Clinical guidelines for prevention of mother-to-child transmission of hepatitis B virus

       The main diagnosis of hepatitis B virus (HBV) infection is based on HBsAg positivity. Mother-to-child transmission is the main cause of chronic HBV infection in China, so prevention of infants and children is emphasized. All pregnant women need prenatal screening for hepatitis B serological markers (commonly known as hepatitis B two-and-a-half). If a pregnant woman is HBsAg positive, her newborn is at high risk of HBV infection and must be injected with hepatitis B immunoglobulin (HBIG) within 12h after birth, in addition to hepatitis B vaccination. In order to standardize the preventive measures for mother-to-child transmission of HBV in China and to reasonably prevent HBV infection in newborns, experts in epidemiology and obstetrics have jointly developed this guideline based on recognized research findings at home and abroad and with reference to relevant information from other countries.  I. Clinical diagnosis of HBV infection Chronic HBV infection is defined as HBsAg positivity lasting for more than 6 months. If liver function is normal, it is called chronic HBV carrier; if liver function is abnormal and other causes are excluded, the diagnosis is chronic hepatitis B. Chronic HBV carriers need to review liver function and other necessary tests every 6-12 months. mother-to-child transmission of HBV, i.e. HBV transmission from HBsAg-positive mothers to their offspring, occurs mainly during and after delivery, and Vertical transmission (intrauterine infection before delivery) has an infection rate of <3%..., mostly in hbeag-positive pregnant women. Testing for serologic markers of hepatitis B, namely HBsAg, hepatitis B surface antibodies (anti. HBs), HBeAg, hepatitis B e antibodies (anti-HBe), and hepatitis B core antibodies (anti. HBc), can determine the presence or absence of infection or immunity. positive HBeAg is a sign of active viral replication, high viral load, and high infectivity. Anti-HBs is a neutralizing antibody, and serum anti-HBs level ≥10mIU/ml is protective. Fluorescence real-time quantitative PCR technique to detect HBVDNA level can reflect the level of viral load. However, about 30% of pregnant women who are HBsAg positive and HBeAg negative (commonly known as minor triplets), or even a few HBeAg positive (commonly known as major triplets), have HBVDNA below the lower limit of detection, which is called “HBVDNA negative”, but still have HBV in their blood and are infectious. Therefore, when a pregnant woman is positive for HBsAg, regardless of her HBVDNA level, or even “negative”, her newborn will have the possibility of infection if she does not take immunoprophylaxis.  Second, the management of chronic HBV-infected patients during pregnancy 1, the timing of pregnancy: chronic HBV-infected women planning pregnancy, it is best to be assessed by a specialist in infection or hepatology liver function. Infected patients whose liver function is always normal can have a normal pregnancy; those with abnormal liver function can have a pregnancy if they return to normal after treatment and are rechecked normal for more than 6 months after stopping medication. Pregnancy during antiviral therapy must be done with caution. Interferon can inhibit the growth of the popular child, and contraception must be used during its use. Among the nucleoside (acid) analogues, adefovir and entecavir have adverse effects on fetal development or teratogenic effects orally1 and are contraindicated in the first 6 months of pregnancy and during pregnancy. Tenofovir and telbivudine belong to class B drugs for pregnancy pupil] and have no significant effect on the fetus when used in mid- and late pregnancy b Lamivudine belongs to class C drugs, but does not increase neonatal birth defects when used to prevent HIV I mother-to-child transmission in early, mid- and late pregnancy mouth]. Nevertheless, if pregnancy occurs during the use of any antiviral drug, the patient must be informed of the various risks of the drug used, and a consultation with the relevant physician must be sought to decide whether to interrupt the pregnancy or whether to continue antiviral therapy.  2. Pregnancy follow-up: After pregnancy, liver function must be reviewed regularly in chronic HBV-infected patients, especially in the early and late stages of pregnancy. If the liver function is normal in the first test, if there are no clinical symptoms of hepatitis, it should be rechecked once every 1 to 2 months; if the alanine transferase (ALT) is elevated but does not exceed 2 times the normal value (<80>80U/L), or if the bilirubin level is elevated, it is necessary to consult a relevant professional physician, and if necessary, hospitalization, and in serious cases, termination of pregnancy.  