Viral hepatitis vaccination during pregnancy

Abstract

Viral hepatitis is a serious global public health problem. It is also a common cause of jaundice and gestational complications in pregnant women. Moreover, infected mothers can transmit the virus to their fetus or neonate, which may increase disease burden and decrease quality of life. To date, commercial vaccines have been developed for hepatitis A, B, and E and are available to the general population. The Advisory Committee on Immunization Practices currently accepts emergency vaccination against hepatitis A and B during pregnancy due to benefits that overweight the potential risks. While there are limited data from trials with limited numbers of samples that suggest the efficacy or safety of hepatitis B and E vaccines in pregnant women, additional data are necessary to provide evidence of vaccination during pregnancy.

Keywords:

• pregnant women
• vaccination
• viral hepatitis

Introduction

Viral hepatitis, mainly caused by the hepatitis A, B, C, D, and E viruses, is an inflammation of the liver and an important global health challenge. More than 400 million people are estimated to be infected worldwide, and 1.4 million die annually from viral hepatitis.^1,2 Viral hepatitis also causes liver disease during pregnancy, prevention and control of mother-to-child transmission is an important issue for pregnant population.

Vaccination can effectively prevent horizontal and vertical transmission of hepatitis B or C, which directly decreases the global burden of this disease.³ While the inactive vaccines administered to pregnant women are theoretically believed to not increase the risk of adverse outcomes for mothers or fetuses,^4-6 the Advisory Committee on Immunization Practices (ACIP) currently accepts administration of only 2 vaccines (influenza and Tdap [tetanus, diphtheria, and pertussis]) during pregnancy.⁷ The administration of other vaccines to pregnant women should be based on whether the benefits outweigh the risks.⁸ Viral hepatitis vaccination during pregnancy benefits not only the mothers but also developing fetuses owing to passive protection from the mother.³ Therefore, vaccination of susceptible or high-risk pregnant women should be considered.^9,10 The current study reviews data on viral hepatitis vaccination during pregnancy.

Hepatitis A

Hepatitis A virus (HAV) infection is a leading cause of acute hepatitis worldwide. However, this infection is associated with fewer than 2% of hepatitis cases in pregnant women,^11-13 with fewer than 1/1,000 pregnant women infected with acute hepatitis A.^14,15 Chronic hepatitis A infections during pregnancy have not been reported.^14,16 Although HAV infection is not a risk factor for fetal teratogenicity,^17-19 it may cause premature contractions, placental separation, and uterine bleeding, which may lead to preterm delivery .^20,21

Efficacy and safety of HA vaccines

Inactive and live attenuated HA vaccines are used in the general population. Inactive vaccines with a 2-dose schedule, such as Havrix®, Vaqta®, Epaxal®, are effective and safe in children and adults.^22-25 Live, attenuated HA vaccines, such as the H2 strain vaccine, are also reportedly immunogenic and safe for children in China^26-29 and India.^30,31

Several surveys have assessed the safety of inactive HA vaccines before or during pregnancy. One study on the risk of pregnancy outcomes among pregnancies conceived after human papillomavirus virus and HAV vaccination³² reported no obvious evidence to support that HAV vaccination before conception was associated with miscarriage. In the Vaccine Adverse Event Reporting System (VAERS) from 1996 to 2013,³³ severe adverse effects were reported in 4.9% and 6.3% of pregnant women who received HA and hepatitis AB vaccines, respectively; the most common adverse pregnancy outcome was spontaneous abortion. While GlaxoSmithKline also registers data on pregnancy and infant outcomes after administration of the hepatitis AB vaccine, no results have been published.³³ Additional reliable trials and surveys are necessary to explore the effectiveness and safety of inactive HA vaccines in pregnant women.

