standard cholera treatment guidelines but with earlier, more intense fluid replacement + antibiotic treatment

None died during hospitalization, 226 (86%) were discharged with a preserved pregnancy and 16 (6%) had live fullterm singleton births, of whom 2 died within the first 5 days postpartum. The remaining 21 pregnancies (8%) resulted in intrauterine fetal death.

The risk of fetal death was associated with factors reflecting severity of the cholera episode: after adjusting for confounding factors, the strongest risk factor for fetal death was severe maternal dehydration, followed by severe vomiting

None died during hospitalization, 226 (86%) were discharged with a preserved pregnancy and 16 (6%) had live fullterm singleton births, of whom 2 died within the first 5 days postpartum. The remaining 21 pregnancies (8%) resulted in intrauterine fetal death. The risk of fetal death was associated with factors reflecting severity of the cholera episode: after adjusting for confounding factors, the strongest risk factor for fetal death was severe maternal dehydration (adjusted risk ratio for severe vs. mild dehydration was 9.4, 95% CI 2.5–35.3, p=0.005), followed by severe vomiting (adjusted risk ratio 5.1, 95% 1.1–23.8, p = 0.041).

The major limitation of this analysis is that there was no control group A limitation of these results is that no suspected cholera cases were confirmed by a laboratory.

The main risk factor identified for fetal death was severity of dehydration. Our experience suggests that establishing specialized multidisciplinary units which facilitate close follow-up of both pregnancy and dehydration status due to cholera could be beneficial for patients, especially in large epidemics.

Centre for Vaccine Sciences, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh

The duration of diarrhea prior to admission tended to be higher in pregnant compared to non-pregnant patients (p=0.08), but other clinical characteristics did not differ.

Patients enrolled for the study received the normal standard of care provided at the icddr,b for cholera. Dehydration was corrected either by infusing intravenous cholera saline or by oral rehydration solution depending on the severity of the dehydration and clinical condition of the patient. A short course of oral antibiotics was given. Non pregnant adult females with stool culture positive for V. cholerae received 300 mg of doxycycline in a single dose, whereas pregnant women with cholera received erythromycin (500 mg every six hours) for three days.

Among reproductive age women enrolled between January 2001 and May 2006, 9.7% (14/144) were pregnant. The duration of diarrhea prior to admission tended to be higher in pregnant compared to non-pregnant patients (p=0.08), but other clinical characteristics did not differ. Antibody responses to cholera toxin B subunit (CtxB), toxin-coregulated pilus A (TcpA), Vibrio cholerae lipopolysaccharide (LPS), and serum vibriocidal antibody responses, were comparable between pregnant and non-pregnant patients. There were no deaths among the pregnant cases or non-pregnant controls, and no adverse fetal outcomes, including stillbirths, during 21 days of follow up of pregnant cases.

The main limitation of this study is the fact that the cohort consisted of only patients with severe cholera requiring hospitalization.Another limitation of this study is that we had a small sample size (14 pregnant women with cholera) and only followed pregnancy outcomes until 21 days after infection and we did not gather data on later fetal outcomes. Also, we did not assess mucosal immune responses using the antibody-secreting cell or antibody-in-lymphocyte supernatant assay for all the patients in this study.

pregnant woman early in pregnancy has comparable clinical illness and subsequent immune responses compared to non-pregnant women. These findings suggest that the evaluation of safety and immunogenicity of oral cholera vaccines in pregnancy should be an area of future investigations.

