HBsAG and HBeAG markers among pregnant women in Manila, Philippines

TRANSACTIONS OF THE ROYALSOCIETY OF TROPICALMEDICINEAND HYGIENE(1986)80, 767-770

HBsAG

and

HBeAG

markers

among pregnant Philippines

women

767

in Manila,

NUNILON E. SY’, VIRGINIA BASACA-SEVILLA*, TAGUMPAY ESGUEFCRA~, R. PALMER BEASLEY~, Lu-Yu HWANG~ AND JOHN H. CROSS’

‘U.S. Naval Medical Research Unit No. 2, APO San Francisco, California 96528, USA; ‘Bureau of Research and Laboratories, Ministry of Health and 3Fabella Memorial Hospital, Manila, Philippines; 4University of Washington Medical Research Unit, Taipei, Taiwan, Republic of China.

Abstract

The sera of 5,684 pregnant women were tested for HBsAG and 432 (7.6%) were found positive. Positive HBsAG serawere then tested for the e antigen and of 413 tested. 115or 27.8% were oositive. The over-all prevalence rate of e antigen was 2.63%. All women were asymptomatic. S-k of 13 HBsAG-HBeAg-positive mothers delivered infants who becameHBsAg-positive within two years of age for a rate of 46%. The findings support earlier studies on the importance of the e antigen as an index of perinatal transmission. Also, they support evidence of unusually high rates of transmission among Asian ethnic groups. Introduction

Hepatitis B virus (HBV) infection is a worldwide problem but there is marked geographical variation in its frequency. In some places, including China and Southeast Asia, most people experience HBV infections before they reach adulthood (BEASLEY & HWANG,in press). Infections in early life are particularly serious becausethey are more likely to result in the chronic HBsAg carrier state (STEVENSet al., 1975; BEASLEYet al., 1982). Carriers are a problem because they may be infectious and because they develop chronic liver disease, including hepatitis, cirrhosis and hepatocellular carcinoma. HBV carrier rates in highly developed countries are generally low. The prevalence of HBsAg carriers among the populations of the USA, Australia and most Western European countries is only about 0.2% (SOBESLAVSKY,1980). In contrast, carrier rates throughout Southeast Asia are very high, usually 10% or more. Even within Asia there is substantial variation: 15 to 20% in Taiwan (BEASLEYet al., 1981; TONG et al., 1971), and 8 to 12% in Thailand (SOBESLAVSKY, 1980), while Japan has a rate of only 2.3% (OKOCHI et al., 1970). In the Philippines, reported rates range from 7 to 16% (LINGAO et al., 1981; BASACA-SEVILLA et al., 1981). The reasons for these marked geographical variations are unknown. There are several mechanisms of transmission of HBV and their relative importance also varies geographically (BEASLEY& HWANG,in press). In the past it was believed that HBV was only transmitted by transfusion from carriers or by unsterilized inoculation equipment. Screening programs to eliminate HBsAg-positive blood donations have effectively controlled post transfusion hepatitis in many parts of the world, but HBV continues to be a problem, and it is now apparent that most HBV infections are transmitReprint requeststo PublicationsOffice, U.S. Naval Medical ResearchUnit No. 2, APO SanFrancisco,California96528, USA, or 4th Flr. AccelerandoBldg., 395 Sen. G. Puyat

Avenue (formerly Buendia Ext.), Makati, Metro Manila,

Philippines.

ted by intimate contact between a carrier and a non-carrier. Transmission from a carrier mother to her infant is particularly important becauseit is very common and frequently results in the carrier state when it occurs. It usually occurs during labour and delivery, probably by microhaematological leaks across the placenta and/or exposure of the infant to infectious maternal secretions in the birth canal (STEVENSet al., 1975; BEASLEY& HWANG, 1983). Once infected at least 90% of infants becomecarriers, but not all carrier women are equally infectious for their infants (BEASLEYet al., 1983a, b). Two parameters in carrier mothers, HBeAg positivity and/or high titre of HBsAg, serve as good indicators of whether they will infect their babies (STEVENSet al., 1975; BEASLEYet al., 1977). Approximately 85 to 90% of infants of HBeAg-positive mothers become infected, in contrast to 5% or less of the infants of HBeAg-negative women. Mother -to infant transmission has been called “vertical” or. alternativelv. “nerinatal” transmission. Strictly speaking, neither i&m is completely accurate. To zoologists, vertical transmission means infection passed through the maternal germ cells, which apnears not to be the case with HBV. Perinatal transmission means infection during or shortly after birth. While this is probably usually the case, approximately 5% of maternal-infant transmission appears to have occurred in utero (BEASLEY & HWANG, in press). It is now possible to prevent HBV by immunization, but an appropriate approach must be tailored to the epidemiology of each place. For reasons that are unknown, there is considerable variation in the frequency of transmission of HBV carrier women in different parts of the world. Optimal prevention of perinatal transmission requires that immunoprophylaxis be initiated within the first few hours of life. This study was undertaken to estimate the frequency of mother to infant HBV transmission in the Philiopines.

