Safety of a killed oral cholera vaccine (Shanchol) in pregnant women in Malawi: an observational cohort study

Abstract

SummaryBackgroundPregnancy increases the risk of harmful effects from cholera for both mothers and their fetuses. A killed oral cholera vaccine, Shanchol (Shantha Biotechnics, Hydrabad, India), can protect against the disease for up to 5 years. However, cholera vaccination campaigns have often excluded pregnant women because of insufficient safety data for use during pregnancy. We did an observational cohort study to assess the safety of Shanchol during pregnancy.MethodsThis observational cohort study was done in two adjacent districts (Nsanje and Chikwawa) in Malawi. Individuals older than 1 year in Nsanje were offered oral cholera vaccine during a mass vaccination campaign between March 30 and April 30, 2015, but no vaccines were administered in Chikwawa. We enrolled women who were exposed to oral cholera vaccine during pregnancy in Nsanje district, and women who were pregnant in Chikwawa district (and thus not exposed to oral cholera vaccine) during the same period. The primary endpoint of our analysis was pregnancy loss (spontaneous miscarriage or stillbirth), and the secondary endpoints were neonatal deaths and malformations. We evaluated these endpoints using log-binomial regression, adjusting for the imbalanced baseline characteristics between the groups. This study is registered with ClinicalTrials.gov, number NCT02499172.FindingsWe recruited 900 women exposed to oral cholera vaccine and 899 women not exposed to the vaccine between June 16 and Oct 10, 2015, and analysed 835 in each group. 361 women exposed to the vaccine and 327 not exposed to the vaccine were recruited after their pregnancies had ended. The incidence of pregnancy loss was 27·54 (95% CI 18·41–41·23) per 1000 pregnancies among those exposed to the vaccine and 21·56 (13·65–34·04) per 1000 among those not exposed. The adjusted relative risk for pregnancy loss among those exposed to oral cholera vaccine was 1·24 (95% CI 0·64–2·43; p=0·52) compared with those not exposed to the vaccine. The neonatal mortality rate was 11·78 (95% CI 5·92–23·46) per 1000 livebirths for infants whose mothers were exposed to oral cholera vaccine versus 8·91 (4·02–19·77) per 1000 livebirths for infants whose mothers were not exposed to the vaccine (crude relative risk 1·32, 95% CI 0·46–3·84; p=0·60). Only three newborn babies had malformations, two in the vaccine exposure group and one in the no-exposure group, yielding a relative risk of 2·00 (95% CI 0·18–22·04; p=0·57), although this estimate is unreliable because of the small number of outcomes.InterpretationOur study provides evidence that fetal exposure to oral cholera vaccine confers no significantly increased risk of pregnancy loss, neonatal mortality, or malformation. These data, along with findings from two retrospective studies, support use of oral cholera vaccine in pregnant women in cholera-affected regions.FundingBill & Melinda Gates Foundation.

Oral cholera vaccines and their impact on the global burden of disease

“…42 The Haiti study, conducted with 263 women with cholera-like illness, also suggested that severe maternal dehydration (risk ratio = 9.4; 95% CI: 2.5-35.3) and severe vomiting (5.1; 95% CI: 1.1-23.8) were risk factors for fetal death. 43,44 These data imply that an OCV should not be counter-indicated during pregnancy, and studies conducted in Guinea, 45 Zanzibar, 46 Malawi, 47 and Bangladesh 48 have not observed statistically significant adverse outcomes to fetus, newborn, or mother from OCV exposure. Given the risk to the fetus from maternal cholera and the excellent vaccine safety record, there is no scientific basis to withhold OCVs from pregnant women.…”

Safety of oral cholera vaccines during pregnancy in developing countries

“…On the basis of our current understanding of the vaccine and evidence from different studies, pregnant women should not be excluded from oral cholera vaccines during vaccination campaigns. 15,17,18 Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.…”

“…Fetal exposure to the OCV conferred no significantly increased risk of pregnancy loss, neonatal mortality, or malformation. 17 An ongoing evaluation is being performed in a randomized controlled trial of Shanchol in over 205,000 individuals in which women who inadvertently received the OCV is being analyzed for pregnancy outcomes in a prospective cohort design.…”

Pregnancy outcomes after a mass vaccination campaign with an oral cholera vaccine: a systematic review and meta‐analysis

“…Finally, five studies remained which met our criteria. 6,9,10,15,16 Information on the study characteristics is presented in Table 1 and Table S2. Studies were performed between 2009 and 2015 and published between 2012 and 2019.…”

“…8 Indeed, the nature of the vaccines, consisting of killed whole cells of Vibrio cholerae incapable of replicating in the gastrointestinal tract, suggests they are likely safe. Studies of the inadvertent vaccination of women who were unaware of their pregnancy status, 6,9 as well as more recent studies of vaccination campaigns where pregnant women were intentionally included, [10][11][12] are now available. Given these emerging clinical studies and the importance of continual evaluation of the safety profiles of pharmacological agents administered during pregnancy, we have conducted the first meta-analysis of pregnancy outcomes following administration of oral cholera vaccines during mass-vaccination campaigns.…”