At present, the clinical medical problems faced by women with hepatitis B virus (HBV) infection during childbirth have been attracting more and more attention. In order to further standardize and optimize the management and treatment of these patients, some domestic experts have compiled and analyzed relevant data to form the “Expert Consensus on the Management of Fertility in Women with Hepatitis B Virus Infection” (hereinafter referred to as the Consensus). This Consensus is based on the latest achievements in the field and is prepared in accordance with the principles of evidence-based medicine. It summarizes the clinical issues and management faced by women with HBV infection in childbirth and can be used as a guide for women with HBV infection in childbirth. The expert committee will continue to update the content of the Consensus as relevant clinical evidence continues to accumulate.
I. Overview of mother-to-child transmission of hepatitis B virus
The main routes of transmission of hepatitis B virus are: transmission through blood and blood products, mother-to-child transmission, transmission through broken skin and mucous membranes, and sexual contact transmission. In China, mother-to-child transmission is the most important transmission route of hepatitis B. About 30% to 50% of HBV infections come from mother-to-child transmission. 2 billion people worldwide have been infected with HBV, of which 350 million HBV infected people, about 1 million people die each year from liver failure, cirrhosis and primary liver cancer, about 150 million to 170 million women are infected, 5% of pregnant women are chronic HBV infected , of which more than 50% are HBeAg(+) (A1).
HBV infection may have an impact on pregnancy through the following aspects: ① alteration of the bone marrow hematopoietic microenvironment and hypersplenism may lead to thrombocytopenia and increase the risk of postpartum hemorrhage; ② high incidence of hypoalbuminemia and anemia, resulting in inadequate nutritional supply to the fetus; ③ decreased glucose tolerance and increased risk of gestational diabetes mellitus; ④ leukopenia and immune deficiency, which reduces the immune function of pregnant women and makes them susceptible to various infections; ⑤ abnormal liver function, which makes them susceptible to the risk of gestational diabetes. (5) abnormal liver function, resulting in reduced inactivation of many hormones and vasoactive substances and an increased risk of gestational hypertension. Meanwhile, the aggravation of liver disease during pregnancy is related to two factors: (1) a series of physiological changes in the mother, which increase the burden on the liver; (2) maternal endocrine changes and elevated levels of adrenocorticotropic hormones, which may lead to high HBV replication and contribute to hepatitis B activity (B1).
Mother-to-child transmission of HBV can be intrauterine infection, intrapartum infection, and postpartum infection. Intrauterine infection refers to fetal HBV infection during maternal growth and development; intrapartum infection refers to HBV infection of the infant caused by maternal blood, amniotic fluid, vaginal secretions swallowed by the newborn during the perinatal period, or during labor, due to the rupture of the placental villi by uterine contraction, resulting in the leakage of a small amount of maternal blood into the fetal circulation; postpartum infection belongs to HBV infection between the mother and the infant. Postpartum infection is a horizontal transmission between HBV-infected mother and infant, mainly from close contact in life (A1).
It is currently believed that high HBV load in pregnant women is the main risk factor for mother-to-child transmission, and reducing viral load can reduce mother-to-child transmission. When pregnant women are HBsAg-positive but HBeAg-negative, their newborns have a protection rate of 98% to 100% after regular immunization; 5% to 15% of newborns of HBeAg-positive pregnant women still have chronic infection after regular immunization (A1).
II. Maternity management for women with hepatitis B virus infection
(A) Selection of the timing of childbirth
It is recommended that all HBV-infected women of childbearing age go to a professional medical institution for preconception screening.
Recommendation 1: For HBV carriers, routine blood tests, liver function, HBVDNA, AFP, color Doppler ultrasound of the liver, gallbladder and spleen are recommended, followed by liver tissue biopsy if necessary, and pregnancy after adequate assessment of the risk of pregnancy and mother-to-child transmission (A1).
