- Email: [email protected]
Intrapartum hepatitis B screening
Intrapartum Scott Petermann, Winston-Salem,
hepatitis B screening
BA, and J.M. Ernest,
MD
North Carolina
OBJECTIVE: The purpose of this study was to determine the prevalence of acute hepatitis B in intrapartum patients and to describe the birth-to-administration interval of the hepatitis B vaccine and immune globulin in hepatitis B surface antigen-positive patients detected by intrapartum screening. STUDY DESIGN: Hepatitis B screening was performed on 8712 laboring patients admitted to Forsyth Memorial Hospital in Winston-Salem, North Carolina, between July 1, 1992, and Jan. 31, 1994. RESULTS: Fourteen laboring patients had positive results for hepatitis B surface antigen (prevalence O.lS%), and two of the 14 had a profile consistent with acute disease. The average interval from birth to administration of the hepatitis B immune globulin and hepatitis B virus vaccine was 18.6 hours (range 3.9 to 31 .O hours) for hepatitis B virus-infected patients whose hepatitis B surface antigen status was unknown before labor. CONCLUSION: lntrapartum screening allows for diagnosis of the asymptomatic patient with acute hepatitis B virus infection whose hepatitis B surface antigen status was unknown before labor who would not have received hepatitis B immune globulin had only early prenatal screening been performed. (AM J OBSTET GYNECOL 1995;173:369-74.)
Key words:
Hepatitis
B virus, pregnancy,
intrapartum
In pregnancy the hepatitis B virus (HBV) is thought to be transmitted primarily at the time of delivery. Vertical transmission is an effective route for neonatal infection, and approximately 10% to 85% of infants born to hepatitis B surface antigen (HBsAg)-positive mothers will become infected, depending on the hepatitis B e antigen (HBeAg) status of the mother. The morbidity and mortality is significant for these infants infected, with 90% having chronic infection and 25% of these ultimately dying of complications of liver disease.’ In spite of this, 90% of infections can be prevented if HBsAg-positive mothers are identified and their offspring are treated promptly after delivery with hepatitis B immune globulin and the HBV vaccine.2-4 Current recommendations from the Centers for Disease Control and Prevention (CDC) and The American College of Obstetricians and Gynecologists include adding HBsAg to routine early prenatal tests and early notification of the pediatrician as to the HBV status of the mother so the newborn can be given HBV vaccination and hepatitis B immune globulin, as appropriate.‘, ’ In spite of these recommendations, some practitioners remain reluctant to add the cost of HBsAg screening to the current battery of early prenatal tests. Of those who do From the Department of Obstetrics and Gynecology, Bowman Gray School of Medicine of Wake Forest University. Presented at the Fi$y;seventh Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, January 28-31, 1995. Reprint requests: J.M. Ernest, MD, Department of Obstetrics and Gynecology Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1066. Copyright 0 1995 by Mosby-Year Book, Inc. 0002-9378/95 $3.00 + 0 6/6/&5566
screening
screen, many are concerned that women may acquire HBV during pregnancy, yet remain asymptomatic during the interval from the early prenatal screen to delivery. Additional concerns include the population of untested women without prenatal care and the logistics of transferring the results of maternal HBV testing done early in pregnancy to the pediatrician at the time of delivery. Because of these potential problems, we asked the following questions: (1) Will intrapartum screening for HBsAg detect women with acute HBV infection who might have gone undetected by a single early prenatal screen? (2) Are intervals longer than the recommended 12 hours from birth-to-administration of hepatitis B immune globulin effective in reducing the vertical transmission of HBV in the newborn? The first question was addressed by the current study and the second question by a review of the literature. Material
and
methods
From July 1, 1992, until Jan. 31, 1994, all patients in labor admitted to Forsyth Memorial Hospital were screened for HBsAg. Approximately 5000 Forsyth County, North Carolina, residents are delivered annually at Forsyth Memorial Hospital, in addition to 300 to 400 deliveries per year for women transferred for highrisk obstetric care by residents and faculty of the Bowman Gray School of Medicine from a 1 g-county referral area. The patient population was described in a previous report.6 Approximately 50% of the patients received a routine early prenatal screen for HBsAg as recommended by the American Academy of Pediatrics and the CDC. In addition, all patients were screened on arrival at the 369
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Ernest
hospital in labor for HBsAg with the AUSRIA II-125 radioimmunoassay. The assay was performed once daily, and positive test results (defined as counts 2 2.1 times the mean of negative controls) were confirmed with standard hepatitis B profiles including HBeAg and antibodies to hepatitis B core (combined immunoglobulin [Ig] G/IgM and IgM) and HBsAg. All assay kits were manufactured by Abbott Laboratories of North Chicago, Illinois. Positive test results were determined as described in the package inserts. Acute infections were differentiated from chronic infections by the presence of anti-HBc IgM. The test results were reported as positive when the IMx Core-M assay had an index of z 1.2, as described in the manufacturer’s insert. Results During the 18 months from July 1, 1992, until Jan. 31, 1994, 87 12 laboring patients were screened for HBsAg (in addition to the early prenatal screens as described above). Fourteen patients (nine public patients and five private patients) were found to have positive results at the time of labor, for a prevalence of 0.16%. Seven of the 14 patients had received a routine early prenatal HBsAg screen and had been found to be HBsAg positive before the onset of labor. Two of the fourteen patients had patterns consistent with acute hepatitis B infection with positive HBsAg, positive antiHBc IgM, and negative anti-HBs (antibodies to the hepatitis B surface antigen).’ One of these two patients, who had not been screened prenatally, was also positive for HBeAg, putting her at high risk for vertical transmission to her newborn.” ’ This patient was a public black patient who had one recorded prenatal visit, no identifiable risk factors, and who was asymptomatic for hepatitis B. The other patient with a profile consistent with acute disease was a white private patient whose husband was known to have acute hepatitis B and who therefore had an identifiable risk factor as outlined by the Advisory Committee on Immunization practices of the CDC.” The average interval from birth to administration of the hepatitis B immune globulin for the seven patients whose HBsAg status was unknown before labor was 18.62 hours (range 3.9 to 30.9 hours). The average for all HBsAg-positive patients was 10.7 hours (range 0.7 to 30.9 hours) (Table I). Comment Differentiation of acute and chronic disease was particularly important in our study because of our goal of identifying women in whom acute disease may have developed between the time of an early prenatal screen and delivery. Separation of acute and chronic hepatitis B viral infection on the basis of viral markers such as
August 1995 Am J Obstet Gynecol
HBsAg, anti-HBs, anti-HBe, and total anti-HBc is difficult because most of these markers can be detected during chronic phases of disease.” In some cases of acute disease HBsAg and HBeAg are transient and may become undetectable before their respective antibodies can be detected.‘1-‘3 Total anti-HBc (both IgM and IgG antibodies) can be detected before the onset of symptoms; however, these antibodies can last longer than anti-HBs and may be detectable indefinitely.“‘, I*, I5 Several studies have shown that anti-HBc IgM is the only specific marker for the diagnosis of acute infection with hepatitis B.‘“.*’ Therefore we considered patients to have acute disease only in the presence of anti-HBc IgM. Vertical transmission of HBV is important in women with both acute and chronic disease. Infants who are born to women who are HBsAg positive have a 10% to 20% risk of HBV infection, which increases to 90% if the HBeAg is also positive.‘O Of those infected, 90% become carriers, and up to 25% of these will die of chronic liver disease as adults.‘” The development of the carrier state can be presented in 85% to 90% of infants born to HBsAg- and HBeAg-positive mothers by prompt administration of hepatitis B immune globulin and a series of HBV vaccinations.2-4 Current recommendations from both the CDC and ACOG are that HBsAg screening should be added to the battery of tests done at an early prenatal visit. It is also recommended that HBsAg testing be repeated late in pregnancy in patients at high risk for HBV infection, for women who have clinically apparent hepatitis, and for women without prenatal testing. Finally, according to CDC and ACOG recommendations, infants born to all HBsAg-positive mothers should receive both the hepatitis B immune globulin and first dose of HBV vaccine within 12 hours of birth, although the risk of vertical transmission is lower in the HBsAg-positive, HBeAg-negative woman than when both antigens are positive.‘, ’ Potential problems with the above recommendations include the logistics of transferring records obtained by the obstetrician early in pregnancy to the pediatrician at the time of birth. Difficulties relaying this information could possibly delay administration of treatment. Also, institutions that routinely receive large numbers of transfer patients or large numbers of unregistered patients may have patients who were not screened prenatally or may have patients whose HBsAg status is unavailable or unknown. In the current study 8712 patients were screened intrapartum for HBsAg, with an assay performed once daily. Fourteen were HBsAg-positive, and two of the 14 had patterns consistent with acute disease (HBsAgpositive, anti-HBc IgM positive, anti-HBs negative).’ Of these two patients, one was clinically asymptomatic and
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2
Table I. Interval from birth to administration newborns born to HBsAg-positive mothers
Patient
No.