HA vaccines immunization

Several countries, including the United States³⁴ and China,³⁵ recommend routine HA immunization in children ≥1 year of age, and target vaccination is accepted in high-risk groups,³⁶ such as travelers to regions of intermediate or high endemicity.³³ The ACIP recommends administration of inactivated HA vaccines during pregnancy only if the benefits outweigh the potential risks,^3,7,17,37-39 and inactive HA vaccines during pregnancy should be administered at 0 and 6 months.⁵ However, while the Food and Drug Administration (FDA) categorizes inactive HA vaccines as C-class drugs in pregnant women,⁴⁰ the Global Advisory Committee on Vaccine Safety has not drawn any conclusions about HAV vaccination in the pregnant population.⁴¹ Furthermore, there is a suggestion that immune globulin is considerable during pregnancy to prevent post exposure.^42,43 In the Vaccine Safety Datalink (VSD) project conducted during 2002–2009,⁴⁰ the rate of HAV vaccination was 2.34/1,000 pregnancies, and HA vaccines were mostly administered during the first trimester to women less than 18 y of age, suggesting that the parents or obstetrics and gynecology specialists may not have been aware of the pregnancies at the time of vaccination.^40,44

Hepatitis B

Hepatitis B virus (HBV) infection causes the most severe symptoms, and is a major cause of chronic liver disease, cirrhosis, and liver cancer.⁴⁵ Among pregnant women, hepatitis B is a pre-existing or concurrent liver disease,⁴⁶ and the clinical symptoms in infected pregnant women are similar to those of non-pregnant women.^47,48 HBV infection does not directly threaten maternal or fetal lives;^49-55 however, gestational diabetes mellitus, antepartum hemorrhage, and preterm labor have been reported in chronic carriers.^56-58 The most significant risk of HBV infection during pregnancy is the potential for viral transmission to the fetus or neonate,^7,59-62 which is associated with 4.5 million cases annually.⁶³ More than 90% of neonates with chronic infections received hepatitis B virus from their mothers.^59,64-66 Therefore, prevention of vertical HBV transmission is important.

Efficacy and safety of HB vaccines

There are 2 kinds of Hepatitis B (HB) vaccines: plasma-derived vaccines and recombinant HB vaccines, however, only recombinant HB vaccines are used globally. Recombinant HB vaccines with 3- or 4-dose schedules, such as Engerix-B, are effective and safe for infants^67,68 and adults.^69-71

To our knowledge, no large-scale randomized controlled trials (RCTs) have yet assessed the efficacy and safety of HB vaccines in pregnant women,⁷² likely due to ethical issues.⁸ However, several studies with small numbers of samples have reported the immunity and safety of recombinant HB vaccines^73-80 and Heptavax,^51,61,81 during pregnancy (Tables 1 and 2), and Heptavax has been replaced by the former vaccines since the 1990s.

Table 1. Vaccination characteristics during pregnancy.

Study	Study region/time	Study design (sample size)/follow-up	Vaccinated pregnant women	Vaccination protocols
HB vaccines
Ayoola 1987^61	Nigeria/—	Prospective cohort (V:72,C:86 [including 65 anti-HBs+, 21 HBs-Ag+])/ All (mothers and infants): 12 months after delivery	Age range: 19–27 y; Gestational age: 3^rd trimester	V: Heptavax 20ug/per dose at 0,1month; C: vitamin B at 0, 1 month
Levy 1991^51	Canada/—	Cohort (10)/All: 1 year after delivery	All vaccinated at 1^st trimester	Heptavax
Grosheide 1993^79 ^#	Netherlands/1988–1989	Prospective cohort (16)/ Mothers: 7 months after initial vaccination; infants: 22 months	Mean age: 32.5 y; First dose at the 1^st trimester: 6/16, Fourth dose after delivery: 9/14.	RV 10ug/per dose at 0, 1, 2, and 6 months +HBIG (125 IU/ml) at 0, 1 month
Reddy 1994^172	India/—	Cohort (15)/ All: for 6 months post-delivery	Age range:22–27 y; Gestational age: 2^ndand 3^rd trimester	Heptavax 3 doses at 4–6 weeks intervals
Ingardia 1999^74	America/1996–1997	Retrospective cohort (80)/ mothers: 36–40 week of gestation age	Healthy gravitas; mean age: 23.8 y	RV 20ug/dose at 0, 1, 6 months
Ingardia 1999^75	America/1997	Retrospective cohort (37)/ All: until delivery	Healthy gravidas: HBsAg (−) and HBsAb (−)	RV 20 ug/dose at 0, 1, 6 months
Sheffield 2011^77,78	Texas/2000–2006	Cohort (200)/Mothers: 1–2 months after the third injection	High-risk population;^* Age range: 16–45 y; Gestational age at first vaccination: <25 weeks	RV 0, 1, 4 month
HE vaccine
Wu 2012^162	China/2007–2009	RCT (V:36;C:31)/—	Incidental vaccination	V(HEV239 vaccine): 30 ug/per does at 0, 1, 6 month; C (HB vaccine) at 0, 1, 6 month

