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Pregnancy outcomes among chronic carriers of hepatitis B virus
IJG-07955; No of Pages 5 International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Pregnancy outcomes among chronic carriers of hepatitis B virus Sirinart Sirilert, Kuntharee Traisrisilp, Pannee Sirivatanapa, Theera Tongsong ⁎ Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
a r t i c l e
i n f o
Article history: Received 24 September 2013 Received in revised form 13 February 2014 Accepted 10 April 2014 Keywords: Gestational diabetes Hepatitis B e antigen Hepatitis B surface antigen Hepatitis B virus infection Pregnancy Preterm birth
a b s t r a c t Objective: To compare pregnancy outcomes of women with chronic HBV infection with those of HBV-negative women. Methods: A retrospective cohort study was undertaken to analyze singleton pregnancies of women without medical/surgical disease and with known HBsAg status. Pregnancy outcome measures were compared among the control group, women with positive HBsAg status (case group), and those with positive HBeAg status. Results: Among 26 350 enrolled pregnant women, 21 812 in the control group and 1446 in the case group were compared. Only the proportion of preterm births was significantly higher among pregnancies with positive HBsAg status (RR 1.013 [95% CI, 1.001–1.025]). Among women with positive HBsAg status who had been screened for HBeAg, GDM was significantly higher among women with positive HBeAg status (RR 1.434 [95% CI, 0.999–2.057]). Preterm births and low birth weight were also significantly higher among women with positive HBeAg status (RR 1.250 [95% CI, 1.000–1.563] and 1.258 [95% CI, 1.053–1.505], respectively). Conclusion: Chronic carriers of HBV had a minimally increased risk of preterm birth and low birth weight but the risk was more pronounced in women with positive HBeAg status. Women with positive HBeAg status also had an increased risk of GDM. © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hepatitis B virus (HBV) infection is one of the most common health problems worldwide. The prevalence varies from country to country. In endemic regions such as China and Southeast Asia, the prevalence of HBV infection among women of childbearing age may be as high as 10%–20% [1], whereas in the USA it is only 0.4% [2]. Most pregnant women with HBV infection are chronic carriers, indicated by positive hepatitis B surface antigen (HBsAg) status. Most studies of pregnant women who are chronic carriers of HBV infection (positive HBsAg) have focused on the vertical transmission of HBV to children [3–5]. Although a few studies have explored the impact of this asymptomatic infection on pregnancy outcomes [6–10], the findings from the different studies were not consistent. For example, Reddick et al. [8] demonstrated an increased risk of preterm birth as well as prepartum hemorrhage with HBV infection, whereas Lao et al. [9] did not find such a relationship. Moreover, a significantly increased risk of gestational diabetes mellitus (GDM) and of fetal macrosomia has also been reported [9,11,12]. Most previous studies included both asymptomatic chronic carriers and those with chronic active disease, which theoretically would have a direct effect on the pregnancy outcome. The objective of the present study was to explore whether or not HBsAg and ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: + 66 53 946429; fax: +66 53 946112. E-mail address: [email protected] (T. Tongsong).
hepatitis B e antigen (HBeAg) status among asymptomatic pregnant women had an impact on pregnancy outcomes. 2. Materials and methods A retrospective cohort study was conducted at a tertiary teaching hospital following ethical approval by the institutional review board. The present study did not require informed consent owing to its retrospective nature with anonymous review. The study population comprised pregnant women who attended the prenatal care clinic at Chiang Mai University, Thailand, and were admitted to Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University, Thailand, for delivery between January 1, 2002, and December 31, 2012. The medical records of the patients involved in the study were reviewed by maternal–fetal medicine specialists and digitally stored in the prospective database of the Maternal–Fetal Medicine Unit at the time of discharge. Inclusion criteria consisted of: singleton pregnancy; absence of medical or surgical disease such as liver disease, pregestational diabetes mellitus, chronic hypertension, or heart disease; known HBsAg status; and complete medical records for the main outcomes. Nearly all of the women were local residents in the northern part of Thailand and were ethnic Thai. Hepatitis B surface antigen status was routinely screened by enzymelinked immunosorbent assay at the booking appointment. From 2002 to 2006, most women with positive HBsAg status were also screened for HBeAg. However, from 2007 onwards, screening for HBeAg was no longer routinely performed. Most pregnant women with positive HBsAg status were asymptomatic and a liver function test was not
http://dx.doi.org/10.1016/j.ijgo.2014.02.019 0020-7292/© 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Sirilert S, et al, Pregnancy outcomes among chronic carriers of hepatitis B virus, Int J Gynecol Obstet (2014), http:// dx.doi.org/10.1016/j.ijgo.2014.02.019
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S. Sirilert et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
