Abstract.
Universal immunoprophylaxis against hepatitis B virus (HBV) is regarded as a key element to prevent perinatal HBV infection. The aim of the present study was to investigate the changes in the hepatitis B surface antigen (HBsAg)- and hepatitis B envelope antigen (HBeAg)-positive rates in native and immigrant pregnant women, to realize the impact of immigrants, and to identify any weaknesses 30 years after the implementation of hepatitis B vaccination in Taiwan. A total of 20,020 test results of HBsAg and HBeAg in pregnant women—2,915 (14.6%) immigrant women and 17,105 native Taiwanese—from 1996 to 2015 were analyzed for changes during this 20-year retrospective cohort study. Native Taiwanese have a higher HBsAg-positive rate than immigrant women (P < 0.001). However, the HBsAg-positive rates decreased by 0.6% per year among native women, but did not decrease significantly (only by 0.18% per year) among immigrant women. The overall HBsAg-positive rate remained at high levels, 4.8% in the year 2015. The HBeAg-positive rate decreased significantly, by 0.22% per year, in the total women as well as by 0.23% per year in the native women (all P < 0.001); by contrast, the HBeAg-positive rate in immigrants decreased at a slower rate (0.10% per year), without a significant decreasing trend (P = 0.300). Higher HBeAg (+)/HBsAg (+) rate was found for the immigrants than for the native women (P < 0.001). To quickly and effectively lower the risk of vertical transmission, new approaches combined with vaccination may be needed in the post-immunization era.
INTRODUCTION
According to a report from the WHO, the global prevalence of infection by the hepatitis B virus (HBV) in the general population is approximately 3.5%, with 257 million persons living with chronic HBV infection in 2015. The highest prevalence remains in the African (6.1%) and Western Pacific (6.2%) regions.1 Persons with chronic hepatitis B infection are at risk for serious outcomes. For 2015, it was estimated that 887,220 persons died as a result of HBV infection globally, 337,454 due to hepatocellular carcinoma, 462,690 due to cirrhosis, and 87,076 due to acute hepatitis.2 People are more likely to be chronic carriers of HBV when they are infected during the perinatal period (90%), rather than during childhood (20%) or adulthood (0–7%).3 Hepatitis B envelope antigen (HBeAg) is a hepatitis B viral protein. It is an indicator of active viral replication. Children with HBeAg-positive mothers appear more likely both to be infected and to become chronic carriers.4 Universal immunoprophylaxis against HBV is regarded as a key element to prevent perinatal HBV infection. Taiwan’s universal HBV immunization program was introduced in July 1984. During the first 2 years (July 1984–June 1986), only children born of hepatitis B surface antigen (HBsAg)-positive mothers received vaccinations; after June 1986, coverage was extended to all newborns. Plasma-derived vaccines were used before July 1992; thereafter, three-dose recombinant vaccines were used (vaccinated after 0, 1, and 6 months). Since 1984, hepatitis B immunoglobulin (HBIG) has been administered within 24 hours of birth to newborns of HBeAg-positive mothers.5 According to a report from the Taiwan CDC, the national HBV vaccine coverage rate of the three doses in infants increased from 86.9% in 1986–1987 to 93.2% in 1996–1997, and reached 96.5% in 2008–2009. This program has successfully decreased the HBV carrier rate from 10.5% to less than 0.8% among children younger than 6 years.6,7 It has also successfully prevented the vertical (mother-to-child) transmission and decreased the incidence of liver cancer in vaccinated children.8 After three decades, with these vaccinated women now at childbearing age, the benefits of this vaccination program will be seen in the second generation. Nevertheless, a relatively high proportion of Taiwanese men have married women from China and Southeast Asian countries, where HBV has remained endemic. Over the past 16 years (2001–2016), a total of 380,837 Taiwanese men married foreign wives from China and other Southeast Asian countries, accounting for 15.6% of the total number of marriages.9 The infants born to these immigrant mothers from China and other Southeast Asian countries account for 9.6% of the total number of babies during this period.9 In this 20-year retrospective study, we investigated the trends in seroprevalence of HBsAg-positive rates, the HBeAg-positive rates, and the HBeAg seroconversion rates in both native and immigrant pregnant women, with the aim of identifying any shortfalls in the hepatitis B vaccination program 30 years after its implementation.
