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ORIGINAL RESEARCH |
From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Hartford Hospital, Hartford, Connecticut.
Address reprint requests to: Charles J. Ingardia, MD Division of Maternal Fetal Medicine Prenatal Testing Center, Hartford Hospital 80 Seymour Street Hartford, CT 06102 E-mail: cingard{at}harthosp.org
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Abstract |
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Methods: Records of 80 healthy gravidas who elected hepatitis B vaccination during pregnancy, after being identified as hepatitis B surface antigen (HbsAg) and antibody (HbsAb) negative on initial prenatal screen, were analyzed retrospectively. Each gravida was begun on a series of three recombinant hepatitis B vaccines at 0, 1, and 6 months. At 36–40 weeks’ gestation, all gravidas were rescreened for seroprotective levels of HbsAb using qualitative enzyme-linked immunosorbent assay analysis. The women 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), number of vaccinations received, race-ethnicity, gestational age at vaccination, and vaccination-to-rescreening interval. Data were compared by t test, 
2 test, or Fisher exact test. Stepwise logistic regression analysis was done.
Results: At rescreening, 39 (49%) of the 80 women had seroprotective HbsAb conversion. After two vaccinations, obese women (BMI at least 30) (P = .04), women at least 25 years old (P = .04), and women with smoking histories (P = .005) were significantly less likely to respond to the vaccine. Logistic regression analysis for predicting failure of seroprotective response after two vaccinations showed significantly increased odds for severe obesity with 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).
Conclusion: Maternal obesity, advancing age, and smoking have negative influences on the efficacy of hepatitis B vaccination in pregnant women.
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.
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Materials and Methods |
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-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, 2 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.
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Results |
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). 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.
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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.
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Discussion |
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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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Footnotes |
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Received September 24, 1998. Received in revised form November 30, 1998. Accepted December 10, 1998.
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References |
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2. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep 1991;40:1–25.[Medline]
3. Lazizi Y, Badur S, Perk Y, Liter O, Pillot J. Selective unresponsiveness to the HBsAg vaccine in newborns related with an in utero passage of hepatitis B virus DNA. Vaccine 1997;15:1095–100.[Medline]
4. Mahoney FJ, Woodruff BA, Erben JJ, Coleman PJ, Reid EC, Schatz GC, et al. Effect of a hepatitis B vaccination program on the prevalence of hepatitis B virus infection. J Infect Dis 1993;167: 203–7.[Medline]
5. Lo KJ, Lee SD, Tsai YT, Wu TC, Chan CY, Cheng GH, et al. Long-term immunogenicity and efficacy of hepatitis B vaccine in infants born to HBeAg-positive HBsAg-carrier mothers. Hepatology 1988;8:1647–50.[Medline]
6. Levy M, Koren G. Hepatitis B vaccine in pregnancy: Maternal and fetal safety. Am J Perinatol 1991;8:227–32.[Medline]
7. Ayoola EA, Johnson A. Hepatitis B vaccine in pregnancy: Immunogenicity, safety and transfer of antibodies to infants. Int J Gynaecol Obstet 1987;25:297–301.[Medline]
8. Grosheide PM, Schalm SW, van Os HC, Fetter WP, Heijtink RA. Immune response to hepatitis B vaccine in pregnant women receiving post-exposure prophylaxis. Eur J Obstet Gynecol Reprod Biol 1993;50:53–8.[Medline]
9. Garner P, Schaffner W. Immunization of adults. N Engl J Med 1993;328:1252–8.
10. Mahoney FJ, Burkholder BT, Matson CC. Prevention of hepatitis B virus infection. Am Fam Physician 1993;47:865–74.[Medline]
11. Guidelines for hepatitis B virus screening and vaccination during pregnancy. ACOG Committee opinion: Committee on Obstetrics: Maternal and Fetal Medicine (no. 111). Int J Gynaecol Obstet 1993;40:172–4.[Medline]
12. Alter MJ, Hadler SC, Margolis HS, Alexander WJ, Hu PY, Judson FN, et al. The changing epidemiology of hepatitis B in the United States: Need for alternative vaccination strategies. JAMA 1990;263: 1218–22.[Abstract]
13. Update on adult immunization. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep 1991;40:1–94.
14. Hess G, Hingst V, Cseke J, Bock HL, Clemens R. Influence of vaccination schedules and host factors on antibody response following hepatitis B vaccination. Eur J Clin Microbiol Infect Dis 1992;11:334–40.[Medline]
15. Weber DJ, Rutala WA, Samsa GP, Santimaw JE, Lemon SM. Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine. JAMA 1985;254:3187–9.[Abstract]
16. Noble RC, Penny BB. Comparison of leukocyte count and function in smoking and nonsmoking young men. Infect Immun 1975;12: 550–5.
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