Sharda Patra

Maternal and Fetal Outcomes in Pregnant Women with Acute Hepatitis E Virus Infection

Context Hepatitis E virus (HEV) infection causes severe liver disease in pregnant women. Contribution In a case series of 220 pregnant women with jaundice and acute viral hepatitis, the authors observed that women with HEV infection more often died and had more obstetric complications and worse fetal outcomes than did women with other forms of viral hepatitis. Caution The series was restricted to symptomatic women at a referral center. Implication Infection with HEV not only causes more severe liver disease in pregnant women but also appears to contribute to worse obstetric and fetal outcomes compared with other forms of viral hepatitis. The Editors Hepatitis E virus (HEV) is a single-stranded RNA virus that causes large-scale epidemics and sporadic cases of acute viral hepatitis in developing countries (1, 2). Infection with HEV also poses a significant risk for acute viral hepatitis to travelers in endemic areas (3). The main source of transmission of HEV is contaminated drinking water (4, 5). In men and nonpregnant women, the disease is usually self-limited and has a low case-fatality rate (<0.1%) (6). However in pregnant women, HEV infection is more severe, often leading to fulminant hepatic failure and death in up to 15% to 20% of cases. This high mortality rate was first reported in an epidemic setting in the early 1980s (7) and was reported again in a sporadic setting in 2003 (8). Information is limited and conflicting on the effect of HEV infection on maternal, obstetric, and fetal outcomes (9, 10). Therefore, we describe the prevalence and clinical outcomes of acute viral hepatitis in a series of HEV-infected pregnant women and compare their maternal, obstetric, and fetal outcomes with those of pregnant women without HEV infection. Methods Setting and Participants The study was conducted at the Department of Obstetrics and Gynecology, Lady Hardinge Medical College, and Shrimati Sucheta Kriplani Hospital, New Delhi, India (a large tertiary care hospital), in collaboration with the Department of Gastroenterology, G.B. Pant Hospital, New Delhi. Consecutive pregnant women at any gestational stage who presented between January 2003 and July 2005 with acute viral hepatitis were systematically assessed for hepatitis virus infection by using liver function tests and serologic analysis. Acute viral hepatitis was diagnosed (7) by a serum bilirubin level of 34 mol/L or greater (2 mg/dL); a serum alanine aminotransferase level 2.5 times the upper limit of normal or greater; and positivity for any hepatotropic virus by using the following serologic tests: hepatitis B surface antigen; antibody to hepatitis C virus; and IgM antibodies to hepatitis A virus, hepatitis B core antigen, hepatitis delta virus, and HEV. We excluded patients with negative results on viral serologic examination, those with dual viral infection, those with clinical evidence of other causes of jaundice (such as biliary obstruction, the HELLP syndrome [hemolytic anemia, elevated liver enzyme level, low platelet count], acute fatty liver of pregnancy, hemolytic jaundice, and drug-induced jaundice), and those with clinical or laboratory evidence of chronic liver disease. Women who met the case definition of acute viral hepatitis were managed in a separate hepatitis hospital ward. Management depended on whether the patients acute viral hepatitis was complicated by fulminant hepatic failure, which was diagnosed when hepatic encephalopathy developed in a patient with acute viral hepatitis within 4 weeks of the onset of jaundice (11). Patients without fulminant hepatic failure were given standard care and were monitored for signs and complications of acute viral hepatitis (fever, edema, ascites, paralytic ileus, nasal and gastrointestinal hemorrhage, high leukocyte count, high creatinine concentration, hepatic encephalopathy, clinically significant coagulation defect [international normalized ratio> 2.0], hypoglycemia, hyponatremia, hypernatremia, hypokalemia, hyperkalemia, and hypocalcemia), and obstetric complications (antepartum, intrapartum, or postpartum hemorrhage; premature rupture of membranes; and intrauterine death). If their condition improved, patients were discharged and instructed to return for regular outpatient follow-up visits until delivery. Patients with fulminant hepatic failure were managed with supportive care in the intensive care unit because liver transplantation facilities are not available in the hospital. They were monitored for increased intracranial tension along with other medical and obstetric complications. They received 20% mannitol, lactulose, antibiotics, parenteral nutrition, and ventilatory support, as needed. Women without fulminant hepatic failure who had fetal distress, meconium staining of amniotic fluid, no progress of labor, or obstructed labor underwent cesarian section. Termination of pregnancy was considered in cases of intrauterine death, severe