MATERIALS AND METHODS
Subjects.
From 1996 to 2015, a total of 20,020 pregnant women—2,915 (14.6%) immigrant women from China and other Southeast Asian countries and 17,105 native Taiwanese—who received prenatal examinations in the early second trimester at Fooyin University Hospital were recruited into this retrospective cohort study. The HBsAg and HBeAg were compulsory tests for pregnant women during their prenatal care visits and were paid by the National Health Insurance (NHI); therefore, all pregnant women were included into this study and no one was excluded. All mothers tested negative for HIV. The parities, birthdates, birthplaces, test dates, and test results of these women were collected from the hospital information system. In addition, 218 HBeAg-positive primiparous women who experienced their second parity in Fooyin University Hospital were included to compare the rate of e-antigen seroconversion. No one had received nucleoside/nucleotide analogs in their birth spacing, as determined by checking the medical records. The study protocol was reviewed and approved by the Fooyin University Hospital Ethics Review Board (IRB no: FYH-IRB-1067-07-01-A).
Serological test.
Before May 2010, the levels of HBsAg and HBeAg in blood were analyzed through a microparticle enzyme immunoassay using an AsXYM analyzer (Abbott Laboratories, Chicago, IL). Thereafter, a chemiluminescent microparticle immunoassay was performed using an ARCHITECT i2000 SR analyzer (Abbott Laboratories). In the HBsAg and HBeAg (qualitative) tests, samples having a ratio of signal/cutoff (s/co) of less than one were considered negative, whereas a s/co ratio greater than or equal to one was considered positive. Any sample with s/co greater than or equal to one was retested in duplicate, as described in the package insert. A previous report revealed good concurrence between the data obtained using the AsXYM and Architect i2000 systems: 98.8% for HBsAg and 98.4% for HBeAg, respectively.10
Statistics analysis.
Data were analyzed annually from 1996 to 2015. The subjects were divided into native and immigrant women, and categorized into three birth cohort groups: before July 1984, July 1984–June 1986, and July 1986 onward, to observe the impact of the nationwide hepatitis B vaccination program in Taiwan. The data were also stratified into four interval groups—1996–2000, 2001–2005, 2006–2010, and 2011–2015—to compare changes in the HBsAg-positive rates over this long period of time. The continuous data are expressed as mean ± 1 SD; the HBsAg and HBeAg-positive rates are provided with 95% CI. The differences in the categorical variables between groups were examined through a χ2 test; continuous variables were checked through a Student’s t-test. A simple linear regression analysis was used to investigate the changes in the HBsAg and HBeAg-positivity rates. Logistic regression was performed to estimate the risks, measured in crude and adjusted odds ratios, in the hepatitis B infection rates. A P-value of less than 0.05 was regarded as statistically significant. Data were analyzed using the software SPSS 20.0 for Windows (SPSS, Chicago, IL).
RESULTS
A total of 20,020 of pregnant women—2,915 (14.6%) immigrants and 174,105 (85.4%) native Taiwanese—were included in this retrospective study of the period 1996–2015. Their ages ranged from 14 to 48 years, and women from Vietnam, China, and Indonesia accounted for 93.6% of immigrants. The HBsAg-positive rate was 12.4% (95% CI: 12.0–12.9%) in total. Taiwanese women and immigrants from China and Cambodia had high HBsAg-positive rates, 12.9 (95% CI: 12.4–13.4%), 12.7 (95% CI: 10.0–15.4%), and 13.8% (95% CI: 4.9–22.7%), respectively, whereas women from Thailand had the lowest HBsAg-positive rate, 3.1% (95% CI: −2.9–9.2%). The HBeAg-positive rate in the total population was 4.0% (95% CI: 3.7–4.3%). The HBeAg-positive rates among women with HBsAg-positive were 32.0% (95% CI: 30.2–33.8%) in total and 30.5% (95% CI: 28.6–32.4%) in native Taiwanese women. Immigrant women from Vietnam, Indonesia, Cambodia, and the Philippines had highest HBeAg-positive rates among the women who were HBsAg positive, 49.4 (95% CI: 41.7–57.0%), 54.5 (95% CI: 33.7–75.4%), 62.5 (95% CI: 29.0–96.0%), and 57.1% (95% CI: 20.5–93.8%), respectively (Table 1). Table 2 shows significant differences of HBsAg (+) in total women and HBeAg (+) in women with HBsAg (+) between native and immigrant women (all P < 0.001), but no significant difference in HBeAg (+) in population between two groups (P = 0.542).
