Hepatitis B virus is a major global health problem infecting two billion people worldwide and causing chronic infection in 350 million.1 It is estimated that 600,000 people die each year from acute or chronic liver disease as a result of hepatitis B virus.1 In the United States, 800,000–1.4 million people are living with chronic hepatitis B infection, and it is the underlying cause of 3,000 deaths per year.2,3
In 1991, the Advisory Committee on Immunization Practices recommended a comprehensive hepatitis B immunization strategy. The primary objective was the prevention of chronic hepatitis B and one of the main components of the strategy was the prevention of perinatal hepatitis B virus transmission.4 The American College of Obstetricians and Gynecologists then released a recommendation in 1993 and again in 2007 that pregnant women at high risk for hepatitis B should receive vaccination.5 However, successful implementation is difficult as a result of failure to complete an entire hepatitis B vaccine series at 0, 1, and 6 months in the course of pregnancy.
Recent studies have shown an accelerated (0, 1, and 4 months) and superaccelerated (0, 7–14, 21–28, and 360 days) vaccination schedule to be as immunogenic as the standard schedule.6–9 The superaccelerated schedule of 0, 7–14 days, and 21–28 days has been shown to provide rapid protection against hepatitis B virus; however, a fourth dose is required at month 12 to booster immunity.6–8 The current Centers for Disease Control and Prevention guidelines recommend a minimum interval between the first and second dose of 4 weeks and between the first and third dose of 16 weeks for optimal immune response.10 Therefore, a vaccination schedule of 0, 1, and 4 months would be the shortest recommended schedule that still offers protective long-term immunity. The use of an accelerated vaccination schedule has not been evaluated in pregnancy. This study was designed to estimate the feasibility and immunogenicity of implementing an accelerated hepatitis B vaccination schedule of 0, 1 and 4 months in high-risk pregnant women.
MATERIALS AND METHODS
This study was a prospective clinical trial to estimate the efficacy of the inactivated hepatitis B vaccine in high-risk women when given at an accelerated vaccination schedule of 0, 1, and 4 months. It was conducted at Parkland Health & Hospital System in Dallas, Texas, which serves a predominantly indigent prenatal population. Enrollment occurred over a 6-year period beginning in September 2000. The study protocol was approved by the institutional review board of the University of Texas Southwestern Medical Center at Dallas.
Women referred to the Obstetric Infectious Disease Complications Clinic who were hepatitis B surface antigen-negative at presentation for prenatal care were approached for enrollment. Information on the hepatitis B vaccine was provided in both English and Spanish. Initial hepatitis B core antibody and hepatitis B surface antibody were drawn to exclude women with prior hepatitis B infection or vaccination. Women were eligible for the trial if they were 16–45 years of age and less than 25 weeks of gestation (to receive all three doses of vaccine before delivery). Eligible women had a current diagnosis of a sexually transmitted disease, current injection drug use, or both, criteria considered “high risk” for hepatitis B acquisition. Exclusion criteria included a history of hepatitis B vaccination or infection, hepatitis B surface antigen-positive testing, allergy to yeast or hepatitis B vaccine, and immunomodulatory drug use or immunocompromise.
A detailed questionnaire was administered at enrollment after informed consent was obtained. Information regarding demographic characteristics and risk factors for hepatitis B was collected. Recombivax HB, a thimerosal-free recombinant hepatitis B vaccine, was administered intramuscularly in the deltoid and the patient was monitored for 30 minutes after injection. If the initial study laboratory tests revealed a previously unrecognized hepatitis B infection or vaccination, ie, a positive hepatitis B core antibody or hepatitis B surface antibody, the woman was then excluded from the remaining study protocol because she had hepatitis B immunity.
A follow-up study visit was performed 4 weeks after the initial vaccine dose. A second questionnaire detailing possible adverse reactions from the vaccine was administered. Hepatitis B surface antibody serology was performed and the second dose of vaccine given. Four months after the initial dose, the adverse reaction questionnaire was again given, a hepatitis B surface antibody drawn, and the final dose of hepatitis B vaccine administered. A final study visit was scheduled 5–6 months after the original vaccine dose. Any adverse reactions were again ascertained and a hepatitis B surface antibody drawn. Throughout the study period, women received their routine prenatal care in the Obstetric Infectious Disease Complications Clinic, and any pregnancy complications were documented.