intrauterine growth retardation, a nonreactive nonstress test result, postdated pregnancy, and premature rupture of membrane at term only if the patient had improving liver function and a coagulation profile that could be further corrected by giving fresh frozen plasma. Termination of pregnancy was not considered for women with fulminant hepatic failure. All women with manifestations of bleeding were infused with fresh frozen plasma and packed red cells. In keeping with the policy of our institutions, the study did not require institutional review board approval or documented informed consent from patients for study participation because patients received care according to a standard clinical protocol, their care was not influenced by their inclusion in the study, and data were collected and recorded according to ethical standards and norms in India and were analyzed with total anonymity of patients. Statistical Analysis We used the t test and the MannWhitney U test to compare normally distributed data and non-normally distributed data, respectively, of HEV-infected and nonHEV-infected patients. The chi-square test was used to compare discrete values between groups. A P value less than 0.05 was considered significant. Relative risk was calculated for all complications in HEV-infected pregnant women versus nonHEV-infected pregnant women. Statistical analyses were done by using SPSS, version 13.0 (SPSS, Chicago, Illinois). Role of the Funding Source The study received no external funding. Results Patients Of the 33385 pregnant women who were admitted during the study period, 316 (0.9%) presented with jaundice. Ninety-two were excluded for causes of jaundice other than viral hepatitis (intrahepatic cholestasis of pregnancy [41 women], the HELLP syndrome [6 women], acute fatty liver of pregnancy [3 women], drug hepatotoxicity [7 women], hemolytic jaundice [14 women], choledocholithiasis [6 women], and unknown cause [15 women]), and 4 were excluded for dual viral infection. The remaining 220 pregnant women with jaundice met the inclusion criteria for acute viral hepatitis. None had evidence of autoimmune disease. Table 1 shows patient characteristics. The mean maternal age was 22.4 years (SD, 3.2). Sixty-one women (28%) were in the second trimester of pregnancy (mean gestational age, 26.2 weeks [SD, 2.0]) and 159 (72%) were in the third trimester (mean gestational age, 34.2 weeks [SD, 2.6]). The mean duration of jaundice before hospitalization was 4.9 days (SD, 2). Table 1. Patient Characteristics* Cause of Hepatitis Infection with HEV was the most common cause of acute viral hepatitis (132 participants [60%]) (Table 1). Hepatitis B virus (HBV) infection was the most common cause of nonHEV acute viral hepatitis (72 participants [33%]). Fewer HEV-infected patients than nonHEV-infected patients were in their third trimester of pregnancy, corresponding to a lower mean gestational age for HEV-infected patients (31 weeks [SD, 4.1] vs. 33 weeks [SD, 4.4]; P= 0.004) (Table 1). The median duration of jaundice did not differ between HEV-infected women and nonHEV-infected women (4 days [range, 1 to 15 days] vs. 4.5 days [range, 2 to 10 days]; P= 0.68). Fulminant Hepatic Failure Ninety-one women (41%) had fulminant hepatic failure, of whom 54 (59%) had fulminant hepatic failure on admission and 37 (41%) developed fulminant hepatic failure during hospitalization. Fulminant hepatic failure was more common among HEV-infected women than nonHEV-infected women (73 of 132 [55%] vs. 18 of 88 [20%]; relative risk, 2.7 [CI, 1.7 to 4.2]; P< 0.001) (Table 1) and among HEV-infected women in their third trimester (46 of 88 [52%] vs. 11 of 71 [15%] noninfected women; relative risk, 3.4 [CI, 1.9 to 6.0]; P< 0.001). The frequency of fulminant hepatic failure did not statistically significantly differ between HEV-infected women and nonHEV-infected women in their second trimester (27 of 44 [61%] vs. 7 of 17 [41%]; P= 0.26). Jaundice before hospital admission was of longer duration in women with fulminant hepatic failure than in those without fulminant hepatic failure (5.4 days [SD, 2.6] vs. 4.6 days [SD, 1.5]; P= 0.010). In women who developed fulminant hepatic failure, the mean interval from onset of jaundice to onset of encephalopathy was 108 hours (SD, 58) and was similar in HEV-infected and nonHEV-infected women (112 hours [SD, 60] vs. 93 hours [SD, 50]; P= 0.18). The mean duration of encephalopathy before admission was 20 hours (SD, 15) and was similar in HEV-infected and nonHEV-infected women. Maternal Mortality and Complications of Infection Maternal mortality was higher in HEV-infected women and occurred exclusively in women with fulminant hepatic failure (Table 2). Signs and complications of infection that differed by HEV status were an international normalized ratio greater than 2.0, nasal or gastrointestinal hemorrhage, leukocyte count of 11109 cells/L or greater, high serum creatinine concentration (34 mol/L [2 mg/dL]), ascites, and signs of increased intracranial tension. Differenc

