Cholera vaccination: pregnant women excluded no more
Authors: Pedro L Moro, Lakshmi Sukumaran
Journal: The Lancet Infectious Diseases (2017)

Cholera is a serious dehydrating diarrhoeal disease caused by toxigenic serogroups (O1 and O139) of Vibrio cholerae, which is spread by faecal contamination of water and food. It is a disease of poverty and is closely linked to poor sanitation and lack of clean water.1Desai SN Clemens JD An overview of cholera vaccines and their public health implications.Curr Opin Pediatr. 2012; 24: 85-91Crossref PubMed Scopus (18) Google Scholar Cholera affects up to 2·8 million people and kills approximately 91 000 each year.2Ali M Lopez AL Ae You Y et al.The global burden of cholera.Bull World Health Organ. 2012; 90 (18A): 209Crossref PubMed Scopus (325) Google Scholar Children aged younger than 5 years have the greatest incidence of disease in endemic areas. Among pregnant women, cholera can cause serious complications—namely, fetal loss, with rates varying from 2% to 36%.3Ciglenecki I Bichet M Tena J et al.Cholera in pregnancy: outcomes from a specialized cholera treatment unit for pregnant women in Leogane, Haiti.PLoS Negl Trop Dis. 2013; 7: e2368Crossref PubMed Scopus (28) Google Scholar, 4Tran N-T Taylor R Antierens A Staderini N Cholera in pregnancy: a systematic review and meta-analysis of fetal, neonatal, and maternal mortality.PLoS One. 2015; 10: e0132920Crossref Scopus (12) Google Scholar Three vaccines have been prequalified by WHO: Dukoral (Crucell Sweden AB, Stockholm, Sweden),5WHOCholera vaccines: WHO position paper.Wkly Epidemiol Rec. 2010; 85: 117-128PubMed Google Scholar, 6EMADukoral vaccine insert.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000476/WC500037570.pdfGoogle Scholar a monovalent oral killed vaccine based on whole cells of V cholerae O1 and recombinant cholera toxin B subunit, and Shanchol (Shanta Biotechnics Ltd, Telangana, India) and Euvichol (Eubiologics, Chuncheon-si, South Korea), both bivalent oral killed vaccines based on serogroups O1 and O139.5WHOCholera vaccines: WHO position paper.Wkly Epidemiol Rec. 2010; 85: 117-128PubMed Google Scholar, 7ShanthaShanchol vaccine insert.http://www.who.int/immunization_standards/vaccine_quality/pq_250_cholera_1dose_shantha_insert.pdf?ua=1Google Scholar, 8EuBiologicsEuvichol vaccine insert.http://www.who.int/immunization_standards/vaccine_quality/pq_298_euvichol_1dose_eubiologics_PI.pdf?ua=1Google Scholar, 9Desai SN Pezzoli L Martin S et al.A second affordable oral cholera vaccine: implications for the global vaccine stockpile.Lancet Glob Health. 2016; 4: e223-e224Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar The ranges of protective efficacy for Dukoral and Shanchol are 66–86% at 4–6 months after vaccination, 45–62% at 1 year, and 58–77% at 2 years.5WHOCholera vaccines: WHO position paper.Wkly Epidemiol Rec. 2010; 85: 117-128PubMed Google Scholar For Euvichol, efficacy was 65% after 5 years for those older than 5 years.10Bhattacharya SK Sur D Ali M et al.5 year efficacy of a bivalent killed whole-cell oral cholera vaccine in Kolkata, India: a cluster-randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2013; 13: 1050-1056Summary Full Text Full Text PDF PubMed Scopus (174) Google Scholar Findings from studies done before licensure and after marketing of these vaccines have shown favourable safety profiles.5WHOCholera vaccines: WHO position paper.Wkly Epidemiol Rec. 2010; 85: 117-128PubMed Google Scholar, 6EMADukoral vaccine insert.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000476/WC500037570.pdfGoogle Scholar, 7ShanthaShanchol vaccine insert.http://www.who.int/immunization_standards/vaccine_quality/pq_250_cholera_1dose_shantha_insert.pdf?ua=1Google Scholar, 8EuBiologicsEuvichol vaccine insert.http://www.who.int/immunization_standards/vaccine_quality/pq_298_euvichol_1dose_eubiologics_PI.pdf?ua=1Google Scholar, 9Desai SN Pezzoli L Martin S et al.A second affordable oral cholera vaccine: implications for the global vaccine stockpile.Lancet Glob Health. 2016; 4: e223-e224Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 10Bhattacharya SK Sur D Ali M et al.5 year efficacy of a bivalent killed whole-cell oral cholera vaccine in Kolkata, India: a cluster-randomised, double-blind, placebo-controlled trial.Lancet Infect Dis. 2013; 13: 1050-1056Summary Full Text Full Text PDF PubMed Scopus (174) Google Scholar Additionally, a small number of safety evaluations have been done in pregnant women during cholera outbreaks; their findings suggested that these vaccines are safe during pregnancy.11Hashim R Khatib AM Enwere G et al.Safety of the recombinant cholera toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in pregnancy.PLoS Negl Trop Dis. 2012; 6: e1743Crossref PubMed Scopus (32) Google Scholar, 12Grout L Martinez-Pino I Ciglenecki I et al.Pregnancy outcomes after a mass vaccination campaign with an oral cholera vaccine in Guinea: a retrospective cohort study.PLoS Negl Trop Dis. 2015; 9: e0004274Crossref PubMed Scopus (21) Google Scholar However, pregnant women have not generally been included in studies intended to assess the safety of these cholera vaccines. Now, in an observational cohort study reported in The Lancet Infectious Diseases, Mohammad Ali and colleagues13Ali M Nelson A Luquero FJ et al.Safety of a killed oral cholera vaccine (Shanchol) in pregnant women in Malawi: an observational cohort study.Lancet Infect Dis. 2017; (published online Feb 1.)http://dx.doi.org/10.1016/S1473-3099(16)30523-0PubMed Google Scholar provide evidence for the safety of Shanchol in this population, which was used in a 2015 cholera outbreak in Malawi. The investigators assessed the risk of pregnancy loss in 835 women who received the vaccine and 835 