Notes.

* Subjects positive for sexually transmitted disease, current injection drug users, or both.

^# Outbreak due to in vitro fertilization treatment.

RV: recombinant HB vaccines; HB vaccines: hepatitis B vaccines; HE vaccine: hepatitis E vaccine.

V: vaccinated group, C: control group.

Table 2. Efficacy and safety of vaccination during pregnancy.

Study	Most common AE/serious AE	Vaccinated pregnancy outcome	Fetal/neonatal outcome	Immunity in vaccinated pregnant women	Transfer of antibodies to neonates
HB vaccines
Ayoola 1987^61	Pain at injection sites: 9/72 (V), 11/86 (C); Severe AE: none	Stillbirth: 1/72 (V), 1/86 (C)	Abnormal birth: none; HBs-Ag (+) at birth: 9/21 born from mothers with HBs-Ag(+)	Anti-HBs (+) at 0, 1 (second injection), 6 month after delivery, 12 month after delivery: 0, 24/72, 61/72, 60/72 (prevalence of anti-HBs was lower than control group (65/86))	Anti-HBs (+) at birth, 1,2,3,6 month: 36/61,28/61,18/61,14/61,3/61 (prevalence of anti-HBs was lower than control group).
Levy 1991^51	Injection pain: 2/10	—	Congenital abnormalities: none; physically and developmentally normal for their ages at 2–12 months	—	—
Grosheide 1993^79^#	Major AE: none	Spontaneous abortion^and: 1/16 (first trimester); congenital defects: 0/16	Growth development at 22 months was normal.	(anti-HBs ≥10 IU/l): At 1, 2, 6,and 7 month after first vaccine dose: 13/14, 15/15, 9/12,11/11	—
Reddy 1994^172		Congenital defects: none; stillbirths: none	—	—	Passive transfer of antibodies to the neonates was 100% at birth, but these levels declined rapidly.
Ingardia 1999^74	—	—	—	(anti-HBs ≥10 mIU/ml): Total: 39/80 = 49%; 3 doses: 7/9 = 77%; 2 doses: 29/64 = 45%	—
Ingardia 1999^75	—	—	—	(anti-HBs ≥10 mIU/ml): Total: 18/37 = 49%; 3 dose: 5/8 = 62%; 2 dose:12/28 = 43%	(anti-HBs≥10 mIU/ml): cord blood:88%
Gupta 2003^73	None	—	—	Rate of non-responders: Group with 2 doses: 8%; Group with 3 doses: 6.2%.	(anti-HBs >15 mIU/ml): Group with 2 doses: 66%; Group with 3 doses: 100%.
Sheffield 2011^77,78	Mild discomfort at injection: 18/168; Severe AE: none	No increase in preterm delivery rates, morbidity/mortality compared to general population	No increased neonatal intensive care admission, morbidity/mortality compared to general population	(anti-HBs ≥10 mIU/ml): 3 dose: 90%; 2 doses: 77%; 1 doses: 56%	—
HE vaccine
Wu 2012^162	Serious AE: none; Pain from injection: 1/36(V)	Elective abortion: 51.3% (V), 41.2% (C); Spontaneous abortion: none	Congenital anomalies: None	HEV infection: none	—

Notes.

