RSVpreF Vaccine Safety 

Surveillance in Pregnancy from 

The Vaccine Safety Datalink

Malini DeSilva, MD, MPH

ACIP meeting

September 22, 2023

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Vaccine Safety Datalink (VSD), 2023

• Collaborative project between 

CDC and integrated healthcare 

organizations

• Monitors safety of vaccines 

used in the U.S., primarily 

through real-world data of 

rare and serious events 

following vaccination

• Includes data on ~15.5 million 

individuals across all sites 

annually

• ~ 115,000 annual live births

• Data is organized using a 

common data model with 

standardized coding systems

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Vaccine Safety Datalink (VSD) data structure

• Distributed data model – each VSD site creates standardized data files

• Define cohort 

• Vaccines

• Diagnoses & procedures from inpatient/outpatient/emergency

• Birth and death files

• Dynamic pregnancy episode file – validated algorithms for identifying 

ongoing & completed pregnancies, updated weekly

• Pregnancy start, last menstrual period (LMP)

• Gestational age 

• Pregnancy outcome (when available)

• Mom-baby linkage

• Ancillary drug or lab files available ad-hoc for specific studies

• Automated data files supplemented with chart review, as needed

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Prenatal RSVpreF

Vaccine Background • RSVpreF (Pfizer) effective against 

severe RSV-associated LRTI in infants

• RSVpreF clinical trial data on safety in 

pregnant persons • Injection site pain most common 

reactogenicity event 

• Imbalance in preterm births in 

vaccinated group • Most late preterm (34

–<37 

weeks)

• Most occurred >30 days after 

vaccination 

• Most prominent in a single 

country 

• GSK RSV prenatal vaccine clinical trial 

halted due to imbalance in preterm 

birth in vaccinated

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Goal & Challenges 

Prenatal RSVpreF Vaccine Surveillance

• Goal: To evaluate the safety of RSVpreF vaccine administered 

during pregnancy in the VSD’s large, real-world population 

• Challenges:

• Vaccine uptake 

• Healthy vaccinee bias

• Uncertain recommendations for RSVpreF use & administration

• Coadministration of COVID-19, influenza, Tdap

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Pregnancy Outcomes

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1

st trimester 2nd trimester 3

rd trimester

LMP

LMP = Last menstrual period

Pregnancy
Pregnancy Outcomes

8

1

st trimester 2nd trimester 3

rd trimester

LMP 20 weeks 26 weeks

Non-viable

Periviable

Preterm Term

37 weeks

Live Birth

LMP = Last menstrual period

Pregnancy
Pregnancy Outcomes

9

1

st trimester 2nd trimester 3

rd trimester

LMP 20 weeks 26 weeks

Non-viable

Periviable

Preterm Term

37 weeks

Spontaneous Abortion Stillbirth

IUFD

Live Birth

IUFD = Intrauterine Fetal Demise

LMP = Last menstrual period

Pregnancy
Pregnancy Outcomes

10

1

st trimester 2nd trimester 3

rd trimester

LMP 20 weeks 26 weeks

Non-viable

Periviable

Preterm Term

37 weeks

Spontaneous Abortion Stillbirth

IUFD

Live Birth

IUFD = Intrauterine Fetal Demise

LMP = Last menstrual period

Pregnancy

RSVpreF

32 weeks
Pregnancy Outcomes

11

1

st trimester 2nd trimester 3

rd trimester

LMP 20 weeks 26 weeks

Non-viable

Periviable

Preterm Term

37 weeks

Spontaneous Abortion Stillbirth

IUFD

Live Birth

IUFD = Intrauterine Fetal Demise

LMP = Last menstrual period

Pregnancy

RSVpreF

32 weeks
Prenatal RSVpreF Surveillance

• Bimonthly surveillance 

• Use validated algorithms applied to electronic health data in 

VSD to identify pregnant persons 16–49 years at ≥20 weeks’ 

gestation

• Exclude pregnancies: ending in therapeutic abortion, multiple 

gestation, and with insufficient information to date pregnancy

• Exposure: RSVpreF vaccination ≥28 weeks gestation

• Match 1:1, vaccinated: unvaccinated

• VSD Site & gestational age

• Create propensity scores to account for confounding using readily 

available variables (e.g., age, pregnancy start date, race, ethnicity, 

medical comorbidities)

