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Copyright ©The Author(s) 2004.

Effect of hepatitis B immunoglobulin on interruption of HBV intrauterine infection
Xiao-Mao Li, Min-Feng Shi, Yue-Bo Yang, Zhong-Jie Shi, Hong-Ying Hou, Hui-Min Shen, Ben-Qi Teng
Xiao-Mao Li, Yue-Bo Yang, Zhong-Jie Shi, Hong-Ying Hou, Hui-Min Shen, Ben-Qi Teng, Department of Obstetrics and Gynecology, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
Min-Feng Shi, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
Author contributions: All authors contributed equally to the work.
Supported by the Science and Research Foundation of Guangzhou Science and Technology Committee, No.1999-J-005-01
Correspondence to: Professor Xiao-Mao Li, Department of Obstetrics and Gynecology, Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China. tigerlee777@163.net
Telephone: +86-20-85515609 Fax: +86-20-87565575
Received: February 6, 2004
Revised: February 19, 2004
Accepted: February 26, 2004
Published online: November 1, 2004

AIM: To evaluate the efficacy of hepatitis B immunoglobulin (HBIG) in interrupting hepatitis B virus (HBV) intrauterine infection during late pregnancy.

METHODS: We allocated 112 HBsAg positive pregnant women into 2 groups randomly. Fifty seven cases in the HBIG group received 200 IU (unit) HBIG intramuscularly every 4 wk from the 28 wk of gestation to the time of delivery, while 55 cases in the control group received no special treatment. HBsAg, HBeAg, HBcAb, HBeAb, HBsAb and HBV DNA levels were tested in the peripheral blood specimens from all of the mothers at 28 wk of gestation, just before delivery, and in blood from their newborns within 24 h before administration of immune prophylaxis.

RESULTS: The intrauterine infection rate in HBIG group and control group were 10.5% and 27.3%, respectively, with significant difference (P < 0.05). It showed ascendant trend as HBV DNA levels in the peripheral blood increased before delivery.

CONCLUSION: HBIG is potent to cut down HBV intrauterine infection rate significantly when administered to pregnant women regularly during late pregnancy. The possibility of HBV intrauterine infection increases if maternal blood HBV DNA ≥ 108 copies/mL.



Citation: Li XM, Shi MF, Yang YB, Shi ZJ, Hou HY, Shen HM, Teng BQ. Effect of hepatitis B immunoglobulin on interruption of HBV intrauterine infection. World J Gastroenterol 2004; 10(21): 3215-3217

INTRODUCTION

China is a high incidence area of hepatitis B virus (HBV) infection, with a mean HBsAg positive rate of about 10%. Forty to fifty percent of chronic HBV carriers are caused by vertical transmission, which ranks it among the important modes of HBV infection and an important reason of so many HBV carriers in the crowd. Also, it has close correlations with chronic hepatitis, liver cirrhosis and liver cancer. Intrauterine transmission is one of the main resources of hepatitis B virus (HBV) vertical infection, but there is no definite prophylaxis up to now[1-6]. Through HBV DNA quantitation by fluorogenic quantitative polymerase chain reaction (FQ-PCR), we evaluated the efficacy of HBIG in interrupting HBV intrauterine infection during late pregnancy and analyzed the relation between maternal HBV DNA level and the rate of intrauterine transmission.

MATERIALS AND METHODS
Patients

The subjects were drawn from pregnant women who had undergone regular prenatal check-up, and had been admitted for labor and followed up at the Obstetric Department of the Third Affiliated Hospital of Sun Yat-Sen University from December 1999 to October 2001.

The following eligible criteria should all be met: (1) single pregnancy; (2) gestational age ≤ 28 wk; (3) HBsAg positive in serum; (4) normal liver and kidney functions; (5) serial tests were negative for HAV, HCV, HDV and HEV; (6) exclusion of fetal anomalies by B-ultrasonography; (7) no receipt of other agents that were under research, anti-virus, immunomodulating, cytotoxic or steroid hormones during pregnancy; (8) their husbands were not HBV carriers or hepatitis B patients; and (9) ability to give written informed consent.

Methods

A total of 112 pregnant women according to the criteria set above and their newborns of 112 cases were chosen. The pregnant women were randomly divided into a HBIG group (57 cases) and a control group (55 cases). Each case in the HBIG group received 200 IU of HBIG ( produced by Sichuan Shuyang Pharmaceutical Ltd.) intramuscularly (im) every four weeks from 28 wk of gestation till delivery, while patients in the control group were given no special treatment. Blood specimens were tested for HBsAg, HBeAg, HBsAb, HBeAb, and HBcAb by enzyme linked immunosorbent assay (ELISA, assay kits produced by Zhongshan Biological Products Ltd.), and HBV DNA quantitation by FQ-PCR (assay kits produced by Da’an Genetic Diagnosis Center of Sun Yat-Sen University) in all the subjects at 28 wk and on the day of delivery, and their newborns (blood from femoral vein) 24 h after birth before the administration of immune prophylaxis. All the subjects followed-up regularly during pregnancy.

