Obstetrics and Gynecology
HEPATITIS B IN PREGNANCY
1. What every clinician should know
Pregnant women are routinely screened for hepatitis B surface antigen (HBsAg). Approximately 1% will screen positive. A majority of those who test positive are chronic carriers of hepatitis B.
Hepatitis B may be acquired vertically (from an infected mother), via sexual transmission from an infected partner, and following exposure to contaminated blood or body fluids. Because blood is screened for HBsAg prior to transfusion, this mode of transmission occurs almost exclusively in percutaneous drug users. However, more than one half of infected pregnant women have no identifiable risk factors for infection.
Hepatitis B infection and chronic Hepatitis B are endemic in many countries, but are becoming rare in the United States with current blood screening practices and the use of Hepatitis B vaccine. Acute Hepatitis B is rare in pregnancy, but should be treated as in the non-pregnant patient - i.e. primarily supportive care.
2. Diagnosis and differential diagnosis
After a pregnant woman tests positive for HBsAg, the provider should perform the following evaluation: repeat HBsAg with HB core antibody, surface antibody, and liver function tests. Chronic carriers will have a positive surface antigen at the same time as a positive core IgG antibody. Women who are recovering from acute Hepatitis B will either have a positive core IgM or will now have a negative surface Ag and a positive surface antibody upon retesting. Women with acute Hepatitis B will have a markedly elevated SGOT and SGPT, while those who are in the recovery phase or are chronic carriers may have normal or mildly elevated liver function tests.
Following confirmation that the patient is a chronic carrier, additional evaluation includes a quantitative viral load (VL), and Hepatitis Be antigen (HBeAg) and antibody. Those with a high VL and who are HBeAg positive (30% of HBV patients in North America) are more likely to transmit infection to close contacts and to their neonates. Because coinfections are common, antibodies to Hepatitis C and Human Immunodeficiency virust (HIV) should also be obtained. Women with chronic hepatitis B should also be referred to a gastroenterologist with expertise in hepatitis, as medical therapy may be indicated. The long term risks of chronic hepatitis B include cirrhosis and hepatic adenocarcinoma.
Preconceptual - Patients should be counselled that having chronic hepatitis B should not increase the risk of pregnancy complications, with the exception of the possibility of vertical transmission. Becoming pregnant does not seem to worsen the prognosis of chronic hepatitis B, although some medications commonly used for chronic hepatitis B are of concern during pregnancy.
Vertical transmission is dependent upon maternal viral load and HBeAg status, and is significantly reduced by reducing the maternal viral load and by neonatal HBIG and hepatitis vaccine administration.
Common medications prescribed for chronic hepatitis B
Pegalated interferon-alpha (Category C), administered subcutaneously or IM, is effective in achieving a sustained seroconversion from HBeAg positive to e antigen negative. There appears to be minimal transplacental transfer of this large molecule, nor does it appear in breast milk in significant quantities. There have been reports of growth restriction associated with PEG-interferon use during pregnancy, possibly due to its antiproliferative effects. Due to the limited safety data, the use of this medication during pregnancy is not advised, though there are numerous cases of successful pregnancies following PEG-interferon use.
Lamivudine (Category C) administered PO twice daily is a nuceleoside reverse transcriptase inhibitor. Its longterm use results in improved liver histology, suppression of VL, hepatitis e antigen seroconversion and improved ALT levels. Lamivudine crosses the placenta via simple diffusion and appears to concentrate in the amniotic fluic and breast milk, although the dosage ingested by the neonate is minimal. There has been no evidence to date of any teratogenic effects. Due to the development of resistance by the hepatitis B virus with long term use, the use of lamivudine for chronic hepatitis B infection has waned in recent years.
Because of its use in treating HIV, there is a great deal of experience in prescribing lamivudine during pregnancy, and it appears to be a safe drug to use in pregnancy. To date, with over 4000 first trimester exposures, there has been no evidence that lamivudine is a teratogen. A study by Yu et al revealed that the use of lamivudine in late pregnancy in women with a positive hepatitis B e antigen and a viral load of 10,000,000 or above reduced the risk of vertical transmission from 7.5% to zero (P = 0.05). In addition, use of lamivudine decreased the VL and resulted in 31% of women with undetectable VL (vs none in the control group, P < .001)
A meta analysis confirmed that maternal lamivudine treatment beginning at 28 weeks gestation reduces the risk of mother to child tranmission and was more effective than maternal administration of HBIG. In addition, the use of either maternal lamivudine or HBIG in the third trimester to prevent perinatal hepatitis B virus transmission appears to be cost-effective.
However, there are concerns that the hepatitis B virus may quickly develop resistance to the drug. For this reason, more recent recommendations have suggested the use of tenofavir, particularly if the mother will require long term treatment. Because post-treatment flares occur in up to 25% of non-pregnant patients and have been seen in pregnant patients as well, it is common practice to continue treatment through 4 weeks postpartum.
