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 Table of Contents  
Year : 2017  |  Volume : 6  |  Issue : 2  |  Page : 106-108

Maternal chronic hepatitis B and entecavir therapy associated with meconium peritonitis in a neonate

1 Department of Paediatrics, North West Regional Hospital, Tasmanian Health Service, Tasmania, Australia
2 Clinical School, University of Tasmania, Private Bag 68, HOBART TAS 7001, Australia

Date of Web Publication13-Apr-2017

Correspondence Address:
Anutosh Shee
North West Regional Hospital, Tasmanian Health Service, Tasmania
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_96_16

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We present a case of meconium peritonitis in a neonate born to a mother with chronic hepatitis B virus (HBV) infection with low viral load treated with entecavir. There have been a small number of case reports describing maternal acute or fulminant HBV associated with meconium peritonitis, but this case is the first to our knowledge to represent this association in the setting of chronic infection with low viral load, suggesting an alternate mechanism does exist possibly related to the chronic inflammation. There have been no adequately controlled trials of entecavir therapy in pregnant women to date, thus its effects on the human fetus are currently unknown. This case report suggests that further investigation is required into the effects of chronic HBV and its antiviral treatment on fetal development in utero.

Keywords: Chronic hepatitis B, entecavir, meconium peritonitis

How to cite this article:
Shee A, Fracalossi N. Maternal chronic hepatitis B and entecavir therapy associated with meconium peritonitis in a neonate. J Clin Neonatol 2017;6:106-8

How to cite this URL:
Shee A, Fracalossi N. Maternal chronic hepatitis B and entecavir therapy associated with meconium peritonitis in a neonate. J Clin Neonatol [serial online] 2017 [cited 2020 May 27];6:106-8. Available from: http://www.jcnonweb.com/text.asp?2017/6/2/106/204520

  Introduction Top

Chronic hepatitis B infection affects more than 350 million people worldwide. It is a global health problem of immense importance. Incidence of chronic hepatitis B virus (HBV) infection in pregnancy varies widely, between 0.1% to 20% around the world [1] depending on different race and ethnicity in low-prevalence areas.[2] There is a lack of data on pregnancy outcomes in the setting of maternal hepatitis B infection, but case reports and studies have indicated increased incidence of neonatal morbidity including prematurity, low birth weight, and congenital malformations although no specific teratogenicity has been described.[3] A small number of reports in the literature regarding meconium peritonitis in the neonates have shown to be associated with maternal acute HBV infection.[4],[5],[6] One of them had fulminant hepatitis,[7] suggesting a possible link between these entities. We report a case of meconium peritonitis in a neonate born to a mother with chronic hepatitis B infection with compensated liver cirrhosis and portal hypertension, who had low viral load following the treatment of entecavir throughout the pregnancy.

  Case Report Top

A 29-year old pregnant woman, migrated from Africa with incidentally detected chronic hepatitis B about 4 years ago, delivered a preterm baby girl at 29 weeks of gestation, weighing 1534 gm following antepartum hemorrhage. Liver cirrhosis, portal hypertension, and splenomegaly were confirmed about 2 years before the pregnancy. She was commenced on entecavir (0.5 mg a day) 5 months prior to the conception, which was continued throughout the pregnancy. Additional comorbidities in this patient included thrombocytopenia and gestational diabetes mellitus (GDM) which was well controlled by diet only. Her clinical condition remained stable throughout the pregnancy.

Antenatal serology detected maternal hepatitis B surface antigen (HBsAg), anti-hepatitis B e-antibody, and anti-hepatitis B core antibody but tested negative for hepatitis B surface antibody and hepatitis B e-antigen (HBeAg). Hepatitis B viral load remained low measuring <15 IU/ml throughout pregnancy, assessed four times (using Roche AmpliPrep/COBAS Taqman HBV test version 2.0, with dynamic normal range of 20 IU/ml – 1.7 × 108 IU/ml), throughout and after the pregnancy. HIV 1 and 2, syphilis, cytomegalovirus, and hepatitis C were negative, and she was rubella immune. Maternal aminotransferase levels and coagulation profile were both normal. Antenatal fetal ultrasonography at 23 weeks showed multiple small echogenic areas across the liver and bowel which continued to progress on the subsequent scans (see [Figure 1]). The neonate received hepatitis B immunoglobulin and hepatitis B vaccine soon after birth. HBsAg was negative in the neonate measured at birth and at 6 months of age.
Figure 1: Initial X-ray showing intra-abdominal calcified ring lesion in the left subcostal area and some stippled calcification, predominately in the right and left hypochondrium