Public Public Public Public Public Public Private Public Private Public Private Private Public Private known
to be HBsAg
positive
and hepatitis
B immune
Yes Yes Yes Yes Yes No Yes No No No No No No Yes before
labor
had
received
had no identifiable risk factors for HBV infection. This patient was also HBeAg-positive and therefore highly infectious.‘, ’ Under the current recommendations she may have gone undiagnosed, and consequently the neonate would not have received hepatitis B immune globulin in a timely fashion. Although our intrapartum screening method did not allow for reporting of every patient’s HBsAg status within 24 hours of birth nor for the administration of hepatitis B immune globulin and HBV vaccine within the 12 hours recommended by the CDC and ACOG, a review of the literature that shaped this policy may illustrate that strict administration of the hepatitis B immune globulin and HBV vaccine within 12 hours is not as critical as implied in recent articles.” ’ Beasley and Steven? in 1978 gave infants born to mothers positive for both HBsAg and HBeAg 0.2 ml of hepatitis B immune globulin shortly after delivery. All seven of the infants that received hepatitis B immune globulin after 48 hours became carriers. Of those who received hepatitis B immune globulin within 48 hours, only 43% became carriers. This suggested that timing was critical for delivery of hepatitis B immune globulin. Since then the importance of timing has been disputed by Okuda,” who achieved results similar to those of Beasley and Stevens. In his study a single 0.16 ml/kg dose of hepatitis B immune globulin given at 5 days resulted in a carrier rate of 42.5%. When multiple doses were given at 5 days, 1 month, and 3 months, the carrier rate dropped to 19%. In 1981 Beasley et al.” showed that 1 ml of hepatitis B immune globulin given at a mean of 36 minutes after birth (in the same patient population as reported in 1978) resulted in a carrier rate of 45% and that infants who received 0.5 ml of hepatitis B immune globulin at similar intervals after birth and at 3 months and 6
globulin
Child
routine
in
Interval (hr) j+om birth to hepatitis B immune globulin and HB V vaccine &ven
Known positivity before admission*
Type of prenatal care
1 2 3 4 5 6 7 8 9 10 11 12 13 14 *Patients
of HBV vaccine
371
early
prenatal
died
0.7 0.9 1.7 2.4 3.0 3.9 4.6 7.5 10.4 22.9 24.3 30.4 30.9 shortly after
delivery
screening.
months had a carrier rate of only 23%. In 1983, again with a similar patient population, Beasley et al.* used a single dose of hepatitis B immune globulin (0.5 ml) within 3 hours of birth and multiple injections of a formalin-inactivated HBV vaccine with and without hepatitis B immune globulin in three different dosing schedules. The three different schedules resulted in similar carrier rates (2.0% to 8.6%) that were not statistically different. In this report schedules with injections at birth of hepatitis B immune globulin and at 3 months with hepatitis B immune globulin and HBV vaccine were no better than serial HBV vaccinations and a single hepatitis B immune globulin injection at birth. In 1984 Wong et aL3 approximated the results of Beasley et al. when study groups received either multiple hepatitis B immune globulin injections and a series of plasma-derived, heat-inactivated HBV vaccinations, a single hepatitis B immune globulin injection at birth with a similar series of HBV vaccinations, or a series of HBV vaccinations without the hepatitis B immune globulin. Carrier rates were 2.9%, 6.8.%, and 2 l%, respectively, with no statistically significant differences between the two groups that received hepatitis B immune globulin. All groups received the first injection within ‘1 hour of birth. Finally, Xu et a1.“6 in 1985 used a formalin-inactivated vaccine (produced by the National Institute of Allergy and Infectious Disease) given within 24 hours of birth. In this study the carrier rate was 11%. The carrier rate and efficacy were similar for infants born to HBsAgpositive mothers and to mothers positive for both HBeAg and HBsAg. The results of this trial indicate that hepatitis vaccine alone, when administered shortly after birth, can substantially reduce perinatally acquired HBV disease. In summary, recommendations for infants born to
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HBsAg-positive mothers to receive hepatitis B immune globulin and HBV vaccine within 12 hours of birth are artificially set. Early studies indicated that administration of hepatitis B immune globulin within 48 hours was critical, whereas others found administration within several days to be acceptable. Multiple injections of hepatitis B immune globulin were shown to be more efficacious in preventing the carrier state than was a single injection when hepatitis B immune globulin was used alone. However, when HBV vaccination is added in conjunction with hepatitis B immune globulin administration, not only does the efficacy improve, but the need for multiple injections of hepatitis B immune globulin is removed. Finally, HBV vaccination alone when given within 24 hours of birth has been shown to have similar efficacy to a combination of vaccination and hepatitis B immune globulin administration. It is clear that HBV vaccination alone or in conjunction with hepatitis B immune globulin is important in the prevention of the carrier state in infants born to HBsAg- and HBeAg-positive mothers. Because current recommendations require all infants to be vaccinated, early administration of vaccine (within 24 hours) should become universal. The question remains regarding the need for, and timing of, the administration of hepatitis B immune globulin. It is difficult to compare one study with another directly because of different vaccines, different schedules, and different doses. However, the data support hepatitis B immune globulin administration and HBV vaccination to begin as early as possible. No studies have demonstrated conclusively that administration of hepatitis B immune globulin within 12 hours is critical or is more efficacious than administration between 12 and 48 hours. In the current study once-daily intrapartum screening (running the HBsAg assay once a day) allowed for prompt delivery of hepatitis B immune globulin and HBV vaccine, with a mean time from birth to administration of 18.6 hours to infants born to HBsAg-positive mothers whose HBV status was unknown before labor. Although not meeting strict CDC criteria, the availability in the hospital of daily screening and testing of HBsAg for intrapartum patients may permit the identification of patients with acute HBV infection and others with chronic disease that may go untreated if current recommendations are strictly followed. This study has several obvious limitations. Because of the low prevalence of HBsAg in the study population and the time frame of the study, no long-term follow-up of the neonates was done to determine whether a chronic carrier state did develop in an infant who received HBV vaccine and hepatitis B immune globulin more than the recommended 12 hours from birth. A second limitation is the method of diagnosing acute HBV disease, because at least haIf the patients tested intrapartum had not been screened prenatally for HBsAg. The use of the anti-HBc