There is a small study of the use of telbivudine in late pregnancy which reported a reduction in HBV DNA levels and hepatitis B e antigen levels at the time of delivery. There was a statistically significant reduction in intrauterine transmssion between the telbivudine and control groups (zero vs 18%, P<0.05), with no serious adverse effects noted for either mothers or their infants. Because the experience with this drug during pregnancy is limited, its use is not routinely recommended.
Tenofavir (Category B) is a nucleotide analogue with activity against HIV reverse transcriptase and HBV polymerase and is a powder administered once daily. Its use results in decreased HBV VL and the development of resistance is low. With over 1,000 reports of first trimester exposure, there has been no evidence of teratogenicity. Excretion in breast milk has not yet been studied.
Other antiviral medications that are sometimes used include adefovir dipivoxil, entecavir and telbivudine. Although effective in the treatment of chronic hepatitis B, there are little to no data on placental transfer nor on their use in pregnancy and lactation. For these reasons, the use of these medications during pregnancy and lactation is not advised.
Hepatitis B is not a teratogen. Neither chronic nor acute hepatitis B appears to increase the risk of poor pregnancy outcomes. If a woman becomes pregnant while on antiviral medication, the risks of the medication must be balanced against the risk of a hepatitis flare if the medication is discontinued. In consultation with the hepatologist, given the available data, switching to lamivudine or tenofavir may be indicated.
In those women who are diagnosed during pregnancy, treatment should not be delayed if clinically indicated. In those who are not on therapy or decline treatment during pregnancy, there is evidence that administration of antiretrovirals in the third trimester of pregnancy may decrease the risk of neonatal transmission in women with high viral loads. Treatment seems to be particularly effective in women whose viral loads in the third trimester are 106 or above. Although data in pregnancy are limited, the maternal use of lamivudine, tenofavir, or HBIG appears to be effective in reducing neonatal transmission. These women, who are at high risk for neonatal transmission, should be offered therapy following a discussion of the risks and benefits of therapy.
A cesarean section should be performed for the usual obstetric indications, as there is no evidence that performing a cesarean section will reduce the risk of neonatal transmission. Although there is no evidence that the use of scalp elctrodes or performing scalp pH sampling increases the risk of neonatal transmission, these procedures should be avoided if possible. The nursery and the baby's pediatrician should be alerted to the mother's hepatitis status so that hepatitis immune globulin (HBIG) and hepatitis B vaccine can be administered expediently.
Although the hepatits B virus may be isolated from breast milk, there is no evidence that neonatal transmission is increased by breast feeding.
In the United States, the current recommendation is for all neonates to be administered the hepatitis B vaccine series. In addition, neonates born to women who are hepatitis B surface antigen positive are administed hyperimmune hepatitis B globulin (HBIG) within 12 hours of delivery. The addition of HBIG reduces the risk of vertical transmission to neonates from HBeAg positive mothers from approximately 34% to 13%, and from 7% to 1% in babies born to HBeAg negative mothers. In resource-limited settings, universal vaccine administration alone appears to be a cost-effective intervention.
In approximately 5% of cases, infected patients will fail to clear the hepatitis B virus and become chronic carriers, leading to hepatic cirrhosis in 25%. Approximately 20% of patients with cirrhosis as a result of chronic hepatitis B develop hepatocellular carcinoma, and 25% of chronic hepatitis B carriers die prematurely as a result of these complications. Up to 90% of perinatally infected infants develop chronic hepatitis B, with lower rates in infants born to HBeAg-negative mothers.
5. What is the evidence for specific management and treatment recommendations
Yu, N, Jiang, Q, Ji, Y. "The efficacy and safety of antiviral therapy with lamivudine to stop the vertical transmission of hepatitis B virus". Eur J Clin Microbiol Infect Dis. vol. 31. 2012. pp. 2211-8.(A randomized study of lamivudine in pregnant women with positive e antigen and a viral load of 1 x 107 or above, stratified by ALT results. Use of lamivudine significantly reduced the rate of perinatal transmission and slo reduced VL in the mothers.)
Giles, M, Visvanathan, K, Sasadeusz, J. "Antiviral therapy for hepatitis B infection during pregnancy and breastfeeding". Antiviral Therapy. vol. 16. 2011. pp. 621-8.(A comprehensive review of the the safety in pregnancy and lactation of medications used in the treatment of chronic Hepatitis B.)
Unal, ER, Lazenby, GB, Lintzenich, AE, Sipson, KN, Newman, R, Goetzl, L. "Cost-effectiveness of maternal treatment to prevent perinatal hepatitis B virus transmission". Obstet Gynecol. vol. 118. 2011. pp. 655-62.(A cost-effectiveness analysis of the maternal administration of either lamivudine or HBIG in the third trimester of pregnancy, to prevent perintal transmission of hepatitis B virus.)
Han, L, Zhang, HW, Xie, JX, Zhang, Q, Wang, HY, Cao, GW. "A meta-analysis of lamivudine for interruption of mother-to-child transmission of hepatitis B virus". World J Gastroenterol. vol. 17. 2011. pp. 4321-33.(A meta analysis of maternal lamivudine to prevent perinatal transmission which concludes that treatment is effective and safe.)
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