Hepatitis B infection is a serious perinatal problem because of potential long-term sequelae of neonates who are chronic hepatitis B antigen carriers.1 Fetuses can acquire infection through the placenta or by vertical transmission at delivery. The focus of perinatal prevention has been detection of chronic carrier status of gravidas through hepatitis B surface antigen (HbsAg) testing during pregnancy, followed by treatment of neonates with hepatitis B immune globulin, if gravidas have chronic hepatitis B antigenemia, as well as universal neonatal hepatitis B vaccination.2 Although such programs ideally identify infants at risk, they require one or more assays for HbsAg during pregnancy and ignore prevention for the mother. Also, infants who test positive for hepatitis surface antigen at birth might have diminished response to neonatal hepatitis B vaccination.3
Hepatitis B vaccination, when used for primary prevention, has effectively reduced risk of infection in most populations.4,5 There has been little effort to promote hepatitis B vaccination during pregnancy, despite potential benefits for women in preventing life-threatening illness through active immunization and conferring passive immunity to their fetuses. Immunization with recombinant hepatitis B vaccine during pregnancy is considered safe,6 and compliance with the vaccination schedule can be monitored because of the frequency of prenatal visits. Few data are available on the efficacy of the vaccine during pregnancy6–8 or factors in pregnancy that might alter immunologic response. We conducted a retrospective analysis of seroprotective response to the vaccine given to healthy gravidas.
Materials and Methods
Women attending the Women's Ambulatory Health Services at our institution were offered recombinant hepatitis B vaccines as part of routine prenatal care as of November 1, 1996, if they were found to be negative for HbsAg and hepatitis B surface antibody (HbsAb). The study population consisted of the first 80 healthy gravidas who met screening criteria and had elective immunization between November 1, 1996, and July 31, 1997. Study subjects were excluded if they were positive for human immunodeficiency virus (HIV) or if follow-up rescreening for HbsAb was not done. The vaccine (Engerix-B; SmithKline Beecham, Philadelphia, PA) was given as a series of 20 μg doses into the deltoid muscle with a 1½-inch needle. Three vaccinations were given on the recommended dosing schedule of 0, 1, and 6 months.
At 36–40 weeks' gestation, all gravidas were rescreened to determine seroprotective response to the vaccine, using an enzyme-linked immunosorbent assay (AUSAB-EIA, Abbott Labs, Abbott Park, IL). An assay indicating titer at or above 10 mIU/mL of HBsAb was considered evidence of seroprotection. Subjects were grouped by maternal age (less than 25 years or at least 25 years), smoking history, maternal weight, body mass index (BMI) (less than 30, at least 30, less than 34, or at least 34), race-ethnicity, gestational age in weeks at first vaccination, vaccination-to-rescreening interval, and number of vaccinations. Body mass index was calculated as weight in kilograms divided by height in meters squared. All weight calculations were based on data from initial prenatal visits. Obesity was defined as having a BMI of 30 or more, and severe obesity was defined as having a BMI of at least 34. Smoking history during the pregnancy was elicited by questioning at initial prenatal intake. The vaccination-to-rescreening interval was calculated as the number of weeks between the last vaccine dose and repeat antibody testing. The demographics for the study group are noted in Table 1. Data were compared by the t test, χ2 test, or Fisher exact test. Stepwise logistic regression was done to identify risk factors statistically significantly associated with lack of seroprotection after two doses of vaccine.
Of the first 89 vaccinated women, nine were excluded from analysis (one was HIV-positive and follow-up rescreening for HbsAb was not done in eight), resulting in 80 study subjects. At rescreening, 39 (49%) of the 80 had seroprotective HbsAb levels. Of the total seven (9%) received one vaccination, 64 (80%) received two vaccinations, and nine (11%) received all three vaccinations by the time of rescreening. Subsequent statistical analysis was done on data from gravidas who received two vaccinations, to eliminate the potential confounding variable of vaccination number. There were demographic differences between the seroprotected and nonseroprotected groups after vaccination (Table 2). There was a significant difference in the ability of the vaccine to confer immunity in obese gravidas. Mean maternal weight was significantly different for gravidas who did not respond to vaccination (75.5 kg) compared with those who developed a seroprotective antibody rise (64 kg) (P = .003). Among the 64 gravidas who received two vaccines, 19 had BMIs equal to or greater than 30. In that group, five (26%) had immunity, compared with 24 (53%) of 45 with BMIs less than 30 (P = .04). Among the 11 severely obese women (BMIs equal to or greater than 34), immunity was detected in only one (9%). This rate was significantly lower than that for the 53 women with BMIs less than 34, 28 (53%) of whom developed immunity (P = .008). The mean BMI in vaccine responders also was significantly lower (24.9) than in nonresponders (30.3) (P = .002). Proportional decreases in seropositivity after vaccination with increasing BMI were noted. When BMI groups were subdivided (less than 25, 25–29, and 30 or more), immunity was found to have occurred in 18 (67%) of 27, six (33%) of 18, and five (26%) of 19 (P = .012), respectively.
