Variation of ALT and HBV Virus During Pregnancy and Puerperium
Unexpectedly, a high rate of hepatic flare (11.94%) was observed in the first trimester (Fig. 2A). Then the rate decreased gradually along with development of the fetus during pregnancy and dramatically dropped to 2.10% at delivery. When the mothers were divided into antiviral therapy group and untreated group, a similar trend of ALT flare was observed (Fig. 2B). Two bursts of hepatic flare (19.78% and 17.05%) were observed at 1 and 3 months after delivery, respectively, consistent with previous reports showing the emergence of hepatic flare in the initial 3 months after delivery.12,13 The ALT elevation was mild to moderate (range, 41 to 262 U/L), and there were no cases with liver failure in this cohort, which was consistent with prior studies.28,30,31 The majority of the ALT elevation was asymptomatic and resolved without special treatment. In addition, the median level of ALT in the first trimester was the highest during pregnancy (Fig. 2A).
Among the 1097 gravidas, antiviral therapy was initiated in 629 mothers from the second trimester (range, 24th to 28th week of gestation). In most cases, treatment was administrated for high viremia (median, 7.2 log IU/mL; range, 4.3 to 9.44 log IU/mL) to reduce the risk of mother-to-infant transmission, whereas 115 mothers initiated antiviral treatment to control both the hepatic flare (41 to 262 U/L) and high viremia. Moreover, majority (97%, 610/629) of the mothers continued antiviral treatment until 3 months after parturition. Owing to antiviral therapy, a decrease of HBV was shown from 28th week of gestation. An average of 5.24 log10 IU/mL decline was obtained in mothers receiving antiviral therapy. However, it only took 1 year for the viral load to rebound to the baseline level (Fig. 2C). It is noteworthy that a slight decrease was shown in titers of HBsAg and HBeAg after delivery, especially the HBeAg level.
When the subjects were further divided into high (>6 log10 IU/mL), intermediate (3 to 6 log10 IU/mL), and low (<3 log10 IU/mL) levels of HBV DNA groups as shown in Figure 2D, mothers from high HBV DNA group displayed the highest frequency of hepatic flare during pregnancy and puerperium. At the beginning of gestation, 18.47% from the high-level group presented hepatic flare, whereas only 1.01% from the low-level group presented hepatic flare. Furthermore, in the first 3 months of postpartum, there were 27.54% and 11.60% mothers exhibiting hepatic flares in the high and low viral level groups (χ2=29.238, P<0.001), respectively.
Independent Factors Associated With Initial Postpartum Hepatic Flare
To identify factors associated with initial postpartum hepatic flare, we performed univariate analysis to determine the correlation of various factors with hepatic flare. Among the assessed factors are age, parity, delivery mode, antiviral therapy, ALT at baseline, HBV DNA at baseline, HBsAg at baseline, HBeAg at baseline, ALT level at delivery, HBV DNA at delivery, HBsAg at delivery, and HBeAg at delivery. The results showed that HBV DNA at baseline (P=0.005) and at delivery (P=0.033) were positively associated with the occurrence/level of hepatic flare. Subsequent multivariate analysis that incorporated the significant variables in univariate analysis identified that HBV DNA level at baseline was the only independent predictor of hepatic flare in the initial postpartum period (P=0.045; 95% CI, 1.012-3.049; Table 2).
Predictive Rates of Initial Postpartum Hepatic Flare
Using the multivariate logistic regression model listed in Table 2, predictive rates of initial postpartum hepatic flare were evaluated. At viral load levels of 8, 7, 6, 5, 4, 3, and 2 log10 IU/mL, the predictive rates were 30.60% (95% CI, 25.18%-36.03%), 28.30% (95% CI, 22.84%-37.76%), 16.67% (95% CI, 8.82%-24.52%), 16.13% (95% CI, 2.42%-29.84%), 16.98% (95% CI, 6.53%-27.43%), 17.28% (95% CI, 8.87%-25.70%), and 11.6% (95% CI, 7.92%-15.29%), respectively (Fig. 3).
The immunopathogenesis of HBV infection is initiated and propelled by intricate interactions between the host immune function and the virus. Host immune responses to viral particles and proteins predominately mediate the progression of disease and hepatic injury.32 During pregnancy, it is evolutionarily advantageous to reduce inflammatory immune responses and to increase anti-inflammatory responses. As a result, both the outcome of pregnancy and susceptibility to infectious diseases are affected.9 There is a paucity of data on the natural changes in hepatic necroinflammatory activity during pregnancy and puerperium. In this large, prospective, multicenter study, we profiled changes of ALT and virological markers during pregnancy and puerperium and identified HBV DNA level at baseline as a predictive factor for hepatic flare in the initial postpartum period.
