Maternal and fetal outcomes of pregnancies complicated by acute hepatitis E and the impact of HIV status: A cross-sectional study in Namibia

Background & Aims: Namibia has been suffering from an outbreak of hepatitis E genotype 2 since 2017. As nearly half of hepatitis E-related deaths were among pregnant and postpartum women, we analysed maternal and fetal outcomes of pregnancies complicated by acute hepatitis E and assessed whether HIV-status impacted on outcome. Methods: A retrospective cross-sectional study was performed at Windhoek Hospital Complex. Pregnant and postpartum women, admitted between 13 October 2017 and 31 May 2019 with reactive IgM for Hepatitis E, were included. Outcomes were acute liver failure (ALF), maternal death, miscarriage, intra-uterine fetal death and neonatal death. Odds ratios (OR) and 95% confidence interval (CI) were calculated. Results: Seventy women were included. ALF occurred in 28 (40.0%) of whom 13 died amounting to a case fatality rate of 18.6%. Sixteen women (22.9%) were HIV infected, compared to 16.8% among the general pregnant population (OR 1.47, 95% CI 0.84-2.57, P =.17). ALF occurred in 4/5 (80%) HIV infected women not adherent to antiretroviral therapy compared to 1/8 (12.5%) women adherent to antiretroviral therapy (OR 28.0, 95% CI 1.4-580.6). There were 10 miscarriages (14.3%), five intra-uterine fetal deaths (7.1%) and four neonatal deaths (5.7%). Conclusions: One in five pregnant women with Hepatitis E genotype 2 died, which is comparable to genotype 1 outbreaks. Despite small numbers, HIV infected women receiving antiretroviral therapy appear to be less likely to develop ALF in contrast with HIV infected women not on treatment. As there is currently no curative treatment, this phenomenon needs to be assessed in larger cohorts. This retrospective cross‐sectional study was performed in Windhoek Hospital Complex, which has around 12 000 births annually. The first HEV case of the outbreak in Namibia was reported on 13 October 2017 in Khomas region, in which the capital Windhoek is located. The outbreak continued in the city and by August 2019, there were 6151 reported cases nationally and the outbreak had spread to 10 of the 14 regions with sporadic cases in the other regions as well. 9 The national case fatality rate (CFR) was 0.9% with 56 fatalities. 9 The majority of HEV cases were reported to be among people from informal settlements. These settlements are densely populated with limited access to sanitation, safe drinking water and hygiene. Most people live in the capital for work but travel to different parts of the country to visit family members several times a year. This continuous movement to different regions has likely facilitated the spread of HEV throughout the country. In 2018, two blood samples were tested for genotyping and showed HEV genotype 2. There are reports from two previous outbreaks in Namibia. Both were in the informal settlements of Rundu, a town in northern Namibia, of which the first outbreak was in 1983 because of HEV genotype 1 and the second outbreak in 1995 because of genotype 2. 14 , 15 Whereas most outbreaks last on average a year, the outbreak in Namibia which started in 2017 has been ongoing for more than 3 years. 2 According to the national HIV guidelines, all adults with HIV are started on antiretroviral therapy (ART) in Namibia, regardless of CD4 count or clinical stage. 16 In comparison to their neighbouring countries, Namibia performs well in implementation of the ART services: in 2017, 97.1% of HIV‐infected females were on ART and of these, 92.2% were virally suppressed. 11 All pregnant women and women whose birth was terminated less than 42 days earlier, who were admitted to Windhoek Hospital Complex between 13 October 2017 and 31 May 2019 with acute HEV, confirmed by a reactive HEV immunoglobulin M (IgM), were eligible for inclusion in this study. Women were excluded if no positive IgM test result was available, the woman was not admitted to a health facility, her pregnancy or recent pregnancy could not be confirmed, or her clinical file could not be traced. The Ministry of Health and Social Services, together with the World Health Organization, developed clinical management guidelines, recommending all pregnant and postpartum women with jaundice to be admitted and tested for reactive HEV IgM, regardless if other clinical symptoms were present. Therefore, many women with mild disease were admitted and included in our cohort. Cases were identified using a list of all suspected HEV cases in Khomas region from the Ministry of Health and Social Sciences of Namibia, which was established from the start of the outbreak, as hepatitis E is a notifiable disease. Because of budget restrictions, it was not possible to apply this list to other affected regions. Nevertheless, our cohort included the majority of pregnant women with HEV in Namibia, as the capital and it’s referring regions were most severely affected by the outbreak. In the referring regions intensive care unit (ICU) facilities were not available and nearly all pregnant women with a confirmed HEV infection were therefore transferred to our study site for further monitoring and care. In the hospital complex the capital ICU facilities were available to provide supportive care for patients with ALF. For identification of possible missed cases, data from the National Maternal Death Review Committee of the Ministry of Health and Social Services was used. This committee analysed all maternal deaths occurring in the country between 1st of April 2018 and 31st of March 2019 and all cases of severe morbidity between 1st of March 2018 and 31st of May 2018 in the capital and between 1st of October 2018 till 31st of March 2019 nationally. 