IgM to confirm acute disease in the two patients described should reduce the false-positive diagnosis of acute disease, even in the absence of a negative early HBsAg screen. Finally, the finding of only one patient of > 8700 screened over an 18-month period with evidence of acute disease that might have been undetected had only early HBsAg screening been done is less-thancompelling evidence for a major change in recommendations. In spite of these limitations, we feel that these patients represent a subgroup that may benefit from intrapartum rather than early prenatal HBsAg screening. If daily testing for HBsAg is possible from the hospital laboratory personnel and cost-effectiveness standpoint and if administration of hepatitis B immune globulin within 24 to 48 hours of birth is as efficacious as administration within the more stringent 12-hour time frame previously recommended, intrapartum screening could be considered as an acceptable and possibly preferable alternative to early prenatal screening. After reviewing the literature and conducting the current review, we propose the following. (1) Hospitals with the capability should screen (run the test) for HBsAg once daily for intrapartum pregnant women. If the number of deliveries is sufficient to be cost effective, running the assay for HBsAg twice daily could be initiated and could meet current recommendations for delivery of hepatitis B immune globulin and HBV vaccination within 12 hours of birth. Intrapartum screening could then eliminate the need for screening early in pregnancy. (2) All infants should receive the first dose of the HBV vaccine within 24 hours, regardless of the final HBsAg status of the mother. (3) When the results of the HBsAg screen become available, infants whose mothers are HBsAg positive should receive 0.5 ml of hepatitis B immune globulin within 48 hours after birth, or as soon as possible. (4) Subsequent vaccinations in appropriate doses should be given at 1 and 6 months. (5) Support should continue for a rapid HBsAg test that would be inexpensive and simple enough to run throughout the day, shortening the potential time even more between birth and the availability of test results. REFERENCES
Centers for Disease Control. 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 WklvI ReD 1 1991:40: l-25.
Beasley RP, Lee X-Y, Roan C-H, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983;2:1099-102. Wong VCW, Reesink HW, Ip HM, et al. Prevention of the HBsAg carrier state in newborn infants of mothers who are chron; carriers of HBsAg and HBeAg by administration of hepatitis-B vaccine and hepatitis-B immunoglobulin. Lancet 1984;1:921-6. Stevens CE, Taylor PE, Tong MJ, et al. Yeast-recombinant
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5.
6. 7. 8.
9. 10.
11.
12.
13. 14. 15. 16.
17.
18.
19. 20. 21.
22.
23.
24. 25.
hepatitis B vaccine: efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission IAMA 1987:257:2612-6. American College of Obstetricians and Gynecologists. Committee on Obstetrics: Maternal and Fetal Medicine. Guidelines for hepatitis B virus screening and vaccination during nregnancv. Int I Gvnecol Obstet 1993;40:172-4. Err& JM,“Givner LB,-Pool R. Intrapartum hepatitis B screening in a low-risk population. AM J OBSTET GYNECOL 1990;163:978-80. Eble K, Clemens J, Krenc C, et al. Differential diagnosis of acute viral hepatitis using rapid, fully automated immunoassays. J Med Virol 1991;33:139-50. Okada K, Kamiyama I, Inomata M, Imai M, Miyakawa Y, Mayumi M. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B to their infants. N Engl J Med 1976;294:746-9. Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977;105:94-8. Centers for Disease Control. Protection against viral hepatitis: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep 1990;39:1-26. Overby LR, Ling CM, Decker RH, Mushahwar IK, Chau KH. Serodiagnostic profiles in viral hepatitis. In: Szmuness W, Alter HJ, Maynard JE, eds. Viral hepatitis. Philadelphia: Franklin Institute Press, 1981:169-81. Kryger P, Aldershvile J, Mathiesen LR, Nielsen JD, Copenhagen Hepatitis Acuta Programme. Acute type B hepatitis among HBsAg negative patients detected by anti-HBc IgM. Hepatology 1982;2:50-3. Mortimer PP, Vandervelde EM, Parry JV, Cohen BJ, Tedder RS. The anti-HBc IgM response in acute and convalescent phases of acute hepatitis. J Infect 1981;3:339-47. Hansson BG. Persistence of serum antibody to hepatitis B core antigen. J Clin Microbial 1977;6:209-11. Hoofnagle JH, Cerety RJ, Barker LF. Antibody to hepatitis B virus core in man. Lancet 1973;2:869-73. Hawkes RA, Boughton CR, Ferguson V, Lehmann NI. Use of immunoglobulin M antibody to hepatitis B core antigen in diagnosis of viral hepatitis. J Clin Microbial 198O;ll: 581-3. Roggendorf M, Deinhardt F, Frosner GG, Scheid R, Bayer LB, Zachoval R. Immunoglobulin M antibodies to hepatitis B core antigen: evaluation of enzyme immunoassay for diagnosis of hepatitis B virus infection. J Clin Microbial 1981;13:618-26. Lemon SM, Gates NL, Simms TE, Bancroft WH. IgM antibody to hepatitis B core antigen as a diagnostic parameter of acute infection with hepatitis B virus. J Infect Dis 1981;143:803-9. Chau KH, Hargie MP, Decker RH, Mushahwar IK, Overby LR. Serodiagnosis of recent hepatitis B infection by IgM class anti-HBc. Hepatology 1983;3:142-9. Kryger P. Significance of anti-HBc IgM in the differential diagnosis of viral hepatitis. J Virol Methods 1985;lO: 283-9. Govindarajan S, Ashcavai M, Chau KH, Nevalainen DE, Peters RL. Evaluation of enzyme immunoassay for antiHBc IgM in the diagnosis of acute hepatitis B virus infection. Am J Clin Path01 1984;82:323-5. Beasley RP, Hwang L-Y. Epidemiology of hepatocellular carcinoma. In: Vyas GN, Dienstag JL, Hoofnagle JH, eds. Viral hepatitis and liver disease. New York: Grune & Stratton, 1984:209-24. Beasley RP, Stevens CE. Vertical transmission of HBV and interruption with globulin. In: Vyas GN, Cohen SN, Schmid R, eds. Viral hepatitis. Philadelphia: Franklin Institute Press, 1978:333-45. Okuda N. Prevention of perinatally acquired hepatitis B infection. Hokkaido Med I 1982;57:151-6. Beasley RP, Lin C-C, Wang K-Y, et al. Hepatitis B immune
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globulin (HBIG) efficacy in the interruption of perinatal transmission of hepatitis B virus carrier state. Lancet 1981;2:388-93. 26. Xu Z-Y, Liu C-B, Francis DP, et al. Prevention of perinatal acquisition of hepatitis B virus carriage using vaccine: preliminary report of a randomized, double-blind placebo-controlled and comparative trial. Pediatrics 1985;76: 713-8.