performed. Viral load or liver function tests were performed only in some selected cases, particularly for women with symptoms or clinical features suggestive of active hepatitis, usually based on the decision of the hepatologist. Women with active liver disease were excluded from the study. Gestational diabetes mellitus was screened following the guidelines of the American College of Obstetricians and Gynecologists [13], using the 50-g oral glucose challenge test as a screening test and the 3-hour glucose tolerance test as a diagnostic test. The pregnancy outcome measures in the present study included obstetric complications such as pre-eclampsia, preterm birth, cesarean delivery, prepartum hemorrhage, and GDM; and fetal outcome, including low birth weight, intrauterine growth restriction, macrosomia, abortion, stillbirth, and low Apgar scores (b7). To compare women with a negative HBsAg status (control group) with women with a positive HBsAg status (case group) or HBeAg status, data were analyzed using SPSS version 21.0 (IBM, Armonk, NY, USA). Categorical variables were compared using the χ2 test and relative risk (RR) ratios with a 95% confidence interval (CI) calculation. Continuous variables were expressed as means ± SD and compared using the t test. P b 0.05 was considered to be statistically significant. 3. Results In total, 26 350 pregnant women were enrolled, reviewed, and recorded in the unit’s database. Among these, 2547 women were
excluded from the study because of various medical or other serious complications, or because their medical records were incomplete. The remaining 23 803 pregnant women were included in the analysis: 1472 (6.2%) had a positive HBsAg status (case group) and 22 331 (93.8%) had a negative HBsAg status (control group). There was no significant difference between the two groups in the proportion of abortions (2.3% in the control group vs 1.8% in the case group; P = 0.166; Fig. 1). After excluding pregnancies that were aborted, the pregnancy outcomes of the remaining 21 812 women in the control group and 1446 women in the case group were compared (Fig. 1). Among the 1446 women with positive HBsAg status, 775 were also screened for HBeAg status. Among them, 301 women tested positive for HBeAg. Regarding baseline characteristics, there was no significant difference in terms of maternal age and parity between the women in the case group and the women in the control group (Table 1). However, the proportion of older pregnant women (aged 35 years or more) was slightly, but significantly, greater in the control group (14.9% vs 12.8% in the case group; P = 0.016) and the mean number of prenatal visits was significantly higher in the case group (9.13 ± 3.37 vs 8.82 ± 3.59 in the control group; P = 0.003). There was no significant difference between the two groups for most of the pregnancy outcomes (Table 2); however, the proportion of preterm births was slightly, but significantly, higher among pregnant women with positive HBsAg status (11.8% vs 10.0%; RR 1.013 [95% CI, 1.002–1.026]; P b 0.05). Furthermore, women with a positive
Total deliveries 26 350
Excluded (2547) because of: • Multifetal pregnancy (543) • Medical complications (1820) • Incomplete records (59) • Other (125)
Available for analysis 23 803
Comparison 1
HBsAg negative
HBsAg positive
22 331
1472
Abortion (excluded)
Abortion (excluded)
519
26
Comparison 2
Comparison 3
HBsAg negative
HBsAg positive
21 812
1446
HBeAg negative
HBeAg positive
HBeAg not screened
474
301
671
Fig. 1. Groups and subgroups of the study population with respect to hepatitis B virus status. Abbreviations: HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.
Please cite this article as: Sirilert S, et al, Pregnancy outcomes among chronic carriers of hepatitis B virus, Int J Gynecol Obstet (2014), http:// dx.doi.org/10.1016/j.ijgo.2014.02.019
S. Sirilert et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx Table 1 Baseline characteristics of the patients.a Characteristics
HBsAg negative (n = 22 331)
HBsAg positive (n = 1472)
P value
Maternal age, y Older pregnant woman (N35 y) Nulliparity Prior preterm birth Number of prenatal care visits Educationb Low Intermediate High Occupation Agriculture Commercial or business Employee Government officer or state enterprise Housewife Other Height, cm Weight, kg BMI
27.82 ± 7.36 3332 (14.9) 12 672 (56.7) 830 (3.7) 8.82 ± 3.59
27.69 ± 5.67 189 (12.8) 849 (57.7) 55 (3.7) 9.13 ± 3.37
0.518 0.016 0.251 0.969 0.003 0.734
9642 (43.2) 2580 (11.6) 4582 (20.5)
644 (43.8) 177 (12.0) 285 (19.4) 62 (4.2) 160 (10.9) 770 (52.3) 106 (7.2)
4554 (20.4) 1454 (6.5) 155.35 ± 6.13 50.04 ± 5.994 20.84 ± 3.05
289 (19.6) 85 (5.8) 156.20 ± 6.31 50.08 ± 6.06 20.63 ± 3.01
between the control group and the case group (Table 2), the proportion of newborns with low birth weight was significantly higher (P = 0.005) among women with positive HBsAg and HBeAg status compared with women with positive HBsAg status but negative HBeAg status (21.9% vs 14.1%). Finally, the proportion of small for gestational age (SGA) newborns was higher among women with a positive HBsAg and a positive HBeAg status compared with women who were HBeAg negative, although this trend was not statistically significant. 4. Discussion
0.209 854 (3.8) 2200 (9.9) 11 355 (50.8) 1914 (8.6)
3
0.300 0.718 0.201
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by square of height in meters); HBsAg, hepatitis B surface antigen. a Values are given as mean ± SD, compared with t test, or number (percentage), compared with χ2 test, unless otherwise indicated. b Low, middle school or lower; intermediate, high school–vocational certificate; high, diploma or bachelor degree or higher. The education status of some patients was unknown.
