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BNT162b2
Module 1 .14.1.5 Summary of Literature Search on Pregnancy, Lactation, and Reproductive Potential
CONFIDENTIAL
Page 1Coronavirus D isease 2019 (COVID -19) Vaccine
Summary of Literature Search on the Use of Coronavirus Disease 2019 (COVID -19)
Vaccine During Pregnancy, Lactation, and on the Drug’s Potential Effects on Fertility
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Module 1 .14.1.5 Summary of Literature Search on Pregnancy, Lactation, and Reproductive Potential
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Page 2TABLE OF CONTENTS
1.INTRODUCTION ................................ ................................ ................................ ................. 3
2.LITERATURE SEARCH S TRATEGY ................................ ................................ ................ 3
3.LITERATURE SUMMARY REGARDING PREGNANCY ................................ ............... 5
3.1. Human Data ................................ ................................ ................................ ............... 5
3.1.1. Structural Abnormalities ................................ ................................ ............... 5
3.1.2. Embry o-fetal and/or Infant Mortality ................................ ........................... 5
3.1.3. Functional Impairment ................................ ................................ .................. 5
3.1.4. Alterations to Growth ................................ ................................ ................... 6
3.1.5. Change of Drug Pharmacokinetics Associated with Pregnancy ................... 6
3.2. Summaries on the Effects of COVID-19 Vacc ine on Pregnancy ............................. 6
4.LITERATURE SUMMARY REGARDING LACTATION ................................ ................. 6
4.1.Human Data ................................ ................................ ................................ ............... 6
4.1.1. Pharmacokinetics of Drug in Breast Milk ................................ .................... 6
4.1.2. Estimated I nfant Dose Obtained from Breast Milk ................................ ......6
4.1.3. Pharmacokinetics of Drug in Women who are Lactating............................. 6
4.1.4. Pharmacod ynamics ................................ ................................ ....................... 6
4.1.4.1. Impact of Medication on L actation (Changes in Volume
Produced) ................................ ................................ ............................. 6
4.1.4.2. Impact of Medication Consumed From Breast Milk on
Infant................................ ................................ ................................ ....6
4.2. Summaries on the Effects of COVID-19 Vaccine on Lactation ............................... 7
5. LITERATURE SUMMAR Y REGARDING REPRODUCTI VE POTENTIAL .................. 7
5.1. Human Data ................................ ................................ ................................ ............... 7
5.2. Summaries on the Effects of COVID- 19 Vaccine on Reproductive Potential ......... 7
6.REFERENCES CI TED IN LITERATURE SUMMARY ................................ ..................... 8
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Page 31.INTRODUCTION
The BNT162b2 vaccine contains modified messenger RNA (modRNA), which is formulated
in lipid particles th at enable the delivery of the RNA into host cells to allow expression of the
severe acute respiratory syndrome coronavirus 2 (SARS -CoV -2) viral spike antigen, which in
turn elicits a host immune response to this viral antigen. BNT162b2 is authorized for use
under an Emergency Use Authorization (EUA 27034; Pfizer -BioNTech COVID -19 Vaccine )
for active immunization to prevent coronavirus disease 2019 (COVID -19) caused by
SARS -CoV -2 in individuals 16 y ears of age and older. BNT162b2 is a suspension for
injectio n and contains a volume of 0.45 mL . Each dose of BNT162b2 contains 30 µg of a
nucleoside -modified messenger RNA encoding the viral spike (S) gl ycoprotein of SARS -
CoV -2. The vaccine is administered intramuscularly as a series of two doses (0.3 mL each)
3weeks apart .1
In the draft prescribing information , available data for BNT162b2 administered to pregnant
women are insufficient to inform vaccine- associated risks in pregnancy . In addition, data are
not available to assess the effects of BNT162b2 on the breastfed infant or on milk production
or excretion.
On 04 December 2014, the US Food and Drug Administration (FDA) published a draft
guidance document on the content and format of labeling for human prescription drug and
biological products regarding pre gnancy , lactation, and reproductive potential.2The
Pregnancy and Lactation Labeling Rule (PLLR) became effective on 30 June 2015 and
requires a change to the structure and content of labeling for human prescription drug and
biologic products with regard t o pregnancy and lactation, and creates a new subsection for
information with regard to reproductive potential.