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The neonate had an emergency laparotomy performed at 20 h of age following the confirmation of multiple intra-abdominal calcified masses by postnatal ultrasound scan, which resembled meconium peritonitis associated with three ileal perforations, each accompanied by calcified meconium pseudocyst. The temporary ileostomy was subsequently reanastomosed in a second procedure 8 weeks later. Postoperatively, multiple intra-abdominal collections were identified which eventually resolved with external drainage and long-term antibiotics (see [Figure 2]). Histology confirmed nonspecific chronic inflammatory changes in the ileal biopsy sample. Over the course of both operations, the neonate had approximately 10 cm of ileum removed but demonstrated satisfactory weight gain while receiving initial total parenteral nutrition and extensively hydrolyzed formula feeds later on.
Figure 2: Abdominal ultrasound scan showing multiloculated collection

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  Discussion Top

Meconium peritonitis is classically associated with cystic fibrosis (CF) and is also seen in association with small bowel atresia, meconium ileus, and volvulus. Extensive CF genetic testing was negative in this neonate. Although testing does not identify all possible CF mutations, incidence of CF in children of African origin is believed to be exceptionally rare.[8] Intraoperative findings did not indicate any evidence of anatomical abnormalities such as microcolon, ileal atresia, or volvulus to justify the presence of meconium peritonitis. Hirschsprung disease was also considered as a potential cause of ileal perforation in this case, but rectal biopsy determined the presence of ganglion cells.

Maternal-fetal transmission of hepatitis B most commonly occurs during delivery through the exposure of infected blood and vaginal secretions [9] but in rare cases can also occur transplacentally in utero and postnatally.[10] In our case, there was no evidence of perinatal maternal-fetal transmission of hepatitis B, a finding which is consistent with the mother's and neonate's HBeAg-negative status. Of the reports, regarding meconium peritonitis associated with maternal HBV; only one report was associated with positive cord blood specimens for HBsAg.[4] This suggests that fetal infection with HBV is not necessarily implicated as the causation of meconium peritonitis.

This report is the first to our knowledge to present a case of chronic maternal hepatitis B infection, with low viral load, associated with meconium peritonitis in the neonate. Chronic HBV has largely been considered as relatively benign to the fetus without any specific teratogenicity.[11] Most women experience stable clinical state during pregnancy, while some experience flaring up following delivery, but there are little data in the literature regarding pregnancy outcomes.[2] One study found that women who were HbsAg positive during pregnancy had increased risk of GDM, antepartum hemorrhage, and preterm labor.[12] This and another similar study have suggested that an increased level of pro-inflammatory cytokines induced by chronic HBV may explain this association with GDM.[12],[13] Whether the meconium peritonitis is due to this similar chronic inflammatory response is not clear. There are some case reports of congenital malformations associated with maternal HBV.[3],[4],[5],[14] Management of pregnancies associated with chronic maternal HBV focuses largely on the prevention of maternal-fetal transmission, but our case suggests that additional factors on the fetus may need to be explored, perhaps related to the pro-inflammatory state observed in chronic HBV mothers by Lao et al.[13] and Tse et al.[12]

The role of entecavir in the outcome of this case should also be considered. Entecavir is a guanosine nucleoside analog with selective activity against HBV polymerase. It is phosphorylated to its active form by cellular kinases, and it competes with the natural substrate deoxyguanosine triphosphate and inhibits the activity of the HBV polymerase. Entecavir is listed as pregnancy category C by the US Food and Drug Administration, indicating that there are no adequate and well-controlled studies of the use in humans, but animal trials have indicated evidence of harm including carcinogenic potential with long-term use, retarded embryofetal development at maternotoxic doses and skeletal malformations at maternal doses >883 times human levels, in the absence of maternal toxicity.[15] There were no signs of embryofetal or maternal toxicity when pregnant animals received oral entecavir at approximately 28(rat) and 212 (rabbit) times over the highest recommended human dose of 1 mg/kg/day. Exact mechanism of adverse effects on animals varies from species to species and possibly linked to the species-specific chemotaxis. Gastrointestinal adverse effects seen in animal models include fibrin microthrombosis, necrosis of villi, inflammation, and hemorrhage in rats (at 200 mg/kg/day in a 2-week study) and dogs (at 100/50 mg/kg/day in the 2-week study).[16] In our case report, it is not clear, whether prolonged exposure of therapeutic dose of entecavir in pregnancy has caused any similar fetal intestinal inflammation leading to meconium peritonitis.