HBsAg status showed a trend for delivering newborns with low birth weight, although this was not significant. The proportion of cesarean deliveries tended to be lower, but was not significant, among pregnant women with a positive HBsAg status (20.3% vs 21.8% in the control group; P = 0.176). To evaluate the effect of HBeAg status on pregnancy outcomes, women with both positive HBsAg and HBeAg status were compared with women with positive HBsAg but negative HBeAg status (Table 3). Women who had screened positive for HBsAg but had not been screened for HBeAg status were excluded from the analysis (Fig. 1). Although there was no significant difference between the two groups for most of the pregnancy outcomes, the proportion of GDM was significantly higher among women with positive HBsAg and positive HBeAg status (17.8% vs 9.2%; RR 1.434 [95% CI, 0.999–2.015]). The proportion of preterm births was also significantly higher among pregnant women with positive HBeAg and HBsAg status compared with women with negative HBeAg status (13.6% vs 8.6%; RR 1.250 [95% CI, 1.000–1.563]). Furthermore, although low birth weight was not significantly different
The present study established a relationship between chronic HBV infection with positive HBeAg status and adverse pregnancy outcomes. Although there was little adverse impact on pregnancy outcomes among pregnant women with asymptomatic positive HBsAg status compared with the control group, adverse pregnancy outcomes were more pronounced when HBeAg status was also positive. Although the mechanism is unclear, a positive HBeAg status might also reflect a higher viral load in the patient, increasing the degree of severity of subtle disorders compared with that observed for women who screened positive for HBsAg but negative for HBeAg. Hepatitis B e antigen is secreted from cells and accumulates in serum as an immunologically distinct soluble antigen; it serves as a marker of active replication in chronic hepatitis or as a qualitative surrogate marker of viral copy number. The present findings indicate that HBV infection increased the risk of adverse pregnancy outcomes in terms of preterm birth and GDM. Assuming that a positive HBeAg status is directly related to a greater number of viral copies, the degree of impact on pregnancy outcomes could be associated with the number of viral copies. To elucidate this issue, further studies are required to determine whether the number of viral copies or viral load is correlated with preterm births and GDM. Previous studies have used logistic regression analysis to correct confounding factors [9,14]. However, this was unnecessary in the present study because patients with potential confounders for adverse pregnancy outcomes, such as medical complications and behaviors such as smoking and drug abuse, were excluded. Furthermore, baseline characteristics of possible confounders such as preterm birth in previous pregnancies were not significantly different between the two groups. Whether or not chronic HBV infection is associated with an increased risk of GDM remains controversial. For example, Wong et al. [15] did not find such a relationship, whereas Lao et al. [9] demonstrated a significantly higher prevalence of GDM among pregnant women with positive HBsAg status compared with pregnant women with a normal level of risk of developing GDM, although they found that the greater prevalence of GDM was confined to the milder form of impaired glucose tolerance. Lao et al. [9] suggested that further studies should be
Table 2 Pregnancy outcomes with respect to HBsAg status.a Outcomes
HBsAg negative
HBsAg positive
Relative risk (95% confidence interval)
P value
Abortion Pre-eclampsia GDM Placenta previa Cesarean delivery Cesarean delivery due to fetal distress Gestational age, wk Preterm birth Macrosomia Birth weight, g Low birth weight Small for gestational age Apgar score b7 (1 min) Apgar score b7 (5 min) Stillbirth
519/22 331 (2.3) 1496/21 812 (6.9) 1290/9498 (13.6) 238/21 812 (1.1) 4750/21 812 (21.8) 617/21 812 (2.8) 37.74 ± 3.22 2181/21 812 (10.0) 787/21 812 (3.6) 2922 ± 640 3102/21 812 (14.2) 1533/21 812 (7.0) 2061/21 812 (9.4) 973/21 812 (4.5) 662/21 812 (3.0)
26/1472 (1.8) 91/1446 (6.3) 98/648 (15.1) 10/1446 (0.7) 293/1446 (20.3) 41/1446 (2.8) 37.37 ± 2.91 171/1446 (11.8) 53/1446 (3.7) 2875 ± 601 229/1446 (15.8) 108/1446 (7.5) 119/1446 (8.2) 50/1446 (3.5) 33/1446 (2.3)
0.985 (0.966–1.004) 0.994 (0.982–1.007) 1.009 (0.994–1.025) 0.977 (0.952–1.002) 0.994 (0.987–1.002) 0.998 (0.739–1.020) — 1.013 (1.001–1.025) 1.001 (0.983–1.019) — 1.008 (0.998–1.018) 1.004 (0.991–1.018) 0.991 (0.981–1.002) 0.985 (0.971–1.001) 0.984 (0.968–1.002)
0.166 0.409 0.130 0.152 0.176 0.988 0.001 0.026 0.910 0.006 0.080 0.526 0.123 0.078 0.103
Abbreviations: GDM, gestational diabetes mellitus; HBsAg, hepatitis B surface antigen. a Values are given as mean ± SD or number (percentage) unless otherwise indicated.
Please cite this article as: Sirilert S, et al, Pregnancy outcomes among chronic carriers of hepatitis B virus, Int J Gynecol Obstet (2014), http:// dx.doi.org/10.1016/j.ijgo.2014.02.019
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Table 3 Pregnancy outcomes among women with respect to HBeAg status.a Outcomes
HBeAg negative
HBeAg positive
Relative risk (95% confidence interval)
P value
Pre-eclampsia GDM Placenta previa Cesarean delivery Gestational age, wk Preterm birth Macrosomia Birth weight, g Low birth weight Small for gestational age Apgar score b7 (1 min) Apgar score b7 (5 min) Stillbirth
32/474 (6.8) 18/195 (9.2) 3/474 (0.6) 89/474 (18.8) 37.87 ± 3.05 41/474 (8.6) 8/474 (1.7) 2896 ± 599 67/474 (14.1) 32/474 (6.8) 40/474 (8.4) 19/474 (4.0) 12/474 (2.5)
16/301 (5.3) 24/135 (17.8) 4/301 (1.3) 59/301 (19.6) 37.31 ± 2.51 41/301 (13.6) 8/301 (2.7) 2725 ± 566 66/301 (21.9) 28/301 (9.3) 19/301 (6.3) 9/301 (3.0) 5/301 (1.7)
0.912 (0.740–1.123) 1.434 (0.999–2.057) 1.431 (0.607–3.372) 1.021 (0.883–1.181) — 1.250 (1.000–1.563) 1.306 (0.787–2.170) — 1.258 (1.053–1.505) 1.159 (0.908–1.479) 0.894 (0.743–1.076) 0.898 (0.691–1.166) 0.863 (0.632–1.180)
0.419 0.022 0.318 0.776 0.009 0.028 0.228 b0.001 0.005 0.065 0.277 0.459 0.295
Abbreviations: GDM, gestational diabetes mellitus; HBeAg, hepatitis B e antigen. a Values are given as mean ± SD or number (percentage) unless otherwise indicated.