This clinical literature summary has been created to support the Biologics Licens e
Application (BLA) for BNT162b2.
2.LITERATURE SEARCH ST RATEGY
The constructed clinical searches included 3 major key word groups: Pregnancy , Fertility , and
Lactation. The search included the following key words for COVID -19 Vaccine for clinical
studies. Databases searched included LactMed, OVID MEDLINE and OVID MEDLINE (R)
In-Process & Epub Ahead of Print, BIOSIS Previews, and Embase. The search timeframe
was from 01- DEC- 2020 to 26- FEB-2021.
Key words used for the literature search criteria for Pregnancy , Lactation, and Potential Effects
on Fertility for COVID -19 Vaccine are listed below.
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Page 4Pregnancy :
pregnancy , pregnancy outcome, pregnancy complications, pregnant,
pregnancies
abortion, induced abortion, spontaneous abortion, miscarriage, embry o
implantation, fetal resorption, embry o loss, nidation
missed abortion, fetal death, stillbirth, neonatal death
birth, parturition, fetus, embry o, in utero, childbirth, fetal, preterm
birth, premature birth
labor and delivery
developmental toxicity
epidemiology or causality or incidence (and pregnancy ), prevalence
(and pregnancy )
malformation, birth or congenital abnormalities, defects or
deformities, dysmorphology , fetal anomalies, teratogenicity , prenatal
exposure delay ed effects, structural abnormalities, functional
impairment, growth impairment, growth restriction, excessive growth
functional toxicity , deafness, endocrinopathy , neurodevelopmental
effects, impairment of reproduction, delay ed maturation, early
maturation
neonate, neonatal, newborn, newl y born
prenatal/perinatal exposure, prenatal drug exposure, maternal
exposu re, paternal exposure, fetus mortalit y, embryo mortalit y
pharmacokinetics during pregnancy
fetal exposure to drug
Pregnancy & Pharmacokinetics:
pharmacokinetics, drug distribution, drug absorption, drug
metabolism, drug elimination, absorption (and pregnancy )
drug excretion in milk
lacteal elimination
distribution, absorption, metabolism, elimination (and pregnancy ,
lacteal, breast milk, milk)
Lactation:
breast -feeding, breast secretion, lactation, milk
exposure through breastmilk
drug excretion in milk
alteration in lactation
milk supply
Females & Males of Reproductive Potential:
fertility , reproduction, reproduction process, fecundity , fecundability ,
placentation, sperm, testis, ovary , implantation, ovum
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Page 5Utilizing the recommended literature search criteria and methodology , preliminary literature
search generated 158 results. Assessment of these literature search results was done b y
identification of potentially relevant studies based on abstract content, followed b y further
evaluation of the identified literature b y reviewing their full text articles and appraising for
relevancy . In this clinical literature search and review, 8 articles were reviewed in full, of
which none w asassessed to provide pertinent clinical data for inclusion in this c linical PLLR
literature s ummary . The information provided by the articles reviewed are detailed in the
accompan ying PLLR Literature Summary Table.
3.LITERATURE SUMMARY R EGARDING PREGNANCY
3.1.Human Data
Review of the published medical literature for COVID-19 Vaccine has been organized below
within the following four groups of developmental toxicities, as defined in FDA’s guidance
for industry ,Reproductive and Developmental Toxicities – Integrating Study Results to
Assess Concerns:
1.Structural abnormalities, which describes d ysmorphology , and includes malformations,
variations, deformations, and disruptions .
2.Embry o-fetal and/or infant mortality , which describes developmental mortality , and
includes miscarriage, stillbirth, and infant death (including neonatal death) .
3.Functional impairment, which describes functional toxicity , and includes such outcomes
as deafness, endocrinopathy , neurodevelopmental effects, and impairment of
reproduction.
4. Alterations to growth, which describes outcomes such as growth restric tion, excessive
growth, and delay ed and earl y maturations.
Doses of COVID -19 Vaccine and duration of exposure are outlined below, where provided.
Within each category , literature describing both negative and positive experiences of in-utero
exposure to COV ID-19 Vaccine are presented.
3.1.1. Structural Abnormalities
There is no relevant published information or data available on structural abnormalities
resulting from maternal exposure to COVI D-19 Vaccine, as of this revision date.
