The hepatitis B virus (HBV) is a DNA virus belonging to the hepadnavirus family. The viral nucleocapsid (core) is comprised of double-stranded circular DNA and the hepatitis B core antigen. The hepatitis B e antigen (HBeAg) is a derivative of hepatitis B core antigen. The surface antigen (HBsAg) comprises the outer shell of the virus. HBV affects humans and chimpanzees.
In the United States, approx 20,000 infants are born to HBsAg-positive mothers each year. HBV-infected individuals exhibit high viral concentrations in blood, and lower levels in tears, saliva, synovial fluid, vaginal fluid, semen, stool, and breast milk. Cases of intrauterine transmission of HBV have been reported, but this does not seem to be a significant source. Perinatal transmission of HBV occurs as a result of exposure to maternal blood. Exposure of infant traumatized surfaces or intact mucous membranes to maternal fluids, as well as to placental tears, appear to be the routes of perinatal transmission of HBV.
Acute HBV infection during pregnancy does not appear to adversely affect the clinical course of the gestation. The risk of infectivity to the neonate, however, appears to be related to the time of acute HBV infection. Acute maternal infection during the third trimester of pregnancy markedly increases the risk of HBV vertical transmission. All neonates born to infected mothers, regardless of the time of infection, ought to receive the transmission-preventive treatment discussed later.
Chronic HBV infection has little effect on the pregnancy. Female HBV carriers usually have less liver inflammation than male carriers, and are less likely to develop liver cirrhosis. Consequently, most young female HBV carriers have a lower risk to develop hepatic failure, or any other decompensation of liver disease, during pregnancy or delivery. Pregnancy has no adverse effects on the course of HBV infection, and does not result in meaningful changes in AT levels.
Interferon is not used in pregnancy to treat chronic hepatitis B virus infection. Lamivudine (LAM), a nucleoside analog useful in the treatment of hepatitis B, has been used in pregnancy for the treatment of HIV infection. Concentrations of LAM in maternal serum, amniotic fluid, and neonatal serum are similar, probably because of free transplacental diffusion of the drug. LAM has also been found in breast milk (6). Adverse pregnancy outcomes, such as frequent prematurity or biliary malformations caused by use of LAM have been reported (7). Based on those reports, the use of LAM for treatment of HBV infection in pregnancy cannot be recommended, until further data are obtained.
Vertical transmission of HBV is responsible for the majority of cases of the chronic-carrier state worldwide, particularly in endemic areas, such as Southeast Asia and Africa (8). Consequently, it is essential that all infected mothers are identified prior to or at the time of delivery, in order to take appropriate measures to prevent transmission to the neonate.
Many countries recommend testing pregnant women for HBsAg. Approximately one-half of those who are found to be positive, on rou tine testing, do not fit into any high-risk groups, and could potentially be missed, if more universal testing is not implemented.
The HBsAg carrier rate in pregnant women varies widely, from 0.15% in white U.S. women, to 8.9% in Asian women born outside the United States (9). The AT levels may be normal or only slightly elevated in many HBsAg-positive individuals. For epidemiologic purposes, persons with detectable HBsAg should be considered infectious. Mothers who are HBsAg-positive should not be discouraged from breastfeeding, as long as the infant has received prophylactic treatment.
Individuals who are HBeAg-positive usually have higher viremia levels, and have higher rates of vertical HBV transmission (10). Mothers who are hepatitis B e antibody-positive may also transmit HBV to their neonates, but at a much lower rate (11). If untreated, approx 90% of infants born to HBeAg-pos-itive mothers, compared to 10% of infants born to HBeAg-negative mothers, will become infected with HBV.
The majority of HBV-infected infants are asymptomatic, and become HBsAg-positive several weeks to months postpartum. When HBsAg is detectable in the neonate at birth, transplacental infection is suspected (10). Prophylactic treatment is not effective in this group of infants, and chronic infection is likely to develop. It is possible, that in infants, some degree of immune tolerance to the viral antigens results in a significantly decreased response to the prophylactic treatment (12).