3, the application of HBIG in late pregnancy has no role in preventing mother-to-child transmission: some scholars have proposed that HBV-infected pregnant women can prevent intrauterine infection in the fetus by applying HBIG in late pregnancy, but the following problems exist in the relevant studies: (1) the protection rate after immunoprophylaxis of neonates in the control group was only 55%-85%, which is significantly lower than the accepted protection rate, suggesting that there is no formal prevention in the control group; (2) the diagnostic criteria are incorrect and exaggerated the rate of intrauterine infection; (3) some studies had contradictory results before and after their own. In addition, there is no anti.HBsHo in the newborn after HBIG in pregnant women; gorilla experiments and studies on prevention of reinfection after liver transplantation in HBV-infected patients suggest that HBIG injections of 200-400 U every 4 weeks in late pregnancy are unlikely to reduce HBV viral load p1; and there are also reports from China that the regimen does not reduce mother-to-child transmission M41. Therefore, it is important for HBV-infected pregnant women in late pregnancy do not need to apply HBIG. 4, the problem of antiviral treatment during pregnancy: high levels of HBV in pregnant women is the main risk factor for the occurrence of mother-to-child transmission, and reducing the amount of virus 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 prevention. Therefore, there is no need to use antiviral therapy to prevent mother-to-child transmission in HBeAg-negative infected pregnant women.  Chronic HBV infection still occurs in 5%-15% of newborns of HBeAg-positive pregnant women after regular prophylaxis. Although, it has been reported that treatment with lamivudine or tebivudine in the middle and late stages of pregnancy can reduce mother-to-child transmission, the number of cases in some studies is very small, and there are cases in which mother-to-child transmission still occurs after treatment in some control groups of newborns who may not have formal prophylaxis. Therefore, HBeAg-positive pregnant women cannot yet be treated with routine antiviral therapy as an indication for reducing mother-to-child transmission.  The following factors are also reasons for caution in anti-HBV therapy for pregnant women: (1) nucleoside (acid) analogs do not clear the virus, and the virus will return to its original level or even higher after discontinuation, even inducing serious liver function damage; (2) long-term medication will increase the economic burden and cause the virus to mutate and produce drug resistance and other side effects; (3) 85% to 95% of HBeAg-positive pregnant women are not treated with anti-HBV therapy even if their newborns are not treated. (3) 85% to 95% of HBeAg-positive pregnant women can be protected after regular prophylaxis of their newborns even without anti-HBV therapy; (4) anti-HBV therapy usually starts in mid- and late pregnancy and is not effective for intrauterine infection in early and mid-pregnancy. In conclusion, whether anti-HBV therapy is needed to reduce mother-to-child transmission in HBeAg-positive pregnant women remains to be studied in more rigorously designed, rigorously controlled, large-sample, multicenter studies. In addition, abnormal liver function during pregnancy in HBV-infected patients does not increase the risk of mother-to-child transmission of HBV, and most pregnant women will return to normal liver function after delivery. Therefore, routine anti-HBV treatment cannot be given to those with abnormal liver function, and the indications for anti-HBV treatment should be strictly controlled.  Third, cesarean delivery can not reduce mother-to-child transmission It was previously believed that natural childbirth due to uterine contractions “squeeze” the placenta, prompting the virus in the mother into the fetus, causing intrauterine infection, so theoretically cesarean delivery can reduce the mother-to-child transmission of HBV. However, recent studies have demonstrated that the difference between the rate of HBV infection in neonates delivered by cesarean section and those delivered naturally after regular prophylaxis of chronically infected pregnant women is not statistically significant (P>0.05), indicating that cesarean section does not reduce the mother-to-child transmission of HBV. Therefore, cesarean delivery cannot be chosen for the purpose of interrupting mother-to-child transmission of HBV.  Prevention of mother-to-child transmission of HBV Vaccination against hepatitis B is the most effective measure to prevent HBV infection. The active ingredient of the hepatitis B vaccine is HBsAg, which induces the body to actively produce anti-HBs and play a role. After the first dose of vaccine, most anti-HBs are still negative or below the lower limit of detection; about 1 week after the second dose, anti-HBs turns positive, i.e. 35-40 d after the start of vaccination, there is immunity to HBV; the third dose of vaccination can significantly increase the level of anti-HBs and prolong the protection period. The anti-HBs positive conversion rate of newborns after full vaccination is as high as 95% to 100%, and the protection period can be more than 22 years. The human body has immune memory after actively producing anti-HBs, and even if the anti-HBs turns negative, the body can produce anti-HBs within a short period of time when exposed to HBV again, therefore, non-high-risk groups do not need booster vaccination against hepatitis B.  1. HBV prevention for full-term newborns: When a pregnant woman is HBsAg negative, regardless of HBV-related antibodies, newborns are vaccinated according to the “0, 1, 6 months” program, and HBIG is not necessary. When a pregnant woman is HBsAg positive, regardless of whether