Cholera; immune response; pregnancy

a International Centre for Diarrheal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh

About 16% of pregnant women exposed to OCV had pregnancy loss, as compared to 12% of unvac- cinated pregnant women (P = 0.38). One congenital anomaly was observed and occurred in women non- exposed to OCV group. Models that adjusted for baseline characteristics that were unbalanced between the exposed and non-exposed groups, revealed a no elevation of risk of adverse pregnancy outcomes in vaccinees versus non-vaccinees (Adj. OR (95% CI): 0.45 (0.11–1.88).

major limitation of this study was the small number of women who received OCV while preg- nant (n = 69), with a small number of detected adverse fetal out- comes, which reduced our ability to detect an elevated risk of adverse fetal outcomes if one existed in the exposure group. More- over, the substantial loss to follow-up of a large proportion of the cohort of vaccinated women could have led to a bias. As well, exposure or non-exposure to the vaccine was not randomized, and factors related to the risk of adverse pregnancy outcome could have been imbalanced between the compared groups and biased our results. Nonetheless, residual confounding due to unmeasured variables could have affected our results. Thirdly, bias from differential recall of pregnancy outcomes in the two groups cannot be ruled out, since the interviews were car- ried out retrospectively, with longer post-outcome recall intervals for unvaccinated than vaccinated women, although the direction of such a bias is difficult to predict.

No excess of adverse fetal outcomes associated with receipt of OCV was observed in this study.

The crude incidence of pregnancy loss was 3.7% (95%CI 2.7–4.8) for fetuses exposed to BivWC vaccine and 2.6% (0.7–4.5) for non-exposed fetuses. The incidence of malformation was 0.6% (0.1–1.0) and 1.2% (0.0–2.5) in BivWC-exposed and non-exposed fetuses, respectively. In both crude and adjusted analyses, fetal exposure to BivWC was not significantly associated with pregnancy loss (adjusted risk ratio (aRR = 1.09 [95%CI: 0.5–2.25], p = 0.818) or malformations (aRR = 0.50 [95%CI: 0.13–1.91], p = 0.314).

the incidence of preg- nancy loss was lower than expected both in vaccinated and non-vaccinated women, especially in the first trimester. Second, less than 25% of the women could present a vaccination card, leading to potential misclassification of their vaccination status. Another possible bias influencing our results is the presence of a seasonal component in pregnancies and pregnancy losses

In this large retrospective cohort study, we found no association between fetal exposure to BivWC and risk of pregnancy loss or malformation. Despite the weaknesses of a retrospec- tive design, we can conclude that if a risk exists, it is very low.

The pooled maternal death rate for 1991-2013 studies was 0.2% (95% CIs 0.0-0.7), and 5.0% (95% CIs 0.0-16.0) for 1969-1990. there were no significant differences in the RR for neonatal or maternal death

The pooled fetal death rate for 4 studies during 1991-2013 was 7.9% (95% CIs 5.3-10.4), significantly lower than that of 3 studies from 1969-1990 (31.0%, 95% CIs 25.2-36.8). There was no difference in fetal death rate by trimester. Compared with published national mortality estimates, the RR for fetal death of 5.8 (95% CIs 2.9-11.3) was calculated for Haiti (2013), 1.8 (95% CIs 0.3-10.4) for Senegal (2007), and 2.6 (95% CIs 0.5-14.9) for Peru (1991)

The pooled neonatal death rate for 1991-2013 studies was 0.8% (95% CIs 0.0-1.6), and 6.4% (95% CIs 0.0-20.8) for 1969-1990. there were no significant differences in the RR for neonatal or maternal death

The meta-analysis included seven studies that together involved 737 pregnant women with cholera from six countries. The pooled fetal death rate for 4 studies during 1991-2013 was 7.9% (95% CIs 5.3-10.4), significantly lower than that of 3 studies from 1969-1990 (31.0%, 95% CIs 25.2-36.8). There was no difference in fetal death rate by trimester. The pooled neonatal death rate for 1991-2013 studies was 0.8% (95% CIs 0.0-1.6), and 6.4% (95% CIs 0.0-20.8) for 1969-1990. The pooled maternal death rate for 1991-2013 studies was 0.2% (95% CIs 0.0-0.7), and 5.0% (95% CIs 0.0-16.0) for 1969-1990. Compared with published national mortality estimates, the RR for fetal death of 5.8 (95% CIs 2.9-11.3) was calculated for Haiti (2013), 1.8 (95% CIs 0.3-10.4) for Senegal (2007), and 2.6 (95% CIs 0.5-14.9) for Peru (1991); there were no significant differences in the RR for neonatal or maternal death.