3.1.2. Embryo -fetal and/or Infant Mortal ity
There is no relevant published information or data available on embry o-fetal and/or infant
mortality resulting from maternal exposure to COVID -19 Vaccine, as of this revision date.
3.1.3. Functional Impairment
There is no relevant published information or dat a available on functional impairment
resulting from maternal exposure to COVI D-19 Vaccine, as of this revision date.
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Page 63.1.4. Alterations to Growth
There is no relevant published information or data available on alterations to growth resulting
from maternal exposur e to COVID -19 Vaccine, as of this revision date.
3.1.5. Change of Drug Pharmacokinetics Associated with Pregnancy
There is no relevant published information or data available on the change of drug
pharmacokinetics associated with pregnancy resulting from maternal exposure to COVID -19
Vaccine, as of this revision date.
3.2.Summaries o nthe Effects of COVID -19 Vaccine on Pregnancy
The current review of clinical literature did not identify relevant published data or
information on the effects of COVID -19 Vaccine on pregn ancy .
4. LITERATURE SUMMARY RE GARDING LACTATION
4.1.Human Data
4.1.1. Pharmacokinetics of Drug in Breast Milk
There is no relevant published information or data available on the pharmacokinetics of
COVID -19 Vaccine in breast milk, as of this revision date.
An additional publication identifi edafter the search cutoff date b y Baird et al (2021)3
reported significantly elevated levels of SARS -CoV -2 specific IgG and IgA antibodies in
breast milk beginning at Day 7 after the initial vaccine dose, with an IgG -dominant response
in a prospective cohort study of 6 lactating women who received 2 doses of Pfizer/BioNTech
or Moderna SARS -CoV -2 vaccine (3 in each group). This publication is not y et
peer-reviewed and no safety data were reported.
4.1.2. Estimated Infant Dose Obtained from Breast Milk
There is no relevant published information or data available on the estimated infant dose of
COVID -19 Vaccine obtained from breast milk, as of this revision date.
4.1.3. Pharmacokinetics of Drug in Women who are Lactating
There is no relevant publishe d information or data available on the pharmacokinetics of
COVID -19 Vaccine in lactating women, as of this revision date.
4.1.4. Pharmacodynamics
4.1.4.1. Impact of Medication on Lactation (Changes in Volume Produced)
There is no relevant published information or data available on the impact of COVID-19
Vaccine on lactation, as of this revision date.
4.1.4.2. Impact of Medication Consumed from Breast Milk on Infant
There is no relevant published information or data available on the impact of COVID -19
Vaccine consumed from breast mi lk on infant, as of this revision date.
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Page 74.2.Summaries o nthe Effects of COVID -19 Vaccine on Lactation
The current review of clinical literature did not identify relevant published data or
information on the effects of COVID -19 Vaccine on lactation.
5.LITERATURE SUMMARY REGARDING RE PRODUCTIVE POTENTIAL
5.1.Human Data
There is no relevant published information or data available on the effects of COVID -19
Vaccine on human reproductive potential, as of this revision date.
5.2. Summaries on the Effects of COVID- 19 Vaccine on Reproductive Potential
The current review of clinical literature did not identify relevant published data or
information on the effects of COVID -19 Vaccine on male or female reproductive potential.
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Module 1 .14.1.5 Summary of Literature Search on Pregnancy, Lactation, and Reproductive Potential
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Page 86.REFE RENCES CITED IN LITE RATURE SUMMARY
1Full Emergency Use Authorization ( EUA ) Prescribing Information : Pfizer -BioNTech
COVID -19 Vaccine . Revised 25 February 2021
2U.S. Department of Health and Human Services, Food and drug Administration,
Center for Drug Evaluation and Research (CDER), Center for Biological Evaluation
and Research (CBER). Guidance for Industry –Pregnancy , Lactation, and
Reproductive Potential: Lab eling for Human Prescription Drug and Biological
Products –Content and Format. Draft Guidance, July 2020 , Accessed March 2021:
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM425398.pdf )
3Baird JK, Jensen SM, Urba WJ, et al. SARS- CoV -2 antibodies detected in human
breast milk post-vaccination. Preprint: https://doi.org/10.1101/2021.02.23.21252328
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