undertaken to investigate the link between HBV infection and development of GDM in the general obstetric population. Lao et al. [9] hypothesized that increased insulin resistance induced by pregnancy is exacerbated in women with HBV infection because several mechanisms are likely to act together, resulting in the development of GDM in women who would otherwise be glucose tolerant. Based on the findings in the present study, only the subgroup of women who were both HBsAg positive and HBeAg positive showed a significantly increased risk of GDM. Although these results partly support the findings of Lao et al. [9], such a relationship may be minimal and might not be clinically significant, particularly in asymptomatic patients with negative HBeAg status. Based on the present findings, screening all pregnant women with positive HBsAg status for GDM may not be warranted and might not be cost effective. The impact of being a chronic carrier of HBV on pregnancy outcomes seems to be minimal, even though the slight increase in preterm birth among women with a positive HBsAg status was significant. The proportion of preterm births was significantly higher among women with positive HBeAg status compared with women with negative HBeAg status. It is reasonable to assume that the significantly higher proportion of low birth weight newborns in the HBeAg-positive subgroup was directly associated with preterm birth rather than with intrauterine growth restriction, given that the proportion of SGA infants was not significantly different from that in the HBeAg-negative subgroup. This finding implies that being a chronic carrier of HBV infection with positive HBsAg and HBeAg status is likely to affect preterm labor but not placental function. Reddick et al. [8] reported the rate of preterm births to be as high as 21.9% among pregnant women with HBV infection. This finding may be explained by the inclusion of patients with active hepatic disease in the study. Nevertheless, based on the present study, the RR of preterm birth and low birth weight is minimal and may not be clinically significant. Although the association between preterm birth and HBV infection was not as strong as that shown by previous studies [8,14], the significantly higher proportion of preterm births among mothers with positive HBeAg status might be the same effect but reflect a difference in the extent of such an adverse impact. Although the pathophysiology of preterm birth is heterogeneous, we hypothesize that HBV DNA, which possibly accumulates in the placenta and trophoblastic cells, may initiate a placental inflammatory response, which is a known predisposing factor to preterm birth. Furthermore, it is possible that such a response may be even more severe if HBeAg status is positive, resulting in more obvious effects, as seen in the present study. Lao et al. [11] and Saleh-Gargari et al. [12] found that chronic carriers of HBV had an increased risk of fetal macrosomia, probably secondary to an increased incidence of GDM. However, this finding was not observed in the present study, possibly because the prevalence of GDM in the present study was not as high.
The retrospective nature of the present study and the inability to eliminate several subtle factors that might have affected pregnancy outcomes were limitations. Furthermore, a liver function test was not performed in asymptomatic patients. As a result, women with subtle chronic active hepatitis may have been included in the study. Although all patients with recorded potential confounders were excluded from analysis, several cases might have been missed from screening at the prenatal care clinic. The strengths of the present study were as follows: the large sample size should yield reliable conclusions; known confounders of adverse pregnancy outcomes were excluded from the study; the maternal– fetal medicine team developed the high-risk database by reviewing all medical records rather than relying on the hospital central database system; and the study population had a high level of homogeneity— nearly all were ethnic Thai from the northern part of Thailand and all were asymptomatic. Therefore, the results may be more relevant for counseling asymptomatic patients with positive HBsAg. In conclusion, chronic carriers of HBV (positive HBsAg status) may have a minimally increased risk of preterm birth, particularly those with positive HBeAg status. In addition, pregnant women with positive HBsAg and positive HBeAg status have increased risk of GDM; however, this is not the case for pregnant women with positive HBsAg status but negative HBeAg status. The observations indirectly suggest that adverse outcomes of pregnancy may be associated with the amount of viral load. Acknowledgments The present research was financially supported by the Faculty of Medicine Research Fund of Chiang Mai University, and the National Research University Project under Thailand's Office of the Higher Education Commission. Conflict of interest The authors have no conflicts of interest. References [1] Chen CJ, Wang LY, Yu MW. Epidemiology of hepatitis B virus infection in the AsiaPacific region. J Gastroenterol Hepatol 2000;15:E3–6 Suppl. [2] Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11(2):97–107. [3] Rani M, Yang B, Nesbit R. Hepatitis B control by 2012 in the WHO Western Pacific Region: rationale and implications. Bull World Health Organ 2009;87(9):707–13. [4] Degli ES, Shah D. Hepatitis B in pregnancy: challenges and treatment. Gastroenterol Clin North Am 2011;40(2):355–72. [5] Piratvisuth T. Optimal management of HBV infection during pregnancy. Liver Int 2013;33(Suppl. 1):188–94. [6] Lao TT, Sahota DS, Suen SS, Lau TK, Leung TY. Chronic hepatitis B virus infection and rubella susceptibility in pregnant women. J Viral Hepat 2010;17(10):737–41.
Please cite this article as: Sirilert S, et al, Pregnancy outcomes among chronic carriers of hepatitis B virus, Int J Gynecol Obstet (2014), http:// dx.doi.org/10.1016/j.ijgo.2014.02.019
S. Sirilert et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx [7] Elefsiniotis I, Tsoumakas K, Vezali E, Glynou I, Drakoulis N, Saroglou G. Spontaneous preterm birth in women with chronic hepatitis B virus infection. Int J Gynecol Obstet 2010;110(3):241–4. [8] Reddick KL, Jhaveri R, Gandhi M, James AH, Swamy GK. Pregnancy outcomes associated with viral hepatitis. J Viral Hepat 2011;18(7):e394–8. [9] Lao TT, Chan BC, Leung WC, Ho LF, Tse KY. Maternal hepatitis B infection and gestational diabetes mellitus. J Hepatol 2007;47(1):46–50. [10] Nguyen G, Garcia RT, Nguyen N, Trinh H, Keeffe EB, Nguyen MH. Clinical course of hepatitis B virus infection during pregnancy. Aliment Pharmacol Ther 2009;29(7):755–64. [11] Lao TT, Sahota DS, Suen SS, Law LW, Leung TY. Maternal HBsAg status and infant size–a Faustian bargain? J Viral Hepat 2012;19(7):519–24.