Recommendation 2: Young patients with chronic hepatitis B who have indications for antiviral therapy are recommended to use interferon alpha therapy or nucleoside (acid) analogues under the guidance of a specialist. If the criteria for discontinuation are not met, lamivudine (LAM), telbivudine (LdT) or tenofovir (TDF) can be switched to oral medication according to the situation, and pregnancy can be carried out after 6 months of switching and with normal liver function (A1).
Recommendation 3: For older patients with urgent childbearing requirements and treatment indications, if no previous antiviral therapy has been performed, it is recommended to use a fixed course of interferon alpha therapy for pregnancy 6 months after the end of treatment, or use LAM or LdT antiviral therapy, and pregnancy can be carried out during drug administration after normal liver function. For those who were previously treated with Entecavir (ETV) and Adefovir (ADV) for the first time, pregnancy can be carried out after 6 months of treatment with LAM, LdT or TDF before pregnancy, or if there is a history of LAM or LdT resistance, it is recommended to switch directly to TDF after pregnancy. All of the above require that the patient be fully informed of the underlying birth defect rate and its associated risks and sign an informed consent form (A1).
Recommendation 4: Patients with compensated cirrhosis who have strong fertility requirements or are already pregnant are recommended to be referred to an experienced specialist hospital for comprehensive investigations such as routine blood tests, HBV serological markers, HBVDNA, liver function, coagulation function, gastroscopy, ultrasound, AFP, liver tissue biopsy, liver fibrosis index, etc., and are recommended to first choose LAM, LdT or TDF for antiviral therapy. In principle, pregnancy is not recommended for both compensated and decompensated cirrhotic patients (A1).
(II) Management during pregnancy
1. Regular obstetric examination and close monitoring
In addition to routine prenatal checkups, monthly monitoring of liver function is recommended during pregnancy in women with HBV infection for early detection of liver disease activity during pregnancy. The first antenatal checkup should also include HBV serological markers, HBVDNA, liver ultrasound and other tests to comprehensively assess the risk of pregnancy and mother-to-child transmission. HBVDNA is recommended to be retested at 26-28 weeks of gestation to determine the strategy of mother-to-child blockade; HBVDNA is retested every 4-8 weeks during antiviral drugs and before delivery to observe the efficacy and prevent the occurrence of drug resistance; LAM, LdT, TDF and other drugs can effectively inhibit HBV replication and improve the success rate of mother-to-child blockade in pregnant women with high HBV replication after informed consent (A2).
2. HBV mother-to-child transmission interruption
Currently, there are two theories on the mechanism of intrauterine infection: (1) hematogenous route (placental leakage theory): factors that can cause rupture of the placental microvasculature lead to weakening or destruction of the placental barrier, resulting in HBV in maternal blood entering the uterus and causing fetal infection; (2) cellular route (placental infection theory): there may be a “cellular transfer” of HBV from the maternal side to the fetal side in the placenta The “cellular transfer” process.
More than 80% of intrauterine infections occur in late pregnancy, probably due to the gradual thinning of the fetal membranes and trophoblast layer, increased permeability of the chorionic capillary membrane, and weakened placental barrier during mid- to late pregnancy, which makes it easier for HBV to “cellularly transfer” layer by layer and break through the placental barrier, leading to intrauterine infection (B1).
Several studies have confirmed that LAM in late pregnancy can effectively reduce maternal serum HBVDNA levels and improve the success rate of HBV mother-to-child blockade, and that the use of LAM in late pregnancy is safe and effective and can significantly reduce the risk of HBV mother-to-child transmission. Some studies have confirmed that the success rate of LdT mother-to-child blockade can be as high as 98.3% to 100%, and no adverse effects on the mother and fetus have been found. Recently, Tran (USA) and Boland (Netherlands) have suggested that the use of LAM, TDF or LdT antiviral therapy for mothers with high viral load HBV infection in late pregnancy can be an effective measure to prevent mother-to-child transmission of HBV.