* subjects were positive for sexually transmitted disease, current injection drug users, or both.

^# Outbreak due to in vitro fertilization treatment.

^& No evidence to support that adverse pregnancy outcome was related to immunization.

RV: recombinant HB vaccines; HB vaccines: hepatitis B vaccines; HE vaccine: hepatitis E vaccine.

V: vaccinated group, C: control group.

HBV vaccination during pregnancy is reported to be immunogenic,^{61,74-77,79,80} with a passive transfer of antibodies to the fetus.^61,73,81 However, one study with a limited sample size observed lower anti-HBs titers among infants born to women vaccinated during pregnancy than those born to mothers who acquired immunity before pregnancy,⁷⁹ an observation that may suggest that pregnant women should be vaccinated before becoming pregnant. Maternal obesity may also interfere with the efficacy of hepatitis B vaccination in pregnant women.^75,77

Although data are somewhat limited regarding the safety of HB vaccines during pregnancy, none have reported significantly higher adverse outcomes in vaccinated pregnant women than those who did not receive vaccination; moreover, evidence has shown the major adverse effects of injection to be mild and generally limited to a local reaction.^51,77,78 In contrast, one study described adverse pregnancy outcomes in the VAERS database, reporting that approximately 50% of 88 women reported pregnancy complications, including spontaneous abortions, stillbirths, congenital abnormalities, and preterm labor, although the actual number of cases may be underreported.⁸ Overall, the available data do not offer consistent findings regarding the efficacy and safety of HB vaccines during pregnancy.

HB vaccine immunization

The World Health Organization (WHO) recommends that all infants receive the first HB vaccine dose as soon as possible after birth.⁸² Routine vaccination of infants has been implemented in countries including but not limited to mainland China, Taiwan, Indonesia, and Thailand.^60,83-85 The ACIP recommends emergency HB immunization in high-risk pregnant populations^6,10,86-89; “high-risk” is defined as having a sex partner positive for hepatitis B surface antigen (HBsAg), having multiple sex partners within the past 6 months, requiring sexually transmitted disease evaluation or treatment, or current or recent injection drug use.^5,7,39 The American College of Obstetricians and Gynecologists (ACOG),⁹⁰ and the public health agency of Canada⁸⁸ have approved the recommendations of the ACIP. The HB vaccine is typically administered to women in 3 doses over a period of 6 months before, during, and after pregnancy. Like HA vaccines, the FDA classifies HB vaccines as a C-level drug for pregnant women,⁴⁰ and the Global Advisory Committee on Vaccine Safety has also not drawn any conclusions about the advisability of HBV vaccination in pregnant population.⁴¹

In fact, vaccination in pregnant women is rare. In Mayotte Island, 18.6% of pregnant women have received HB vaccinations.⁹¹ In the 2002–2009 VSD, the frequency of HBV vaccination was 3.73/1,000 pregnancies; however, vaccination was possible in cases where the woman and/or provider were unaware of the pregnancy.⁴⁰ A Chinese study conducted in 2002 reported a lower anti-HB positive rate (56.3%) in pregnant women,⁹² which may suggest the extended HBV vaccination in women of child-bearing age should be considered.

