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.