768

HEPATITIS

SEROLOGY

IN

PREGNANT

Materials and Methods Venous blood specimens were obtained by Vacutainerz from all pregnant women seeking prenatal consultations between June 1982 and October 1983 at the Fabella Memorial Hospital, a government maternity hospital in Manila, Philippines, primarily serving lower socio-economic groups. The sera were removed from the clotted bloods and kept frozen until tested. The sera were tested for HBsAg in the Bureau of Research and Laboratories using enzyme immunoassay? EIA (Auszyme Abbott Laboratories North Chicago, Illmois, USA). Sera that were HBsAg-positive were tested for HBeAg by radioimmunoassay in the laboratories of the University of Washington Medical Research Unit (Abbott - HBe RIA). HBsAg-HBeAg-positive mothers were informed by mail of the findings and requested to bring their infants to NAMRU-2 to be tested for HBV, but most were not responsive. Only a few mothers responded to letters encouraging them to return with their children for hepatitis marker testing. It was very difficult to convince the mothers that they should have their children tested and most failed to understand the importance of the testing. Often, names and addressesgiven were fictitious and, most of the time, apathy was encountered.

Table I-Hepatitis Philippines

B markers

1 Mother Infant

Age (yrs/mtlts) 19 6

2 Mother Infant

among

WOMEN

HBeAg

PHILLIPINES

Results Blood was obtained from 5,684 women, 15 to 45 vears of age (mean age 21) and HBsAp; was detected in ihe sera Gf ‘431 or-7.6%. 413 of %e 431 HBsAgpositive sera were further tested for the e antigen and 115 (27.8%) were positive. Among the total study population, the e antigen prevalence was 2+/o. Among the 114 HBeAg-positive HBsAg carriers, only 19 returned with their infants for initial followup testing. All the infants tested were delivered at a time when their mothers were found positive for hepatitis markers. Of the 19, six were excluded because of inability to obtain a second follow-up. There were, therefore, 13 infants tested for both HBsAg and HBeAg on two occasions, the Iirst at age one to eight months (mean 3.9 months), and the second at age 15 to 23 months (mean 18.1 months) (Table I). On initial testing, one infant was found to be both HBsAg and HBeAg-positive, two were HBsAgpositive and three were HBeAg-positive. The remain-

13 HBeAg-positive

1st Test HBsAg

IN

carrier

Age (months)

mothers

and their children,

2nd Test HBsAg HBeAg

Manila,

Anti-HBe

+ +

+ +

+ +

+ +

-

18

18 2

+ -

+ +

16

+ +

+ -

-

3 Mother Infant

25 2

+ -

+

+ +

+ +

-

16

4 Mother Infant

21 1

+ -

+ +

+ +

+ +

-

16

5 Mother Infant

25 3

+ +

+

+ +

+ +

-

18

6 Mother Infant

23 3

+ +

+

+ +

+ qns*

-

15

7 Mother Infant

21 3

+ -

+

16

f -

-

+

8 Mother Infant

30 7

+ -

+

21

+ -

-

+

9 Mother Infant

30 5

+ -

+

19

+ -

-

+

10 Mother Infant

29 4

+ -

+

19

+ -

-

+

23

+ -

+ -

-

30 8

+ -

+

l1 EitF 12 Mother Infant

24 5

+ -

+ -

20

+ -

+ -

-

19 2

+ -

+ +

18

+ -

+ -

-

I3 EE’ *Quantity not sufficient

N.