Recommendation 5: Pregnant women with HBVDNA ≤106 copies/ml can be treated without intervention; pregnant women with HBVDNA ≥106 copies/ml can be treated with oral LAM, TDF or LdT antiviral therapy starting at 28 weeks of gestation to reduce the risk of mother-to-child transmission of HBV, with adequate information about the risks, weighing the pros and cons, and signing an informed consent form; maternal compliance is a guarantee of successful mother-to-child blockade and risk reduction. Maternal compliance is the guarantee of successful mother-to-child blockade and risk reduction, and should be emphasized and the understanding and cooperation of pregnant women should be obtained before drug administration (A1).
Recommended maternal-infant blockade regimen: ①Regardless of the maternal-infant blockade regimen used during pregnancy, liver function and HBVDNA should be monitored closely during the drug administration; ②LAM: 100 mg/d, starting at 28 weeks of pregnancy; ③LdT: 600 mg/d, starting at 28 weeks of pregnancy, and creatinine and creatine kinase should be monitored regularly; ④TDF: 300 mg/d, starting at 28 weeks of pregnancy, and renal function and blood phosphorus should be monitored regularly (A1). Regular monitoring of renal function and blood phosphorus (A1).
3. Treatment of special conditions during pregnancy
(1) Oral antiviral drugs
The problem of unplanned pregnancy during treatment: about 8% of women of childbearing age in China are chronic HBV infected, and 1/3 of them have entered the immune clearance phase of HBV and become chronic hepatitis B patients. Therefore, the choice of medication and the safety of the medication for the mother and the fetus in women with HBV infection who are on treatment and who need treatment also deserve attention.
Some studies have shown no increase in the incidence of maternal and neonatal adverse events with LAM and LdT during full-term pregnancy, but full-term antivirals are generally not recommended. In case of unplanned pregnancy while taking antiviral drugs, if LAM or pregnancy level B drugs (LdT or TDF) are applied, the pregnancy may be continued with adequate information about the risks, weighing the pros and cons, and signing an informed consent. In case of unintended pregnancy during interferon alpha treatment, termination of pregnancy is recommended. If pregnancy grade C drugs such as ADV and ETV are applied, the pregnancy should be switched to LAM or other pregnancy grade B drugs (LdT or TDF) with adequate information about the risks, weighing the pros and cons, and with the patient signing an informed consent (A1).
(2) Amniocentesis during pregnancy in women with HBV infection
It is still controversial whether performing amniocentesis during pregnancy in pregnant women with high risk of Down’s screening can increase intrauterine transmission of HBV. China’s guidelines for the prevention and treatment of chronic hepatitis B state that HBsAg-positive pregnant women should avoid amniocentesis and should shorten the duration of delivery to ensure placental integrity and reduce the chance of neonatal exposure to maternal blood. However, there are reports in the literature that confirm that amniocentesis in HBV-infected pregnant women does not increase the risk of mother-to-child transmission of HBV. One study looked at 40 pregnant women with HBVDNA ≤5×102 copies/ml and none of their neonates had HBV infection after delivery; 17 pregnant women with HBVDNA ≤107 copies/ml had 1 neonate with HBV infection and 3 of the 6 pregnant women with HBVDNA ≥107 copies/ml had neonatal infection, suggesting that amniocentesis in pregnant women with a high carrier of HBV infection may increase the risk of mother-to-child transmission. Amniocentesis may increase the risk of mother-to-child transmission (B1).
Recommendation 6: It is recommended that pregnant women with HBV infection should be cautious in performing amniocentesis; amniocentesis can be considered after informed consent for low replication of HBVDNA or undetectable; amniocentesis is generally not recommended for those with high replication of HBVDNA unless there are special reasons (A1).
(3) Management of liver disease during pregnancy
HBV-infected pregnant women with abnormal liver function during pregnancy should be treated promptly, except for other causes of liver disease, to avoid aggravation of the disease.