Table 1.
HBsAg- and HBeAg-positive rates among pregnant immigrant, 1996–2015
| No. of participants (n) | Prevalence rate (%) | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Country of origin | Total | HBsAg (+) | HBeAg (+) | HBsAg (+) in group | (95% CI) | HBeAg (+) in group | (95% CI) | HBeAg (+) in women with HBsAg (+) | (95% CI) |
| Taiwan | 17,105 | 2,214 | 675 | 12.9 | (12.4–13.4) | 3.9 | (3.7–4.2) | 30.5 | (28.6–32.4) |
| Immigrant | |||||||||
| Vietnam | 1,843 | 164 | 81 | 8.9 | (7.6–10.2) | 4.4 | (3.5–5.3) | 49.4 | (41.7–57.0) |
| China | 581 | 74 | 19 | 12.7 | (10.0–15.4) | 3.3 | (1.8–4.7) | 25.7 | (15.7–35.6) |
| Indonesia | 304 | 22 | 12 | 7.2 | (4.3–10.1) | 3.9 | (1.8–6.1) | 54.5 | (33.7–75.4) |
| Cambodia | 58 | 8 | 5 | 13.8 | (4.9–22.7) | 8.6 | (1.4–15.8) | 62.5 | (29.0–96.0) |
| Philippines | 84 | 7 | 4 | 8.3 | (2.4–14.2) | 4.8 | (0.2–9.3) | 57.1 | (20.5–93.8) |
| Thailand | 32 | 1 | 1 | 3.1 | (−2.9–9.2) | 3.1 | (−2.9–9.2) | NE | |
| Others* | 13 | 1 | 0 | 7.7 | (−6.8–22.2) | 0.0 | (0.0–0.0) | NE | |
| Total | 20,020 | 2,491 | 797 | 12.4 | (12.0–12.9) | 4.0 | (3.7–4.3) | 32.0 | (30.2–33.8) |
HBeAg = hepatitis B envelope antigen; HBsAg = hepatitis B surface antigen; NE = not estimated because of small sample size.
* Others include Malaysia, Myanmar, South Korea, and Turkey.
Table 2.
Comparison of HBsAg- and HBeAg-positive rates in Taiwanese and immigrant women
| Variable | Taiwanese | Immigrant women | P-value |
|---|---|---|---|
| Total number | 17,105 | 2,915 | – |
| HBsAg (+) in total women (%; 95% CI) | 2,214/17,105 (12.9; 12.4–13.4) | 277/2,915 (9.5; 8.4–10.6) | < 0.001 |
| HBeAg (+) in total women (%; 95% CI) | 675/17,105 (3.9; 3.7–4.2) | 122/2,915 (4.2; 3.5–4.9) | 0.542 |
| HBeAg (+) in women with HBsAg (+) (%; 95% CI) | 675/2,214 (30.5; 28.6–32.4) | 122/277 (44.0; 38.2–49.9) | < 0.001 |
HBeAg = hepatitis B envelope antigen; HBsAg = hepatitis B surface antigen.
Figure 1 presents the changes in the HBsAg-positive rates from 1996 to 2015. In the total women, the HBsAg-positive rate decreased significantly, by 0.58% per year (P < 0.001); native women also exhibited a significant decrease in the HBsAg-positive rate, by 0.60% per year (P < 0.001), dropping from a high of 18.7% in 2002 to a low of 4.8% in 2015; nevertheless, the HBsAg-positive rate in immigrant women underwent a slower rate of decrease (0.18% per year), with no decreasing trend (P = 0.055). The HBsAg-positive rate was still keeping high level (8.0%) in 2015. Figure 2 displays the changes in the HBeAg-positive rates in all pregnant women from 1996 to 2015. The HBeAg-positive rate decreased significantly, by 0.22% per year, in the total women as well as by 0.23% per year in the native women (P < 0.001); by contrast, the HBeAg-positive rate in all immigrant women decreased at a slower rate (0.10% per year), without any significant decreasing trend (P = 0.300).