SY

ing seven were negative with respect to both HBV markers on initial testing, even though their mothers were HBsAg-positive at the time of delivery. None of the 13 infants was anti-HBs positive on initial testing. On the occasion of the second examination, all 13 mothers were still HBsAg-positive, although only nine were still HBeAg-positive, while the other four had become anti-HBe positive. All three of the children who were positive for the HBsAg the year before remained positive, and were asymptomatic. Three other children who had been negative for HBsAe when oriainallv tested. had become HBsAnpositi& on subse&entiesting. ‘There were, therefore, a total of six children who were positive for HBsAg out of the nine who were born to the HBsAg-HBeAgpositive, anti-HBeAg negative mothers (66.7%). The four children of anti-HBeAg positive mothers were negative for HBsAg and anti-HBs. Discussion This study demonstrates a pattern of perinatal transmission of HBV similar to that observed in Taiwan, Hong Kong, Singapore, Mainland China and Japan. Six infants becameHBsAg carriers among the nine born to HBeAg-positive, HBsAg carrier mothers, a frequency which is only slightly lower and not different statistically from those reported from other Asian populations. In a previous study from the Philippines, Lingao et al., (unpublished report) found a carrier rate of six among six infants of HBeAgpositive, HBsAg carrier mothers. Three of our six carrier infants were HBsAenegative on the first specimen tested, all when thgy were under three months old, which is consistent with other studies which have shown that there is a two- to three-month incubation period following perinatal infection. During that period serum HBsAg is usually negative. But, as in other studies, we found that the infants remained HBsAg-positive when the infection was established later. Three infants were HBeAg-positive even though they were HBsAg negative at one and two months of age. These observations are consistent with passive transfer from the mother of the small HBeAg molecule. HBsAa and the whole henatitis virus are much larger and do not pass through the intact placenta. Thus, in the first few months of life, some infants are HBeAg-positive but HBsAg-negative. The 7.6% HBsAg prevalence observed among the women in this study is lower than carrier rates previously reported from the Philippines, even though we used one of the most sensitive tests available. NISHIOKA et al. (1975) reported 16% HBsAg positivity among asymptomatic individuals and in studies by LINGAO et al. (1981), a 12% HBsAg positivity rate was reported among volunteer blood donors and 11 to 14% in two population based surveys. BASACA-SEVILLA et al. (1979, 1981), using RIA, reported 8.7% to 16.1% HBsAg-positivity rates among various groups in Manila and from residents of different areas in the Philippines. Higher prevalence rates, varying from 14.2% to 17%, were found among commercial blood donors. Among selected groups of women, prevalence of HBsAg varied from 49% in a religious group to 8.7% among “hospitality girls”. In men, the rates were higher - 12.4% in a Reserve Officer Training Corps group and 13.2% in personnel

et al.

769

in the Philippine Armed Forces. These data indicate that the carrier rate in males may exceed that in females by a ratio of two or three to one. Among pregnant women, the present study is the largest to be done. LINGAOer al. (1983), in their study of 277 pregnant women, reported a positivity rate of 105% using the Reverse Passive Haemagglutination Test (RPHA) supplemented with RIA, which is higher than the rate of 7.6% in the present study in which an immunoxyme method was used. Lingao’s 277 pregnant women, of whom 29 (10.5%) were HBsAg-positive, showed six mothers who were HBeAg-positive (21%) which is similar to our own 27.8%. All the infants of these six mothers became HBsAg-positive within one year. Our own study showed a similar high rate of transmission of hepatitis B from mothers with detectable s and e antigens. Mothers with e antibodies failed to transmit their infection although they were found to be e antigen positive prenataJly. Perinatal transmission has been imnhcated as the most probable cause of the high prevalence rates of HBsAg carriers in Asia. But it is less common in Africa-and perhaps the Middle East. A high prevalence of HBeAe amone HBsAa carriers annears to be associated with high mfectioi rates in -&fants and children. In Taiwan, approximately 40% of infants of mothers who are carriers of HBsAg, and 85 to 90% of those with HBeAg-positive mothers, become carriers within the first three months of life (BFXLEY et al.. 1977, 1981). This is in contrast to the very low infectivity rates of infants born to Caucasian HBsAg carrier mothers who have much lower rates of HBeAg wsitivitv (SCHWEITZER et al.. 1975: SKINHOT et al.. i976). A study in England of infants of &ferent ethnic groups showed that perinatal infections were most common among the Chinese, moderate among African blacks and least among Caucasians(DERSO et al., 1978). The major implication of this study is that an effective programme for prevention of chronic HBV infections in the PhiliDDiIKS must nlace a maior emphasis on the preve&on of per&al infections. The findings are consistent with other studies in Asia indicating that maternal-infant transmission is a common and important mechanism of maintaining the chronic HBV carrier state. Thus an effective prevention programme in the Philippines must begin with infants of HBsAg carrier mothers. Interruption of this transmission link will probably be the key to control of chronic HBV infections and hepatocellular carcinoma in the Philippines. Acknowledgements We thank Dr. Josefina B. Cadoma for her assistance in the house to house campaign to draw blood from mothers and infants. This study was supported through funds provided by the Bureau of Research and Laboratories, Philippine Ministry of Health and the Naval Medical Researchand Development Command, Navy Department, Work Unit 3M161102.BSlO.AF429 and the Far East Foundation. The opinions and assertions contained herein are those of-the authors and are not to be cons-wed as official or reflecting the views of the U.S. -Navy Department or the Naval Service at large.

770

HEPATITIS

SEROLOGY

IN

PREGNANT

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PHILLIPINES

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for publication 16th May, 1985.