Multiple studies have been conducted using different doses and regimens of HBV vaccine in combination with hepatitis B immunoglobulin. The combination prophylactic treatment is approx 95% effective in preventing HBV infection in the neonate exposed at birth. Premature neo-nates exhibit rates of response comparable to that in full-term infants. Prophylactic treatment started at birth provides prolonged protection.
Studies of prophylactic treatment, with the HBV vaccine alone, have provided promising results. In one study (13), the vaccine was 85% successful in preventing infection. Another study (14) revealed good results with a combined intramuscular-intradermal vaccination regimen. In another study (15), infants were vaccinated within 1 wk of birth, regardless of maternal HBsAg status. The prevalence of HBsAg was 4-5x greater in nonimmunized infants than in vaccinated ones after 1 yr. The above findings suggest that, in poor countries, it may be more cost-efficient to vaccinate all neonates, rather than to test the mothers for the presence of HBV.
The majority of the world's countries test pregnant women for HBsAg. Infants born to HBsAg-positive mothers receive hepatitis B immunoglo-
bulins at birth. They should also be immunized with the HBV vaccine at d 1, mo 1, and mo 6 after birth (16). Side effects of the vaccine are uncommon, and include irritability, mild fever, and local irritation at the injection site.
The goal of immunization is to develop a protective hepatitis B surface antibody level above 100 IU/L. The rate of decline of antibody titer is well-known, with a titer of 100 IU/L falling to less than 10 IU/L in approx 5 yr. There are no universal recommendations regarding routine follow-up of antibody levels in infants or women of childbearing age.
In 1991, the Centers for Disease Control and Prevention of the U.S. Public Health Service recommended the vaccination of all infants against HBV infection. Two yr later, two-thirds of U.S. infants were being immunized with the HBV vaccine, along with the other regularly scheduled childhood vaccinations. By then, one-half of all U.S. hospitals were offering HBV vaccines at birth.
The World Health Organization recommended the universal HBV vaccination of all infants to all countries, starting in 1992. In 1994, a goal of reducing the incidence of newly infected children by 80% by the year 2001 was established. Many nations adopted the routine HBV immunization of children; other nations elected to vaccinate only infants born to HBsAg-positive mothers. The tidal wave of new data revealing the efficacy of universal immunization should convince the latter nations to change their immunization policies and follow WHO recommendations.
Adverse effects following HBV vaccination of children have been reported in recent years. Allergic reactions, such as urticaria, ocular inflammation, and asthma, appear to be the most commonly reported HBV-vaccine-induced effects. There have also been reports of delayed neurologic development in children who received the vaccine, although a causal relationship has not been proven. These adverse effects have been attributed to the presence of the preservative, thimerasol, a mercury derivative, in the vaccine preparation (17). Newer HBV vaccines are free of thimerasol or any other mercury derivative.
The hepatitis C virus (HCV), an RNA virus in the flavivirus family, is the etiologic agent in the majority of cases of what was previously referred to as non-A, non-B hepatitis. It is also the virus responsible for the majority of cases of posttransfusion hepatitis in the United States, and the predominant bloodborne virus in injection drug users who share equipment. In excess of 170 million people worldwide have chronic HCV infection. Children can be infected by vertical spread from infected mothers, and evidence for sexual transmission has been documented. Sporadic infec tion without an identifiable risk factor is also responsible for some infections. Since the introduction of donor screening in 1990, transfusion-associated HCV infection has declined dramatically.
Data on acute HCV infection in pregnancy are scarce. Recent polymerase chain reaction (PCR) and HCV antibody data have been available for both mother and infant. Some reports have identified PCR and antibody-positive infants born to mothers who had acute HCV in the last trimester. Other reports show that infants born to mothers, under similar conditions, were not infected. More information is needed to determine whether acute infection has any effect on the progress of gestation. Further information is also needed to determine whether the natural history of the acute infection is altered by pregnancy.
Currently available data (18) reveal that chronic HCV infection in the mother does not influence pregnancy outcomes or complications. Data (19) also suggest that pregnancy does not adversely affect the course of hepatitis. Several studies reveal that the majority of HCV antibody-positive mothers maintain normal AT levels during pregnancy.