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• Acute outcomes

• Use algorithm developed for other VSD safety surveillance and 

modified for pregnant population 

• Diagnoses associated with outpatient, emergency department, 

and hospital encounters

• Chart confirmation for selected outcomes

• Pregnancy related and birth outcomes

• Preeclampsia/eclampsia – ICD-10 codes

• Preterm birth – gestational age at birth

• Stillbirth – ICD-10 codes with chart review confirmation

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Adverse outcomes evaluated
Acute Outcomes

Outcome Risk window(s) 

(days)

VSD Background 

rate/10,000*

Anaphylaxis 0–1 n/a

Fever 1–7 3.3

Malaise / fatigue 1–7 11.4

Skin and soft tissue or local allergic reactions 1–7 7.0

Acute disseminated encephalomyelitis 1–21, 1–42 0

Acute myocardial infarction 1–21, 1–42 0.3

Appendicitis 1–21, 1–42 0.6

Bell's Palsy 1–21, 1–42 0.8

Cerebral venous sinus thrombosis (CVST) 1–21, 1–42 0.1

Disseminated intravascular coagulation (DIC) 1–21, 1–42 0.3

Guillain-Barré syndrome 1–21, 1–42 0

Immune thrombocytopenic purpura (ITP) 1–21, 1–42 7.6

Lymphadenopathy / lymphadenitis 1–21, 1–42 4.6

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*Identified from unvaccinated pregnant persons, COVID-19 medically attended acute outcomes 1–7 or 1–21 day evaluation
Acute Outcomes, continued

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Outcome Risk window (d) Background 

rate/10,000*

Myocarditis / pericarditis 1–21, 1–42 0

Pulmonary embolism (PE) 1–21, 1–42 0.1

Seizure 1–21, 1–42 0.8

Stevens-Johnson syndrome or toxic epidermal necrolysis 1–21, 1–42 n/a

Stroke, hemorrhagic 1–21, 1–42 0.4

Stroke, ischemic 1–21, 1–42 0.4

Thrombosis with thrombocytopenia syndrome (TTS) 1–21, 1–42 n/a

Thrombotic thrombocytopenic purpura (TTP) 1–21, 1–42 n/a

Transverse myelitis 1–21, 1–42 n/a

Trigeminal neuralgia and related disorders 1–21, 1–42 0.1

Venous thromboembolism (VTE) 1–21, 1–42 0.4

*Identified from unvaccinated pregnant persons, COVID-19 medically attended acute outcomes 1- 21 day evaluation
Pregnancy related and birth outcomes

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Outcome Risk window Pfizer phase 3 

RSVpreF trial, n (%)¥

Preeclampsia and eclampsia 1-21, 1-42 68/3682 (1.8) ¥

Preterm birth (<37 w) Up to 37 weeks 126/2494 (5.1) ∆

Stillbirth 1-21, 1-42 10/3682 (0.3) ¥

¥ RSVPreF Phase 3 clinical trial: Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants | NEJM

∆Preterm birth rate in high-income countries (Slide 23 Evidence to Recommendations Framework: (cdc.gov))
Prenatal RSVpreF Surveillance Analysis

• Risk ratios with corresponding 95% CI using Poisson distribution 

with robust variance using generalized estimating equation 

(GEE)

• Censoring within risk windows when no longer at risk, due to 

pregnancy outcome, or if an unvaccinated match is vaccinated

• Adjustments for known confounders

• If preterm births signal detected, exploration into etiology

• Sensitivity Analysis: alternative matching strategies

• Exploratory: Coadministration of Tdap and RSVpreF

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Example timeline

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Vaccines start 2 months 1

st data pull

2-month data lag

10/1/2023 11/30/2023 1/22/2024

42-day follow-up

3/22/2024

Repeat analyses every 60 days/2 months
Our Team

HealthPartners

• Malini DeSilva

• Elyse Kharbanda

• Jacob Haapala

• Gabriela Vazquez-Benitez

• Leslie Kuckler

• Robyn Kaiser

• Jingyi Zhu

• Sunita Thapa

• Sheryl Kane

• Nicole Trower

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Weill Cornell Medicine

• Heather Lipkind

Kaiser Northwest

• Kimberly Vesco

CDC

• Eric Weintraub

• Elizabeth Quincer

Other VSD sites

• Acumen

• Denver Health

• Harvard Pilgrim

• Indiana University

• Kaiser Permanente Northwest

• Kaiser Permanente Colorado

• Kaiser Permanente Southern 

California

• Kaiser Permanente Northern 

California

• Kaiser Permanente Washington

• Kaiser Permanente Mid-Atlantic 

States

• Marshfield Clinic

• OCHIN