Discussion BRENDA SMITH PEACOCK, Washington, North Carolina (Official Guest). The authors’ objectives were to describe the prevalence of acute hepatitis B intraparturn in a relatively low-risk population, thus pointing to potential flaws in the current universal prenatal screening guidelines of ACOG and the CDC. Approximately 3.5 million prenatal patients are now screened annually’; if a patient had negative results early on, she could potentially be undetected as infectious, if indeed asymptomatic, not known to be at risk, and not rescreened. The authors also questioned the 12-hour maximum interval between birth and administration of hepatitis B immune globulin and HBV vaccine, as recommended by ACOG and the CDC, demonstrating difficulty meeting such criteria if patients undergo intrapartum screening. Patients most at risk of transmitting significant disease to their infants are either HBeAg positive (70% to 90% transmission) or acquired acute hepatitis B in the third trimester (80% to 90% transmission). Fortunately, HBeAg positivity in the western (non-Asian) carrier population is quite low, at 0% to 10%. However, at least one patient in this study group posed a significant risk to her infant. Only seven of the authors’ 14 HBsAg-positive patients were recently diagnosed; two of these seven met criteria for acute disease, testing positive for hepatitis B core antigen IgM, which is a reliable indicator of acute or recent infection, remaining positive G months or longer.’ Unfortunately, there are no known negative early screens on these two patients to confirm actual onset of infection during pregnancy, the third trimester in particular. The patient with acute infection whose husband was known to be a carrier was an obvious risk. She certainly was a candidate for vaccination early on, if indeed HBsAg negative then. The second patient’s history, reported as asymptomatic, and with “at least one prenatal visit,” leads to the question of the adequacy of her prenatal care. Ethnic status is known to weigh into risk for hepatitis B, and many authors feel that poor prenatal care should be a recognized risk factor as well.” If so, then both of these patients were at risk and should have been rescreened or vaccinated by current ACOG guidelines. Therefore these two patients failed to support the authors’ conclusion that acute disease would be missed with current management. A number of prophylactic regimens have been shown to be effective, including HBV vaccine alone given shortly after birth. However, the most effective regimen seems to be administration of HBV vaccine and hepatitis B immune globulin just after birth, completing the DR.
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vaccine series. Current CDC guidelines mandate universal neonatal vaccination within 12 hours of birth if the mother is known to be HBsAg positive or if her status is unknown.” The CDC advises treating unknown status as positive, with the addition of hepatitis B immune globulin within 12 hours for known positive or unknown status4 ACOG has recommended the addition of hepatitis B immune globulin as soon as unknown status is confirmed as positive, recognizing potential delays in testing results. The average interval from birth to treatment in this previously “unknown” study group was 18.62 hours. In all likelihood, this regimen is successful, as the authors propose. It would be hoped that the CDC will soon be able to evaluate the effectiveness of .prophylaxis within 12 hours, versus longer intervals because of unknown status, because universal vaccination has now been in effect for at least 1 year. The logistic problems noted by the authors seem to be what would weigh most against their recommendations. According to a study in 1993,5 > 75% of United States hospitals surveyed already had maternal HBV screening policies in effect, requiring results before or on admission. With protocols in effect, most information will surely be appropriately transferred. Obviously, larger institutions have the most potential for problems. However, only 6% of United States hospitals deliver >5000 infants yearly; 50% deliver 5 1000 yearly and probably manage transfer of information appropriately. A 1992 ACOG Committee Opinion’ advised confirming a patient’s status before delivery, acknowledging that one third of United States hospitals do not perform HBsAg testing on site. This is obviously a smaller institution problem, as demonstrated by a survey of hospitals in eastern North Carolina. Only three of seven hospitals, all three with over 250 beds, performed testing on site. Such limitations would prohibit universal intrapartum screening as an effective means of detecting disease and preventing perinatal transmission, beyond what universal neonatal vaccination alone would do. Certainly those patients most at risk for an infection during pregnancy, after an initial negative screen, are those in high-risk categories, as at least one of the study’s patients demonstrates. The problem here seems to be appropriate use of prenatal vaccination. Obviously, compliance is an issue, but ACOG does support prenatal vaccination of high-risk patients.’ If indeed no early screens were done at all, the entire oportunity to prevent disease, rather than detect it, would be missed. Development of a rapid HBsAg test would certainly be useful for many institutions, primarily for that untested laboring population or those needing repeat testing in labor. It may also be useful in general screening, particularly before vaccination for those at risk. In closing, the authors’ case for changing to intraparturn screening is based on one patient with IgM status consistent with recent disease and with questionable risk status. Therefore it seems that existing ACOG recommendations for universal prenatal screening, re-
peat testing, or vaccination as indicated and HBV vaccination of all infants, adding hepatitis B immune globulin when appropriate, is indeed the most widely applicable and therefore most potentially effective plan of action. The following questions are addressed to the authors: (1) Were any patients offered prenatal vaccination? (2) Were any other carriers HBeAg positive? (3) Did all other HBsAg positive patients fall into “at risk” categories? (4) Did the “acute” HBeAg-positive patient have adequate prenatal care? (5) Were both “acute” patients asymptomatic in retrospect? (6) Were all HBsAg patients tested for IgM to hepatitis B core antigen and all others found to be negative? REFERENCES 1. Koretz L. Universal prenatal hepatitis B testing: is it costeffective? Obstet Gynecol 1989;74:808-14. 2. Baker DA. Hepatitis B infection in pregnancy. In: Mead PB, Hager WD, eds. Infection protocols for obstetrics and gynecology. Montvale, New Jersey: Medical Economics, 1992: 125-30. 3. Simms J, Duff P. Viral hepatitis in pregnancy. Semin Perinatol 1993;17:384-93. 4. Centers for Disease Control and Prevention. 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. 5. Centers for Disease Control and Prevention. Maternal hepatitis B screening practices-California, Connecticut, Kansas, and United States, 1992-1993. MMWR Morb Mortal Wkly Rep 1994;43:31 l-20. 6. American College of Obstetricians and Gynecologists. Guidelines for hepatitis B virus screening and vaccination during pregnancy. Washington: American College of Obstetricians and Gynecologists, 1992; ACOG Committee Opinion no 111. 7. American College of Obstetricians and Gynecologists. Hepatitis in pregnancy. Washington: American College of Obstetricians and Gynecologists, 1992: l-10; ACOG Technical Bulletin no 174.