The HCV PCR levels in blood of pregnant women appear to increase during the second and third trimesters. Ward et al. (20) found that, among pregnant women seeking medical attention in inner London, the prevalence of HCV antibody-positive is 0.8%, the rate of HCV PCR-positive is 0.6%, and 69% of cases were newly diagnosed during pregnancy. Baldo et al. (21), in Padua, Italy, found that the characteristics independently associated with HCV antibody positivity in pregnant women were unmarried status, unemployed condition, and history of previous abortion.
Perinatal transmission of HCV has been extensively studied since serologic testing became available in 1990. Many studies show that, in the absence of human immunodeficiency virus (HIV) co-infection, perinatal transmission of HCV is uncommon. In Italy, Resti et al. (22) found that mothers with chronic HCV, who had previously delivered a HCV antibody-positive infant, were at no greater risk of infecting a subsequent infant. They also found that the chronicity of maternal infection is not a risk factor for perinatal transmission, and that each baby had an independently similar risk for contracting the infection. Zanetti et al. (23), in Milan, Italy, found that there was no correlation between HCV genotype and risk of perinatal transmission. The rate of perinatal transmission is estimated to be 3.6-5%.
Studies of perinatal transmission, based solely on detection of HCV antibody, may just reflect the passive transfer of maternal antibody. It is estimated that up to 50% of neonates born to infected mothers have detectable antibodies that usually disappear by 6-24 mo postpartum. More accurate studies of perinatal transmission require the use of PCR for the detection of virus.
Maternal co-infection with HIV and HCV is associated with an increased risk for acquiring HCV infection at birth. A study conducted in Florence, Italy (24), revealed that the risk of transmission increased as much as threefold, when mothers were co-infected with HIV, and had high levels of viremia. This increased risk of transmission is attributed to the increased HCV viremia found in HIV-infected persons, as the result of immunosuppression.
Available data suggest that the rate of perinatal transmission of HCV is not related to the route of infant delivery, i.e., vaginal delivery or cesarean section. In Germany, however, Hillemmans et al. (25) found that infants born by cesarean section, to mothers who were HCV antibody-positive, had a twofold risk of being antibody-positive after birth. Of this group of infants, 3.4% remained HCV PCR-positive 12 mo postpartum.
Concerning the possibility of HCV transmission via breast milk, a study conducted in Hamburg, Germany (26), revealed that none of 76 samples of breast milk obtained from infected mothers contained HCV by PCR. Current reports reveal that infants breastfed by infected mothers, with high viral counts in blood, appear to be free of infection 12 mo postpartum. Delamare et al. (27) reported one case of possible HCV transmission via transplacental amniocentesis.
Mast et al. (28) found that mode of delivery and breastfeeding were not associated with HCV transmission. They also found that the overall risk of transmission was 4% for PCR-positive mothers, compared to 0% for PCR-negative mothers. Factors associated with an increased risk for transmission were prolonged duration of membrane rupture, use of internal fetal monitoring devices, and meconium-stained amniotic fluid. Obstetricians may be able to alter two of these factors to decrease the risk of perinatal transmission.
Current data reveal that, among 31 European medical centers, there were no uniform antenatal HCV-screening guidelines or breastfeeding recommendations (29). Regarding to prevention of mother-to-infant transmission of HCV, immunoglobulin preparations have been ineffective against development of HCV infection, and HCV vaccines are not available.
Not much is known about the natural history of chronic HCV infection in infants infected during the perinatal period. The variability of infection factors, such as the genotype, level of viremia, and concomitant diseases, e.g., HIV, makes it difficult to interpret the results of available clinical studies. One study (30) revealed that up to 40% of HCV-infected children present evidence of mild-to-moderate chronic hepatitis after 3 yr of documented infection. Other small studies have not shown similar results. Given the paucity of long-term studies of HCV-infected infants, it is not possible to establish firm treatment guidelines at this time.
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The first trimester is very important for the mother and the baby. For most women it is common to find out about their pregnancy after they have missed their menstrual cycle. Since, not all women note their menstrual cycle and dates of intercourse, it may cause slight confusion about the exact date of conception. That is why most women find out that they are pregnant only after one month of pregnancy.