women not exposed to the vaccine.13Ali M Nelson A Luquero FJ et al.Safety of a killed oral cholera vaccine (Shanchol) in pregnant women in Malawi: an observational cohort study.Lancet Infect Dis. 2017; (published online Feb 1.)http://dx.doi.org/10.1016/S1473-3099(16)30523-0PubMed Google Scholar They found that the vaccine was not associated with an increased risk of stillbirth or neonatal mortality. Although they noted no increased risk of spontaneous abortion in vaccinated women, few of the enrolled women received the vaccine during the first trimester. Moreover, the rate of spontaneous abortion was well below the national background rates (15%) of spontaneous abortion in both study groups. The study's findings also showed no increased risk of birth defects in pregnant women exposed to the vaccine. However, the small number of exposures in the first trimester limits the clinical importance of this finding. Additionally, this study was not powered to assess for the risk of birth defects, which are rare. Only two other studies, both retrospective cohort studies, have assessed the safety of cholera vaccines in pregnancy. Hashim and colleagues11Hashim R Khatib AM Enwere G et al.Safety of the recombinant cholera toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in pregnancy.PLoS Negl Trop Dis. 2012; 6: e1743Crossref PubMed Scopus (32) Google Scholar assessed the safety of Dukoral among 196 pregnant women in Zanzibar and compared pregnancy and infant outcomes with those of 955 unvaccinated pregnant women. They noted no statistically significant differences in spontaneous abortions, infant deaths, or infant abnormalities among both groups.8EuBiologicsEuvichol vaccine insert.http://www.who.int/immunization_standards/vaccine_quality/pq_298_euvichol_1dose_eubiologics_PI.pdf?ua=1Google Scholar In a second study, Grout and colleagues12Grout L Martinez-Pino I Ciglenecki I et al.Pregnancy outcomes after a mass vaccination campaign with an oral cholera vaccine in Guinea: a retrospective cohort study.PLoS Negl Trop Dis. 2015; 9: e0004274Crossref PubMed Scopus (21) Google Scholar assessed the safety of Shanchol in 1543 pregnant women in Guinea. Among 1312 fetuses exposed to the vaccine and 272 fetuses unexposed to the vaccine from these pregnancies, no statistically significant differences were reported in the rate of pregnancy loss, infant deaths, or malformations.12Grout L Martinez-Pino I Ciglenecki I et al.Pregnancy outcomes after a mass vaccination campaign with an oral cholera vaccine in Guinea: a retrospective cohort study.PLoS Negl Trop Dis. 2015; 9: e0004274Crossref PubMed Scopus (21) Google Scholar In both studies, the rates of spontaneous abortion in vaccinated and unvaccinated groups were well below the expected background rate of spontaneous abortion in the populations studied. In an ideal study, pregnant women would be randomly assigned to receive the cholera vaccine or a placebo. However, pregnant women are considered special populations in clinical research, with specific regulations to protect the pregnant woman and her fetus.14Office for Human Research ProtectionsCode of Federal Regulations, Title 45, Department of Health and Human Services; Part 46: protection of human subjects.https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46#Google Scholar For this reason, there are ethical considerations for administering the vaccine in a clinical trial. However, because pregnant women are at an increased risk of morbidity and mortality from disease, there are also ethical considerations in withholding a potentially life-saving vaccine during a cholera epidemic. Although the study by Ali and colleagues13Ali M Nelson A Luquero FJ et al.Safety of a killed oral cholera vaccine (Shanchol) in pregnant women in Malawi: an observational cohort study.Lancet Infect Dis. 2017; (published online Feb 1.)http://dx.doi.org/10.1016/S1473-3099(16)30523-0PubMed Google Scholar adds important safety information about Shanchol in pregnant women, gaps in knowledge about the safety of this vaccine in pregnancy—specifically, if administered during the first trimester—persist. Future studies will need to further clarify the safety of cholera vaccines through inclusion of more pregnant women exposed during the first trimester and active capture of data about early losses, which might be missed or not reported. In areas endemic for cholera, pregnant women are at risk of severe diarrhoeal disease that can result in dehydration and pregnancy loss.1Desai SN Clemens JD An overview of cholera vaccines and their public health implications.Curr Opin Pediatr. 2012; 24: 85-91Crossref PubMed Scopus (18) Google Scholar, 4Tran N-T Taylor R Antierens A Staderini N Cholera in pregnancy: a systematic review and meta-analysis of fetal, neonatal, and maternal mortality.PLoS One. 2015; 10: e0132920Crossref Scopus (12) Google Scholar Although good sanitation measures (eg, clean water and sewage systems) are ideal, these measures are beyond the reach of many areas, especially during cholera outbreaks. The available cholera vaccines recommended by WHO offer an additional preventive approach and, on the basis of available data, they can be safely used during pregnancy. We declare no competing interests. We thank CDC's Immunization Safety Office staff whose work allowed this activity to be conducted. This commentary is a US Government-initiated project and received no external funding. The findings and conclusions in this Comment are those of the authors and do not necessarily represent the official position of the CDC. Safety of a killed oral cholera vaccine (Shanchol) in pregnant women in Malawi: an observational cohort studyOur 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. Full-Text PDF Open Access