HBV intrauterine infection was defined as follows: HBsAg and/or HBV DNA positive in peripheral blood of newborns in 24 h after birth before the administration of active or passive immune prophylaxis.

Statistics

The quantity of HBV DNA was transformed to the form of log10 and then expressed as mean ± SD. All data were analyzed as χ2 (chi-square) test for positive difference and t test for comparisons of means between the 2 groups using SPSS 10.0 for windows. For all comparisons, P < 0.05 was considered statistically significant.

RESULTS
Clinical characteristics of pregnant women

There were no significant differences between the two groups as for age, nation, gravidity, abortive parity, gestational weeks, way of delivery, or pregnant complications (P > 0.1, Table 1).

Table 1
Table 1 Clinical characteristics of pregnant women of each group.
Intrauterine transmission of HBV

There were 6 cases of intrauterine infection in HBIG group. The counterpart in control group was 15. HBV intrauterine infection rate in HBIG group and control group were 10.5% and 27.3%, respectively, with significant difference (P < 0.05, Table 2).

Table 2
Table 2 Characters of neonatal HBV intrauterine infection.
Intrauterine transmission and the level of HBV DNA in maternal serum

The levels of HBV DNA were divided into 7 grades according to the fluorescent signals set by the operation manual, with grade 0 (< 105 copies/mL), grade 1 (< 106 copies /mL), grade 2 (< 107 copies/mL), grade 3 (< 108 copies/mL), grade 4 (< 109 copies/mL), grade 5 (< 1010 copies/mL), and grade 6 (< 1011 copies/mL). The intrauterine infection rate increased with the increase in HBV DNA level in maternal blood, with odds ratio (OR) increasing. The results of rank correlation and χ2 test indicated that although it showed an ascendant trend, there were no significant differences in intrauterine infection rate between grade 2 and grade 1, grade 3 and grade 2, grade 5 and grade 4. But there was significant difference between grade 3 and grade 4 (P < 0.05, Table 3).

Table 3
Table 3 HBV DNA levels in blood of mothers at delivery and HBV intrauterine infection.
Safety

No adverse events such as fever, rigor, skin rash, inflammation and scleroma at local injected area, or impairment of renal function as well as other discomforts were found during the medication of HBIG. As to Apgar score and development reference such as weight and height of the newborns at delivery, there were no significant difference between the 2 groups (P > 0.1, Table 4).

Table 4
Table 4 Development indices of neonates and Apgar score (mean ± SD).
DISCUSSION

Several studies have proved that maternal infectivity is the most important factor in intrauterine transmission of HBV[7], in which HBV DNA shows directly the condition of replication and infectivity of the virus in vivo. The latter can be exactly reflected through HBV DNA quantitation by FQ-PCR test clinically[8,9]. With the prominent sensitivity and specificity of the FQ-PCR test, our study indicated that the intrauterine infection rate had significant correlation with the level of HBV DNA in the maternal serum before delivery, which showed an ascendant trend; the intrauterine infection rate significantly increased at the level of HBV DNA ≥ 108 copies/mL, which was consistent with the findings by Ngui et al[10]. Those findings suggest that the threshold of HBV DNA ≥ 108 copies/mL is a potent index of HBV intrauterine infection. To those pregnant women whose serum levels of HBV DNA are high and have high infectivity, we propose to apply highly effective and safe anti-viral medicines to compress the replication of HBV and, therefore, rapidly and dramatically decrease HBV DNA level to interrupt intrauterine infection[11].

In this study, the intrauterine infection rate in the HBIG group and control group were 10.5% and 27.3%, respectively, which suggested that the intramuscular administration of HBIG regularly before delivery could effectively interrupt HBV intrauterine infection[12]. HBIG is a kind of passive antibody. One of its components, HBsAb, can combine with HBsAg, activate the complements, clear HBV, lower the level of virus in maternal blood, and thereby prevent and decrease the infection of normal cells. It was reported that the interruptive effect of HBV intrauterine infection by HBIG might correlate with the acquisition of neonatal passive immune, because placenta could transmit the antibody of IgG actively from mother to fetus during late pregnancy[13]. However, HBsAb was detected in none of the newborns in our study. The potential reason might be that the HBV level in maternal blood was so high (higher than the quantity that can be neutralized by the passive antibody) that the HBIG administrated to mother might not be enough to enter fetal body through placenta. So, we consider to increase the quantity of HBIG in our further studies of HBV intrauterine interruption.