MR. PETERMANN (Closing). I cannot answer the first question about offering patients hepatitis B vaccinations, because I did not have access to all the patients’ prenatal charts. Appropriate use of vaccination should be based on CDC and ACOG literature. As to the question regarding e antigen positivity, four of the 14 surface antigen-positive patients were also e antigen positive. Of course, there were two additional patients who were e antigen positive. One of the four patients had a pattern consistent with acute disease. As to the question regarding other patients falling into the highrisk category, the answer is no. Five of the 14 patients had identifiable risk factors, whether it was sexually transmitted diseases, ethnicity, or drug abuse. There were nine other patients who had no risk factors at all. Regarding the adequacy of prenatal care in the patient with acute disease, the answer is no. All patients were screened for IgM antibodies and hepatitis B core, and only two of the 14 had such a profile.
hepatitis B screening
BA, and J.M. Ernest,
MD
North Carolina
OBJECTIVE: The purpose of this study was to determine the prevalence of acute hepatitis B in intrapartum patients and to describe the birth-to-administration interval of the hepatitis B vaccine and immune globulin in hepatitis B surface antigen-positive patients detected by intrapartum screening. STUDY DESIGN: Hepatitis B screening was performed on 8712 laboring patients admitted to Forsyth Memorial Hospital in Winston-Salem, North Carolina, between July 1, 1992, and Jan. 31, 1994. RESULTS: Fourteen laboring patients had positive results for hepatitis B surface antigen (prevalence O.lS%), and two of the 14 had a profile consistent with acute disease. The average interval from birth to administration of the hepatitis B immune globulin and hepatitis B virus vaccine was 18.6 hours (range 3.9 to 31 .O hours) for hepatitis B virus-infected patients whose hepatitis B surface antigen status was unknown before labor. CONCLUSION: lntrapartum screening allows for diagnosis of the asymptomatic patient with acute hepatitis B virus infection whose hepatitis B surface antigen status was unknown before labor who would not have received hepatitis B immune globulin had only early prenatal screening been performed. (AM J OBSTET GYNECOL 1995;173:369-74.)
Key words:
Hepatitis
B virus, pregnancy,
intrapartum
In pregnancy the hepatitis B virus (HBV) is thought to be transmitted primarily at the time of delivery. Vertical transmission is an effective route for neonatal infection, and approximately 10% to 85% of infants born to hepatitis B surface antigen (HBsAg)-positive mothers will become infected, depending on the hepatitis B e antigen (HBeAg) status of the mother. The morbidity and mortality is significant for these infants infected, with 90% having chronic infection and 25% of these ultimately dying of complications of liver disease.’ In spite of this, 90% of infections can be prevented if HBsAg-positive mothers are identified and their offspring are treated promptly after delivery with hepatitis B immune globulin and the HBV vaccine.2-4 Current recommendations from the Centers for Disease Control and Prevention (CDC) and The American College of Obstetricians and Gynecologists include adding HBsAg to routine early prenatal tests and early notification of the pediatrician as to the HBV status of the mother so the newborn can be given HBV vaccination and hepatitis B immune globulin, as appropriate.‘, ’ In spite of these recommendations, some practitioners remain reluctant to add the cost of HBsAg screening to the current battery of early prenatal tests. Of those who do From the Department of Obstetrics and Gynecology, Bowman Gray School of Medicine of Wake Forest University. Presented at the Fi$y;seventh Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, Virginia, January 28-31, 1995. Reprint requests: J.M. Ernest, MD, Department of Obstetrics and Gynecology Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1066. Copyright 0 1995 by Mosby-Year Book, Inc. 0002-9378/95 $3.00 + 0 6/6/&5566
screening
screen, many are concerned that women may acquire HBV during pregnancy, yet remain asymptomatic during the interval from the early prenatal screen to delivery. Additional concerns include the population of untested women without prenatal care and the logistics of transferring the results of maternal HBV testing done early in pregnancy to the pediatrician at the time of delivery. Because of these potential problems, we asked the following questions: (1) Will intrapartum screening for HBsAg detect women with acute HBV infection who might have gone undetected by a single early prenatal screen? (2) Are intervals longer than the recommended 12 hours from birth-to-administration of hepatitis B immune globulin effective in reducing the vertical transmission of HBV in the newborn? The first question was addressed by the current study and the second question by a review of the literature. Material
and
methods
From July 1, 1992, until Jan. 31, 1994, all patients in labor admitted to Forsyth Memorial Hospital were screened for HBsAg. Approximately 5000 Forsyth County, North Carolina, residents are delivered annually at Forsyth Memorial Hospital, in addition to 300 to 400 deliveries per year for women transferred for highrisk obstetric care by residents and faculty of the Bowman Gray School of Medicine from a 1 g-county referral area. The patient population was described in a previous report.6 Approximately 50% of the patients received a routine early prenatal screen for HBsAg as recommended by the American Academy of Pediatrics and the CDC. In addition, all patients were screened on arrival at the 369
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hospital in labor for HBsAg with the AUSRIA II-125 radioimmunoassay. The assay was performed once daily, and positive test results (defined as counts 2 2.1 times the mean of negative controls) were confirmed with standard hepatitis B profiles including HBeAg and antibodies to hepatitis B core (combined immunoglobulin [Ig] G/IgM and IgM) and HBsAg. All assay kits were manufactured by Abbott Laboratories of North Chicago, Illinois. Positive test results were determined as described in the package inserts. Acute infections were differentiated from chronic infections by the presence of anti-HBc IgM. The test results were reported as positive when the IMx Core-M assay had an index of z 1.2, as described in the manufacturer’s insert. Results During the 18 months from July 1, 1992, until Jan. 31, 1994, 87 12 laboring patients were screened for HBsAg (in addition to the early prenatal screens as described above). Fourteen patients (nine public patients and five private patients) were found to have positive results at the time of labor, for a prevalence of 0.16%. Seven of the 14 patients had received a routine early prenatal HBsAg screen and had been found to be HBsAg positive before the onset of labor. Two of the fourteen patients had patterns consistent with acute hepatitis B infection with positive HBsAg, positive antiHBc IgM, and negative anti-HBs (antibodies to the hepatitis B surface antigen).’ One of these two patients, who had not been screened prenatally, was also positive for HBeAg, putting her at high risk for vertical transmission to her newborn.” ’ This patient was a public black patient who had one recorded prenatal visit, no identifiable risk factors, and who was asymptomatic for hepatitis B. The other patient with a profile consistent with acute disease was a white private patient whose husband was known to have acute hepatitis B and who therefore had an identifiable risk factor as outlined by the Advisory Committee on Immunization practices of the CDC.” The average interval from birth to administration of the hepatitis B immune globulin for the seven patients whose HBsAg status was unknown before labor was 18.62 hours (range 3.9 to 30.9 hours). The average for all HBsAg-positive patients was 10.7 hours (range 0.7 to 30.9 hours) (Table I). Comment Differentiation of acute and chronic disease was particularly important in our study because of our goal of identifying women in whom acute disease may have developed between the time of an early prenatal screen and delivery. Separation of acute and chronic hepatitis B viral infection on the basis of viral markers such as
August 1995 Am J Obstet Gynecol
HBsAg, anti-HBs, anti-HBe, and total anti-HBc is difficult because most of these markers can be detected during chronic phases of disease.” In some cases of acute disease HBsAg and HBeAg are transient and may become undetectable before their respective antibodies can be detected.‘1-‘3 Total anti-HBc (both IgM and IgG antibodies) can be detected before the onset of symptoms; however, these antibodies can last longer than anti-HBs and may be detectable indefinitely.“‘, I*, I5 Several studies have shown that anti-HBc IgM is the only specific marker for the diagnosis of acute infection with hepatitis B.‘“.*’ Therefore we considered patients to have acute disease only in the presence of anti-HBc IgM. Vertical transmission of HBV is important in women with both acute and chronic disease. Infants who are born to women who are HBsAg positive have a 10% to 20% risk of HBV infection, which increases to 90% if the HBeAg is also positive.‘O Of those infected, 90% become carriers, and up to 25% of these will die of chronic liver disease as adults.‘” The development of the carrier state can be presented in 85% to 90% of infants born to HBsAg- and HBeAg-positive mothers by prompt administration of hepatitis B immune globulin and a series of HBV vaccinations.2-4 Current recommendations from both the CDC and ACOG are that HBsAg screening should be added to the battery of tests done at an early prenatal visit. It is also recommended that HBsAg testing be repeated late in pregnancy in patients at high risk for HBV infection, for women who have clinically apparent hepatitis, and for women without prenatal testing. Finally, according to CDC and ACOG recommendations, infants born to all HBsAg-positive mothers should receive both the hepatitis B immune globulin and first dose of HBV vaccine within 12 hours of birth, although the risk of vertical transmission is lower in the HBsAg-positive, HBeAg-negative woman than when both antigens are positive.‘, ’ Potential problems with the above recommendations include the logistics of transferring records obtained by the obstetrician early in pregnancy to the pediatrician at the time of birth. Difficulties relaying this information could possibly delay administration of treatment. Also, institutions that routinely receive large numbers of transfer patients or large numbers of unregistered patients may have patients who were not screened prenatally or may have patients whose HBsAg status is unavailable or unknown. In the current study 8712 patients were screened intrapartum for HBsAg, with an assay performed once daily. Fourteen were HBsAg-positive, and two of the 14 had patterns consistent with acute disease (HBsAgpositive, anti-HBc IgM positive, anti-HBs negative).’ Of these two patients, one was clinically asymptomatic and
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Table I. Interval from birth to administration newborns born to HBsAg-positive mothers
Patient
No.