Figure 1.
Changes in hepatitis B surface antigen positivity rates, with 95% CIs, in total, native, and immigrant populations of pregnant women from 1996 to 2015. This figure appears in color at www.ajtmh.org.
Figure 2.
Changes in hepatitis B envelope antigen positivity rates, with 95% CIs, in total, native, and immigrant populations of pregnant women from 1996 to 2015. This figure appears in color at www.ajtmh.org.
Analysis of the HBsAg-positive rate through logistical regression revealed (Table 3) that the HBsAg-positive rate of the immigrant women was lower than that of the Taiwanese women (P < 0.001), especially for the immigrant women from Vietnam (P < 0.001) and Indonesia (P = 0.004). These differences disappeared, however, after adjusting for other factors. We observed decreased HBsAg-positive rates in the more recent periods (2001–2015) and showed a decreasing trend when compared with the earlier period (1996–2000) (P < 0.05). When we stratified the data into three different cohorts according to the period of the nationwide hepatitis B vaccination program in Taiwan, we also found that there were decreasing trends in HBsAg-positive rates after implementation of the vaccination program, as compared with the rate before implementation of the vaccination program (P < 0.001 in each case). The significance of the screening periods and birth cohorts remained unchanged after adjusting for other factors.
Table 3.
Crude and adjusted ORs of factors associated with HBsAg-positive rate among pregnant women
| Variable | HBsAg | Crude OR | (95% CI) | P-value | Adjusted OR* | (95% CI) | P-value | |
|---|---|---|---|---|---|---|---|---|
| No. of negative | No. of positive | |||||||
| Immigration | ||||||||
| No (Taiwanese) | 14,891 | 2,214 | 1.00 | (Reference) | – | 1.00 | (Reference) | – |
| Yes | 2,638 | 277 | 0.71 | (0.62–0.81) | < 0.001 | 0.48 | (0.06–3.71) | 0.483 |
| Country | ||||||||
| Vietnam | 1,679 | 164 | 0.66 | (0.56–0.78) | < 0.001 | 1.39 | (0.18–10.78) | 0.752 |
| China | 507 | 74 | 0.98 | (0.77–1.26) | 0.884 | 2.05 | (0.26–15.98) | 0.495 |
| Indonesia | 282 | 22 | 0.53 | (0.34–0.81) | 0.004 | 1.11 | (0.14–8.95) | 0.922 |
| Cambodia | 50 | 8 | 1.08 | (0.51–2.27) | 0.847 | 1.97 | (0.22–17.32) | 0.541 |
| Philippines | 77 | 7 | 0.61 | (0.28–1.33) | 0.213 | 1.07 | (0.12–9.48) | 0.952 |
| Thailand | 31 | 1 | NE | – | – | NE | – | – |
| Others† | 12 | 1 | NE | – | – | NE | – | – |
| Screening year‡ | ||||||||
| 1996–2000 | 4,699 | 855 | 1.00 | (Reference) | – | 1.00 | (Reference) | – |
| 2001–2005 | 5,546 | 910 | 0.90 | (0.82–1.00) | 0.045 | 1.00 | (0.90–1.11) | 0.951 |
| 2006–2010 | 4,027 | 482 | 0.66 | (0.58–0.74) | < 0.001 | 0.81 | (0.71–0.91) | 0.001 |
| 2011–2015 | 3,257 | 244 | 0.41 | (0.36–0.48) | < 0.001 | 0.66 | (0.56–0.77) | < 0.001 |
| Birth cohort§ | ||||||||
| Before July 1984 (no vaccination) | 14,239 | 2,318 | 1.00 | (Reference) | – | 1.00 | (Reference) | – |
| July 1984–June 1986 (newborns of HBsAg (+) mother) | 1,236 | 113 | 0.56 | (0.46–0.69) | < 0.001 | 0.68 | (0.56–0.84) | < 0.001 |
| July 1986 onward (all newborns) | 2,034 | 60 | 0.18 | (0.14–0.24) | < 0.001 | 0.23 | (0.18–0.31) | < 0.001 |
HBsAg = hepatitis B surface antigen; OR = odds ratio; NE = not estimated because of small sample size.