Hepatitis B vaccination with or without hepatitis B immunoglobulin at birth to babies born of HBsAg-positive mothers prevents overt HBV transmission but may not prevent occult HBV infection in babies: a randomized controlled trial

Vertical transmission of Hepatitis B virus HBV can result in a state of chronic HBV infection and its complications. HBV vaccination with or without hepatitis B immunoglobulin (HBIG) prevents transmission of overt infection to the babies. However, whether it also prevents occult HBV infection in babies is not known. Consecutive pregnant women of any gestation found to be HBsAg positive were followed till delivery, and their babies were included in the study. Immediately after delivery, babies were randomized to receive either HBIG or placebo in addition to recombinant HBV vaccine (at 0, 6, 10 and 14 weeks). The primary end‐point of the study, assessed at 18 weeks of age, was remaining free of any HBV infection (either overt or occult) plus the development of adequate immune response to vaccine. The babies were further followed up for a median of 2 years of age to determine their eventual outcome. Risk factors for HBV transmission and for poor immune response in babies were studied. Of the 283 eligible babies, 259 were included in the trial and randomized to receive either HBIG (n = 128) or placebo (n = 131) in addition to recombinant HBV vaccine. Of the 222 of 259 (86%) babies who completed 18 weeks of follow‐up, only 62/222 (28%) reached primary end‐point. Of the remaining, 6/222 (3%) developed overt HBV infection, 142/222 (64%) developed occult HBV infection, and 12/222 (5%) had no HBV infection but had poor immune response. All 6 overt infections occurred in the placebo group (P = 0.030), while occult HBV infections were more common in the HBIG group (76/106 [72%] vs. 66/116 [57%]; P = 0.025). This may be due to the immune pressure of HBIG. There was no significant difference between the two groups in frequency of babies developing poor immune response or those achieving primary end‐point. The final outcome of these babies at 24 months of age was as follows: overt HBV infection 4%, occult HBV infection 42%, no HBV infection but poor immune response 8% and no HBV infection with good immune response 28%. Women who were anti‐HBe positive were a low‐risk group, and their babies were most likely to remain free of HBV infection (occult or overt) and had good immune response to the vaccine. Maternal HBeAg‐positive status and negativity for anti‐HBe predicted not only overt but also any infection (both overt and occult) in babies. In addition, high maternal HBV DNA and treatment with vaccine alone were significant factors for overt HBV infection in babies. The current practice of administration of vaccine with HBIG at birth to babies born of HBsAg‐positive mothers is not effective in preventing occult HBV infection in babies, which may be up to 40%. Because the most important risk factors for mother‐to‐baby transmission of HBV infection are the replicative status and high HBV DNA level in mothers; it will be worthwhile investigating the role of antivirals and HBIG administration during pregnancy to prevent mother‐to‐child transmission of HBV infection.

Prevalence, risk factors and virological profile of chronic hepatitis B virus infection in pregnant women in India.

A large program was conducted by the Government of India to study the prevalence and profile of chronic hepatitis B virus (HBV) infection and its risk factors in pregnant women attending a tertiary care hospital in India. From September 2004 to December 2008 consecutive pregnant women attending the antenatal clinic were screened and those found positive for HBsAg were enrolled. Healthy non‐pregnant women of child‐bearing age, who presented for blood donation during the same period, served as controls. Women with symptoms of liver disease or those aware of their HBsAg status were excluded. Of the 20,104 pregnant women screened, 224 (1.1%) and of the 658 controls, 8 (1.2%) were HBsAg positive (P = ns). Previous blood transfusions and surgery were significant risk factors for infection with HBV. Of the women who were HBsAg positive, the ALT levels were normal in 54% of the women and HBV DNA levels were above 2,000 IU/ml in 71% of women. The median HBV DNA levels were higher in women who were HBeAg positive compared to the HBeAg negative group. The most common HBV genotype was D (84%) followed by A + D and A (8% each). In conclusion, the prevalence of HBsAg positivity among asymptomatic pregnant women in North India is 1.1% with 71% having high HBV DNA levels. These women may have a high risk of transmitting infection to their newborns. J. Med. Virol. 83:962–967, 2011.

