Follow-up of Pregnant Women After a Mass Vaccination of Oral Cholera Vaccine (ShancholTM) in Nsanje Malawi

Although there are good reasons for women of reproductive age to participate in
interventions that prevent cholera, cholera vaccination programs and studies have generally
excluded pregnant women since there is little specific information on the safety of the
vaccine during pregnancy. However, there are several biological reasons why inactivated OCVs
are unlikely to have a harmful effect on fetal development. First, the bacteria in the
vaccine are killed and do not replicate. Second, the vaccine antigens act locally on the
gastrointestinal mucosa, are not absorbed, and do not enter the maternal or fetal
circulation. Finally, the vaccines do not trigger systemic reactions (e.g., fever)
associated with miscarriage in early pregnancy.According to the latest WHO position paper in
relation to OCV, vaccination in countries where cholera is endemic may include groups that
are particularly vulnerable to the severe forms of cholera, and for whom the vaccines are
not contraindicated, such as pregnant women and HIV-infected individuals.

While WHO recommends vaccination for pregnant women, the package inserts for Dukoral® and
ShancholTM are more cautious and suggests that the vaccines are not recommended for use in
pregnant women. Even so, the ShancholTM package insert states that, "Administration of
ShancholTM to pregnant women may be considered after careful evaluation of the benefits and
risks in case of a medical emergency or an epidemic". In the most recent results published
in 2012, pregnant women inadvertently vaccinated with Dukoral® during the mass vaccination
campaign in Zanzibar in 2009 did not experience any harmful effects. On the other hand,
there is no information on the safety of ShancholTM vaccine in pregnant women. New evidence
is needed to inform decisions on the true safety of this vaccine in pregnancy. If it is
safe, this vaccine will be a valuable tool in reducing the burden of cholera in a population
that disproportionately suffers from this disease.

On January 13, 2015, the President of the Republic of Malawi declared a state of disaster
following the persistent rains that resulted in floods affecting 15 of the 28 districts in
the country. The first confirmed case of cholera was reported in Malawi on February 11,
2015. As of 4 March 2015, Malawi had registered 72 cases with 2 deaths. To stop the outbreak
of cholera, a cholera vaccination campaign program was carried out between 30 March 2015 and
May 3 2015 targeting the camps and the nearby communities in Nsanje District. This campaign
provided two doses of vaccine to all age eligible people irrespective of pregnancy status.
This study is designed to do a follow-up of only the pregnant women aiming at the following
objectives:

Specific Objective 1: To conduct surveillance of pregnant women to detect adverse pregnancy
outcomes within communities in Nsanje District, Malawi that received oral cholera vaccine in
a reactive vaccination campaign that started on 30 March 2015. Through household surveying
and enrollment of pregnant women with monthly follow-up visits, the investigators will
determine the cumulative incidence of adverse pregnancy outcomes among vaccinated and
unvaccinated women in Nsanje and Chikwawa Districts, Malawi.

Specific Objective 2: To compare the cumulative incidence of pregnancy loss (miscarriage and
stillbirth) of women who received oral cholera vaccine while they were pregnant to women who
were vaccinated and became pregnant after the end of the final round of vaccination in
Nsanje and Chikwawa Districts, Malawi.

Specific Objective 3: To compare the incidence of newborn malformations in a cohort of
infants that had fetal exposure to oral cholera vaccine compared to those without such
exposure in Nsanje and Chikwawa Districts, Malawi.

Inclusion criteria:

- Women aged 15-49 years old at time of consent (all cohorts)

- Urine sample provided if pregnancy test required (Not required if: experienced
delivery outcome between March 30 and enrollment date, OR visibly pregnant AND has
due date indicated in Health Passport) (all cohorts)

- Received at least one dose of OCV in 2015 (must be verified with OCV Vaccination
Card) (Cohorts 1 & 2)

- Estimated last menstruation at least 3 weeks before the first dose of OCV received
(Nsanje) or before March 30, 2015 (Chikwawa) (Cohorts 1 & 3)

- Estimated last menstruation at least 2 weeks after the final dose of OCV received
(Nsanje) or after the last day of OCV Round 2 (Chikwawa) (Cohorts 2 & 4)

- Residing in Nsanje or Chikwawa Districts since the first day of the vaccination
campaign (30 March 2015) (Cohorts 2 & 3)

- Provides informed consent (with additional consent by the parent or legal guardian
for unmarried <18 years old) (All Cohorts)

Exclusion Criteria

- Received at least one dose of OCV in 2015 (Cohorts 3 & 4)

- An otherwise eligible pregnant women who is unable to be contacted after the second
attempt within 48 hours after the first attempt to enroll (All cohorts)