* Adjusted ORs were mutually adjusted for immigrant, country of birth, screening year, and birth cohort.
† Others include Malaysia, Myanmar, South Korea, and Turkey.
‡ A decreasing trend in screening year (P < 0.001).
§ A decreasing trend for birth cohort (P < 0.001).
Table 4 presents the rate of HBeAg seroconversion in second parity among 218 HBeAg-positive primiparous women. A successful HBeAg seroconversion means a change from HBeAg positive to negative when these women were pregnant with their second parity. A total of 35 (16.1%) women who successful HBeAg seroconversion at an average interval of 2.4 years. There was no significant difference in the HBeAg seroconversion rates between native Taiwanese and immigrant women (P = 0.553).
Table 4.
Comparison of rate of HBeAg seroconversion in second parity among 218 HBeAg-positive primiparous (first parity) women
| Variable | Total | Taiwanese | Immigrant women | P-value |
|---|---|---|---|---|
| Number | 218 | 186 | 32 | – |
| HBeAg titer in first parity (s/co) | 295 ± 121 | 302 ± 120 | 262 ± 125 | 0.178 |
| Age in first parity (years) | 24.1 ± 4.2 | 24.1 ± 4.3 | 23.8 ± 3.4 | 0.622 |
| Interval, second–first parity (years) | 2.4 ± 1.7 | 2.4 ± 1.6 | 2.5 ± 1.9 | 0.700 |
| HBeAg seroconversion rate (%) | 35/218 (16.1) | 31/186 (16.7) | 4/32 (12.5) | 0.553 |
HBeAg = hepatitis B envelope antigen. HBeAg seroconversion = conversion from HBeAg positive to HBeAg negative. Data are means ± SD. s/co: ratio of sample relative light unit (RLU) to cutoff RLU.
DISCUSSION
In this study, we found that the HBsAg-positive rates decreased by 0.60% and 0.18% per year among the native and immigrant women during this study period. In 2015, the last year of the study, the overall HBsAg-positive rate remained at a high level of 4.8% among all pregnant women. This value is relatively high when compared with the infection rates of women in Western countries.11–14 In this study, the rate of decrease was 0.58% per year among all pregnant women. At this rate, it will take 9 years for the hepatitis B infection rate to reach 0.8%, the same level as that of vaccinated children in Taiwan.6
The HBsAg-positive rate in immigrants lingered near 8.0% in 2015, with no significantly decreasing trend when compared with the earlier times. In the data for this present study, immigrant women from Vietnam, China, and Indonesia accounted for 93.6% of the marriages of immigrant women. Hepatitis B virus universal vaccination programs in these countries were introduced later than in Taiwan, and may therefore be the main reason for high level of HBsAg-positive rate in immigrants. Besides, the changes in the number and composition of country of origin in immigrant women time may also contribute to our findings. Universal infant HBV vaccination was implemented in Vietnam in 2003. The vaccination coverage increased from 46.1% to 84.0% after undertaking the three-dose series.15 China has implemented routine HBV immunization of infants since 1992, but, unlike other Expanded Program on Immunization vaccines, families had to pay for the HBV vaccines. Beginning in 2005, the Chinese government adopted a completely free HBV vaccination program for all neonates. The immunization coverage with the three doses of HBV vaccine was 70% in 1998.16 An universal hepatitis B vaccination program for infants was adopted in Indonesia in 1997, but the birth dose vaccination coverage was less than 50%.17 The launch years for universal immunization in Vietnam, China, and Indonesia were later than those in Taiwan, and there were low vaccination coverage; as a result, the benefits of universal immunization may not be apparent in the immigrant women at present. In contrast to the vaccination programs in immigrants’ countries of origin, Taiwan’s universal HBV immunization program was introduced as early as 1984, and the vaccine coverage rate was greater than 95%. Furthermore, HBIG has been routinely administered within 24 hours of birth to newborns of HBeAg-positive mothers.5 These approaches may have resulted in decreasing trends of HBV infection in Taiwanese women.