The study sample size was based on the precision of our estimate. We anticipated a final seroconversion rate of at least 85%; a sample size of 200 allowed the precision of the 95% confidence interval to be 5%. Vaccine immunogenicity was estimated based on the number of women who achieved seroimmunity with each successive dose of vaccine. Seroimmunity was defined as a hepatitis B surface antigen titer 10 milli-international units/mL or greater. Normally distributed continuous data were analyzed using a two-tailed unpaired Student's t test. Wilcoxon rank sum was used for nonnormally distributed data. An uncorrected chi-square test was used to analyze categorical data. P<.05 was considered significant.
Two hundred thirty-six women were enrolled in the study and received the first dose of vaccine. Thirty-six women had a positive hepatitis B surface antigen and were excluded. This left a cohort of 200 women in the study group. Thirty-two women (16%) did not complete the three doses of vaccine. Women who did not complete the series were younger (21.3±4.1 compared with 25.3±5.2, P<.001). Seventy-one percent of African American women received all three vaccines compared with 81% white, 90% Hispanic, and 100% Asian women (P<.001) (Table 1). Of note, there were no differences in preterm delivery in the two groups, so early delivery was not a factor in vaccine series completion. Overall, one hundred sixty-eight women (84%) received all three doses of vaccine (0, 1, and 4 months), and seroconversion rates were calculated using this cohort.
Seroconversion (hepatitis B surface antigen 10 milli-international units/mL or greater) after one dose of recombinant hepatitis B vaccine was 56% (95% confidence interval [CI], 49–63%). This increased to 77% (95% CI, 71–83%) after two doses and reached 90% (95% CI, 85–94%) after three doses of vaccine.
Factors influencing hepatitis B seroconversion using the 0-, 1-, and 4-month accelerated schedule are depicted in Table 2. Race, maternal age, gestational age at first vaccination, tobacco use, and alcohol use were not significant factors affecting seroconversion. However, body mass index (BMI, calculated as weight (kg)/[height (m)]2) was inversely associated with seroconversion rates (26 [23–30] compared with 36 [29–40]; P<.001) (Fig. 1). There was no single BMI cutoff above which seroconversion did not occur.
Adverse reactions within 48 hours of each vaccine dose were assessed (Table 3). There were no serious adverse events reported and no woman withdrew from the study secondary to side effects. The most prevalent complaint was mild discomfort at the injection site (10.5%). There was no increase in preterm delivery rates nor in neonatal intensive care admissions as compared with our general obstetric population (data not shown).
Our study shows that an accelerated hepatitis B vaccination schedule in pregnancy (0, 1, and 4 months) is both feasible and has comparable seroconversion rates to the standard 0-, 1-, and 6-month schedule (56%, 77%, and 90% compared with 30–55%, 75%, and greater than 90% nationally in healthy adults 40 years of age or younger).10 Compliance for vaccine series completion was 84% with African American ethnicity and young age associated with failure of completion rates. Body mass index was the only factor associated inversely with seroconversion. The vaccine was well tolerated in our pregnant women with no serious adverse events noted.
The American Medical Association, the American College of Obstetricians and Gynecologists, and the U.S. Public Health Services Advisory Committee on Immunization Practices all endorse comprehensive vaccination programs for children, adolescents, and adults.5,11 One of the largest groups that remain unvaccinated is reproductive-aged women. Although these women are often seen annually or for prenatal care, the hepatitis B vaccine series is seldom recommended by their healthcare provider. Reasons for underuse are ignorance of high-risk groups, patients' fear of vaccination and side effects, and, during pregnancy, the overall reluctance to vaccinate a pregnant woman.