Efficacy and safety of Hepatitis B immune globulin (HBIG)

Screening of pregnant women and passive-active vaccination at birth may not be effective in preventing intrauterine infection, which typically occurs in the last trimester of pregnancy.^52,93 Some reports support administration of HBIG to pregnant women infected with HBV in order to prevent HBV infection in the uterus.^94-96 In the UK, HBIG is accepted for mothers positive for hepatitis B e antigen (HBeAg) or with HBV-DNA levels above 1.0×10⁶ IU/mL.^97,98 HBIG is also administered to HBsAg-positive mothers in China. A study conducted in district-level hospitals of Wuhan City, China from 2004–2006 reported that 90.5% of HBsAg-positive pregnant women received HBIG.⁹⁹

Several studies have assessed the use of HBIG during pregnancy for prevention of fetal infection, but its efficiency and safety during pregnancy remain controversial.¹⁰⁰ Pregnant women typically receive 200 IU per dose as intramuscular injections once monthly from 28 weeks of gestation. RCTs conducted in China supported the claim that, compared with a control group receiving a placebo or no intervention, HBsAg-positive and/or HBeAg-positive pregnant women receiving HBIG had significantly decreased probability of intrauterine hepatitis B infection,^96,101-106 and infants born to mothers administered HBIG during pregnancy had higher HBsAb positive rate at birth and lower prevalence of chronic HBV infection.¹⁰² Related to the safety of administration of HBIG during pregnancy, the limited data show no severe adverse effects in mothers or infants.^107-112

Hepatitis C

Hepatitis C virus (HCV) infection is also an important cause of chronic liver disease, cirrhosis, and liver cancer. An estimated 1–8% of pregnant women worldwide are positive for HCV infection^113,114; however, the prevalence of HCV infection in pregnant women is difficult to confirm owing to the lack of large-scale, representative surveys.^18,115 Acute HCV infection is usually asymptomatic and rarely reported in pregnant women, ¹¹⁶ but chronic HCV infection is common in pregnancy.^18,116 Maternal and neonatal outcomes, including gestational diabetes, preterm delivery, and low birth weights, have been reported.^117-120 In addition, vertical transmission plays a major role in pediatric hepatitis C¹²¹; the prevalence of mother-to-child transmission from HCV-infected women without HIV infection is an estimated 2–8%,^{18,115,122,123} and 2–3 times higher in mothers co-infected with HIV. ^124-127

There is currently no vaccine for hepatitis C,^15,128 and immune globulin is not effective in preventing pre- or post-exposure HCV infection.^128,129 Moreover, the ACOG recommends HCV screening only for pregnant women with risk factors, such as illegal drug use.^90,130

Hepatitis D

Hepatitis D infections occur only in the presence of HBV infection.¹³¹ An estimated 15 million of 240 million chronic HBV carriers are also infected with hepatitis D virus (HDV).¹³² Co-infection typically leads to acute HDV infection, while super-infection causes chronic infection in more than 90% of cases.¹³³ The disease burden of HDV infection has declined in regions where universal HBV vaccination are carefully designed and efficiently implemented.^131,133 Acute HDV infection does not directly lead to death during pregnancy,^133,134 but chronic hepatitis D infection may promote HBV-related liver disease;¹³⁴ thus, hepatitis D is considered one of the most severe forms of viral hepatitis in humans.^131,135

There are no HD vaccines or immune globulin to prevent hepatitis D,¹³⁶ but measures to prevent hepatitis B are also generally effective against HDV infection.^16,137 A mathematical model predicted that coverage of HB vaccination to be an important factor influencing the outcome of HDV infection.¹³⁷

Hepatitis E

Hepatitis E virus (HEV) infection is a common cause of non-A, non-B, enterically transmitted acute viral hepatitis worldwide.¹³⁸ Compared with other types of viral hepatitis, pregnant women have increased risk of HEV infection.^139,140 A distinctive feature among pregnant women infected with HEV is high morbidity and mortality due to acute hepatic failure,^141-144 and adverse maternal outcomes, such as abortion, premature delivery, stillbirth, and intra-uterine death are common in infected cases.^145-148 A survey in rural Bangladesh attributed 9.8% of pregnancy-associated deaths to acute HEV infections;¹⁴⁹ Gurley et al.¹⁵⁰ concluded that HEV infection was responsible for 58% of deaths in pregnant patients with acute liver disease or fluminant hepatitis in HEV endemic regions. In 2005, the possibility of death in HEV-infected pregnant women was an estimated 0.198, with up to 3,000 stillbirths in 9 Global Burden of Disease regions.¹⁵¹ Moreover, some surveys have observed vertical transmission among infected mothers.^152-154