In this study, higher HBeAg-positive rates among HBsAg-positive mothers were encountered in immigrant women: 62.5% in Cambodia, 57.1% in the Philippines, 54.5% in Indonesia, and 49.4% in Vietnam, respectively. Perinatal transmission due to elevated maternal HBeAg positive plays an important role in the vertical mother-to-child HBV transmission. Previous studies have shown that HBeAg seroconversion in genotype C–infected patients occurs later than in those with other genotypes. Thus, HBV genotypes can affect the natural history of chronic HBV infection as well as the mother-to-infant HBV transmission.18–20 Wen demonstrated that HBeAg-positive mothers had higher viral loads than did HBeAg-negative mothers. Maternal viral load is significantly associated with the risk of infection.21 Without prophylaxis, the risk is highest: approximately 70–90% HBV vertical transmission occurs in HBsAg- and HBeAg-positive mothers. Neonatal immunization may result in a 75–90% decrease in the carrier rate, with active immunization (vaccines) alone or active-plus-passive immunization HBIG given at birth.22 According to Chen et al.,4 the HBsAg-positive rate was much higher in children born to HBeAg-positive mothers than in those born to HBeAg-negative mothers: 9.26% versus 0.23%. Children with HBeAg-positive mothers were more likely to both be infected and become chronic carriers once infected with HBV. Active and passive immunization alone cannot interrupt all vertical transmissions of HBV, especially in HBeAg-positive mothers.
Nucleoside/nucleotide analog therapy can suppress HBV replication effectively by inhibiting HBV polymerase.23 In cases of a high maternal viral load, third-trimester prophylaxis with a class B drug (telbivudine or tenofovir) could further diminish the risk of vertical transmission.24 Pan et al.25 demonstrated that women with CHB given telbivudine during the second or third trimester of pregnancy lowered their rates of vertical transmission. Telbivudine produced no adverse events in mothers or infants 28 weeks after birth. Another study, conducted by the Taiwan Study Group for the Prevention of Mother-to-Infant Transmission of HBV (PreMIT Study), found that treatment with tenofovir disproxil fumarate for higher viremic mothers decreased the level of infant HBV DNA at birth and the degree of infant HBsAg-positive rate at 6 months.26 Although the HBsAg-positive rate remains high in Taiwan, the nucleoside/nucleotide analog drugs may offer a promising path to benefit these women and effectively lower the risk of vertical transmission of HBV infection.
The strength of the present study was that we have observed the changes in hepatitis B prevalence for immigrant and native pregnant women in Taiwan over a continuous period of 20 years. Our study has some limitations. First, we collected data from only a single regional hospital; tests for HBsAg and HBeAg are, however, compulsory prenatal examinations for all pregnant women and are covered by NHI. Thus, all test results were included in the present study, so there is no selection bias. Second, we were unable to collect the immunization records of the studied women and, therefore, we assumed that the native women were vaccinated in the mass immunization program because of the high vaccination coverage rate (> 95%) in Taiwan.6 Third, when investigating HBeAg seroconversion, we checked the medical records and the NIH system to confirm that no one received nucleoside/nucleotide analog therapy. These women might, however, have received such therapy at other clinics or hospitals after self-paying. The high cost of nucleoside/nucleotide would severely limit the number of such cases.
In conclusion, in this 20-year retrospective study, we found that the HBsAg-positive rate decreased significantly by 0.60% among the native women, but did not observe a similar decreasing trend among the immigrant women (0.18% per year) during this study period. The HBsAg positivity rate in all pregnant women remained as high as 4.8% in 2015. The HBeAg-positive rate decreased significantly by 0.23% per year in the native women (P < 0.001). By contrast, the HBeAg-positive rate in all immigrant women decreased at a slower rate (0.10% per year), without any significant decreasing trend (P = 0.300). Higher HBeAg (+)/HBsAg (+) rate was found in immigrant women than in Taiwanese women (P < 0.001). New approaches, such as the use of nucleoside/nucleotide analog therapy, combined with vaccination may be needed further to decrease the risk of vertical transmission in the postimmunization era.
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