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Baseline Hepatitis B Virus Titer Predicts Initial Postpartum Hepatic Flare: A Multicenter Prospective Study

Liu, Jinfeng, MD, PhD*; Wang, Jing, MD, PhD; Qi, Caijing, MD, PhD; Cao, Furong, MD§; Tian, Zhen, MD*; Guo, Dandan, MD*; Yan, Taotao, MD, PhD*; Li, Qian, MD*; Yang, Shujuan, MD*; Fu, JianJun, MD*; Tang, Xianmei, MD*; Kou, Xiaoni, MD*; Liu, Na, MD*; Jiang, Zicheng, MD*; Zhao, Yingren, MD, PhD*; Chen, Tianyan, MD, PhD*

doi: 10.1097/MCG.0000000000000877

Background and Goals: A series of changes in the immune system occur during pregnancy and puerperium. Currently, we aim to characterize both the natural changes in liver inflammation and its association with hepatitis B viremia during this special period.

Patients and Methods: Chronic hepatitis B (CHB) gravidas were recruited and followed up to 52 weeks postpartum. Virological and biochemical parameters were assessed throughout the period.

Results: A total of 1097 CHB mothers had finished the entire follow-up including 451 accepting telbivudine, 178 accepting tenofovir, and 468 without antiviral therapy. Among the mothers, 11.94% went through hepatic flare in the first trimester and the rate decreased to 2.1% at the time of delivery. Nevertheless, a much higher frequency (19.78%) was observed in the early postpartum. Interestingly, alanine aminotransferase level decreased along with the development of pregnancy and then suddenly increased in the first month of puerperium. In addition, a downward trend was observed on the titer of HBsAg and HBeAg after delivery. Of note, an obvious higher frequency of alanine aminotransferase flare was revealed in mothers with high viremia (>6 log10 IU/mL). With multivariate analysis, only hepatitis B virus titer at baseline was strongly associated with hepatic flare during early postpartum (95% confidence interval, 1.012-3.049, P=0.045). The predictive rates of hepatic flare at baseline viral load of 6, 7, and 8 log10 IU/mL were 16.67%, 28.30%, and 30.60%, respectively.

Conclusions: CHB gravidas with high viremia should be monitored closely during entire pregnancy, and extended antiviral therapy is recommend to those mothers with baseline viremia >7 log10 IU/mL.

Departments of *Infectious Disease

Rheumatology and Immunology

Gynaecology and Obstetrics

§Neonatology, the First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, Shaanxi Province, China

J.L., J.W., and C.Q. contributed equally.

Supported by funding from the National Science and Technology Projects on Major Infectious Diseases (12th Five Year, China) (Project No. 2012ZX10002007-001-001 and 2012ZX10002007-002-007) and from the National Natural Science Fund (Project No. 81670537).

The authors declare that they have nothing to disclose.

Address correspondence to: Yingren Zhao, MD, PhD and Tianyan Chen, MD, PhD, The First Affiliated Hospital, Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China (e-mails:;

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Received February 15, 2017

Accepted May 11, 2017

The new infection rate of hepatitis B virus (HBV) has decreased dramatically in the past 15 years in China because of the rigorous implementation of the HBV vaccination program.1 However, chronic hepatitis B (CHB) remains a heavy burden for families and the society due to the largest population in the world and a high prevalence rate of HBV infection. What is more, majority of this HBV infection occur through mother-to-child transmission at birth or in early infancy, which is intimately associated with a high risk of developing end-stage liver diseases such as liver failure and hepatocellular carcinoma.2,3 Although the combined passive-active immunoprophylaxis program is effective in ∼90% chronic HBV mothers, there is still ∼5% to 10% of vertical transmission because of the failure to protect against intrauterine infection,4–8 which becomes the key issue in the prevention of new HBV infection.

A series of changes of hormones and other components in the immune system occur during pregnancy because of tolerating fetal antigens and the development of fetus.9 These changes include the decrease of proinflammatory factors such IL-2 and IL-12, and the increase of anti-inflammatory factors, which facilitate successful pregnancy. Increased susceptibility of gravidas to some infectious disease such as influenza and varicella has also been reported.9 Another study by Gaunt and Ramin10 has confirmed the association of immunologic tolerance to fetal antigens with suppressed cell-mediated immunity. Most of the above-listed changes emerge at the maternal-fetal interface of the placenta. However, systemic changes of immune effectors against HBV infection in chronic HBV mothers have been reported.11,12 In addition, postpartum hepatic flare owing to reconstitution of the maternal immune system and rapid recovery of hormone levels has been observed by us and several other groups.11–13 Furthermore, high HBeAg seroconversion rate in the postpartum period,14 as well as improvement of autoimmune hepatitis15,16 and changes in HCV RNA17,18 have also been reported, indicating dramatic changes of the immune system accompanied with pregnancy and parturition.

