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.