Results are limited by the inconsistencies found across included studies but suggest that maternal cholera is associated with adverse pregnancy outcomes, particularly fetal death.

Department of Obstetrics, The Fourth People’s Hospital of Jinan City, Jinan, Shandong Province, China

2920 exposed and 2664 not exposed (pregnant women and vaccine)

No significant increase in adverse pregnancy outcome (RR 1.03, 95% CI 0.79– 1.34), miscarriage (RR 1.15, 95% CI 0.84–1.57) or stillbirth (RR 1.11, 95% CI 0.69–1.80) following cholera vaccine administration was found compared with control group. There was also no association with an increased risk of preterm delivery (RR 0.61, 95% CI 0.35–1.06) low birthweight (RR 0.84, 95% CI 0.56– 1.26), accidental abortion (RR 1.02, 95% CI 0.77–1.35) or malformation (RR 0.70, 95% CI 0.22–2.25).

There was also no association with an increased risk of preterm delivery (RR 0.61, 95% CI 0.35–1.06) low birthweight (RR 0.84, 95% CI 0.56– 1.26), accidental abortion (RR 1.02, 95% CI 0.77–1.35) or malformation (RR 0.70, 95% CI 0.22–2.25).

No significant increase in adverse pregnancy outcome (RR 1.03, 95% CI 0.79– 1.34), miscarriage (RR 1.15, 95% CI 0.84–1.57) or stillbirth (RR 1.11, 95% CI 0.69–1.80) following cholera vaccine administration was found compared with control group. There was also no association with an increased risk of preterm delivery (RR 0.61, 95% CI 0.35–1.06) low birthweight (RR 0.84, 95% CI 0.56– 1.26), accidental abortion (RR 1.02, 95% CI 0.77–1.35) or malformation (RR 0.70, 95% CI 0.22–2.25).

Pooling study; small number of studies; under utilization of vaccination documentation; immortal time bias in assessing pregnancy outcomes following vaccination; assessing safety after 1 dose instead of 2; heterogenity of the difinitions used between different studies

This study shows no evidence of an association between oral cholera vaccination and adverse pregnancy outcomes. The findings do not rigorously exclude the possibility that the vaccine protocol may result in some degree of harm.

Oral cholera vaccine, pregnancy, safety.

Immunization Safety Office, division of healthcare quality promotion, centers for disease control and prevention

Dukoral, a monovalent oral killed vaccine based on whole cells of V cholerae O1 and recombinant cholera toxin B subunit, and Shanchol and Euvichol , both bivalent oral killed vaccines based on serogroups O1 and O139.5,7–9

Pregnant women are considered special popilations in clinical research , with specific regulations to protect the pregnant women and her fetus. For this reason , there are ethical considerations for administering the vaccine in a clinical trial. However, because pregnant women are at an increased risk for morbidity and mortality from the disease, there are also ethical considerations in withholding a potentially life saving vaccine during a cholera epidemic. / 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.

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.

Further studies will need to further clarify the safety of cholera vaccines through inclusion of more pregnant woemn exposed during the first trimester and active capture of data about early losses, which might be missed or not reportted.

Department of Industrial Engineering, School of engineering, Tokyo Institute of Technology, Ookayama, Meguro Ku, Tokyo 152- 8552, Japan

Entire Japanese Male poppulation at age 20 (1899-1910) (previously exposed to cholera betwen 1879 and 1890)

After the symptoms start, this acute diarrheal disease causes severe dehydration within hours, which leads to substantial fluid deficit in excess of 10% of the body weight.

