COVID-19 International Drug Pregnancy Registry

Rationale and background: Pharmaceutical companies, academic centers, and other organizations
globally are developing monoclonal antibodies and antiviral drugs to treat COVID-19. Pregnant
women will be treated with these medications which, for the most part, lack scientific
evidence regarding safety for the mother and the developing offspring.

Objective: To estimate the effect that monoclonal antibodies and antiviral drugs indicated
for mild, moderate, or severe COVID-19 have on obstetric, neonatal, and infant outcomes.

Endpoints: Risk of obstetric outcomes (spontaneous abortion, intrauterine growth restriction,
gestational diabetes, gestational hypertension, postpartum hemorrhage, Caesarean delivery),
neonatal outcomes (major congenital malformations, low birth weight, small for gestational
age, neonatal infections, stillbirth, neonatal death, preterm birth), and infant outcomes
until 12 months of age (developmental milestones [motor, cognitive, language,
social-emotional, and mental health skills], height, weight, failure to thrive).

Study design: The COVID-PR is an international, non-interventional, post-marketing cohort
study designed to collect safety data among pregnant and recently pregnant women treated with
monoclonal antibodies or antiviral drugs for mild, moderate, or severe COVID-19 from the
first day of the last menstrual period (LMP) to end of pregnancy. For monoclonal antibodies,
the exposure period also includes 90 days prior to the first day of the LMP. Follow-up
continues until the infant's first year of age.

Population: The study population includes pregnant or recently pregnant women 18 years of age
and older treated with monoclonal antibodies or antiviral drugs indicated for mild, moderate,
or severe COVID-19 at any time during pregnancy. For monoclonal antibodies, the exposure
period also includes 90 days prior to the first day of the LMP. Registration and
participation via website especially developed for the COVID-PR are voluntary.

Eligible women can enroll at any time during pregnancy and up to 30 days after the end of
pregnancy. Follow-up continues until the infant's first year of age.

Exposure: Women are considered exposed if they received at least one dose of a monoclonal
antibody or antiviral drug indicated for the treatment of mild, moderate, or severe COVID-19
at any time during pregnancy. For monoclonal antibodies, the exposure period also includes 90
days prior to the first day of the LMP. The reference groups include pregnant women treated
with another therapy for mild, moderate, or severe COVID-19 (active comparator) and pregnant
women who were hospitalized for COVID-19 during pregnancy but were not treated with a
medication specifically indicated for mild, moderate, or severe COVID-19 (unexposed
comparator). The exposed and comparators are matched based on calendar time, country of
residence, gestational week of COVID-19 infection (± 2 weeks), and severity of COVID-19.

Data collection: For women who enroll during pregnancy, the pregnancy information is
collected at enrollment, monthly, and at the end of pregnancy. For women who enroll within 30
days after the end of pregnancy, the pregnancy and birth information (if there was a live
birth) is collected at enrollment. Subsequently, data on liveborn infants are collected every
three months until the infant's 12 months of age. Information is obtained directly from the
participant. Detailed information is collected on COVID-19 symptoms, severity markers, and
treatments. Additionally, a COVID-PR Clinical Research Associate calls the mother within 90
days after birth to answer any questions she may have about the registry and to request any
missing information. The COVID-PR collects data on potential confounding factors (such as
maternal sociodemographic characteristics, behaviors, reproductive history, use of assisted
reproductive techniques, pre-pregnancy history of COVID-19 and test results, chronic
conditions, use of medications, and measures of healthcare utilization) and detailed
information associated with the obstetric, neonatal, and infant outcomes. In addition to
self-reported information, the web-based data collection system requests medical records.
Participants are asked to redact their personal identifiers, take photos of the label,
container, or carton of the medication (if available), medical records from the hospital
discharge, pediatric reports, and any other health care records they consider relevant and
then upload them into the web-based data collection system. These records will be used to
validate maternally reported diagnoses and to allow for potential future adjudication of
outcomes. Given the international nature of the COVID-PR, the questionnaires are available in
the languages spoken where it is conducted. Likewise, the phone call is conducted in the
language spoken by the mother. Participant confidentiality and anonymity are strictly upheld.

Analysis: Exposure to medications indicated for mild, moderate, or severe COVID-19 during
specific etiologically relevant periods will be considered when estimating the risk for each
outcome (e.g., first trimester for miscarriages and malformations). Relative risks and their
95% confidence interval (CI) will be presented unadjusted and adjusted using propensity
scores (PS) to account for imbalances in disease severity, comorbidities, and other
characteristics between the exposed and the reference groups.

Study size: Monoclonal antibodies and antiviral drugs indicated for mild, moderate, or severe
COVID-19 will be analyzed separately by brand. Efforts will be made to collect at least 100
pregnancies treated with each monoclonal antibody or antiviral drug during the first
trimester and at least 100 exposed thereafter during pregnancy. For each exposed pregnancy,
one pregnancy treated with another therapy for mild, moderate, or severe COVID-19 (active
comparator) and one pregnancy with COVID-19 not treated with a medication specifically
indicated for the treatment of mild to severe COVID-19 (unexposed comparator) will be matched
based on calendar time, country of residence, gestational week of COVID-19 infection (± 2
weeks), and severity of COVID-19.

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. 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. Semi-annual and annual interim reports summarizing cumulative results on key
outcomes will be submitted to the Scientific Advisory Committee (SAC) and to financial
contributor pharmaceutical companies for their review and feedback every year of the study. A
final report will be prepared at the end of the study.

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