As a clinician in the department of hepatology, this is one of the questions I often hear when I communicate with patients with hepatitis B: Dr. Fang, I am taking antiviral drugs, but I accidentally got pregnant. Can I still have this child?

Before we answer that question, let’s take a look at some common sense about drug safety in pregnancy.

Before 2015, the United States Food and Drug Administration (FDA) divided drugs into five grades according to their safety during pregnancy, namely: Class A, no harm to embryos was found in animal experiments and clinical application before the drug was put on the market; Grade B: no harm to embryos has been observed in animal experiments, but the safety for fetuses has not been proved clinically; Grade C: it has been proved to have teratogenic or injurious effects on embryos only in animal experiments, but lacks corresponding data for human beings; Grade D: It has been confirmed clinically that it is unsafe for human embryos, but the drug has certain clinical efficacy for pregnant women and no safe drug can replace it, so it should be used after weighing the advantages and disadvantages; X level: clearly prove to have harm to embryo, gestation period is forbidden. In fact, only 0.7 percent of class A drugs are classed as CLASS B, and most drugs are classed as CLASS C.

Because preclinical drug doses used in animal trials are often dozens or even hundreds of times higher than those used in post-clinical trials, the results of animal trials do not prove the same for humans. Class C pregnancy drugs do not mean that they cannot be used during pregnancy, the FDA notes. Doctors, pregnant women and their families often overestimate the risks of drugs to fetal development during pregnancy. The drug may be used if the assessed benefits outweigh the risks to the pregnant woman.

In recent years, the classification of pregnancy safety of drugs has aroused a lot of controversy, and it is believed that such classification is not reasonable and may cause misunderstanding of drugs by doctors, pregnant women and their families. Therefore, since 2016, THE US FDA has no longer made equal classification of pregnancy safety of newly marketed drugs. The results or data on the use of drugs in animals or humans during pregnancy are simply written in instructions for doctors to use.

Clinical anti-hepatitis B virus drugs have two types: oral antiviral drugs and interferon injection. With the passage of time, some oral antiviral drugs with large clinical side effects, poor antiviral effect and easy drug resistance are gradually replaced by drugs with small side effects, good efficacy and low incidence of drug resistance. At present, there are three kinds of first-line oral antiviral drugs recommended by domestic and foreign guidelines: entecavir, tenofovir fumarate, and propofol tenofovir fumarate, as well as polyethylene glycol interferon injections.

Below, I will introduce the pregnancy safety of these antiviral drugs for hepatitis B mothers one by one in combination with the latest version of hepatitis B prevention and treatment guidelines in our country:

1. Entecavir (ETV)

It was the first first-line oral anti-hepatitis B drug to hit the market (2015), and was classified as a class C drug for pregnancy by THE US FDA at the time of marketing, which is not recommended for use during pregnancy. The reason why entecavir is listed as C and drug is that in pre-market animal experiments, when the large dose (tens of times higher than the human dose), entecavir is observed to have certain harm to the embryo development of some animals. At doses ranging from three to 40 times the human dose, the incidence of lung tumors increased in mice. At present, entecavir has been clinically used for more than 10 years, and it is the most widely used anti-hepatitis B drug in clinic. No adverse pregnancy reaction cases have been found clinically, nor has there been a clear literature report of harm to fetal development. According to the latest guidelines for the Prevention and Treatment of Chronic Hepatitis B released in 2019, pregnant women who become pregnant unexpectedly during antiviral treatment are not required to terminate their pregnancy if they are being treated with entecavir, and it is recommended to change to Tenofovir fumarate and continue treatment.