Maternal and perinatal outcome in patients with severe anemia in pregnancy.

Anemia is a major health problem among women of reproductive age particularly in developing countries. The prevalence of anemia among pregnant women is 55.9% worldwide and varies between 35% and 100% in developing countries. Anemia is responsible for 15% to 20% of total maternal mortality. This study assesses maternal and perinatal outcomes among women who were severely anemic in their third trimester of pregnancy with a hemoglobin concentration less than 5 g/dL. The 130 women admitted with severe anemia during the study period represented 9% of all hospital admissions. Such a high prevalence in an urban setting where obstetric services are freely available emphasizes the need to look into the deeper causes of the condition. (excerpt)

Impaired monocyte-macrophage functions and defective toll-like receptor signaling in hepatitis E virus-infected pregnant women with acute liver failure

Acute viral hepatitis resulting due to hepatitis E viral infection (AVH‐E) is often serious in pregnancy and could result in acute liver failure (ALF). The role of monocytes and macrophages (mono‐macs) in the pathogenesis of AVH‐E and development of ALF‐E in pregnancy is unclear. We investigated the functions of mono‐macs in pregnant (P), AVH‐E (n = 44), ALF‐E (n = 12), healthy controls (HC; n = 20) and compared with nonpregnant (NP) AVH‐E (n = 10), ALF‐E (n = 5), and HC (n = 10). We also recruited non‐hepatitis E virus‐related pregnant (P), ALF‐NE (n = 5) and non‐pregnant (NP), ALF‐NE (n = 12) patients with ALF. Mono‐macs, dendritic cell (DC) phenotypes, and Toll‐like receptor (TLR) expressions were studied by flow cytometry and reverse‐transcriptase polymerase chain reaction. Mono‐macs functionality was determined by analyzing their phagocytic activity and reactive oxygen species (ROS) generation by using flow cytometry. Frequency of mono‐macs and DCs was increased during HEV infection compared to HC (P < 0.001). Macrophages were increased (P < 0.002) in ALF‐E(P) compared to ALF‐NE(P). The macrophage phagocytic activity and Escherichia coli‐induced ROS production was significantly impaired in ALF‐E(P) compared to AVH‐E(P) (P < 0.001), ALF‐E(NP), and ALF‐NE(P) patients (P < 0.02). TLR3 and TLR9 expression and downstream MYD88 signalling molecules IRF3 and IRF7 were significantly down‐regulated in ALF‐E(P) (P < 0.00) compared to AVH‐E(P) and ALF‐NE(P). Conclusion: Functionality of mono‐macs is impaired in pregnant ALF‐E patients compared to AVH‐E(P). Reduced TLR3 and TLR7 expression and TLR downstream‐signaling molecules in pregnant ALF‐E patients suggests inadequate triggers for the innate immune responses contributing to development and severity of ALF‐E. Studies using TLR agonists to activate mono‐macs may be of use and in vitro studies should be undertaken using patient samples.(Hepatology 2015;62:1683–1696)

Increased regulatory T cells and impaired functions of circulating CD8 T lymphocytes is associated with viral persistence in Hepatitis B virus-positive newborns

Hepatitis B Virus (HBV) infection in infancy or early childhood leads to high rate of persistent infection (25–90%). The immunological basis of high rate of viral persistence in vertically acquired HBV infections is not completely understood. CD8 T cells play a pivotal role in clearing the Hepatitis B virus infection in adults. Herein, we sought to delineate the role of T cells in viral persistence in HBsAg+ve newborns. At birth peripheral and cord blood of HBsAg+ve (N = 12), HBsAg‐ve (N = 10) and healthy newborns (HC: N = 15) were evaluated for T‐cell frequency and functionality by flow cytometry. No significant differences were observed in the frequency of CD8 and CD4 T cells in all the three groups. However, significantly higher frequency of FoxP3 expressing regulatory T cells were observed in HBsAg+ve (63.79%) compared with HBsAg‐ve (28.12%) and HC (11.06%) (P < 0.05). Moreover, HBsAg+ve newborns showed functional defect in CD8 T cells by decreased IFN‐γ production and lower CD107A expression (cytotoxic capacity) compared with HBsAg‐ve and HC, which positively correlated with decreased TCRζ‐chain expression CD8 T cells (r2 > 0.93, P < 0.05). Despite equal frequency of CD8 T cells in all the three groups, CD8 T cells in HBsAg+ve newborns are dysfunctional. An expansion of regulatory T cells and impaired TCR signalling may represent the immune tolerant state of the adaptive immune system in response to chronic HBV infection.

