COVID-19 Vaccines International Pregnancy Exposure Registry

Rationale and background: COVID-19 vaccines will be used in pregnant populations.
Scientific evidence regarding their safety for pregnant women and the developing fetus is
lacking.

Objective: The objective of the COVID-19 Vaccines International Pregnancy Exposure
Registry (C-VIPER) is to estimate the risk of obstetric outcomes (spontaneous abortion,
antenatal bleeding, gestational diabetes, gestational hypertension, intrauterine growth
restriction, postpartum hemorrhage, fetal distress, uterine rupture, placenta previa,
chorioamnionitis, Caesarean delivery, COVID-19), neonatal outcomes (major congenital
malformations, low birth weight, neonatal death, neonatal encephalopathy, neonatal
infections, neonatal acute kidney injury, preterm birth, respiratory distress in the
newborn, small for gestational age, stillbirth, COVID-19), and infant outcomes
(developmental milestones [motor, cognitive, language, social-emotional, and mental
health skills], height, weight, failure to thrive, medical conditions during the first 12
months of life, COVID-19) among pregnant women exposed to single (homologous) or mixed
(heterologous) COVID-19 vaccine brand series from 30 days prior to the first day of the
last menstrual period (LMP) to end of pregnancy and their offspring relative to a matched
reference group who received no COVID-19 vaccines during pregnancy.

Study design: The C-VIPER is an international, non-interventional, post-marketing cohort
study designed to collect prospective safety data among women vaccinated with a COVID-19
vaccine during pregnancy or within 30 days prior to the first day of the LMP.

Population: The study population includes 2 cohorts of pregnant women 18 years of age and
older matched by country and gestational age (±2 weeks):

- Cohort 1: pregnant women exposed from 30 days prior to the first day of the LMP to
end of pregnancy to at least one dose of a COVID-19 vaccine. These participants are
enrolled as part of the C-VIPER.

- Cohort 2: pregnant women unexposed to a COVID-19 vaccine during pregnancy. These
participants are enrolled through the Pregistry International Exposure Registry
(PIPER) with the same methods as those in Cohort 1. Women vaccinated before 30 days
prior to the first day of the LMP are eligible for inclusion.

Registration and participation via a website especially developed for the C-VIPER are
voluntary. Eligible women can enroll at any time during pregnancy.

Data collection: Pregnancy data are collected at enrollment, monthly, and at the end of
pregnancy. Liveborn infants are followed-up and data are collected at birth and then
every three months until 12 months of age. Information is obtained directly from the
participant. The C-VIPER collects data on potential confounding factors (such as maternal
sociodemographic characteristics, occupation, behaviors, reproductive history, chronic
conditions, results of SARS-CoV-2 tests before and during this pregnancy, new COVID-19
vaccinations, use of medications and other vaccinations, and measures of healthcare
utilization), and information related to obstetric, neonatal, and infant outcomes. Given
the international nature of the C-VIPER, the questionnaires are available in the
languages spoken where it is conducted. Participant confidentiality and anonymity are
strictly upheld.

Analysis: Exposure to the vaccine during specific etiologically relevant periods is
considered when estimating the risk for each outcome (e.g., first trimester for
miscarriages and malformations). Relative risks are presented unadjusted and adjusted
using propensity scores (PS) to account for imbalances in characteristics between the
exposed and the reference groups.

Sample size: At least 200 pregnancies exposed to each branded COVID-19 vaccine during the
first trimester and 300 exposed thereafter during pregnancy are projected. For each
exposed pregnancy, 2 unexposed pregnancies enrolled in the PIPER will be matched by
country and gestational age at enrollment (±2 weeks).

Study Milestones: The total duration of the study will be 5 years. Obstetric, neonatal,
and infant outcomes will be assessed on an ongoing basis as data become available. Data
on pregnancy, neonatal and infant outcomes will be included in the interim reports as
soon as available. The first two years will include, primarily, enrollment of
pregnancies; the third and fourth years will involve follow-up of pregnancies and
newborns; and, the final year, will be for data analyses and publications. Results on
pregnancy and neonatal outcomes, even preliminary, are expected within the first year of
the study. Annual and semi-annual interim reports will be submitted to the Scientific
Advisory Committee (SAC) for their review and feedback as well as abbreviated quarterly
progress reports summarizing cumulative results on key outcomes. A final report will be
prepared at the end of the study.

Governance: The C-VIPER is conducted by Pregistry and includes an internal Safety
Management Team (SMT) of experienced pharmacovigilance professionals and a
dysmorphologist who meet regularly to review individual cases and safety signals.
Additionally, the C-VIPER is in consultation with experts from relevant fields, such as
maternal-fetal medicine, infectious diseases, epidemiology, and biostatistics from
academic institutions, private practice, and/or government agencies. These individuals
constitute the SAC and will provide an independent review of the C-VIPER data.