2. Tenofovir fumarate (TDF)

It was listed in 2008 and has been in clinical application for more than 10 years. In animal experiments before TDF was marketed, it was found that the effects on animal embryo development could also be found when the dose was tens of times larger than human body. Due to the lack of data on the safety of human pregnancy, TDF was classified as a class B pregnancy drug by THE US FDA when it was marketed. Because TDF was first used for the treatment of AIDS, there have been a large number of data on the safety of AIDS pregnant women in clinical practice, and it is found to be safe for pregnancy. Existing large amounts of data also confirmed in pregnant women who applied to hepatitis b is safe for fetal development, and for taking TDF, is rare in the breast milk (only about 0.03% of the therapeutic dose), and the low bioavailability of TDF in breast milk, so such traces of TDF content in milk for newborn almost negligible influence growth and development. At present, TDF is recommended by domestic and foreign guidelines as the preferred anti-hepatitis B drug during pregnancy. It can be used before, during and after pregnancy, and hepatitis B mothers can breastfeed while taking the drug.

3. Propofol Tenofovir dipivoxil (TAF)

TAF was introduced into the market in 2016. Compared with entecavir and Tenofovir fumarate, TAF was put on the market later, because both TDF and TAF were decomposed into tenofovir (TFV) in vivo to play a role. Therefore, TDF was used for reproductive toxicity in animal experiments before marketing. TAF is safer because the dose is much smaller than TDF. At the end of 2021, researchers from the First Affiliated Hospital of Zhengzhou University conducted a multicenter prospective study to evaluate the efficacy and safety of TAF in the treatment of 103 pregnant women with chronic hepatitis B and the prevention of mother-to-child transmission of HBV. The results showed that: For pregnant women with active chronic hepatitis B and their infants, TAF is safe and effective to be administered throughout pregnancy or early in pregnancy. Therefore, TAF will also become a drug with good safety during pregnancy.

4. Polyethylene glycol interferon (PEG-IFN)

Peginterferon has been on the market since 2005 and has been contraindicated in pregnant women because of reproductive toxicity found in pre-marketing animal tests. “Peg-ifn can be used before pregnancy to complete treatment within the first six months of pregnancy, and reliable contraceptive measures should be taken during the treatment for patients with antiviral therapy indications,” the 2019 version of China’s Guidelines for the Prevention and Treatment of Chronic Hepatitis B states. According to limited literature reports, interferon pregnancy harms are mainly abortion, fetal growth retardation, low weight children, etc., but there are no reports of teratogenicity, so, China’s guidelines also point out: “If a pregnant woman has an unintended pregnancy during peG-IFN antiviral therapy, it is recommended that she and her family be fully informed of the risks, and that she decide whether to continue the pregnancy or switch to TDF treatment if she continues the pregnancy.” Guidelines in the United States and Europe are similar, suggesting changing medications and not terminating a pregnancy. Therefore, for older pregnant women, in this case, it is necessary to fully consider the patient’s reproductive age, the risk of abortion and the impact of abortion on future fertility, and then decide whether to terminate pregnancy after weighing the advantages and disadvantages.

5. Other antiviral drugs

These included prior use of lamivudine, adefovir dipivoxil, tibivudine, and common interferon. Lamivudine and tibivudine have been classified as pregnancy B drugs by FDA in the past, and their use during pregnancy has been found to be safe in clinical practice. There are few data on the safety of adefovir dipivoxil in pregnancy, and there are reports that there is no effect on fetal growth and development when adefovir dipivoxil is used in pregnancy. The pregnancy safety of common interferon is the same as peg-interferon. These drugs are not recommended as first-line antiviral drugs at present because of their efficacy, side effects and drug resistance.

As mentioned above, the effect of anti-hepatitis B drugs on hepatitis B mothers is not as serious as people think, and the effect on hepatitis B fathers is even less. Therefore, hepatitis B mothers and hepatitis B fathers, do not worry too much about the safety of antiviral drugs for the fetus, the most important thing is to find a specialist before pregnancy to check and evaluate, timely safe and effective intervention when needed, in order to block the occurrence of vertical transmission of hepatitis B virus from mother to child, to avoid the transmission of hepatitis B virus to the next generation.