A rate of 0.3% to 3% hepatic flare has been described owing to increasing metabolic load on the liver during pregnancy.19,20 It remains unclear whether the alterations in immune system during pregnancy and postpartum may have an impact on the activity of HBV infection. With adjustment of immune system and physiological changes for successful pregnancy, the hepatic flare was found to be mitigated even in chronically HBV-infected gravidas.21,22 Nevertheless, severe pregnancy complications, even fulminant liver disease, have also been reported in CHB gravidas, mortality as high as 43% to 80% of those women with liver failure has been reported.23,24 Outcome of CHB gravidas depends on the complicated interactions between HBV, immune system, and gravidas. In our and others’ studies, it is well accepted that antiviral treatment during pregnancy can mollify inflammation-induced liver damage,25,26 and benefit of CHB mother with hepatic flare from extended antiviral therapy after delivery has also been described recently.27–29 It is essential for us to clarify the hepatic flare during pregnancy and puerperium.

The purpose of this study was to prospectively observe the natural changes in liver inflammation [assessed by changes in alanine aminotransferase (ALT)] and virological markers, and evaluate the association of ALT fluctuation with viremia. Moreover, the predictors of hepatic flare during the early puerperium, regarded as a valuable therapy opportunity for women of childbearing age was also assessed.

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Female patients who were HBsAg(+) for at least 6 month and underwent routine consultation from the first trimester, were recruited from 16 different hospitals in Shaanxi province, China. Ethics approval was obtained from the Human Research and Ethics Committees from the 16 institutions involved in the study. After informed consent was obtained, all participants were followed continuously. Written consent for the participation of their infants was also obtained upon birth. Mothers were excluded if they were coinfected with other virus, diagnosed with cirrhosis, or were receiving concurrent treatment with steroids, immune modulators or cytotoxic drugs, and so on. Demographic and clinical data were collected together with virological (HBV DNA load and titers of viral markers) and biochemical parameters at the timing of their first outpatient appointment during the first trimester, which was defined as the baseline. The gravidas were routinely monitored at 4-week intervals from the 20th week of gestation to 1 month after parturition, and then followed every 3 to 6 months in postpartum.

All infants received combined immunoprophylaxis, namely hepatitis B immunoglobulin (200 IU; Hualan Biological Engineering Inc., Henan, China) within 12 hours postpartum and hepatitis B vaccine (10 μg; Shenzhen Kangtai Biological Products Co. Ltd, Guangdong, China) within 12 hours, at 1 month, and at 6 months after birth. Transmission of HBV to the child was defined as detectable HBsAg or HBV DNA in the child’s blood at 7 months of age. A proportion of the enrolled pregnant women accepted tenofovir (300 mg/d) or telbivudine (600 mg/d) treatment from the 24th or 28th week of gestation according to viral load, liver function, and willing of the patient.

HBV viral markers (HBsAg, anti-HBs, HBeAg, and anti-HBc) were quantified by the Abbott ARCHITECT HBsAg, anti-HBs, HBeAg, and anti-HBc assays (Abbott Laboratories, Chicago, IL). HBV DNA load was quantified using a high-sensitivity fluorescent real-time PCR kit (Daangene, Guangzhou, China) with detection limit ≥1×102 IU/mL. Biochemical parameters were tested with an automated bioanalyzer (Olympus AU5400, Japan). ALT flare was defined as 2 times of the upper limit of normal (40 IU/L), which help catch as much as possible variation during pregnancy and postpartum.

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Statistical Analyses

All statistical analyses were performed with SPSS 13.0 (SPSS Inc., Chicago, IL). Descriptive analysis was conducted. The χ2 test was used to evaluate rates of 2 groups. Univariate and multivariate logistic regression analyses were used to determined odds ratios, adjusted odd ratios, and their 95% confidence intervals (CIs) to different variables. Using the multivariate logistic regression model, predictive rates of initial postpartum hepatic flare were estimated at various HBV DNA load levels at baseline. Statistical significance was set as P<0.05.

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Basic Profile of the Mothers and Infants

Between March 2010 to January 2015, 1191 CHB gravidas were enrolled in their first trimester, 15 subjects withdrew consent during following monitoring, 67 of them were lost for changing hospitals or losing contact information and 12 of them were eliminated because of serious obstetric diseases during pregnancy (Fig. 1). Therefore, 1097 couples of mothers and infants were included in the final analysis, including 451 receiving telbivudine, 178 receiving tenofovir, and 468 without antiviral therapy during pregnancy. The baseline characteristics of the mothers and infants are presented in Table 1. As shown, 58.8% of the mothers were HBeAg(+), and the median level of HBV DNA was 4.66±3.37 (0 to 9.44 log IU/mL) at baseline.





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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.

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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).



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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).



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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.

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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.

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The authors appreciate the guidance provided by Professor Shulin Zhang from the First Affiliated Hospital of Xi’an Jiaotong University.

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hepatitis B; gravida; hepatic flare; predictive factor

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