Recommendation 7: (1) ALT≤2×ULN: can be observed, or oral hepatoprotective drugs with little effect on the fetus can be given, such as silymarin type, liver protection tablets, Aotearoa, S-adenosylmethionine, etc. All need to closely monitor liver function (A1). (2) ALT ≥ 2×ULN and HBVDNA ≥ 105 copies/ml or ALT ≤ 2×ULN but liver biopsy shows hepatitis lesions (≥ G2 and/or ≥ S2); LAM, TDF or LdT antiviral therapy and symptomatic treatment with hepatoprotective drugs may be used with adequate risk communication, weighing the pros and cons, and patient signed informed consent (A1). (3) Patients who develop jaundice with an increasing trend and abnormal coagulation should be alerted to the development of severe hepatitis and early use of antiviral drugs is recommended. Patients with severe hepatitis and cirrhosis combined with pregnancy should be transferred to an experienced specialist hospital for treatment as soon as possible (A1). (4) Pregnant women with HBV infection treated with LAM, LdT and other antiviral drugs should continue treatment if drug resistance occurs during pregnancy and should not be discontinued at will; if ALT is normal and only HBVDNA rebound, treatment with the original drug can be continued or switched to other pregnancy grade B drugs (e.g. TDF); if both ALT and HBVDNA rebound, other pregnancy grade B drugs (e.g. TDF) should be switched immediately (e.g. TDF) for treatment, and add liver-protective drugs (A1) if necessary.
(iii) Management during delivery
The impact of the choice of delivery method on mother-to-child transmission of HBV has been controversial. Although cesarean delivery may reduce the exposure of fetal infants to HBV, the cesarean delivery method does not reduce the rate of HBV blockade failure or intrauterine infection compared with vaginal delivery, and current maternal-infant blockade measures can successfully block infection at delivery.
Recommendation 8: (1) Pregnant women with HBV infection who have normal liver function and no medical complications are recommended to decide on the mode of delivery based on obstetric conditions (A1). (2) Pregnant women with HBV infection with mild to moderate abnormal liver function and no medical complications can have a trial of vaginal delivery if their liver function is normal after liver-protective therapy and there are no obstetric contraindications; if liver function continues to be abnormal, liver function and Child-Pugh classification should be fully evaluated and delivery should be ended by cesarean section at the appropriate time (A1). (3) In patients with compensated and decompensated cirrhosis, liver function and Child-Pugh classification should be fully evaluated to decide the timing of cesarean delivery, and it is recommended to end delivery at 33-35 weeks of gestation (A1). (4) Some studies have shown that overdue pregnancy can increase the risk of mother-to-child transmission of HBV, and it is recommended to avoid overdue pregnancy as much as possible to reduce the chance of intrauterine infection (A1).
(iv) Neonatal management
1. Management of full-term infants
The Guidelines for the Prevention and Control of Chronic Hepatitis B recommend that newborns of HBsAg-positive mothers should be given hepatitis B immune globulin (HBIG) at a dose of ≥100 IU as early as possible within 24 h after birth (preferably 12 h after birth), along with 10 μg recombinant yeast or 20 μg Chinese hamster oocyte (CHO) hepatitis B vaccine at different sites, at the 1st and 6th months of life, respectively The 2nd and 3rd doses of hepatitis B vaccine can significantly improve the effect of blocking mother-to-child transmission. It is also possible to administer one dose of HBIG within 12 h after birth, followed by a second dose of HBIG 1 month later, and a 10 μg recombinant yeast or 20 μg CHO hepatitis B vaccine at different sites, followed by a second and third dose of hepatitis B vaccine 1 month and 6 months apart, respectively.
Recommendation 9: For newborns of HBsAg-positive mothers, HBIG 200IU should be given as early as possible after birth, along with a 10μg dose of recombinant yeast hepatitis B vaccine at different sites, and the second and third doses of hepatitis B vaccine (A1) at 1 and 6 months, respectively.
2. Management of preterm infants
The timing and method of hepatitis B vaccination for preterm infants is still controversial. It is recommended to delay hepatitis B vaccination because preterm infants are not yet immunocompetent and have a low response rate to the vaccine, and because the mercury in the vaccine may have toxic effects on the nerves of preterm infants.