HBeAg is positive or negative, newborns must be vaccinated with HBIG and HBIG in a timely manner. HBIG needs to be administered within 12 hours after birth (theoretically, the earlier the better), and its active ingredient is anti-HBs, which starts to work 15-30 min after intramuscular injection, and the protective anti-HBs can be maintained for at least 42-63 d. At this time, the body has actively produced anti-HBs. If the results of HBsAg in pregnant women are unknown, it is best to give HBIG to the newborn if possible. after taking the above regular preventive measures, the protection rate of newborns of HBsAg-positive and HBeAg-negative pregnant women is 98% to 100%, and the protection rate of newborns of both HBsAg and HBeAg-positive pregnant women is 85% to 95%. If HBIG is not used, only the application of vaccine prevention, the overall protection rate is only 55% to 85%.  2. Immunoprophylaxis for premature infants: premature infants have immature immune systems and usually need 4 doses of hepatitis B. Premature infants of HBsAg-negative pregnant women can be vaccinated according to the 3-dose program at 0, 1 and 6 months of age if their vital signs are stable and their birth mass is ≥2000g, and it is best to strengthen 1 dose at I to 2 years of age; if the vital signs of premature infants are unstable, they should first deal with related diseases and then be vaccinated according to the above program after they are stable. If the vital signs of preterm infants are unstable, they should first be treated for relevant diseases and then be vaccinated according to the above protocol after stabilization. If the premature infant is <2000g, the first injection should be given after the body mass reaches 2000g (if the body mass does not reach 2000g before discharge, the first injection should be given before discharge); after 1 to 2 months, the vaccination should be re-administered according to the 3-shot protocol at 0, 1 and 6 months. A second injection is required after 3-4 weeks. If the vital signs are stable, the first dose of vaccine should be given as soon as possible without considering the body mass; if the vital signs are unstable, the first dose should be given as soon as possible after stabilization; after 1 to 2 months or after the body weight reaches 2000g, the vaccination should be given again according to the 3-dose protocol for 0, 1 and 6 months.  3, HBV-infected pregnant women's newborns breastfeeding: Although, HBsAg and HBVDNA feet can be detected in the milk of HBV-infected pregnant women], and some scholars believe that nipple cracking, excessive sucking or even biting of the nipple by infants may transmit the virus to infants, but these are theoretical analysis, the lack of evidence-based medical evidence. Even without immunoprophylaxis, the infection rate of breastfed and artificially fed newborns is almost the same. More evidence proves that breastfeeding does not increase the risk of infection even if the pregnant woman is HBeAg positive. Therefore, after formal prophylaxis, regardless of whether the pregnant woman is HBeAg positive or negative, her newborn can be breastfed without testing for HBVDNA in the breast milk. 4. Follow-up of newborns of HBsAg-positive pregnant women: the newborns of healthy pregnant women do not need to be regularly checked for hepatitis B serological markers. the newborns of HBsAg-positive pregnant women need to be followed up for hepatitis B serological markers, and the appropriate time is chosen. The purpose is to determine whether immunoprophylaxis has been successful, whether there is HBV infection, and whether booster immunization is needed. Testing for HBsAg and HBeAg in cord blood or newborn Jhgl,week blood, a negative result does not exclude mother-to-child transmission because of the long latency period of HBV infection; a positive result does not confirm intrauterine infection or perinatal infection because HBsAg, HBeAg and related antibodies can enter the fetus through the placenta. In addition, serum HBsAg positivity can also occur within 2 to 3 weeks after vaccination of newborns. Therefore, testing for HBV serum markers before 6 months of age is not recommended for newborns without symptoms of hepatitis.  The appropriate time for follow-up is from 1 month (7 months of age) to 12 months of age after the 3rd vaccine dose; if not, follow-up is still needed after 12 months of age. 7 months of age is when the body has the strongest response to hepatitis B vaccine and the highest titer of anti-HBs, with the following test results: (1) HBsAg negative, anti-HBs positive and >100mU/ml, indicating successful prevention and good response, no special (2) HBsAg negative, anti-HBs positive, but <100mU/ml, indicating successful prevention, but weak response to the vaccine, can be booster vaccination at the age of 2-3 years to extend the years of protection; (3) HBsAg and anti-HBs are negative (or <10mU/m1), indicating no HBV infection, but no response to the vaccine (3) HBsAg and anti-HBs are negative (or <10mU/m1), indicating no HBV infection, but no response to the vaccine, which requires full vaccination again (3-dose regimen) and then rechecking; (4) HBsAg positive and anti-HBs negative, highly suggestive of immunoprophylaxis failure; HBsAg is still positive after 6 months of rechecking, which can