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[12] Saleh-Gargari S, Hantoushzadeh S, Zendehdel N, Jamal A, Aghdam H. The Association of Maternal HBsAg Carrier Status and Perinatal Outcome. Hepat Mon 2009;9(3): 180–4. [13] ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists. Number 30, September 2001 (replaces Technical Bulletin Number 200, December 1994). Gestational diabetes. Obstet Gynecol 2001;98(3): 525–38. [14] Tse KY, Ho LF, Lao T. The impact of maternal HBsAg carrier status on pregnancy outcomes: a case-control study. J Hepatol 2005;43(5):771–5. [15] Wong S, Chan LY, Yu V, Ho L. Hepatitis B carrier and perinatal outcome in singleton pregnancy. Am J Perinatol 1999;16(9):485–8.
Please cite this article as: Sirilert S, et al, Pregnancy outcomes among chronic carriers of hepatitis B virus, Int J Gynecol Obstet (2014), http:// dx.doi.org/10.1016/j.ijgo.2014.02.019
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Pregnancy outcomes among chronic carriers of hepatitis B virus Sirinart Sirilert, Kuntharee Traisrisilp, Pannee Sirivatanapa, Theera Tongsong ⁎ Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
a r t i c l e
i n f o
Article history: Received 24 September 2013 Received in revised form 13 February 2014 Accepted 10 April 2014 Keywords: Gestational diabetes Hepatitis B e antigen Hepatitis B surface antigen Hepatitis B virus infection Pregnancy Preterm birth
a b s t r a c t Objective: To compare pregnancy outcomes of women with chronic HBV infection with those of HBV-negative women. Methods: A retrospective cohort study was undertaken to analyze singleton pregnancies of women without medical/surgical disease and with known HBsAg status. Pregnancy outcome measures were compared among the control group, women with positive HBsAg status (case group), and those with positive HBeAg status. Results: Among 26 350 enrolled pregnant women, 21 812 in the control group and 1446 in the case group were compared. Only the proportion of preterm births was significantly higher among pregnancies with positive HBsAg status (RR 1.013 [95% CI, 1.001–1.025]). Among women with positive HBsAg status who had been screened for HBeAg, GDM was significantly higher among women with positive HBeAg status (RR 1.434 [95% CI, 0.999–2.057]). Preterm births and low birth weight were also significantly higher among women with positive HBeAg status (RR 1.250 [95% CI, 1.000–1.563] and 1.258 [95% CI, 1.053–1.505], respectively). Conclusion: Chronic carriers of HBV had a minimally increased risk of preterm birth and low birth weight but the risk was more pronounced in women with positive HBeAg status. Women with positive HBeAg status also had an increased risk of GDM. © 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Hepatitis B virus (HBV) infection is one of the most common health problems worldwide. The prevalence varies from country to country. In endemic regions such as China and Southeast Asia, the prevalence of HBV infection among women of childbearing age may be as high as 10%–20% [1], whereas in the USA it is only 0.4% [2]. Most pregnant women with HBV infection are chronic carriers, indicated by positive hepatitis B surface antigen (HBsAg) status. Most studies of pregnant women who are chronic carriers of HBV infection (positive HBsAg) have focused on the vertical transmission of HBV to children [3–5]. Although a few studies have explored the impact of this asymptomatic infection on pregnancy outcomes [6–10], the findings from the different studies were not consistent. For example, Reddick et al. [8] demonstrated an increased risk of preterm birth as well as prepartum hemorrhage with HBV infection, whereas Lao et al. [9] did not find such a relationship. Moreover, a significantly increased risk of gestational diabetes mellitus (GDM) and of fetal macrosomia has also been reported [9,11,12]. Most previous studies included both asymptomatic chronic carriers and those with chronic active disease, which theoretically would have a direct effect on the pregnancy outcome. The objective of the present study was to explore whether or not HBsAg and ⁎ Corresponding author at: Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Tel.: + 66 53 946429; fax: +66 53 946112. E-mail address: [email protected] (T. Tongsong).
hepatitis B e antigen (HBeAg) status among asymptomatic pregnant women had an impact on pregnancy outcomes. 2. Materials and methods A retrospective cohort study was conducted at a tertiary teaching hospital following ethical approval by the institutional review board. The present study did not require informed consent owing to its retrospective nature with anonymous review. The study population comprised pregnant women who attended the prenatal care clinic at Chiang Mai University, Thailand, and were admitted to Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University, Thailand, for delivery between January 1, 2002, and December 31, 2012. The medical records of the patients involved in the study were reviewed by maternal–fetal medicine specialists and digitally stored in the prospective database of the Maternal–Fetal Medicine Unit at the time of discharge. Inclusion criteria consisted of: singleton pregnancy; absence of medical or surgical disease such as liver disease, pregestational diabetes mellitus, chronic hypertension, or heart disease; known HBsAg status; and complete medical records for the main outcomes. Nearly all of the women were local residents in the northern part of Thailand and were ethnic Thai. Hepatitis B surface antigen status was routinely screened by enzymelinked immunosorbent assay at the booking appointment. From 2002 to 2006, most women with positive HBsAg status were also screened for HBeAg. However, from 2007 onwards, screening for HBeAg was no longer routinely performed. Most pregnant women with positive HBsAg status were asymptomatic and a liver function test was not