Public Public Public Public Public Public Private Public Private Public Private Private Public Private known
to be HBsAg
positive
and hepatitis
B immune
Yes Yes Yes Yes Yes No Yes No No No No No No Yes before
labor
had
received
had no identifiable risk factors for HBV infection. This patient was also HBeAg-positive and therefore highly infectious.‘, ’ Under the current recommendations she may have gone undiagnosed, and consequently the neonate would not have received hepatitis B immune globulin in a timely fashion. Although our intrapartum screening method did not allow for reporting of every patient’s HBsAg status within 24 hours of birth nor for the administration of hepatitis B immune globulin and HBV vaccine within the 12 hours recommended by the CDC and ACOG, a review of the literature that shaped this policy may illustrate that strict administration of the hepatitis B immune globulin and HBV vaccine within 12 hours is not as critical as implied in recent articles.” ’ Beasley and Steven? in 1978 gave infants born to mothers positive for both HBsAg and HBeAg 0.2 ml of hepatitis B immune globulin shortly after delivery. All seven of the infants that received hepatitis B immune globulin after 48 hours became carriers. Of those who received hepatitis B immune globulin within 48 hours, only 43% became carriers. This suggested that timing was critical for delivery of hepatitis B immune globulin. Since then the importance of timing has been disputed by Okuda,” who achieved results similar to those of Beasley and Stevens. In his study a single 0.16 ml/kg dose of hepatitis B immune globulin given at 5 days resulted in a carrier rate of 42.5%. When multiple doses were given at 5 days, 1 month, and 3 months, the carrier rate dropped to 19%. In 1981 Beasley et al.” showed that 1 ml of hepatitis B immune globulin given at a mean of 36 minutes after birth (in the same patient population as reported in 1978) resulted in a carrier rate of 45% and that infants who received 0.5 ml of hepatitis B immune globulin at similar intervals after birth and at 3 months and 6
globulin
Child
routine
in
Interval (hr) j+om birth to hepatitis B immune globulin and HB V vaccine &ven
Known positivity before admission*
Type of prenatal care
1 2 3 4 5 6 7 8 9 10 11 12 13 14 *Patients
of HBV vaccine
371
early
prenatal
died
0.7 0.9 1.7 2.4 3.0 3.9 4.6 7.5 10.4 22.9 24.3 30.4 30.9 shortly after
delivery
screening.
months had a carrier rate of only 23%. In 1983, again with a similar patient population, Beasley et al.* used a single dose of hepatitis B immune globulin (0.5 ml) within 3 hours of birth and multiple injections of a formalin-inactivated HBV vaccine with and without hepatitis B immune globulin in three different dosing schedules. The three different schedules resulted in similar carrier rates (2.0% to 8.6%) that were not statistically different. In this report schedules with injections at birth of hepatitis B immune globulin and at 3 months with hepatitis B immune globulin and HBV vaccine were no better than serial HBV vaccinations and a single hepatitis B immune globulin injection at birth. In 1984 Wong et aL3 approximated the results of Beasley et al. when study groups received either multiple hepatitis B immune globulin injections and a series of plasma-derived, heat-inactivated HBV vaccinations, a single hepatitis B immune globulin injection at birth with a similar series of HBV vaccinations, or a series of HBV vaccinations without the hepatitis B immune globulin. Carrier rates were 2.9%, 6.8.%, and 2 l%, respectively, with no statistically significant differences between the two groups that received hepatitis B immune globulin. All groups received the first injection within ‘1 hour of birth. Finally, Xu et a1.“6 in 1985 used a formalin-inactivated vaccine (produced by the National Institute of Allergy and Infectious Disease) given within 24 hours of birth. In this study the carrier rate was 11%. The carrier rate and efficacy were similar for infants born to HBsAgpositive mothers and to mothers positive for both HBeAg and HBsAg. The results of this trial indicate that hepatitis vaccine alone, when administered shortly after birth, can substantially reduce perinatally acquired HBV disease. In summary, recommendations for infants born to
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HBsAg-positive mothers to receive hepatitis B immune globulin and HBV vaccine within 12 hours of birth are artificially set. Early studies indicated that administration of hepatitis B immune globulin within 48 hours was critical, whereas others found administration within several days to be acceptable. Multiple injections of hepatitis B immune globulin were shown to be more efficacious in preventing the carrier state than was a single injection when hepatitis B immune globulin was used alone. However, when HBV vaccination is added in conjunction with hepatitis B immune globulin administration, not only does the efficacy improve, but the need for multiple injections of hepatitis B immune globulin is removed. Finally, HBV vaccination alone when given within 24 hours of birth has been shown to have similar efficacy to a combination of vaccination and hepatitis B immune globulin administration. It is clear that HBV vaccination alone or in conjunction with hepatitis B immune globulin is important in the prevention of the carrier state in infants born to HBsAg- and HBeAg-positive mothers. Because current recommendations require all infants to be vaccinated, early administration of vaccine (within 24 hours) should become universal. The question remains regarding the need for, and timing of, the administration of hepatitis B immune globulin. It is difficult to compare one study with another directly because of different vaccines, different schedules, and different doses. However, the data support hepatitis B immune globulin administration and HBV vaccination to begin as early as possible. No studies have demonstrated conclusively that administration of hepatitis B immune globulin within 12 hours is critical or is more efficacious than administration between 12 and 48 hours. In the current study once-daily intrapartum screening (running the HBsAg assay once a day) allowed for prompt delivery of hepatitis B immune globulin and HBV vaccine, with a mean time from birth to administration of 18.6 hours to infants born to HBsAg-positive mothers whose HBV status was unknown before labor. Although not meeting strict CDC criteria, the availability in the hospital of daily screening and testing of HBsAg for intrapartum patients may permit the identification of patients with acute HBV infection and others with chronic disease that may go untreated if current recommendations are strictly followed. This study has several obvious limitations. Because of the low prevalence of HBsAg in the study population and the time frame of the study, no long-term follow-up of the neonates was done to determine whether a chronic carrier state did develop in an infant who received HBV vaccine and hepatitis B immune globulin more than the recommended 12 hours from birth. A second limitation is the method of diagnosing acute HBV disease, because at least haIf the patients tested intrapartum had not been screened prenatally for HBsAg. The use of the anti-HBc