Recommendation 10: As recommended by the Committee on Infectious Diseases of the American Academy of Pediatrics, hepatitis B vaccination should be withheld for premature infants weighing less than 2000 g, but HBIG 100-200 IU should be injected; hepatitis B vaccination should be administered when appropriate when weight reaches 2000 g or more or 1 to 2 months after birth (A1).
(E) Postnatal management
1. Breastfeeding
The Guidelines for the Prevention and Treatment of Chronic Hepatitis B recommend that newborns may receive breastfeeding from HBsAg-positive mothers after HBIG and hepatitis B vaccination within 12h of birth.
Recommendation 11: ①Mothers who are HBeAg positive and have HBVDNA ≥ 106 copies/ml should be informed that breastfeeding may be risky, and if the patient chooses to breastfeed it is recommended to monitor anti-HBs levels regularly; ②Breastfeeding is not recommended if the mother is taking therapeutic drugs whose safety to the infant cannot be determined; ③It is recommended to suspend breastfeeding in the following cases: mother with cracked nipples, oozing blood; The mother’s liver function abnormalities; newborn oral ulcers, mucosal damage (A1).
2. Postpartum review for women with HBV infection
Recommendation 12: (1) Those who did not use antiviral drugs during pregnancy but have abnormal liver function should be closely monitored; those with normal liver function should have their liver function, HBVDNA and HBV serological markers rechecked 1 to 3 months after delivery, and those with abnormalities should be advised to consult the hepatology department immediately (A1). (2) For mothers taking LAM, LdT or TDF for mother-to-child blockade in late pregnancy, liver function and HBVDNA should be rechecked 42 d to 3 months after delivery, and they should be advised to visit the hepatology department to decide whether to continue effective antiviral therapy under the guidance of a hepatologist, and to strengthen regular monitoring of the mother and newborn (A1). (3) Women who took antiviral drugs throughout pregnancy still need to continue antiviral treatment after delivery to avoid recurrence of chronic hepatitis B. Discontinuation criteria refer to ≤ Guidelines for the Prevention and Treatment of Chronic Hepatitis B. The original treatment can be continued or changed to other drugs that are effective and have a higher resistance gene barrier according to the viral response to the drug (A1).
3. Follow-up of newborns born to HBV-infected pregnant women
Newborns born to HBsAg-positive pregnant women require longer-term follow-up of HBV serologic markers to determine the effectiveness of mother-to-child blockade and immunization. A newborn born with negative HBsAg and HBeAg in peripheral blood cannot be excluded from mother-to-child transmission because of the long latency period of HBV infection; a newborn born with positive HBsAg and HBeAg in peripheral blood cannot be judged as mother-to-child transmission because HBsAg, HBeAg and related antibodies can enter the fetus through the placenta. In addition, serum HBsAg positivity can also occur in newborns within 2-3 weeks after hepatitis B vaccination. Therefore, the recommended follow-up period is from 1 month (7 months of age) to 12 months of age after the third dose of vaccine; if follow-up is not done on time, follow-up is still required after 12 months of age. If the test results: ① HBsAg negative, anti-HBs positive, and “100mIU/ml”, it indicates strong antibody protection, and regular monitoring can be continued; ② HBsAg negative, anti-HBs positive, and ≤100mIU/ml, it indicates weak antibody protection, and should be closely tested, and if necessary, one additional dose of hepatitis B vaccine should be given to extend the protection years; ③ HBsAg negative and anti-HBs negative, indicating that protective antibodies have not been produced, need to be vaccinated with hepatitis B vaccine (3-dose regimen) again throughout the whole course, and then rechecked. ④ HBsAg positive and anti-HBs negative indicates failure of mother-to-child blockade (A1).
Appendix: Some abbreviations in the text.
HBV: hepatits B virus, hepatitis B virus
LAM: lamivudine, lamivudine
LdT: telbivudine, tebivudine
TDF: tenofovirdisoproxilfumarate, tenofovir
ETV: entecavir, entecavir
ADV: adefovirdipivoxil, adefovir
HBIG: HBV immune globulin, hepatitis B immune globulin