Postnatal exposure to a cholera epidemic at age 1 had heterogenous stunting effects . While the strongest stunting effects (0.25cm) were observed at the highest decile group of cholera death rates, the effects observed at the 7-8th decile groups were roughly 40% of the maximum stunting effects. Our results also suggest that while exposure at birth year had such stunting effects at the highest decile group, prenatal exposure to cholera epidemic had little effect.

Our data on height are aggragated anually in nature. This kind of aggregation might have attenuated the observed stunting effects.

Early life exposure to a cholera pandemichad heterogneous stunting effects on the final height of men: the magnitude of the stunting effects increased as the intensity of exposure increased.

Pandemic cholera, Final height, Long-run effect, Heterogeneous treatment effects

Cohort 1: 231 OCV and 234 placebo / Cohort 2: 277 OCV and 299 placebo

women who were exposed to an OCV or placebo during pregnancy (cohort 1) and women who were pregnant after the vaccination completed (cohort 2)

whole cell oral cholera vaccine (Shanchol)

Much of the published literature on cholera during pregnancies reported pregnancy loss, with the magnitude varying from 2 to 36%

Our primary endpoint was pregnancy loss (spontaneous miscarriage or stillbirth), and the secondary endpoints were preterm delivery and low birth weight. / Theoretically, an OCV should not produce any adverse pregnancy outcomes due to its inability to replicate in the gut and oral route of intake. / However, the package insert for OCVs still recommends caution for use during pregnancy due to limited safety data in this population group. Since most of the studies were carried out in African countries during cholera outbreaks, more evidence is needed from cholera endemic areas, in particular, from parts of the world known to have a high prevalence of cholera.

In Cohort 1, the incidence of pregnancy loss was 113/1000 and 115/1000 among OCV and placebo recipients, respectively. The adjusted relative risk for pregnancy loss was 0.97 (95% CI: 0.58–1.61; p = 0.91) in Cohort 1. We did not observe any variation in the risk of pregnancy loss between the two cohorts. The risks for preterm delivery and low birth weight were not significantly different between the groups in both cohorts.

First, our study was conducted in an endemic setting were several subejcts may have developed some preexisting immunity... our results may not apply in non-endemic settings. Second, although our aim was to conduct a prospective study, 10% of pregnancies were already terminated at the time of recruitment, Third, we tested only a signle dose, whereas the recommended dose of an OCV is a double dose. Another potential limitation is that we did not find any congenital anoamlies of the infants

Our study provides additional evidence that exposure to an OCV during pregnancy does not increase the risk of pregnancy loss, preterm delivery, or low birth weight, suggesting that pregnanct women in cholera affected regions should not be excluded in a mass vaccination campaign.

OCV, Cholera, Pregnant women, Safety, Bangladesh

Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA

900 women exposed to oral cholera vaccine and 899 women not exposed to the vaccine

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.

cholera during pregnancy can result in pregnancy loss, premature childbirth, or maternal death if the patient is not treated properly.

The primary endpoint of our analysis was pregnancy loss (spontaneous miscarriage or stillbirth), and the secondary endpoints were neonatal deaths and malformations.

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.

The main limitation in our study is the relative paucity of data about possible miscarriage during the first trimester; we were therefore unable to fully characterise the risk of pregnancy loss in the first trimester after oral cholera vaccination. The second limitation of our study is that about 40% of enrolled women were recruited after their deliveries, and therefore information about their pregnancy outcomes was retrospectively collected. The mean time between delivery and data collection for these participants was 6 weeks. A third limitation was the inability to assess the health status of all newborn babies immediately after delivery. Therefore, the self-reported health assessment of the newborn babies could be subject to bias of delayed assessment. Finally, this study was not an individually randomised, placebo-controlled clinical trial, which is generally considered to be the optimal study design.

Fetal exposure to oral cholera vaccine confers no significantly increased risk of pregnancy loss, neonatal mortality, or malformation.