http://dx.doi.org/10.1016/j.ijgo.2014.02.019 0020-7292/© 2014 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Sirilert S, et al, Pregnancy outcomes among chronic carriers of hepatitis B virus, Int J Gynecol Obstet (2014), http:// dx.doi.org/10.1016/j.ijgo.2014.02.019
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S. Sirilert et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
performed. Viral load or liver function tests were performed only in some selected cases, particularly for women with symptoms or clinical features suggestive of active hepatitis, usually based on the decision of the hepatologist. Women with active liver disease were excluded from the study. Gestational diabetes mellitus was screened following the guidelines of the American College of Obstetricians and Gynecologists [13], using the 50-g oral glucose challenge test as a screening test and the 3-hour glucose tolerance test as a diagnostic test. The pregnancy outcome measures in the present study included obstetric complications such as pre-eclampsia, preterm birth, cesarean delivery, prepartum hemorrhage, and GDM; and fetal outcome, including low birth weight, intrauterine growth restriction, macrosomia, abortion, stillbirth, and low Apgar scores (b7). To compare women with a negative HBsAg status (control group) with women with a positive HBsAg status (case group) or HBeAg status, data were analyzed using SPSS version 21.0 (IBM, Armonk, NY, USA). Categorical variables were compared using the χ2 test and relative risk (RR) ratios with a 95% confidence interval (CI) calculation. Continuous variables were expressed as means ± SD and compared using the t test. P b 0.05 was considered to be statistically significant. 3. Results In total, 26 350 pregnant women were enrolled, reviewed, and recorded in the unit’s database. Among these, 2547 women were
excluded from the study because of various medical or other serious complications, or because their medical records were incomplete. The remaining 23 803 pregnant women were included in the analysis: 1472 (6.2%) had a positive HBsAg status (case group) and 22 331 (93.8%) had a negative HBsAg status (control group). There was no significant difference between the two groups in the proportion of abortions (2.3% in the control group vs 1.8% in the case group; P = 0.166; Fig. 1). After excluding pregnancies that were aborted, the pregnancy outcomes of the remaining 21 812 women in the control group and 1446 women in the case group were compared (Fig. 1). Among the 1446 women with positive HBsAg status, 775 were also screened for HBeAg status. Among them, 301 women tested positive for HBeAg. Regarding baseline characteristics, there was no significant difference in terms of maternal age and parity between the women in the case group and the women in the control group (Table 1). However, the proportion of older pregnant women (aged 35 years or more) was slightly, but significantly, greater in the control group (14.9% vs 12.8% in the case group; P = 0.016) and the mean number of prenatal visits was significantly higher in the case group (9.13 ± 3.37 vs 8.82 ± 3.59 in the control group; P = 0.003). There was no significant difference between the two groups for most of the pregnancy outcomes (Table 2); however, the proportion of preterm births was slightly, but significantly, higher among pregnant women with positive HBsAg status (11.8% vs 10.0%; RR 1.013 [95% CI, 1.002–1.026]; P b 0.05). Furthermore, women with a positive
Total deliveries 26 350
Excluded (2547) because of: • Multifetal pregnancy (543) • Medical complications (1820) • Incomplete records (59) • Other (125)
Available for analysis 23 803
Comparison 1
HBsAg negative
HBsAg positive
22 331
1472
Abortion (excluded)
Abortion (excluded)
519
26
Comparison 2
Comparison 3
HBsAg negative
HBsAg positive
21 812
1446
HBeAg negative
HBeAg positive
HBeAg not screened
474
301
671
Fig. 1. Groups and subgroups of the study population with respect to hepatitis B virus status. Abbreviations: HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen.
Please cite this article as: Sirilert S, et al, Pregnancy outcomes among chronic carriers of hepatitis B virus, Int J Gynecol Obstet (2014), http:// dx.doi.org/10.1016/j.ijgo.2014.02.019
S. Sirilert et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx Table 1 Baseline characteristics of the patients.a Characteristics
HBsAg negative (n = 22 331)
HBsAg positive (n = 1472)
P value
Maternal age, y Older pregnant woman (N35 y) Nulliparity Prior preterm birth Number of prenatal care visits Educationb Low Intermediate High Occupation Agriculture Commercial or business Employee Government officer or state enterprise Housewife Other Height, cm Weight, kg BMI
27.82 ± 7.36 3332 (14.9) 12 672 (56.7) 830 (3.7) 8.82 ± 3.59
27.69 ± 5.67 189 (12.8) 849 (57.7) 55 (3.7) 9.13 ± 3.37
0.518 0.016 0.251 0.969 0.003 0.734
9642 (43.2) 2580 (11.6) 4582 (20.5)
644 (43.8) 177 (12.0) 285 (19.4) 62 (4.2) 160 (10.9) 770 (52.3) 106 (7.2)
4554 (20.4) 1454 (6.5) 155.35 ± 6.13 50.04 ± 5.994 20.84 ± 3.05
289 (19.6) 85 (5.8) 156.20 ± 6.31 50.08 ± 6.06 20.63 ± 3.01
between the control group and the case group (Table 2), the proportion of newborns with low birth weight was significantly higher (P = 0.005) among women with positive HBsAg and HBeAg status compared with women with positive HBsAg status but negative HBeAg status (21.9% vs 14.1%). Finally, the proportion of small for gestational age (SGA) newborns was higher among women with a positive HBsAg and a positive HBeAg status compared with women who were HBeAg negative, although this trend was not statistically significant. 4. Discussion
0.209 854 (3.8) 2200 (9.9) 11 355 (50.8) 1914 (8.6)
3
0.300 0.718 0.201
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by square of height in meters); HBsAg, hepatitis B surface antigen. a Values are given as mean ± SD, compared with t test, or number (percentage), compared with χ2 test, unless otherwise indicated. b Low, middle school or lower; intermediate, high school–vocational certificate; high, diploma or bachelor degree or higher. The education status of some patients was unknown.