IgM to confirm acute disease in the two patients described should reduce the false-positive diagnosis of acute disease, even in the absence of a negative early HBsAg screen. Finally, the finding of only one patient of > 8700 screened over an 18-month period with evidence of acute disease that might have been undetected had only early HBsAg screening been done is less-thancompelling evidence for a major change in recommendations. In spite of these limitations, we feel that these patients represent a subgroup that may benefit from intrapartum rather than early prenatal HBsAg screening. If daily testing for HBsAg is possible from the hospital laboratory personnel and cost-effectiveness standpoint and if administration of hepatitis B immune globulin within 24 to 48 hours of birth is as efficacious as administration within the more stringent 12-hour time frame previously recommended, intrapartum screening could be considered as an acceptable and possibly preferable alternative to early prenatal screening. After reviewing the literature and conducting the current review, we propose the following. (1) Hospitals with the capability should screen (run the test) for HBsAg once daily for intrapartum pregnant women. If the number of deliveries is sufficient to be cost effective, running the assay for HBsAg twice daily could be initiated and could meet current recommendations for delivery of hepatitis B immune globulin and HBV vaccination within 12 hours of birth. Intrapartum screening could then eliminate the need for screening early in pregnancy. (2) All infants should receive the first dose of the HBV vaccine within 24 hours, regardless of the final HBsAg status of the mother. (3) When the results of the HBsAg screen become available, infants whose mothers are HBsAg positive should receive 0.5 ml of hepatitis B immune globulin within 48 hours after birth, or as soon as possible. (4) Subsequent vaccinations in appropriate doses should be given at 1 and 6 months. (5) Support should continue for a rapid HBsAg test that would be inexpensive and simple enough to run throughout the day, shortening the potential time even more between birth and the availability of test results. REFERENCES
Centers for Disease Control. 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 WklvI ReD 1 1991:40: l-25.
Beasley RP, Lee X-Y, Roan C-H, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 1983;2:1099-102. Wong VCW, Reesink HW, Ip HM, et al. Prevention of the HBsAg carrier state in newborn infants of mothers who are chron; carriers of HBsAg and HBeAg by administration of hepatitis-B vaccine and hepatitis-B immunoglobulin. Lancet 1984;1:921-6. Stevens CE, Taylor PE, Tong MJ, et al. Yeast-recombinant
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5.
6. 7. 8.
9. 10.
11.
12.
13. 14. 15. 16.
17.
18.
19. 20. 21.
22.
23.
24. 25.
hepatitis B vaccine: efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission IAMA 1987:257:2612-6. American College of Obstetricians and Gynecologists. Committee on Obstetrics: Maternal and Fetal Medicine. Guidelines for hepatitis B virus screening and vaccination during nregnancv. Int I Gvnecol Obstet 1993;40:172-4. Err& JM,“Givner LB,-Pool R. Intrapartum hepatitis B screening in a low-risk population. AM J OBSTET GYNECOL 1990;163:978-80. Eble K, Clemens J, Krenc C, et al. Differential diagnosis of acute viral hepatitis using rapid, fully automated immunoassays. J Med Virol 1991;33:139-50. Okada K, Kamiyama I, Inomata M, Imai M, Miyakawa Y, Mayumi M. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B to their infants. N Engl J Med 1976;294:746-9. Beasley RP, Trepo C, Stevens CE, Szmuness W. The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 1977;105:94-8. Centers for Disease Control. Protection against viral hepatitis: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR Morb Mortal Wkly Rep 1990;39:1-26. Overby LR, Ling CM, Decker RH, Mushahwar IK, Chau KH. Serodiagnostic profiles in viral hepatitis. In: Szmuness W, Alter HJ, Maynard JE, eds. Viral hepatitis. Philadelphia: Franklin Institute Press, 1981:169-81. Kryger P, Aldershvile J, Mathiesen LR, Nielsen JD, Copenhagen Hepatitis Acuta Programme. Acute type B hepatitis among HBsAg negative patients detected by anti-HBc IgM. Hepatology 1982;2:50-3. Mortimer PP, Vandervelde EM, Parry JV, Cohen BJ, Tedder RS. The anti-HBc IgM response in acute and convalescent phases of acute hepatitis. J Infect 1981;3:339-47. Hansson BG. Persistence of serum antibody to hepatitis B core antigen. J Clin Microbial 1977;6:209-11. Hoofnagle JH, Cerety RJ, Barker LF. Antibody to hepatitis B virus core in man. Lancet 1973;2:869-73. Hawkes RA, Boughton CR, Ferguson V, Lehmann NI. Use of immunoglobulin M antibody to hepatitis B core antigen in diagnosis of viral hepatitis. J Clin Microbial 198O;ll: 581-3. Roggendorf M, Deinhardt F, Frosner GG, Scheid R, Bayer LB, Zachoval R. Immunoglobulin M antibodies to hepatitis B core antigen: evaluation of enzyme immunoassay for diagnosis of hepatitis B virus infection. J Clin Microbial 1981;13:618-26. Lemon SM, Gates NL, Simms TE, Bancroft WH. IgM antibody to hepatitis B core antigen as a diagnostic parameter of acute infection with hepatitis B virus. J Infect Dis 1981;143:803-9. Chau KH, Hargie MP, Decker RH, Mushahwar IK, Overby LR. Serodiagnosis of recent hepatitis B infection by IgM class anti-HBc. Hepatology 1983;3:142-9. Kryger P. Significance of anti-HBc IgM in the differential diagnosis of viral hepatitis. J Virol Methods 1985;lO: 283-9. Govindarajan S, Ashcavai M, Chau KH, Nevalainen DE, Peters RL. Evaluation of enzyme immunoassay for antiHBc IgM in the diagnosis of acute hepatitis B virus infection. Am J Clin Path01 1984;82:323-5. Beasley RP, Hwang L-Y. Epidemiology of hepatocellular carcinoma. In: Vyas GN, Dienstag JL, Hoofnagle JH, eds. Viral hepatitis and liver disease. New York: Grune & Stratton, 1984:209-24. Beasley RP, Stevens CE. Vertical transmission of HBV and interruption with globulin. In: Vyas GN, Cohen SN, Schmid R, eds. Viral hepatitis. Philadelphia: Franklin Institute Press, 1978:333-45. Okuda N. Prevention of perinatally acquired hepatitis B infection. Hokkaido Med I 1982;57:151-6. Beasley RP, Lin C-C, Wang K-Y, et al. Hepatitis B immune
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globulin (HBIG) efficacy in the interruption of perinatal transmission of hepatitis B virus carrier state. Lancet 1981;2:388-93. 26. Xu Z-Y, Liu C-B, Francis DP, et al. Prevention of perinatal acquisition of hepatitis B virus carriage using vaccine: preliminary report of a randomized, double-blind placebo-controlled and comparative trial. Pediatrics 1985;76: 713-8.