Of the women who received two vaccinations, 24 had histories of smoking. In that group, there was a decrease in vaccination efficacy, with only five women (21%) showing seroprotection. By contrast, 24 (60%) of 40 women with no smoking histories developed immunity (P = .005). Maternal age also had an influence on efficacy, with six (26%) of 23 women older than 25 years showing immunity, compared with 23 (56%) of 41 younger than 25 years (P = .04). Because the recommended dosing schedule required a 6-month interval between the second and third vaccinations, only nine (11%) of the 80 women received the three vaccinations in the antepartum period. Although seroprotection was noted in seven (77%) of nine women receiving the full series, compared with 29 (45%) of 64 who received two vaccinations, statistical significance between groups by number of vaccinations could not be shown (P = .08) because of the few women who received three vaccinations. The power of the test was approximately .40.
There was no significant difference in mean gestational age at first vaccination between those with and those without seroprotection (18.3 versus 18.9 weeks, P = .8), nor was there a difference in mean gestational age at second vaccination between the two groups (25.1 versus 24.6 weeks, P = .7). There was no significant difference in mean interval from second vaccination to rescreening between those with and those without seroprotection (11.1 versus 11.5 weeks, P = .7). Racial and ethnic characteristics did not have a significant effect on the rate of seroprotection; four (57%) of seven blacks, 22 (44%) of 50 Hispanics, and three (43%) of seven whites developed seroprotective antibodies. Comparable but unequal distribution of ethnic and racial characteristics prevented statistical comparison.
Logistic regression analysis demonstrated significant risk for seroprotection failure at rescreening after two vaccinations with severe maternal obesity (BMI at least 34) (odds ratio [OR] 16.2; 95% confidence interval [CI] 1.7, 154.7), smoking history (OR 7.5; 95% CI 2.0, 27.7), and age at least 25 years (OR 3.9; 95% CI 1.1, 14.4). The results of the logistic regression analysis are shown in Table 3.
Hepatitis B infection remains a major contributor to morbidity and mortality, with an estimated 5000 or more deaths per year in the United States attributable to it. Despite the availability of the vaccine since 1982, only 10% of the US population is vaccinated.9 Reasons cited most often for the low rate of vaccination include limited access of high-risk groups to preventive services and failure of patients to adhere to the vaccination schedules.10
Using hepatitis B vaccine during pregnancy can build active immunity in gravidas and passive immunity in their fetuses. Despite those obvious advantages and the ability to monitor compliance with the vaccination schedule in the antepartum period, vaccination in pregnancy is recommended only in selected cases, based on risk factors.11 However, because 30–40% of people with acute hepatitis B infections have no identifiable risk factors,12 it would seem prudent to offer vaccination to all gravidas, if the vaccine effectively confers immunity. Immunity of gravidas by vaccination also obviates the need for HbsAg testing, if vaccine-induced hepatitis B antibody is present in a subsequent pregnancy.
Few studies have examined safety and efficacy of the vaccine when administered during pregnancy. Ayoola and Johnson7 assessed the results of hepatitis B vaccination in 72 gravidas. In that study, 20 μg of vaccine was administered twice in the third trimester, at an interval of 1 month. Seroconversion (presence of any detectable HbsAb) occurred in 60 gravidas (84%). No information was provided on the rate of seroprotection. Grosheide et al8 studied 14 pregnant women who received the vaccine along with hepatitis B immune globulin as postexposure prophylaxis (active and passive immunization) and found seroprotective levels in nine (75%) of 12 women at 6 months postpartum. Levy and Koren6 followed ten neonates whose mothers had received the vaccine during pregnancy. These investigators noted no adverse effects. In this report, we describe the first analysis of data from women who received hepatitis B vaccine during their pregnancies using the standard dosing schedule recommended by the Centers for Disease Control and Prevention,13 according to a MEDLINE search of the literature from 1976 to November 1998 using the terms “hepatitis B vaccination” and “pregnancy.”
Although little is known about use of the vaccine in pregnancy, factors associated with efficacy of the vaccine in nonpregnant women and men have been studied.14,15 The rate of seroprotection after two of the three vaccinations in our series (45%) was lower than that reported in nonpregnant individuals (59–70%).14 Several host factors clearly affect immunization rate. Weber et al15 found an inverse relationship between weight-height index and seroconversion success after vaccination in study subjects. Likewise, there was an inverse relationship between mean age of subjects and rates of seroconversion. A possible explanation for the negative effect of obesity on vaccine efficacy may be the inadvertent deposition of the vaccine in fat rather than in muscle, resulting in higher failure rates. Deposition of the vaccine antigen into fat can delay absorption, allowing for denaturation of the vaccine antigen by enzymatic action.
A possible explanation for the lower seroprotection rates in smokers in our study is the suppression of blood leukocyte chemotaxis and the inhibitory effect of nicotine on T cell lymphocyte function in smokers.16 Immune response to the vaccine is T cell dependent, so any suppression of T cell function would be expected to inhibit antibody response. Advancing age also might have a negative effect on response to vaccine, because of decreases in chemotactic response or lymphocyte function.14
We recognize that given the small sample of our study, the odds ratio for vaccine failure might not be precise. Despite that, our study showed significant negative effects of obesity, smoking, and older age on efficacy of the vaccine administered during pregnancy. Although those factors might influence efficacy, vaccination during pregnancy appears to be as safe and as efficacious as vaccination in nonpregnant women. Pregnancy affords clinicians a unique opportunity for primary prevention of a potentially fatal illness, and use of the hepatitis B vaccine should be encouraged. More study is needed to determine methods to improve efficacy of the vaccine in subgroups of pregnant women who have reduced response to it. Such methods might include alternate vaccination schedules or delivery systems.
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