Unruptured term pregnancy with a live fetus with placenta percreta in a non-communicating rudimentary horn.

ABSTRACT  Pregnancy in a non‐communicating rudimentary horn is rare and such a pregnancy culminating in the delivery of a live fetus is even rarer. Despite advances in ultrasonography, the accuracy of ultrasound in diagnosing rudimentary horn pregnancy at advanced gestation remains elusive. Confirmatory diagnosis is made only at laparotomy. We report a multigravidae who presented at 37 weeks with transverse lie oligoamnios and decreased perception of fetal movement since quickening. Laparotomy for placenta accreta suspected on ultrasound revealed non‐communicating unruptured rudimentary horn pregnancy with a live fetus and placenta percreta. Successful extraction of a term live fetus weighing 2.7 kg with excision of the rudimentary horn was carried out.

Factors influencing occurrence of postpartum haemorrhage in pregnant women with hepatitis E infection and deranged coagulation profile

Coagulopathy is an important complication associated with hepatitis E virus (HEV) infection in pregnant women. Postpartum haemorrhage (PPH) remains a serious risk while managing the labour of these women. The aim of this paper is to study the factors influencing the occurrence of PPH in pregnant women with hepatitis E infection with coagulopathy. The labours of 38 pregnant women with hepatitis E and deranged coagulation profile were followed. Factors that may predict postpartum bleeding complications in women with HEV infection and deranged coagulation profile were statistically analysed. Of 38 pregnant women with acute viral hepatitis due to HEV, 13 (34%) suffered a PPH while 25 (66%) did not. On univariate analysis low alanine aminotransferase (P = 0.016), high international normalized ratio (P = 0.003), high levels of d-dimer (P = 0.008), presence of hepatic encephalopathy (P = 0.028), intrauterine fetal death (P = 0.001) and gastrointestinal bleeding (P = 0.004) were found to predict PPH. However, on multivariate analysis the only independent variable that predicted PPH was the presence gastrointestinal (GI) bleeding (odds ratio [OR] 11.363; 95% CI: 1.003, 125; P = 0.050). Women with GI bleeding have 11 times higher risk of PPH than those without a GI bleed; however, the confidence interval is very wide. Administration of fresh frozen plasma in the peripartum period reduces the risk of PPH. In conclusion, early recognition of factors which predict the risk of PPH and timely intervention with judicious use of blood and blood components in the peripartum period can improve the outcome of pregnant women with HEV infection with deranged coagulation.

Clinical profile of women with severe anaemia in the third trimester of pregnancy

Anaemia, the most common medical disorder associated with pregnancy, is a silent killer. Most severely anaemic pregnant women are asymptomatic and present late in the third trimester with medical and obstetric complications.

Arterio-venous malformations of uterus – Diagnostic and management dilemmas

Abstract Keeping in mind the life-threatening consequences of curettage in cases of undiagnosed uterine arterio-venous malformation (AVM), its possibility should be considered in patients presenting with abnormal heavy uterine bleeding and negative Human Chorionic Gonadotropin (β-hCG) values. We collected a series of cases in which the patients presented with abnormal heavy uterine bleeding, some not responding to conservative treatment. In the presence of declining or low serum β-hCG levels and ultrasound Doppler showing increased vascularity, patients were investigated to detect the possible presence of uterine AVM. In those patients in whom angiographic confirmation of uterine AVM was made, embolisation was done and the outcome was followed. In those patients in whom hysterectomy was done the histopathogy specimen was studied for the possible cause of increased vascularity. Arterio-venous shunting seen on ultrasound does not always imply a uterine AVM and some cases can present diagnostic and management dilemmas.