Safety of a bivalent, killed, whole-cell oral cholera vaccine in pregnant women in Bangladesh: evidence from a randomized placebo-controlled trial

Cholera remains a fatal disease in resource-limited countries, which is caused by Vibrio cholerae 01 or 0139 that spreads by water and food contaminated with human faeces. If the infected individuals do not promptly receive adequate treatment, the risk of death can be up to 70% [1]. Cholera during pregnancy may have an adverse effect on pregnancy outcome [2, 3]. The effect of cholera on pregnancy outcome has been observed since the nineteenth century [4]. Much of the published literature on cholera during pregnancies reported pregnancy loss, with the magnitude varying from 2 to 36% [2, 5‐9]. A recent study from Haiti reported that pregnant women with severe dehydrating cholera had 9.4 times more risk of delivering a foetal death compared to those with mild dehydrating cholera [10].

A killed whole-cell oral cholera vaccine (OCV) is currently being used as a major tool to control and prevent cholera [11‐14]. Theoretically, an OCV should not produce any adverse pregnancy outcomes due to its inability to replicate in the gut and oral route of intake. The World Health Organization (WHO) recommends that pregnant women be included in OCV campaigns because evidence indicates high potential benefit and minimal risks [15]. A mass vaccination campaign conducted in Zanzibar, Tanzania in 2009 with an OCV, Dukoral, did not cause any harmful effects on pregnancies [16]. A retrospective cohort study performed in Guinea in 2013 also showed no evidence of an increased risk of pregnancy loss after receiving Shanchol [17]. Recently, a retrospective study conducted in Bangladesh and a prospective study conducted in Malawi did not find any harmful effects of an OCV in pregnant women [18, 19]. 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.

We conducted an individually randomized, placebo-controlled trial of a single-dose regimen of the OCV Shanchol. As per the package insert for Shanchol, individuals 1 year or older and non-pregnant were invited to participate in the trial. All married women of childbearing age (13–49 years) were verbally screened for pregnancy before dosing. Since pregnancy in the first trimester may not be visible or some women may experience irregular menstruation, several pregnant women took a study agent unaware of their pregnancy status at the time of dosing. In this study, we evaluated the effect of vaccination on pregnant women who were unaware of their pregnancy status and who inadvertently received an OCV. The main goal of this study was to evaluate the effect of vaccination on pregnant women who received the OCV without knowing their pregnancy status.

A total of 204,700 individuals participated in the clinical trial, of whom 71,202 were women of reproductive age (13–49 years). During the screening visit, we identified 1323 pregnancies. Among them, we could recruit 550 pregnant women in Cohort 1 and 773 in Cohort 2. We lost to follow-up 41 women in Cohort 1 and 76 women in Cohort 2 between vaccination and screening visits. Due to induced or accidental abortion, we excluded 44 women in Cohort 1 and 121 women in Cohort 2. Finally, we analysed 465 women in Cohort 1 and 576 women in Cohort 2. We prospectively followed 405 (87%) of 465 women in Cohort 1 and 535 (93%) of 576 women in Cohort 2, and the rest were followed retrospectively (Fig. 1).

There were 231 OCV recipients and 234 placebo recipients in Cohort 1 and 277 OCV and 299 placebo recipients in Cohort 2. Socio-demographic, nutritional, and obstetric characteristics of the pregnant women were balanced between OCV recipients and placebo recipients except for having diarrhoea in the past 6 months prior to registration in the baseline census among women in Cohort 2 (Table 1). In Cohort 1, there were 26 adverse pregnancy outcomes in the OCV group and 27 in the placebo group. In this cohort, the incidence rate of an adverse pregnancy outcome was 112.6 per 1000 pregnancies among OCV recipients and 115.4 per 1000 pregnancies among placebo recipients (Table 2). Incidence of preterm delivery was 33.8, and of low birth weight was 97.6 per 1000 live births among OCV recipients, and 58.0 and 111.1, respectively, among the placebo recipients. The risk of having an adverse pregnancy outcome among women exposed to the OCV was 0.97 (95% CI: 0.58–1.61, p = 0.907) compared to that of women exposed to placebo. No significant risk was observed for having a preterm delivery or low birth weight among women exposed to the OCV compared to those of the placebo recipients (Table 2).

In Cohort 2, there were 39 adverse pregnancy outcomes in each of the study groups. The incidence rate of an adverse pregnancy outcome in this cohort was 140.8 per 1000 pregnancies among OCV recipients and 130.4 per 1000 pregnancies among placebo recipients (Table 2). The rate of preterm delivery was 50.4 and of low birth weight was 79.8 per 1000 live births in OCV recipients and 80.8 and 100.0, respectively, in placebo recipients. There were a total of 26 adverse pregnancy outcomes, including 20 miscarriages and 6 stillbirths in Cohort 1. In Cohort 2, there were 32 miscarriages, and 7 still births occurred. There was also no statistically significant difference in the risk of pregnancy loss among OCV recipients in Cohort 2 compared to that among placebo recipients of this cohort, and the rates of preterm delivery and low birth weight were similar between the two groups of this cohort (Table 2).