Efficacy and Safety of HE vaccines

To date, the 56 KD vaccine^155-157 and HEV239 vaccine^158,159 have passed phase 2 or 3 clinical trials, and the HEV239 vaccine (Hecolin) is currently commercially available in China.^160,161 Only one survey provided a preliminary analysis of the efficacy and safety of incidental immunization during pregnancy in phase 3 trials of the HEV239 vaccine (Tables 1 and 2) with no HEV-infected cases reported among all HE/HB-vaccinated pregnant women in the study of Wu et al.¹⁶²; the prevalence of adverse effects was similar to non-pregnant women injected with the HEV239 vaccine; moreover, no spontaneous abortions or congenital anomalies were reported in either HE vaccinated or HB vaccinated mothers (placebo group). In addition, immune globulin is not recommended to prevent hepatitis E; although limited, the existing evidence suggests its protective effect on hepatitis E infection.^138,163-165

Studies of mouse models have shown HE vaccine candidates, including recombinant neutralizing epitope protein,¹⁶⁶ and insect larvae-derived recombinant hepatitis E virus ORF-2 proteins,¹⁶⁷ to be well-tolerated, inducing high anti-HEV titers in pregnant mice as well as antibody transfer to offspring¹⁶⁷; however Li et al.¹⁶⁸ believed that pregnant mice were not an appropriate model to explore the efficacy and safety of HE vaccines because female mice are not vulnerable to HEV infection.

Conclusion

Pregnancy should not be a contraindication to immunization with inactivated vaccines or immune globulin,⁸⁶ as vaccination of pregnant women protects susceptible or high-risk mothers, fetuses, and infants.^3,10 Currently, while the ACIP recommends emergency immunization during pregnancy using inactive HA and HB vaccines,^3,7 there are no global policies regarding vaccination during pregnancy. Although HBIG administered to pregnant women infected with HBV can decrease intrauterine infection rates, it is not approved worldwide, possibly due to potential risks or the prohibitive cost of therapy.^99,169 Moreover, compared with hepatitis A, B, C, and D, a higher incidence of fulminate hepatitis failure has been observed in pregnant women with HEV infection;^15,170 the HEV239 vaccine currently available in China could be a candidate for prevention hepatitis E infection in pregnant women. In addition, due to obstacles regarding vaccine clinical trials in pregnant women, observation studies may be useful to explore the efficacy and safety of vaccination during pregnancy. Thus, national or regional surveillance systems such as the VSD⁴⁰ may be useful for addressing this problem.

Abbreviations

HA vaccine	=	Hepatitis A vaccine
HB vaccine	=	Hepatitis B vaccine
HE vaccine	=	Hepatitis E vaccine
HAV	=	Hepatitis A virus
HBV	=	Hepatitis B virus
HCV	=	Hepatitis C virus
HDV	=	Hepatitis D virus
HEV	=	Hepatitis E virus
ACIP	=	Advisory Committee on Immunization Practices
FDA	=	Food and Drug Administration
VSD	=	Vaccine Safety Datalink
HBsAg	=	Hepatitis B surface antigen
HBeAg	=	Hepatitis B e antigen
HBsAb	=	Hepatitis B surface antibody
VAERS	=	Vaccine Adverse Event Reporting System
HBIG	=	Hepatitis B immune globulin
ACOG	=	American College of Obstetricians and Gynecologists
RCTs	=	Randomized controlled trials

Disclosure of potential conflicts of interest

The authors declare that there are no potential conflicts of interest.

Funding

This study was funded by the National Natural Fund (81573258, 81402769) and the Jiangsu Provincial Social Development Fund (BE2013723, SBE2015710027).