10 , 17 , 18 Considering the severe clinical course among pregnant women, these cohorts contained many women with complicated pregnancies because of HEV. For identified cases, data were collected anonymously from medical records using a structured data collection tool, including socio‐demographic characteristics, maternal outcomes, fetal outcomes, obstetric complications, signs of liver failure and HIV status. This was done by AH and MC and verified by SH and MJ, both medical doctors with several years of experience providing obstetric care in Namibia. Laboratory test results on admission and the most abnormal value during admission were collected from the database of the National Institute of Pathology, including alanine aspartate aminotransferases, alanine aminotransferases, bilirubin, haemoglobin, platelets, creatinine and international normalized ratio (INR). Serology test for hepatitis A, B and C were performed by Alinity Abbott. Hepatitis E serology was performed using Aria rapid tests. Glucose values were obtained through capillary blood tests. If the woman was HIV infected, data on ART treatment adherence, latest CD4 count and viral load value were retrieved from medical records, the database of the National Institute of Pathology and additional information was collected through the ART clinic the patient was attending. Data regarding fetal outcome was obtained from the woman’s medical record. If a neonate had been admitted to neonatal ICU, survival status was obtained from neonatal ICU admission records. No neonate was tested for vertical transmission of HEV, as PCR testing was not available. HIV prevalence among the general pregnant population was collected through the Prevention Mother to Child Transmission Program of the Ministry of Health and Social Services. Main maternal outcomes were number of women with acute liver failure (ALF) and death. ALF was defined according to the definition of European Association for the Study of the Liver; acute abnormality of liver blood tests(elevated serum transaminases) in an individual without underlying chronic liver disease followed by hepatic encephalopathy of any grade and a INR > 1.5. 19 Severity of hepatic encephalopathy was graded using the West Haven Criteria, ranging from grade 1 with mild altered mental stage up to grade 4 which is complete coma. Acute hepatitis B was identified with a reactive test for IgM anti‐HBc. Chronic hepatitis B was diagnosed when a woman had a reactive test for both HBsAG and anti‐HBc. Hypoglycaemia was defined as any capillary blood glucose <4.0 mmol/L. Postpartum haemorrhage was defined as >1000 mL blood loss after birth. Premature birth was defined as birth between 26 weeks and 0 days of gestation and 36 weeks and 6 days. Intra‐uterine fetal death was defined as a death before birth in a fetus with a gestational age of 26 weeks and 0 days or more. For miscarriage, the threshold of less than 26 weeks and 0 days was used. Neonatal death was death during the first 28 days of life. All results were reported as numbers (n) and frequencies (%). An ART defaulter was defined as any woman who interrupted her treatment and missed at least one clinic visit. 16 Maternal case fatality rate was defined as the number of maternal deaths divided by the number of pregnancies complicated by acute hepatitis E and presented as a percentage. Fetal case fatality rate was defined as the number of intra‐uterine fetal deaths and neonatal deaths, divided by the number of pregnancies complicated by acute hepatitis E and presented as a percentage. Continuous variables are presented as means with standard deviations and differences in normally distributed variables were assessed using a student t‐test. Missing data were assumed to be ‘no’ for categorical data, whereas complete case analysis was used to handle missing data for continuous variables and data regarding ART adherence. Categorical variables are presented as percentages. Differences were assessed using chi‐square test or Fisher’s Exact test when indicated and odds ratios (OR) with 95% confidence intervals (CI) are presented. Statistical significance was assumed at a two‐sided value of P < .05. Data analysis was performed with SPSS version 26. We followed the STROBE reporting guidelines.