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 68 (2020) 54e65

Conclusion

With growing knowledge in interaction between HBV and pregnancy, the management for women
at risk or infected by HBV, as well as their infants, has been much improved. All infants born to HBsAg-
positive mothers should receive HBIG and HBV vaccine as early as possible, no later than 12 h after
birth. Three doses of HBV vaccine series should be completed according to recommended schedules.
Current guidelines do not recommend elective cesarean delivery for mothers with chronic HBV
infection. Pre-emptive antiviral to highly viremic mothers is proven to reduce MTCT. There is still room
for improvement in identification of HBV infection in pregnant women and continued efforts should be
made for this purpose. Use of antiviral therapy in the third trimester of pregnancy for those highly
viremic HBeAg-positive mothers seems safe and effective. This effect will contribute to the elimination
of chronic HBV infection by 2030, the goal set by WHO.

Practice points

 Screen all pregnant women for chronic hepatitis B by check hepatitis B surface antigen
(HBsAg).
 A reflex test of hepatitis B e antigen (HBeAg) with or without HBV DNA should be consider in
HBsAg-positive pregnant women.
 HBsAg-positive pregnant women should be monitored for active hepatitis, presence of
cirrhosis or sign of decompensation.
 Timely immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and vaccine after birth
prevents around 90% of mother-to-child transmission (MTCT) of hepatitis B virus (HBV)
 Tenofovir disoproxil fumarate (TDF) has been shown to be efficacious to reduce MTCT of
HBV.

Research agenda

 Timing of pre-emptive TDF to prevent MTCT of HBV: second versus third trimester.
 Cost-effectiveness of starting TDF based on serum HBV DNA level versus simply based on
HBeAg status.
 Safety of newer version of tenofovirdtenofovir alafenamide (TAF)din pregnancy.

Funding source

None.

Declaration of Competing Interest

Dr. Grace Wong has served as an advisory committee member for Gilead Sciences, as a speaker for
Abbott, Abbvie, Bristol-Myers Squibb, Echosens, Furui, Gilead Sciences, Janssen and Roche, and
received research grant from Gilead Sciences. Dr. Wan-Hsin Wen declares no competing interests. Dr.
Calvin Pan received grants from Gilead. He also serves as a consultant and a speaker for Gilead.

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