We found that some newborns were HBsAg and HBV DNA negative but HBeAg positive in their blood drawn from femoral vein within 24 h after birth. Whether HBeAg can pass placenta is still under hot debate. It has been suggested that HBeAg can be more easily transmitted via placenta than HBsAg in that it is smaller than the latter and is free from agglutination[14]. HBeAg or the compound of HBeAg and α-HBeIgG can pass the barrier of placenta by means of active-transfer in human body[15]. One study also showed that some babies of HBV infected mothers were HBeAg positive and HBsAg negative in femoral blood at birth, and HBsAg titres of the mothers were significantly higher than HBeAg titres (200 times or more). So the positive HBeAg in neonatal serum could not be interpreted as contamination or leakage from the placenta, but can only be explained by that HBeAg can indeed cross placenta[16]. In our study, babies who were only HBeAg positive were born by mothers who were both HBsAg and HBeAg positive. Moreover, the sensitive and specific HBV-infection marker of HBV DNA quantitation were negative in neonatal peripheral blood, and HBeAg disappeared by 9-12 mo of age. So HBeAg in the neonatal peripheral blood is less likely to be an index of intrauterine infection, but transmitted passively from maternity.

Edited by Kumar M Proofread by Xu FM

1.  Hepatitis B vaccination--United States, 1982-2002.  MMWR Morb Mortal Wkly Rep. 2002;51:549-552, 563.  [PubMed]  [DOI]
2.  Kazim SN, Wakil SM, Khan LA, Hasnain SE, Sarin SK. Vertical transmission of hepatitis B virus despite maternal lamivudine therapy. Lancet. 2002;359:1488-1489.  [PubMed]  [DOI]
3.  Gerdts V, Babiuk LA, van Drunen Littel-van den Hurk PJ. Fetal immunization by a DNA vaccine delivered into the oral cavity. Nat Med. 2000;6:929-932.  [PubMed]  [DOI]
4.  Chen DS. Public health measures to control hepatitis B virus infection in the developing countries of the Asia-Pacific region. J Gastroenterol Hepatol. 2000;15 Suppl:E7-10.  [PubMed]  [DOI]
5.  Mast EE, Mahoney FJ, Alter MJ, Margolis HS. Progress toward elimination of hepatitis B virus transmission in the United States. Vaccine. 1998;16 Suppl:S48-S51.  [PubMed]  [DOI]
6.  Yu XL, Chen CH, Zhong M. [Reasons of failure in blocking mother-infant transmission of HBV by using vaccine and related strategies]. Zhonghua Huli Zazhi. 1997;32:69-71.  [PubMed]  [DOI]
7.  Hamdani-Belghiti S, Bouazzaou NL. [Mother-child transmission of hepatitis B virus. State of the problem and prevention]. Arch Pediatr. 2000;7:879-882.  [PubMed]  [DOI]
8.  Li XM, Liu SL, Li X, Huang HJ, Lu JX, Gao ZL. The relative study of hepatitise B virus DNA in maternal blood, umbilical blood and breastmilk. Acad J SUMS. 2000;21:233-235.  [PubMed]  [DOI]
9.  Yang YB, Teng BQ, Li XM, Lin CS, Hou HY, Shen HM. The application of PCR in the test of HBV DNA quantitation. J Sun Yat Sen University. 2003;24:20-23.  [PubMed]  [DOI]
10.  Ngui SL, Andrews NJ, Underhill GS, Heptonstall J, Teo CG. Failed postnatal immunoprophylaxis for hepatitis B: characteristics of maternal hepatitis B virus as risk factors. Clin Infect Dis. 1998;27:100-106.  [PubMed]  [DOI]
11.  Li XM, Yang YB, Hou HY, Shi ZJ, Shen HM, Teng BQ, Li AM, Shi MF, Zou L. Interruption of HBV intrauterine transmission: a clinical study. World J Gastroenterol. 2003;9:1501-1503.  [PubMed]  [DOI]
12.  Zhu Q, Lu Q, Gu X, Xu H, Duan S. A preliminary study on interruption of HBV transmission in uterus. Chin Med J (Engl). 1997;110:145-147.  [PubMed]  [DOI]
13.  Yue YF, Yang XJ, Zhang SL, Han XB. Clinical study on the prevention of HBV transmission from mother to infant by in-jection of HBIG in pregnant women with HBsAg. Chin J Practi-cal Gynecol Obstet. 1999;15:547-548.  [PubMed]  [DOI]
14.  Rumi MA, Begum K, Hassan MS, Hasan SM, Azam MG, Hasan KN, Shirin M, Khan AK. Detection of hepatitis B surface antigen in pregnant women attending a public hospital for delivery: implication for vaccination strategy in Bangladesh. Am J Trop Med Hyg. 1998;59:318-322.  [PubMed]  [DOI]
15.  Suga M, Shibata K, Kodama T, Arima K, Yamada S, Yachi A. A case of HBs antigen negative fulminant hepatitis with IgM antibody to hepatitis B core antigen persisting more than seven years. Gastroenterol Jpn. 1991;26:661-665.  [PubMed]  [DOI]
16.  Wang JS, Zhu QR. Infection of the fetus with hepatitis B e antigen via the placenta. Lancet. 2000;355:989.  [PubMed]  [DOI]