Shubha Sagar Trivedi

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.

Prospective study of saline infusion sonohysterography in evaluation of perimenopausal and postmenopausal women with abnormal uterine bleeding

Aim:  To evaluate saline infusion sonohysterography as an investigative modality in abnormal uterine bleeding in perimenopausal and postmenopausal women.

Role of Endothelin and Inflammatory Cytokines in Pre‐eclampsia – A Pilot North Indian Study

Citation Sharma D, Singh A, Trivedi SS, Bhattacharjee J. Role of endothelin and inflammatory cytokines in pre‐eclampsia – a pilot north Indian study. Am J Reprod Immunol 2011; 65: 428–432

Teenage pregnancies and their obstetric outcomes.

This study was conducted to evaluate the obstetric performance of teenage women in India. In total, 13,210 women were included in the study, of whom 840 were teenagers (<19 years) and 12,370 were > 20 years. Antepartum, intrapartum and postpartum events were recorded and comparative analysis was done. We found that teenage women were at a significantly higher risk for development of severe anaemia (relative risk [RR] 1.61, P value < 0.02), eclampsia (RR 1.95, P value < 0.05), preterm labour (RR 1.25, P value < 0.001), intrauterine growth retardation (RR 2.29, P value < 0.001) and low birth weight (RR 1.24, P value < 0.001). Assisted delivery (11.78% versus 2.23%, P value < 0.001) was significantly more common and caesarean delivery (9.64% versus 17.18%, P value < 0.001) was significantly less common in teenagers. Moderate anaemia, mild pregnancy-induced hypertension, preeclampsia, premature rupture of membranes, antepartum haemorrhage and post dates were all significantly higher in ≥ 20 years group. To conclude, we found that teenage women are a high-risk group, which is aggravated by social and cultural factors. Special attention is required to educate these women for more positive outcomes.

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)

Trial of labour after previous caesarean section: The predictive factors affecting outcome

A prospective observational study was conducted at Lady Hardinge Medical College and Smt. Sucheta Kriplani Hospital, India on 300 pregnant women with one previous caesarean section fulfilling the eligibility criteria for trial of labour, to study the predictive factors and the outcome of trial of labour. The data obtained were analysed according to mode and outcome of labour and was then subjected to statistical analysis. The success rate of trial of labour was found to be 53.6%. Favourable Bishops score (p = 0.000), spontaneous onset of labour (p = 0.005) and history of previous delivery after caesarean (p = 0.007) were significantly associated with a successful outcome of trial of labour. Higher chances of vaginal delivery were found with breech as an indication of previous caesarean section, i.e. 67.1% as compared to 39% with non-progress of labour as an indication.

Intergenotypic variation of nitric oxide and inflammatory markers in preeclampsia: A pilot study in a North Indian population

Cytokines appeared to contribute to the development of pathologic condition and eNOS gene polymorphism may affect cytokine production. The aim of this study was to evaluate cytokines pattern in preeclampsia and whether there is any relationship between gene and cytokines production and cytokine with disease severity. This cross-sectional study included 100 women with preeclampsia and 100 healthy pregnant women. Their blood samples were analyzed for nitric oxide (NO), inflammatory cytokines, and eNOS gene polymorphism. Decreased NO and increased cytokine (tumor necrosis factor-α, interleukin-2, and interferon-γ) levels were found in preeclampsia (p < 0.001). Significant differences were found in genotype/allele distribution between the two groups. A significant negative correlation was observed between NO and cytokine levels (tumor necrosis factor-α and interferon-γ) in the preeclamptic group (p = 0.001). We conclude that preeclampsia is associated with decreased levels of NO and increased levels of circulating inflammatory cytokines due to single nucleotide polymorphisms, pointing toward the role of endothelial and inflammatory components.

MTHFR C677T polymorphism, folate, vitamin B12 and homocysteine in recurrent pregnancy losses: a case control study among north Indian women

Abstract Aim: The present study attempts to understand the role of methylenetetrahydrofolate reductase C677T (MTHFR C677T) in recurrent pregnancy losses in North Indian women because of hyperhomocysteinemia in light of serum folate and vitamin B12. Methods: One hundred and seven women with three or more consecutive unexplained recurrent pregnancy losses and 343 women with two or more successful and uncomplicated pregnancies were recruited. Plasma homocysteine, serum folate and vitamin B12 were analyzed using chemiluminescence. MTHFR C677T detection was completed in all subjects. Results: MTHFR genotypic distribution among cases and controls showed no significant difference (P=0.409). However, MTHFR C677T polymorphism was found to be significantly associated with increased homocysteine in the case group (P=0.031). Hyperhomocysteinemia and vitamin B12 deficiency were found to be significant risk factors for recurrent pregnancy loss (RPL) (OR=7.02 and 16.39, respectively). Folate deficiency was more common in controls (63.47%) as compared to the case group (2.56%). Conclusion: Low vitamin B12 increases homocysteine, specifically among T allele carrying case mothers, suggesting T allele is detrimental with B12 deficiency. The study emphasizes the importance of vitamin B12 in the prevention of RPL in North Indian women.