Table 3 presents the effect of an OCV on induced or accidental abortion. Among women pregnant during vaccination (n = 509), the rates of induced or accidental abortion were 83.3 and 89.5 per 1000 pregnancies among OCV and placebo recipients, respectively. The risk of induced or accidental abortion was not significant [RR = 0.93, 95% CI: 0.52–1.64]. Among women pregnant after vaccination (n = 697), the rates of induced or accidental abortion were 178.0 and 169.4 per 1000 pregnancies among OCV and placebo recipients, respectively. We found no risk due to the OCV on induced or accidental abortion [RR = 1.05, 95% CI: 0.76–1.45].

The results of our study suggest that administration of an OCV during pregnancy was not associated with adverse pregnancy outcomes. Although not statistically significant, the rate of adverse pregnancy outcomes among the OCV recipients was slightly lower compared to that among the placebo recipients. There were a total of 26 adverse pregnancy outcomes, including 20 miscarriages and 6 stillbirths in Cohort 1. In Cohort 2, there were 32 miscarriages, and 7 still births occurred. Previously reported studies in pregnant women receiving an OCV have observed a non-significant increase in adverse pregnancy outcomes among women receiving the OCV [16, 17]. Unlike those studies, our samples were taken from an individually randomized trial population; therefore, it is less likely that our results are biased by sample selection. Additionally, the different adverse pregnancy outcome rates (miscarriage and stillbirth) were also similar between OCV and placebo recipients, suggesting that an OCV (killed, non-replicating, oral administration) does not have any impact on foetus survival. Our results reinforce previous findings that OCVs do not have any negative impact on preterm delivery, low birth weight or congenital anomalies. Based on several studies, the WHO recommends that an OCV be given to women who are pregnant [18, 19, 24]. Altogether, these data suggest that an OCV can be administered during pregnancy.

In our study, we observed that the miscarriage and stillbirth rates were comparable in both cohorts. In a survey conducted between during 1982 and 2002 in a rural area approximately 55 km southeast of Dhaka, we observed 53 miscarriages per 1000 pregnancies and 30 stillbirths per 1000 births [21]. In another study conducted in northwest Bangladesh during 2001 and 2007, 88 miscarriages per 1000 pregnancies were observed, using a miscarriage definition of < 24 weeks of gestation [25]. According to a recent report, there are 19 stillbirths per 1000 births in Bangladesh [22]. These data suggest that the rate of adverse pregnancy outcomes differs by the setting and by the method of detection in Bangladesh and may vary over time. In addition, it remains difficult to categorize abortion as induced or spontaneous because of legal and moral loopholes. Under the penal code of 1860, induced abortion is illegal in Bangladesh except when performed to save a women’s life.

Cholera causes maternal dehydration during pregnancy, which leads to critical hypovolemia that compromises placental and foetal perfusion and eventually leads to foetal death [24]. As a result, miscarriage or premature delivery may occur. Moreover, different studies have reported that pregnancy may be associated with poor outcomes in cases of delayed rehydration therapy [2, 10]. Women who reported having had cholera while they were pregnant were at 6-fold higher risk of miscarriage and 3-fold higher risk of having a stillborn child than women who did not have cholera [17]. Data from Senegal demonstrated that pregnant women took four times longer to reach a health facility for cholera treatment than the general population [9]. Therefore, preventive measures such as vaccination could be a better choice to prevent cholera during pregnancy, which will reduce the risk of pregnancy loss.

The unique strength of our study is that we drew our samples from a double-blinded randomized study, suggesting that the results of our study are free from sampling bias. We initiated screening immediately after vaccination and could capture many participants (84%) receiving the OCV in their 1st trimester. We also followed the participants prospectively, which minimizes recall bias. The follow-ups were made by trained physicians to correctly classify pregnancy outcomes.

However, our study had some limitations. First, our study was conducted in an endemic setting where several subjects may have developed some preexisting immunity. Although there is no clear knowledge of the effect of preexisting immunity of OCV recipients on foetal survival, our results may not apply in non-endemic settings. Evidence from the studies conducted in the past is not different from our results, suggesting that the pregnancy outcomes among OCV recipients are not influenced by the type of setting. Second, although our aim was to conduct a prospective study, 10% of pregnancies were already terminated at the time of recruitment. Since a large proportion of the women were prospectively followed and the number of women retrospectively followed was similar in both groups, we do not think that the small proportion of the retrospectively followed women affected the analysis. Third, we tested only a single dose, whereas the recommended dose of an OCV is a double dose. Another potential limitation is that we did not find any congenital anomalies of the infants. However, the expected prevalence of congenital anomalies among newborns is approximately 2% [26], and the probability of not detecting such defects by chance is 8% (calculated from a binomial distribution with 500 trials).

Due to insufficient safety data, cholera vaccination campaigns frequently exclude pregnant women based on information in package inserts of the OCV. However, according to the WHO, individuals who are at risk of cholera and for whom vaccines are not contraindicated should be targeted by the OCV. Many inactivated vaccines are already given to pregnant women, including tetanus, diphtheria, hepatitis B, flu, and pneumococcal vaccines [27], whereas the OCV used in this study is also an inactivated killed vaccine given orally and acts locally in the intestine [28].

Women in an endemic or outbreak setting are at risk of cholera, and contraction of the disease during pregnancy can cause miscarriages or stillbirths [3]. Our study confirms that there was no risk of foetal loss due to receiving an OCV during pregnancy. Therefore, when the risk of cholera infection is high, an OCV should be offered to pregnant women since they are particularly at a high risk of losing their foetus if they become infected with cholera.