HBsAg status showed a trend for delivering newborns with low birth weight, although this was not significant. The proportion of cesarean deliveries tended to be lower, but was not significant, among pregnant women with a positive HBsAg status (20.3% vs 21.8% in the control group; P = 0.176). To evaluate the effect of HBeAg status on pregnancy outcomes, women with both positive HBsAg and HBeAg status were compared with women with positive HBsAg but negative HBeAg status (Table 3). Women who had screened positive for HBsAg but had not been screened for HBeAg status were excluded from the analysis (Fig. 1). Although there was no significant difference between the two groups for most of the pregnancy outcomes, the proportion of GDM was significantly higher among women with positive HBsAg and positive HBeAg status (17.8% vs 9.2%; RR 1.434 [95% CI, 0.999–2.015]). The proportion of preterm births was also significantly higher among pregnant women with positive HBeAg and HBsAg status compared with women with negative HBeAg status (13.6% vs 8.6%; RR 1.250 [95% CI, 1.000–1.563]). Furthermore, although low birth weight was not significantly different
The present study established a relationship between chronic HBV infection with positive HBeAg status and adverse pregnancy outcomes. Although there was little adverse impact on pregnancy outcomes among pregnant women with asymptomatic positive HBsAg status compared with the control group, adverse pregnancy outcomes were more pronounced when HBeAg status was also positive. Although the mechanism is unclear, a positive HBeAg status might also reflect a higher viral load in the patient, increasing the degree of severity of subtle disorders compared with that observed for women who screened positive for HBsAg but negative for HBeAg. Hepatitis B e antigen is secreted from cells and accumulates in serum as an immunologically distinct soluble antigen; it serves as a marker of active replication in chronic hepatitis or as a qualitative surrogate marker of viral copy number. The present findings indicate that HBV infection increased the risk of adverse pregnancy outcomes in terms of preterm birth and GDM. Assuming that a positive HBeAg status is directly related to a greater number of viral copies, the degree of impact on pregnancy outcomes could be associated with the number of viral copies. To elucidate this issue, further studies are required to determine whether the number of viral copies or viral load is correlated with preterm births and GDM. Previous studies have used logistic regression analysis to correct confounding factors [9,14]. However, this was unnecessary in the present study because patients with potential confounders for adverse pregnancy outcomes, such as medical complications and behaviors such as smoking and drug abuse, were excluded. Furthermore, baseline characteristics of possible confounders such as preterm birth in previous pregnancies were not significantly different between the two groups. Whether or not chronic HBV infection is associated with an increased risk of GDM remains controversial. For example, Wong et al. [15] did not find such a relationship, whereas Lao et al. [9] demonstrated a significantly higher prevalence of GDM among pregnant women with positive HBsAg status compared with pregnant women with a normal level of risk of developing GDM, although they found that the greater prevalence of GDM was confined to the milder form of impaired glucose tolerance. Lao et al. [9] suggested that further studies should be
Table 2 Pregnancy outcomes with respect to HBsAg status.a Outcomes
HBsAg negative
HBsAg positive
Relative risk (95% confidence interval)
P value
Abortion Pre-eclampsia GDM Placenta previa Cesarean delivery Cesarean delivery due to fetal distress Gestational age, wk Preterm birth Macrosomia Birth weight, g Low birth weight Small for gestational age Apgar score b7 (1 min) Apgar score b7 (5 min) Stillbirth
519/22 331 (2.3) 1496/21 812 (6.9) 1290/9498 (13.6) 238/21 812 (1.1) 4750/21 812 (21.8) 617/21 812 (2.8) 37.74 ± 3.22 2181/21 812 (10.0) 787/21 812 (3.6) 2922 ± 640 3102/21 812 (14.2) 1533/21 812 (7.0) 2061/21 812 (9.4) 973/21 812 (4.5) 662/21 812 (3.0)
26/1472 (1.8) 91/1446 (6.3) 98/648 (15.1) 10/1446 (0.7) 293/1446 (20.3) 41/1446 (2.8) 37.37 ± 2.91 171/1446 (11.8) 53/1446 (3.7) 2875 ± 601 229/1446 (15.8) 108/1446 (7.5) 119/1446 (8.2) 50/1446 (3.5) 33/1446 (2.3)
0.985 (0.966–1.004) 0.994 (0.982–1.007) 1.009 (0.994–1.025) 0.977 (0.952–1.002) 0.994 (0.987–1.002) 0.998 (0.739–1.020) — 1.013 (1.001–1.025) 1.001 (0.983–1.019) — 1.008 (0.998–1.018) 1.004 (0.991–1.018) 0.991 (0.981–1.002) 0.985 (0.971–1.001) 0.984 (0.968–1.002)
0.166 0.409 0.130 0.152 0.176 0.988 0.001 0.026 0.910 0.006 0.080 0.526 0.123 0.078 0.103
Abbreviations: GDM, gestational diabetes mellitus; HBsAg, hepatitis B surface antigen. a Values are given as mean ± SD or number (percentage) unless otherwise indicated.
Please cite this article as: Sirilert S, et al, Pregnancy outcomes among chronic carriers of hepatitis B virus, Int J Gynecol Obstet (2014), http:// dx.doi.org/10.1016/j.ijgo.2014.02.019
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S. Sirilert et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
Table 3 Pregnancy outcomes among women with respect to HBeAg status.a Outcomes
HBeAg negative
HBeAg positive
Relative risk (95% confidence interval)
P value
Pre-eclampsia GDM Placenta previa Cesarean delivery Gestational age, wk Preterm birth Macrosomia Birth weight, g Low birth weight Small for gestational age Apgar score b7 (1 min) Apgar score b7 (5 min) Stillbirth
32/474 (6.8) 18/195 (9.2) 3/474 (0.6) 89/474 (18.8) 37.87 ± 3.05 41/474 (8.6) 8/474 (1.7) 2896 ± 599 67/474 (14.1) 32/474 (6.8) 40/474 (8.4) 19/474 (4.0) 12/474 (2.5)
16/301 (5.3) 24/135 (17.8) 4/301 (1.3) 59/301 (19.6) 37.31 ± 2.51 41/301 (13.6) 8/301 (2.7) 2725 ± 566 66/301 (21.9) 28/301 (9.3) 19/301 (6.3) 9/301 (3.0) 5/301 (1.7)
0.912 (0.740–1.123) 1.434 (0.999–2.057) 1.431 (0.607–3.372) 1.021 (0.883–1.181) — 1.250 (1.000–1.563) 1.306 (0.787–2.170) — 1.258 (1.053–1.505) 1.159 (0.908–1.479) 0.894 (0.743–1.076) 0.898 (0.691–1.166) 0.863 (0.632–1.180)
0.419 0.022 0.318 0.776 0.009 0.028 0.228 b0.001 0.005 0.065 0.277 0.459 0.295
Abbreviations: GDM, gestational diabetes mellitus; HBeAg, hepatitis B e antigen. a Values are given as mean ± SD or number (percentage) unless otherwise indicated.