International Centre for Diarrheal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh

Pregnant women are vulnerable to complications in cholera, and maternal infection with cholera may adversely affect pregnancy outcomes, an observation dating back to the 19th century and now strengthened with more evidence.

Overall, the decision to administer the vaccine should depend on the epidemiological context and after weighing up the potential risks and benefits. 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

oral cholera vaccine; pregnancy; safety

1151 deliveries : 955 not vaccinated, 196 vaccinated (who delivered)

Vaccinated/ Non vaccinated pregnant woman (who delivered)

Recombinant Cholera Toxin B Subunit, Killed Whole-Cell (rBS-WC) Oral Cholera Vaccine

Without prompt rehydration, cholera during pregnancy can result in abortions, premature childbirth and maternal death

There are several reasons why it is thought that oral cholera vaccines are unlikely to have a harmful effect on foetal development. First, the bacteria in the rBS-WC vaccine are killed and do not replicate. Second, the vaccine antigens act locally on the gastro-intestinal mucosa is not absorbed and does not enter the maternal or foetal circulation. Third rBS-WC vaccines don’t trigger systemic reactions (e.g. fever) linked to abortions early in pregnancy. However, no actual safety studies of the rBS-WC vaccine in pregnancy have been carried out

There were no statistically significant differences in the odds ratios for birth outcomes among the exposed and unexposed pregnancies. There was no statistically significant difference in the number of miscarriages among the exposed compared to the unexposed pregnancies [10/ 196 (5%) vs. 27/955 (3%), adjusted odds ratio (AOR) 1.62 (95% confidence interval (95% CI 0.76 to 3.43)]. Similarly, there was no statistically significant difference in the number of infant deaths among the exposed compared to the unexposed non-miscarriage pregnancies [3/186(2%) vs. 13/928 (1%), AOR 1.46 (95% CI 0.41 to 5.29)]. The frequency of infant illness and abnormalities among the live infants verified by a paediatrician was 8/183 (4%) among the exposed versus 46/915 (5%) among the unexposed (AOR 0.79, 95th CI 0.36 to 1.75).

First, foetal losses were probably under-reported since pregnancy is often denied until late into gestation for complex cultural reasons. Second, and more importantly, exposure or non-exposure to the vaccine was not randomized. Third, an element of recall bias can’t be ruled out, namely women may have recalled adverse outcomes more frequently when they had been vaccinated than unvaccinated women. Fourth, the study detected 196 pregnancies. Even though the study is the largest to date, the overall number of pregnancies (196) is small and has limited power to detect infrequent adverse events. Fifth our sampling method does not detect maternal deaths. Finally, 6% of the eligible women did not participate in this birth surveillance study. Considering that the large majority (94%) of eligible women participated in the study it seems unlikely that this finding has introduced bias.

We found no statistically significant evidence of a harmful effect of gestational exposure to the rBS-WC vaccine. These findings, along with the absence of a rational basis for expecting a risk from this killed oral bacterial
vaccine, are reassuring but the study had insufficient power to detect infrequent events.

people at risk of cholera transmission one
year of age and above including pregnant women

ingle dose OCV mass vaccination campaign could reduce the number of cases of cholera and shorten the duration of outbreak in target areas.

Weal surveillance system so comparison of 2019 curves with OCV interventions and 2018 without OCV interventions does not permit to attribute the reduction of cholera cases solely to OCV intervention as other traditional interventions were ongoing

implementing a reactive single dose OCV mass vaccination campaign during outbreak in the North Region of Cameroon could have an impact in reducing the appear- ance of cholera cases and shorten the duration of the outbreak

Cholera outbreak, Oral cholera vaccine, Reactive mass vaccination campaign, Single dose, Epidemic curve, Health district

Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention

Painless watery diarrhea, often profuse, described as “rice-water” stools.

intravenous rehydration and antibiotics

water, sanitation, and hygiene

Reducing cholera morbidity and mortality depends on effective, real-time surveillance, detection and response; timely access to appropriate case management; and the provision of safe water, sanitation, and hygiene