A relatively conservative definition of “hepatic flare” was used in the current study (2 times of the upper limit of normal ALT), which might lead to maximize the sensitivity and identify as many changes in hepatic necroinflammatory. Consistent with previous reports,13,33–35 moderate rates of ALT flare had been observed during pregnancy and puerperium, and the hepatic flares were generally asymptomatic. Although the rise of ALT has been reported mainly during the third trimester,22,33 in current investigation, the “peak” of ALT level was detected in the first trimester, as well as the frequency of hepatic flare, owing to the dynamic and close investigation from the beginning of pregnancy. In addition, a retrospective study has also described ALT flare during the second trimester or even earlier, consistent with our data.34 A decreasing trend of ALT accompanying gestation development suggested the alleviation of necroinflammatory, which facilitates the fetus development. The general efficacy of antiviral therapy (ability to reduce HBV DNA, normalize ALT, and stimulate HBeAg seroconversion) has been extensively discussed in reviews and meta-analyses.36,37 In the current study, we did not find an association between ALT flares frequency and antiviral therapy. This may be the result of interplay between virus and immune system.
Compatible with previously published data,34 a gradual increase of HBV viral load was shown during pregnancy in our investigation,38 supporting the notion that temporal suppression of the immune system might be advantageous for successful pregnancy. Yet the underlying mechanisms such as maternal cytokine levels remain to be elucidated.
More interestingly, ALT level and frequency of hepatic flare were higher in gravidas with higher viremia. As we all know, majority of the women in childbearing age are in immune tolerance period, a state of balance between virus and human immune function. We hypothesize that the balance broken is responsible for hepatic flare owing to immune function and hormone changes after gravidity. For the advantage of fetus, a new balance is achieved and the hepatic flare is resolved along with the progress of pregnancy. Therefore, close monitoring is needed from the very beginning of pregnancy, especially for those with high viremia, to assure safety of gravidas, and to prepare for initiation of antiviral therapy when necessary.
As described previously, a moderate hepatic flare was shown postpartum before antiviral discontinuation. A small, prospective study also found the postpartum hepatic flare independent from antiviral therapy.12 These studies support the notion that this flare is a result of immune reconstruction and recovery of hormone levels after delivery, instead of antiviral therapy. A recent survey reported 2.56 times the risk of postpartum flare in HBeAg(+) gravity women compared with HBeAg(−) mothers, whereas approximately half of the flares occurred in HBeAg(−) mothers.39 Another retrospective study did not observe an association between HBeAg(+) and HBV DNA at baseline.34 In our univariate analysis, both HBV titers at baseline and at delivery showed association with the initial postpartum ALT flare; however, HBV titer at baseline is the only strong predictor for postpartum flare with multifactor analysis. This discordance may be attributed to different definitions of hepatic flare, differences of subject and observation period. Another factor contributing to the inconsistence is the small size of their subjects. Considering the association of virus titer with frequency of ALT flare and predictive value of HBV DNA, in addition to immune reconstruction and hormones recovery, virus may also contribute to the postpartum flare.
Some observations revealed promptly that those immunologic changes after delivery that stimulate immune clearance and are responsible for the higher than expected HBeAg seroconversion are lying in women.13,29,40 In our investigation, the mothers with hepatic flare during pregnancy had achieved substantial higher HBeAg seroconversion with extended antiviral therapy after delivery.13 In current study, a slight decline of HBeAg and HBsAg titer was displayed in the early postpartum period, which also support the standpoint that this may be a valuable antiviral opportunity for CHB-infected women in childbearing age, especially those with high viremia at the beginning of pregnancy (>7 log10 IU/mL); however, the optimized antiviral proposal and duration demand a large sample with longer follow-up.
In current investigation, mild to moderate ALT flare was observed, and there were no cases with liver failure and serious complications in fetuses, which was consistent with previous studies.28,30,31 Majority of the ALT elevation was asymptomatic and resolved spontaneously. The reasons that contribute to this include that the subjects in this study were from outpatient service and accepted close regular interview during pregnancy. Although the influence of hepatitis B on pregnancies has been confirmed41,42; severe complications, such as fetal distress, premature delivery and meconium peritonitis, gestational diabetes and antepartum hemorrhage, etc. have been reported, even liver failure.23,24 Another reason responsible for this discrepancy is the relatively small sample number in those studies mentioned above; in our cross-sectional observation including 11,000 gravidas, comparing with gravidas free of HBV infection, the incidence of intrahepatic cholestasis of pregnancy, thrombocytopenia, postpartum hemorrhage, and anemia was significantly higher in HBsAg(+) pregnant women (unpublished data). Hence, close monitoring is essential for the CHB mothers, especially those with high viral titer.