determine prevention failure and chronic HBV infection. After successful prevention, annual follow-up is not required. For children of HBeAg-positive mothers, review every 2 to 3 years; if the anti-HBs drops below 10mU/ml, it is best to receive a booster vaccination; follow-up is generally not necessary after 10 years of age.  5. Other matters for prevention of mother-to-child transmission of HBV: If women of childbearing age are negative for serological markers of hepatitis B in pre-pregnancy screening, it is best to receive hepatitis B vaccine (10 doug or 20 doug) before pregnancy. If pregnancy occurs during vaccination, no special treatment is required and the full course of vaccination can be completed, as the hepatitis B vaccine has no significant adverse effects on either the pregnant woman or the fetus. HBIG is best given to newborns when there is no screening for HBsAg during pregnancy or when it is not possible to determine whether the pregnant woman is HBsAg positive or negative; HBIG is strongly recommended for newborns if there is a family history of hepatitis B. When the pregnant woman is HBsAg negative but the father of the newborn is HBsAg positive, he is usually in close contact with the newborn because of caring for him, increasing his risk of infection; therefore, it is best for newborns to HBIG injection; semen cannot cause HBV infection in the fetus. similarly, other family members who are HBsAg-positive are better off giving HBIG to the newborn if they are in close contact with the newborn. HBIG is a blood product, and it is best to complete informed consent and sign it before delivery to avoid delays in its use. It is advisable to have HBIG available in obstetrics and gynecology wards so that high-risk newborns born at night, on weekends or during holidays13 can receive timely formal prophylaxis. HBV is likely to be present on the skin surface of newborns of HBV-infected mothers, and it is important to wash and adequately disinfect the skin before any treatment that damages the skin and to inject HBIG before other injectable treatments, etc. Amniocentesis of HBV-infected pregnant women who HBeAg negative, does not increase the risk of mother-to-child transmission of HBV in newborns ugly earth, if HBeAg positive, whether to increase the risk of fetal infection is less studied, and further research is needed.  V. Key points of immunoprophylaxis against hepatitis B in newborns 1. Pregnant women need to be tested for serological markers of hepatitis B before delivery: HBsAg positive, indicating HBV infection and infectiousness; HBeAg positive, highly infectious; anti-HBs positive, immune to hepatitis B.       2, HBsAg negative pregnant women: newborns are vaccinated with hepatitis B vaccine according to the 3-dose program at 0, 1 and 6 months, i.e. 1 dose within 24h of birth, 1 month and 6 months respectively; no need to inject HBIG again. 3, HBsAg positive pregnant women: newborns are injected with 1 dose of HBIG intramuscularly within 12h of birth; at the same time, they are vaccinated with hepatitis B vaccine according to the 3-dose program at 0, 1 and 6 months.  4.Breastfeeding of HBsAg-positive pregnant women: after formal prevention of the newborn, breastfeeding is feasible regardless of whether the pregnant woman is HBeAg-negative or positive.  5, mode of delivery and mother-to-child transmission: cesarean delivery cannot reduce the rate of mother-to-child transmission of HBV.  6, preterm infants: when the birth mass ≥ 2000g, no special treatment. When the body mass <2000g, the first vaccination will be given after the body mass reaches 2000g, and then after an interval of 1-2 months, the 3-dose program will be implemented according to 0, 1 and 6 months. If the pregnant woman is HBsAg negative and the premature baby is in good health, treat as above; if the health condition is not good, treat the related disease first and wait for recovery before vaccination. If the pregnant woman is HBsAg positive, regardless of the health condition of the premature baby, one injection of HBIG will be given intramuscularly within 12 hours, and another injection will be required after an interval of 3-4 weeks; vaccination will be given within 24 hours, 3-4 weeks, 2-3 months and 6-7 months of birth, and follow-up will be conducted.  7, other family members HBsAg positive: If the newborn is in close contact with HBsAg positive members, it is necessary to inject HBIG; without close contact, it is not necessary to inject.  8.Follow-up of newborns of HBsAg-positive pregnant women: at 7-12 months, test for serological markers of hepatitis B. If HBsAg negative and anti-one HBs positive, prevention is successful and resistant; if HBsAg negative and anti-one HBs negative, prevention is successful but requires another 3 doses of vaccination program; if HBsAg positive, prevention fails and becomes chronic infected.  9.Other precautions: Before any operation that damages the skin mucosa, it must be fully cleaned and disinfected before proceeding.  10.Whether anti-HBV treatment should be performed in HBsAg-positive pregnant women to reduce the rate of mother-to-child transmission: when HBeAg-negative, no antiviral is needed; when HBeAg-positive, whether anti-HBV treatment should be performed is inconclusive and requires a rigorous multi-center controlled study.