undertaken to investigate the link between HBV infection and development of GDM in the general obstetric population. Lao et al. [9] hypothesized that increased insulin resistance induced by pregnancy is exacerbated in women with HBV infection because several mechanisms are likely to act together, resulting in the development of GDM in women who would otherwise be glucose tolerant. Based on the findings in the present study, only the subgroup of women who were both HBsAg positive and HBeAg positive showed a significantly increased risk of GDM. Although these results partly support the findings of Lao et al. [9], such a relationship may be minimal and might not be clinically significant, particularly in asymptomatic patients with negative HBeAg status. Based on the present findings, screening all pregnant women with positive HBsAg status for GDM may not be warranted and might not be cost effective. The impact of being a chronic carrier of HBV on pregnancy outcomes seems to be minimal, even though the slight increase in preterm birth among women with a positive HBsAg status was significant. The proportion of preterm births was significantly higher among women with positive HBeAg status compared with women with negative HBeAg status. It is reasonable to assume that the significantly higher proportion of low birth weight newborns in the HBeAg-positive subgroup was directly associated with preterm birth rather than with intrauterine growth restriction, given that the proportion of SGA infants was not significantly different from that in the HBeAg-negative subgroup. This finding implies that being a chronic carrier of HBV infection with positive HBsAg and HBeAg status is likely to affect preterm labor but not placental function. Reddick et al. [8] reported the rate of preterm births to be as high as 21.9% among pregnant women with HBV infection. This finding may be explained by the inclusion of patients with active hepatic disease in the study. Nevertheless, based on the present study, the RR of preterm birth and low birth weight is minimal and may not be clinically significant. Although the association between preterm birth and HBV infection was not as strong as that shown by previous studies [8,14], the significantly higher proportion of preterm births among mothers with positive HBeAg status might be the same effect but reflect a difference in the extent of such an adverse impact. Although the pathophysiology of preterm birth is heterogeneous, we hypothesize that HBV DNA, which possibly accumulates in the placenta and trophoblastic cells, may initiate a placental inflammatory response, which is a known predisposing factor to preterm birth. Furthermore, it is possible that such a response may be even more severe if HBeAg status is positive, resulting in more obvious effects, as seen in the present study. Lao et al. [11] and Saleh-Gargari et al. [12] found that chronic carriers of HBV had an increased risk of fetal macrosomia, probably secondary to an increased incidence of GDM. However, this finding was not observed in the present study, possibly because the prevalence of GDM in the present study was not as high.
The retrospective nature of the present study and the inability to eliminate several subtle factors that might have affected pregnancy outcomes were limitations. Furthermore, a liver function test was not performed in asymptomatic patients. As a result, women with subtle chronic active hepatitis may have been included in the study. Although all patients with recorded potential confounders were excluded from analysis, several cases might have been missed from screening at the prenatal care clinic. The strengths of the present study were as follows: the large sample size should yield reliable conclusions; known confounders of adverse pregnancy outcomes were excluded from the study; the maternal– fetal medicine team developed the high-risk database by reviewing all medical records rather than relying on the hospital central database system; and the study population had a high level of homogeneity— nearly all were ethnic Thai from the northern part of Thailand and all were asymptomatic. Therefore, the results may be more relevant for counseling asymptomatic patients with positive HBsAg. In conclusion, chronic carriers of HBV (positive HBsAg status) may have a minimally increased risk of preterm birth, particularly those with positive HBeAg status. In addition, pregnant women with positive HBsAg and positive HBeAg status have increased risk of GDM; however, this is not the case for pregnant women with positive HBsAg status but negative HBeAg status. The observations indirectly suggest that adverse outcomes of pregnancy may be associated with the amount of viral load. Acknowledgments The present research was financially supported by the Faculty of Medicine Research Fund of Chiang Mai University, and the National Research University Project under Thailand's Office of the Higher Education Commission. Conflict of interest The authors have no conflicts of interest. References [1] Chen CJ, Wang LY, Yu MW. Epidemiology of hepatitis B virus infection in the AsiaPacific region. J Gastroenterol Hepatol 2000;15:E3–6 Suppl. [2] Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11(2):97–107. [3] Rani M, Yang B, Nesbit R. Hepatitis B control by 2012 in the WHO Western Pacific Region: rationale and implications. Bull World Health Organ 2009;87(9):707–13. [4] Degli ES, Shah D. Hepatitis B in pregnancy: challenges and treatment. Gastroenterol Clin North Am 2011;40(2):355–72. [5] Piratvisuth T. Optimal management of HBV infection during pregnancy. Liver Int 2013;33(Suppl. 1):188–94. [6] Lao TT, Sahota DS, Suen SS, Lau TK, Leung TY. Chronic hepatitis B virus infection and rubella susceptibility in pregnant women. J Viral Hepat 2010;17(10):737–41.
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Please cite this article as: Sirilert S, et al, Pregnancy outcomes among chronic carriers of hepatitis B virus, Int J Gynecol Obstet (2014), http:// dx.doi.org/10.1016/j.ijgo.2014.02.019