There are 2 peaks of hepatic flare during pregnancy and postpartum, one is happening during the first trimester and the other is happening during early period of postpartum, and the CHB pregnant women with high viremia (>6 log10 IU/mL) should be monitored closely during pregnancy and puerperium, even from the very beginning of pregnancy. Extended antiviral therapy should be recommended to those mothers with baseline viremia >7 log10 IU/mL for higher serological response.
The authors appreciate the guidance provided by Professor Shulin Zhang from the First Affiliated Hospital of Xi’an Jiaotong University.
1. Liang X, Bi S, Yang W, et al. Epidemiological serosurvey of hepatitis B
in China—declining HBV prevalence due to hepatitis B
vaccination. Vaccine. 2009;27:6550–6557.
2. Stevens CE, Beasley RP, Tsui J, et al. Vertical transmission of hepatitis B
antigen in Taiwan. N Engl J Med. 1975;292:771–774.
3. Lee AK, Ip HM, Wong VC. Mechanisms of maternal-fetal transmission of hepatitis B
virus. J Infect Dis. 1978;138:668–671.
4. Shao ZJ, Zhang L, Xu JQ, et al. Mother-to-infant transmission of hepatitis B
virus: a Chinese experience. J Med Virol. 2011;83:791–795.
5. Zhu Q, Yu G, Yu H, et al. A randomized control trial on interruption of HBV transmission in uterus. Chin Med J (Engl). 2003;116:685–687.
6. Shi Z, Yang Y, Ma L, et al. Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B
virus: a systematic review and meta-analysis. Obstet Gynecol. 2010;116:147–159.
7. Shahmoradi S, Yahyapour Y, Mahmoodi M, et al. High prevalence of occult hepatitis B
virus infection in children born to HBsAg-positive mothers despite prophylaxis with hepatitis B
vaccination and HBIG. J Hepatol. 2012;57:515–521.
8. Bedimo RJ, Drechsler H, Jain M, et al. The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health. PLoS One. 2014;9:e106221.
9. Robinson DP, Klein SL. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav. 2012;62:263–271.
10. Gaunt G, Ramin K. Immunological tolerance of the human fetus. Am J Perinatol. 2001;18:299–312.
11. Giles M, Visvanathan K, Lewin S, et al. Clinical and virological predictors of hepatic flares in pregnant women with chronic hepatitis B
. Gut. 2014;64:1810–1815.
12. Nguyen V, Tan PK, Greenup AJ, et al. Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare. Aliment Pharmacol Ther. 2014;39:1225–1234.
13. Liu J, Wang J, Jin D, et al. Hepatic flare
after telbivudine withdrawal and efficacy of postpartum antiviral therapy for pregnancies with chronic HBV. J Gastroenterol Hepatol. 2017;32:177–183.
14. Lin HH, Chen PJ, Chen DS, et al. Postpartum subsidence of hepatitis B
viral replication in HBeAg-positive carrier mothers. J Med Virol. 1989;29:1–6.
15. Braga AC, Vasconcelos C, Braga J. Pregnancy with autoimmune hepatitis. Gastroenterol Hepatol Bed Bench. 2016;9:220–224.
16. Westbrook RH, Yeoman AD, Kriese S, et al. Outcomes of pregnancy in women with autoimmune hepatitis. J Autoimmun. 2012;38:J239–J244.
17. Price AA, Grakoui A, Honegger JR. HCV adaptations to altered CD8+ T-cell immunity during pregnancy. Future Virol. 2014;9:333–336.
18. Indolfi G, Azzari C, Resti M. Hepatitis: Immunoregulation in pregnancy and perinatal transmission of HCV. Nat Rev Gastroenterol Hepatol. 2014;11:6–7.
19. Harish K, Nitha R, Harikumar R, et al. Prospective evaluation of abnormal liver function tests in pregnancy. Trop Gastroenterol. 2005;26:188–193.
20. Ch'ng CL, Morgan M, Hainsworth I, et al. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut. 2002;51:876–880.
21. Elefsiniotis IS, Tsoumakas K, Kapritsou M, et al. Liver function tests in viremic and nonviremic chronic hepatitis B
virus-infected pregnant women: importance of alanine aminotransferase/sodium ratio. Gastroenterol Nurs. 2013;36:422–428.