One case report of successful entecavir use during pregnancy described a 0.5 mg/day dose instituted at 13 weeks gestation for acute exacerbation on chronic HBV and withdrawn after 32 days of treatment. No complications were reported for the postpartum period, and no congenital anomalies found.[17] Further trials are required for more information on embryotoxicity. There has not been any association drawn between entecavir therapy and meconium peritonitis in any other case reports to date. Regular monitoring of the reporting on the Antiretroviral Pregnancy Registry would be very important in the absence of high-quality trials.

  Conclusion Top

This case report of meconium peritonitis occurring with low-grade maternal chronic hepatitis B demonstrates a potential association between these entities, possibly independent of viral load, in addition to that suggested in the setting of acute HBV. This case also highlights the need for further investigation into the effects on the fetus of maternal chronic HBV and its antiviral treatments, including consideration of the effect of a chronic inflammatory state in pregnancy.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11:97-107.  Back to cited text no. 1
Sinha S, Kumar M. Pregnancy and chronic hepatitis B virus infection. Hepatol Res 2010;40:31-48.  Back to cited text no. 2
Safir A, Levy A, Sikuler E, Sheiner E. Maternal hepatitis B virus or hepatitis C virus carrier status as an independent risk factor for adverse perinatal outcome. Liver Int 2010;30:765-70.  Back to cited text no. 3
Schröter B, Chaoui R, Meisel H, Bollmann R. Maternal hepatitis B infection as the cause of nonimmunologic hydrops fetalis. Z Geburtshilfe Neonatol 1999;203:36-8.  Back to cited text no. 4
Has R, Yüksel A, Topuz S. Hepatitis B infection in pregnancy: Is it really not harmful to the fetus? Prenat Diagn 2001;21:701-2.  Back to cited text no. 5
Nigro G, La Torre R, Mazzocco M, Coacci F, Riosa B, D'Emilio C, et al. Multi-system cytomegalovirus fetopathy by recurrent infection in a pregnant woman with hepatitis B. Prenat Diagn 1999;19:1070-2.  Back to cited text no. 6
Su WH, Wang PH, Yuan CC, Chang SP. Fetal meconium peritonitis in the infant of a woman with fulminant hepatitis B. A case report. J Reprod Med 2002;47:952-4.  Back to cited text no. 7
Feuillet-Fieux MN, Ferrec M, Gigarel N, Thuillier L, Sermet I, Steffann J, et al. Novel CFTR mutations in black cystic fibrosis patients. Clin Genet 2004;65:284-7.  Back to cited text no. 8
Lee AK, Ip HM, Wong VC. Mechanisms of maternal-fetal transmission of hepatitis B virus. J Infect Dis 1978;138:668-71.  Back to cited text no. 9
Ghendon Y. Perinatal transmission of hepatitis B virus in high-incidence countries. J Virol Methods 1987;17:69-79.  Back to cited text no. 10
Sookoian S. Effect of pregnancy on pre-existing liver disease: Chronic viral hepatitis. Ann Hepatol 2006;5:190-7.  Back to cited text no. 11
Tse KY, Ho LF, Lao T. The impact of maternal HBsAg carrier status on pregnancy outcomes: A case-control study. J Hepatol 2005;43:771-5.  Back to cited text no. 12
Lao TT, Tse KY, Chan LY, Tam KF, Ho LF. HBsAg carrier status and the association between gestational diabetes with increased serum ferritin concentration in Chinese women. Diabetes Care 2003;26:3011-6.  Back to cited text no. 13
Pavel A, Tîrsia E, Maior E, Cristea A. Detrimental effects of hepatitis B virus infection on the development of the product of conception. Virologie 1983;34:35-40.  Back to cited text no. 14
Colonno RJ, Genovesi E, Medina I, Lamb L, Durham SK, Huang M-L, et al. Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection. J Inf Dis 2001;184:1236-45.  Back to cited text no. 15
Giles M, Visvanathan K, Sasadeusz J. Antiviral therapy for hepatitis B infection during pregnancy and breastfeeding. Antivir Ther 2011;16:621-8.  Back to cited text no. 16
Kakogawa J, Sakurabashi A, Sadatsuki M, Gomibuchi H, Minoura S. Chronic hepatitis B infection in pregnancy illustrated by a case of successful treatment with entecavir. Arch Gynecol Obstet 2011;284:1595-6.  Back to cited text no. 17


  [Figure 1], [Figure 2]

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1 Entecavir
Reactions Weekly. 2017; 1658(1): 180
[Pubmed] | [DOI]


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