Cholera; Vibrio cholerae; Epidemiology

Department of Medicine, Division of Global Health Equity, Brigham and Women’s Hospital

Cholera diarrhoea cases (n=47) Controls (n=188) and Non-cholera diarrhoea cases (n=42) Controls (n=168

Residents of Bocozel or Grand Saline who were eligible for the vaccination campaign (ie, age ≥12 months, not pregnant, and living in the region at the time of the vaccine campaign)

bivalent whole-cell oral cholera vaccine

acute watery diarrhoea

any vaccination verified through vaccine card or registry (0·35, 0·17–0·72) were associated with a significant reduction in the risk of cholera. no interaction identified between the vaccine and age group (pinteraction=0·70), severity of dehydration (pinteraction=0·94), time since vaccination (pinteraction=0·29), or previous admission to a cholera treatment unit (pinteraction=0·35

vaccine exposure assessment tools

findings contribute to mounting evidence that oral cholera vaccines have an important part to play as a component of comprehensive, integrated cholera control efforts in Haiti.

Pregnant women who passed >3 liquid stools with or without vomiting or dehydration in the previous 24 hours or within 6 hours of seeking treatment

>3 liquid stools with or without vomiting or dehydration

specialized Cholera tretement center and aggressive rehydration

Weak evidence of a difference in effect of severe dehydration on postadmission fetal death between TGs (p = 0.09)

lack of laboratory-confirmed diagnoses, no follow-up of women after dischargE, e long- term effect of treatment on fetal well-being could not be determined. TG outcomes also may have been affected by differences in factors such as women’s access to health services over time.

Global Immunization Division, Centers for Disease Control and Prevention

2-dose OCV cover- age following the 2014 campaign in the targeted communes and commune sections of Artibonite and Centre was 70% and 63%, respectively. 2013 OCV cam- paign in Haiti [14] also led by MSPP, persons !15 years old were less likely to be vaccinated than younger age groups. coverage was markedly lower in Ouest, and our findings suggest that inadequate social mobilization might have played a role.

equal proba- bility of selection of EAs instead of probability proportion to estimated size (PPES) due to the finite number of EAs targeted for the campaign in each department and the out-of-date population estimates that were available. the lack of resources to enumerate selected EAs led to a non-probability sample design with estimated sampling weights that may not produce the unbi- ased estimates that are desired.

OCV provides a useful short- to medium-term intervention in areas where it may be challenging to implement permanent improvements in water, sanitation, and hygiene infrastructure. However, given the high proportion of respondents in this survey who used an unimproved water source and unimproved sanitation, it remains important to improve the integration of WASH interven- tions during OCV campaigns

cholera, cholera vaccine, diarrhea

3 OCVs: Dukoral, the first prequalified OCV, Shantha’s vaccine, AND Euvichol

volu- minous diarrhea containing water and electrolyte

replace lost fluids and electrolytes using oral and intravenous fluids

while achieving universal access to potable water and sanitation is a long- term goal, the development and use of cholera vaccines have become an additional tool for cholera prevention

WASH strategies and OCVs can significantly reduce the global cholera burden

cholera; vaccine; burden; pregnancy; efficacy

Inactivated bacterium (oral vaccine); live attenuated

Improving access to clean potable water, adequate sanitation, and promotion of good water, sanitation and hygiene (WaSH) practices remain the mainstay of prevention of both endemic cholera and cholera outbreaks. Also important for cholera prevention are the establishment and enforcement of standard sanitation laws for food industries, including food vendors, and interventions to promote hand washing with soap and safe food handling. In addition, proper case management is vital in reducing mortality from the disease and limiting its spread. Cholera vaccination is a complementary cholera prevention and control measure, which can be implemented in the short-to-medium term, while access to other primary prevention measures such as safe water and sanitation improve globally.