22. Soderstrom A, Norkrans G, Lindh M. Hepatitis B
virus DNA during pregnancy and post partum: aspects on vertical transmission. Scand J Infect Dis. 2003;35:814–819.
23. Yang YB, Li XM, Shi ZJ, et al. Pregnant woman with fulminant hepatic failure caused by hepatitis B
virus infection: a case report. World J Gastroenterol. 2004;10:2305–2306.
24. Mahtab MA, Rahman S, Khan M, et al. Etiology of fulminant hepatic failure: experience from a tertiary hospital in Bangladesh. Hepatobiliary Pancreat Dis Int. 2008;7:161–164.
25. Hung JH, Chu CJ, Sung PL, et al. Lamivudine therapy in the treatment of chronic hepatitis B
with acute exacerbation during pregnancy. J Chin Med Assoc. 2008;71:155–158.
26. Liu J, Wang J, Jin D, et al. Hepatic flare
after telbivudine withdrawal and efficacy of postpartum antiviral therapy for pregnancies with chronic hepatitis B
virus. J Gastroenterol Hepatol. 2017;32:177–183.
27. Pan CQ, Han GR, Jiang HX, et al. Telbivudine prevents vertical transmission from HBeAg-positive women with chronic hepatitis B
. Clin Gastroenterol Hepatol. 2012;10:520–526.
28. Han GR, Cao MK, Zhao W, et al. A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B
virus infection. J Hepatol. 2011;55:1215–1221.
29. Lu JF, Zhang SB, Liu YL, et al. Effect of Peg-interferon-2a combined with Adefovir in HBV postpartum women with normal levels of ALT and high levels of HBV DNA. Liver International. 2015;35:1692–1699.
30. Pan CQ, Duan Z, Dai E, et al. Tenofovir to prevent hepatitis B
transmission in mothers with high viral load. N Engl J Med. 2016;374:2324–2334.
31. Pan CQ, Trinh H, Yao A, et al. Efficacy and safety of tenofovir disoproxil fumarate in Asian-Americans with chronic hepatitis B
in community settings. PLoS One. 2014;9:e89789.
32. Zou ZQ, Wang L, Wang K, et al. Innate immune targets of hepatitis B
virus infection. World J Hepatol. 2016;8:716–725.
33. Tan HH, Lui HF, Chow WC. Chronic hepatitis B
virus (HBV) infection in pregnancy. Hepatol Int. 2008;2:370–375.
34. Chang CY, Aziz N, Poongkunran M, et al. Serum alanine aminotransferase and hepatitis B
DNA flares in pregnant and postpartum women with chronic hepatitis B
. Am J Gastroenterol. 2016;111:1410–1415.
35. Samadi Kochaksaraei G, Castillo E, Osman M, et al. Clinical course of 161 untreated and tenofovir-treated chronic hepatitis B
pregnant patients in a low hepatitis B
virus endemic region. J Viral Hepat. 2016;23:15–22.
36. Liang J, Jiang MJ, Deng X, et al. Efficacy and safety of telbivudine compared to entecavir among HBeAg plus chronic hepatitis B
patients: a meta-analysis study. Hepatitis Monthly. 2013;13:e7862.
37. Xie F, Yan L, Li JJ, et al. Effects of nucleoside analogue on patients with chronic hepatitis B
-associated liver failure: meta-analysis. Plos One. 2013;8:e54773.
38. Liu J, Feng Y, Wang J, et al. An “immune barrier” is formed in the placenta by hepatitis B
immunoglobulin to protect the fetus from hepatitis B
virus infection from the mother. Hum Vaccin Immunother. 2015;11:2068–2076.
39. Giles M, Visvanathan K, Lewin S, et al. Clinical and virological predictors of hepatic flares in pregnant women with chronic hepatitis B
. Gut. 2015;64:1810–1815.
40. Lin HH, Wu WY, Kao JH, et al. Hepatitis B
post-partum e antigen clearance in hepatitis B
carrier mothers: correlation with viral characteristics. J Gastroenterol Hepatol. 2006;21:605–609.
41. Lao TT, Chan BC, Leung WC, et al. Maternal hepatitis B
infection and gestational diabetes mellitus. J Hepatol. 2007;47:46–50.
42. Tse KY, Ho LF, Lao T. The impact of maternal HBsAg carrier status on pregnancy outcomes: a case-control study. J Hepatol. 2005;43:771–775.
Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
hepatitis B; gravida; hepatic flare; predictive factor