Limited data are available on the use of hepatitis B vaccination in pregnancy.12–14 However, the Centers for Disease Control and Prevention and the American Congress of Obstetricians and Gynecologists indicate pregnancy is not a contraindication to hepatitis B vaccine.2,5 Seroconversion rates are no different in the pregnant and nonpregnant woman13,14 and no fetal risks have been reported. Initial concerns regarding the ability of a pregnant woman to mount an effective immune response to a vaccine are largely unfounded. The T-helper type II response during pregnancy results in a vigorous antibody-mediated immunity to pathogens and vaccine antigens. Pregnancy is an ideal time for preventive care and health maintenance because women frequently seek regular, scheduled health care. However, the antepartum period is limited and a 0-, 1-, and 6-month hepatitis B vaccination series is difficult to complete before delivery. After delivery, compliance rates to complete the series are expected to drop. An accelerated regimen, allowing for all three doses of vaccine to be given before delivery, would be ideal if seroconversion rates were comparable to those in nonpregnant adults.
Studies on the efficacy of accelerated hepatitis B vaccination schedules have shown comparable seroconversion rates to the standard 0-, 1-, and 6-month regimen in the nonpregnant adult.6–8,10,15,16 The Centers for Disease Control and Prevention and Advisory Committee on Immunization Practices guidelines currently recommend a minimal interval between the first and second dose of 4 weeks and between the first and third dose of 16 weeks.10 In healthy adults, seroconversion using the standard 0-, 1-, and 6-month regimen are 30–55% after the first dose, 75% after the second dose, and greater than 90% after the third dose.10,17,18 We found similar seroconversion rates in our study of pregnant women using an accelerated schedule of 0-, 1-, and 4-month vaccination.
Obesity was the only factor in our study that influenced seroconversion. Obesity has been shown to have a negative influence on seroconversion rates in both pregnant and nonpregnant women. Weber et al19 showed that only 29.5% of women with BMI greater than the 75th percentile developed seroprotective hepatitis B surface antigen levels compared with the 63.3% rate seen in all those with BMI under the 75th percentile. Furthermore, Ingardia et al20 evaluated the efficacy of the hepatitis B vaccination in pregnancy and found that the mean BMI in those responding to the vaccine was significantly lower (24.9) compared with the mean BMI (30.3) in nonresponders. Our study lends support to the theory that vaccine deposition into the fat and subsequent enzymatic denaturation accounts for the poor immune response in obese patients. Although limited data are available, small studies have reported improved seroconversion rates in obese patients with increasing needle length, dose and formulation of vaccine, and weight reduction surgery.21–24 Other factors that have been found to correlate poorly with immune response such as smoking and age were not associated with seroconversion in our cohort.
Compliance rates for hepatitis B vaccination completion varies depending on the population. Compliance is high in childhood and adolescent vaccination studies as well as in healthcare workers; however, high-risk groups such as sexual assault victims and commercial sex workers have low vaccine compliance rates (30–50%).9,10,25 Our compliance rate of 84% reflects the benefit of a pregnant population who receive regular healthcare visits. Pregnant women may also be motivated to complete a vaccination series for the possible neonatal protection provided by transplacental passage of protective hepatitis B antibodies.
Ideally, this study would benefit from a comparison in our population of the 0-, 1-, and 4-month regimen to a 0-, 1-, and 6-month regimen. The feasibility of completing the 0-, 1-, and 6-month regimen in our population, requiring enrollment before 16 weeks, was not deemed possible in a reasonable timeframe. However, the similar seroconversion rates in our study to the reported expected seroconversion rates for adults allows for the conclusion that a 0-, 1-, and 4-month regimen is equally effective. There is also a possibility that study participants with a negative initial hepatitis B surface antigen might have been previously vaccinated but lost seroreactivity, although by history they denied vaccine. If this occurred, it would be in a small percentage and should not affect the overall seroconversion rate significantly. Hepatitis B surface antigen continuous titer data would be needed to potentially determine loss of seroreactivity.
In conclusion, an accelerated hepatitis B vaccination schedule at 0, 1, and 4 months in high-risk pregnant women is effective, practical, and well tolerated. This accelerated vaccine schedule in pregnancy provides another strategy to decrease hepatitis B virus disease and transmission that can be completed before delivery.
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