HBV infection is a serious public health problem worldwide. According to WHO statistics, about 5% of mothers are chronic HBV carriers[8
], and the hepatitis B surface antigen positivity rate among fertile women in some high epidemic areas, such as Africa and South Asia, can be as high as 9.2%-15.5%[9-11
]. About one-third of HBV-infected women enter into the immune clearance phase before or during pregnancy, with a high HBV DNA load and abnormal ALT levels. They are not only faced with a high risk of mother-to-infant transmission, but they also have an increased chance of hepatic disease exacerbation during pregnancy, threatening the safety of both mother and infant[12-14
]. It is currently not recommended for chronic HBV-infected fertile women who are not pregnant to take interferon or NA treatment, in line with the guidelines for the prevention and treatment of chronic hepatitis B[7
]. The antiviral efficacy of interferon is limited, and several side effects hinder its use, resulting in treatment failure. NA treatment alone results in only 20% of hepatitis B e antigen (HBeAg)-positive patients achieving HBeAg seroconversion, with only 12% able to stop treatment with a sustained virological response[15
]. Therefore, many chronic HBV-infected fertile women become pregnant during treatment.
It is very dangerous for pregnant women to stop taking antiviral treatment during pregnancy when they have not met the withdrawal standard, as it may exacerbate liver disease, threatening the safety of both mother and infant. However, the safety of infants exposed to antiviral drugs in utero throughout the entire pregnancy is of particular concern, especially in early pregnancy, which is vital for fetal development. Although LAM is already approved as an optional antiviral drug for use in pregnancy, and several studies have reported its safety in late pregnancy[1-3
], all of the studies regarding its safety before or during early pregnancy come from HIV-infected pregnant women[16
]. Furthermore, most of these patients received combination therapy. So far, there have been very few reports about the safety of LAM treatment in chronic HBV-infected women before or during early pregnancy, and systematic observations have been scarce[4-6,17
The present study showed that the abortion rate for HBV-infected women who took LAM treatment in early pregnancy was 11.6%, which was not higher than that of non HBV-infected mothers or HBV-infected mothers according to previous reports (11%-16% and 16.7%-21.9%, respectively)[6,18,19
]. Overall, 72 mothers delivered 73 live infants; none were stillborn. Three fetuses had developmental retardation during pregnancy monitoring, although their development later normalized after treatment; no other fetal developmental abnormalities were reported. Only 4.1% of infants had low birth weight, which was similar to that of women without or with HBV infection according to previous reports (2.7%-7.8% and 5.0%-10.4%, respectively)[20
]. None of the infants had abnormal hearing, congenital phenylketonuria, or hypothyroidism on testing. Two infants were found to have abnormalities (scalp hemangiomas and early cerebral palsy), with a congenital abnormity rate of 2.7%, which is similar to the data from HIV-infected women (3.1%) who took antiretroviral treatment (including LAM) in early pregnancy from 1989 to 2011[16
]. According to the literature, the congenital abnormality rates for infants born to mothers without or with HBV infection were 5.1%-6.3% and 7.2%-10%, respectively[6,20,21
]. The present report suggests that it is safe for fetuses to be exposed to LAM in utero for the entire pregnancy or in early pregnancy, and it does not affect fertilization or fetal development or result in congenital abnormities. Neither does it affect postnatal development.
The most common adverse event for mothers during pregnancy and the perinatal period was vaginitis (16.7%), among which 7 were vulvovaginal candidiasis (9.7%) and 5 were bacterial vaginosis. However, vaginitis is a common genital infectious disease in pregnant and non-pregnant women and the incidence of vaginitis in our study group was similar to that reported in the literature; it has been reported that the detection rate of candidal vaginitis in pregnant women is about 10%[22,23
], and the incidence of bacterial vaginosis among Asian women is 6.1%[24
]. Other adverse events included gestational diabetes, gestational hypertension, nausea and vomiting of pregnancy, oligohydramnios, polyhydramnios, placenta previa, anemia, pre-eclampsia, premature rupture of the membranes, and preterm delivery. The incidence of the above adverse events was not higher than that of mothers without or with HBV infection according to previous reports[25-29
]. Only one patient had 1-2 degree elevation of serum CK levels, and none of the other adverse events could be associated with LAM treatment. These results suggest that it is safe for HBV-infected pregnant women to take LAM treatment in early pregnancy or throughout the entire pregnancy.
Pregnancy can not only increase the burden on the liver, but it can also increase adrenal cortical hormone levels, boosting HBV replication and activation of hepatitis B. Therefore, for HBV-infected women, the average increase in the HBV DNA level was 0.4 log in late pregnancy or postpartum, and 25% of HBeAg(-) pregnant women had an increase of HBV DNA > 1 log, accompanied by elevation of ALT levels in late pregnancy or postpartum[13,29
]. The incidence of severe hepatitis during the perinatal period (in late pregnancy and one month postpartum) was much higher than in nonpregnant women[12-14,30
]. In the present study, all mothers without previous antiviral treatment maintained normal ALT levels throughout the entire pregnancy, and none of them had severe hepatitis. Fifteen mothers who took NA treatment previously had abnormal ALT levels in early pregnancy, but ALT normalized after LAM treatment, and the pregnancy continued. Interestingly, one mother stopped LAM treatment before pregnancy and later developed severe hepatitis in early pregnancy. However, all symptoms later disappeared, liver function normalized and the HBV DNA load became undetectable when she restarted LAM. In addition, 87.5% of patients had HBV DNA below 500 copies/mL antepartum, and the LAM resistance rate was only 8.3% during pregnancy. This suggests that LAM can effectively suppress HBV DNA replication in HBV-infected pregnant women, maintain normal liver function, and lower the incidence of hepatic disease during pregnancy, improving the prognosis of HBV-infected pregnant women.
According to previous reports, for infants born to HBeAg-positive mothers, even after they received passive-active immunoprophylaxis with HBIG and three doses of hepatitis B vaccines, vertical transmission was not blocked in 7%-16.3%[31
]. For mothers with an increased HBV DNA load, vertical transmission was not blocked in as many as 23.4%-32% of infants[32
]. In the present study, 80.4% of mothers was HBeAg-positive, and all of them had a high HBV DNA load before LAM treatment. However, 63 (87.5%) mothers had HBV DNA below 500 copies/mL antepartum, and the blocking rate was 97.1%; blocking failed in only 2 cases. The first mother had poor compliance, resulting in HBV DNA breakthrough, while the other had an HBV-S mutation during treatment, resulting in failure of vaccine immunization. These results suggest that LAM treatment could increase the vertical transmission blocking rate in HBeAg-positive mothers.
This study suggests that it is safe and effective for chronic HBV-infected pregnant women to take LAM treatment in early pregnancy. Treatment does not increase complications or adverse events for mothers during pregnancy or the perinatal period, has no effect on fertilization or embryonic development, and does not increase the incidence of congenital abnormalities in infants. Furthermore, it increases the blocking rate of mother-to-infant transmission. In conclusion, the benefits of taking LAM treatment in early pregnancy outweigh the risks. However, the sample size of this study was small, and the follow-up time was limited; both need to be optimized in later studies to provide greater insight.