Discussion BRENDA SMITH PEACOCK, Washington, North Carolina (Official Guest). The authors’ objectives were to describe the prevalence of acute hepatitis B intraparturn in a relatively low-risk population, thus pointing to potential flaws in the current universal prenatal screening guidelines of ACOG and the CDC. Approximately 3.5 million prenatal patients are now screened annually’; if a patient had negative results early on, she could potentially be undetected as infectious, if indeed asymptomatic, not known to be at risk, and not rescreened. The authors also questioned the 12-hour maximum interval between birth and administration of hepatitis B immune globulin and HBV vaccine, as recommended by ACOG and the CDC, demonstrating difficulty meeting such criteria if patients undergo intrapartum screening. Patients most at risk of transmitting significant disease to their infants are either HBeAg positive (70% to 90% transmission) or acquired acute hepatitis B in the third trimester (80% to 90% transmission). Fortunately, HBeAg positivity in the western (non-Asian) carrier population is quite low, at 0% to 10%. However, at least one patient in this study group posed a significant risk to her infant. Only seven of the authors’ 14 HBsAg-positive patients were recently diagnosed; two of these seven met criteria for acute disease, testing positive for hepatitis B core antigen IgM, which is a reliable indicator of acute or recent infection, remaining positive G months or longer.’ Unfortunately, there are no known negative early screens on these two patients to confirm actual onset of infection during pregnancy, the third trimester in particular. The patient with acute infection whose husband was known to be a carrier was an obvious risk. She certainly was a candidate for vaccination early on, if indeed HBsAg negative then. The second patient’s history, reported as asymptomatic, and with “at least one prenatal visit,” leads to the question of the adequacy of her prenatal care. Ethnic status is known to weigh into risk for hepatitis B, and many authors feel that poor prenatal care should be a recognized risk factor as well.” If so, then both of these patients were at risk and should have been rescreened or vaccinated by current ACOG guidelines. Therefore these two patients failed to support the authors’ conclusion that acute disease would be missed with current management. A number of prophylactic regimens have been shown to be effective, including HBV vaccine alone given shortly after birth. However, the most effective regimen seems to be administration of HBV vaccine and hepatitis B immune globulin just after birth, completing the DR.
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vaccine series. Current CDC guidelines mandate universal neonatal vaccination within 12 hours of birth if the mother is known to be HBsAg positive or if her status is unknown.” The CDC advises treating unknown status as positive, with the addition of hepatitis B immune globulin within 12 hours for known positive or unknown status4 ACOG has recommended the addition of hepatitis B immune globulin as soon as unknown status is confirmed as positive, recognizing potential delays in testing results. The average interval from birth to treatment in this previously “unknown” study group was 18.62 hours. In all likelihood, this regimen is successful, as the authors propose. It would be hoped that the CDC will soon be able to evaluate the effectiveness of .prophylaxis within 12 hours, versus longer intervals because of unknown status, because universal vaccination has now been in effect for at least 1 year. The logistic problems noted by the authors seem to be what would weigh most against their recommendations. According to a study in 1993,5 > 75% of United States hospitals surveyed already had maternal HBV screening policies in effect, requiring results before or on admission. With protocols in effect, most information will surely be appropriately transferred. Obviously, larger institutions have the most potential for problems. However, only 6% of United States hospitals deliver >5000 infants yearly; 50% deliver 5 1000 yearly and probably manage transfer of information appropriately. A 1992 ACOG Committee Opinion’ advised confirming a patient’s status before delivery, acknowledging that one third of United States hospitals do not perform HBsAg testing on site. This is obviously a smaller institution problem, as demonstrated by a survey of hospitals in eastern North Carolina. Only three of seven hospitals, all three with over 250 beds, performed testing on site. Such limitations would prohibit universal intrapartum screening as an effective means of detecting disease and preventing perinatal transmission, beyond what universal neonatal vaccination alone would do. Certainly those patients most at risk for an infection during pregnancy, after an initial negative screen, are those in high-risk categories, as at least one of the study’s patients demonstrates. The problem here seems to be appropriate use of prenatal vaccination. Obviously, compliance is an issue, but ACOG does support prenatal vaccination of high-risk patients.’ If indeed no early screens were done at all, the entire oportunity to prevent disease, rather than detect it, would be missed. Development of a rapid HBsAg test would certainly be useful for many institutions, primarily for that untested laboring population or those needing repeat testing in labor. It may also be useful in general screening, particularly before vaccination for those at risk. In closing, the authors’ case for changing to intraparturn screening is based on one patient with IgM status consistent with recent disease and with questionable risk status. Therefore it seems that existing ACOG recommendations for universal prenatal screening, re-
peat testing, or vaccination as indicated and HBV vaccination of all infants, adding hepatitis B immune globulin when appropriate, is indeed the most widely applicable and therefore most potentially effective plan of action. The following questions are addressed to the authors: (1) Were any patients offered prenatal vaccination? (2) Were any other carriers HBeAg positive? (3) Did all other HBsAg positive patients fall into “at risk” categories? (4) Did the “acute” HBeAg-positive patient have adequate prenatal care? (5) Were both “acute” patients asymptomatic in retrospect? (6) Were all HBsAg patients tested for IgM to hepatitis B core antigen and all others found to be negative? REFERENCES 1. Koretz L. Universal prenatal hepatitis B testing: is it costeffective? Obstet Gynecol 1989;74:808-14. 2. Baker DA. Hepatitis B infection in pregnancy. In: Mead PB, Hager WD, eds. Infection protocols for obstetrics and gynecology. Montvale, New Jersey: Medical Economics, 1992: 125-30. 3. Simms J, Duff P. Viral hepatitis in pregnancy. Semin Perinatol 1993;17:384-93. 4. Centers for Disease Control and Prevention. 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. 5. Centers for Disease Control and Prevention. Maternal hepatitis B screening practices-California, Connecticut, Kansas, and United States, 1992-1993. MMWR Morb Mortal Wkly Rep 1994;43:31 l-20. 6. American College of Obstetricians and Gynecologists. Guidelines for hepatitis B virus screening and vaccination during pregnancy. Washington: American College of Obstetricians and Gynecologists, 1992; ACOG Committee Opinion no 111. 7. American College of Obstetricians and Gynecologists. Hepatitis in pregnancy. Washington: American College of Obstetricians and Gynecologists, 1992: l-10; ACOG Technical Bulletin no 174.
MR. PETERMANN (Closing). I cannot answer the first question about offering patients hepatitis B vaccinations, because I did not have access to all the patients’ prenatal charts. Appropriate use of vaccination should be based on CDC and ACOG literature. As to the question regarding e antigen positivity, four of the 14 surface antigen-positive patients were also e antigen positive. Of course, there were two additional patients who were e antigen positive. One of the four patients had a pattern consistent with acute disease. As to the question regarding other patients falling into the highrisk category, the answer is no. Five of the 14 patients had identifiable risk factors, whether it was sexually transmitted diseases, ethnicity, or drug abuse. There were nine other patients who had no risk factors at all. Regarding the adequacy of prenatal care in the patient with acute disease, the answer is no. All patients were screened for IgM antibodies and hepatitis B core, and only two of the 14 had such a profile.