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Prenatal RSVpreF Vaccine Safety
2023 –2024 Respiratory Season
The Vaccine Safety Datalink (VSD)
Malini DeSilva, MD, MPH
Presentation to ACIP
June 25, 2025
© HealthPartners 2Vaccine Safety Datalink (VSD)
•Collaborative project between
CDC and 13 integrated
healthcare organizations
•Monitors safety of vaccines used
in the U.S., primarily through
observational multisite studies
•Includes data on ~15.5 million
individuals across all sites
annually (~4.5% of U.S.
population)
•Annual birth cohort ~ 115,000
•Data is organized using a
common data dictionary with
standardized coding systems
© HealthPartners 3Prenatal RSVpreF vaccine 2023 –2024 season
•ACIP recommendation 9/22/23:
•32–36 weeks gestation with
seasonal administration
•RSVpreF clinical trial1
identified non -significant
imbalances among vaccinated
compared to placebo in:
•Preterm births
•Gestational hypertension and
preeclampsia
Photomicrograph of RSV using indi rect immunofluorescent
antibody under fluorescent lighting.
https://wwwn.cdc.gov/phil/Details.aspx?pid=6484
1Simoes EAF, Center KJ, Tita ATN, et al. Prefusion F Protein -Based Respiratory Syncytial Virus Immunization in Pregnancy. N Engl J Med . Apr
28 2022;386(17):1615 -1626. doi:10.1056/NEJMoa2106062
© HealthPartners 4❖Acute outcomes within 42 days of vaccination
❖Preterm birth (birth <37 weeks gestational age)
❖Small for Gestational Age (SGA) at birth
❖Stillbirth (antepartum)
❖Hypertensive disorders of Pregnancy (HDP):
•Gestational hypertension (GHTN) - New onset HTN after 20 weeks
gestation
•Preeclampsia - New onset or worsening chronic HTN after 20 weeks
gestation with or without severe features
•Eclampsia - Convulsive manifestation of HDP with no other etiology
•HELLP Syndrome (hemolysis, elevated liver enzymes, and low
platelets)Prenatal RSVpreF vaccine safety outcomes
© HealthPartners 5Methods - Target trial emulation design
Protocol
Component
Eligibility criteria Pregnant women 16 –49 years with gestational age 32 –<37 weeks
during 9/22/2023 – 1/31/24 or 2/29/24 for two sites
Treatment
strategies•RSVpreF vaccination (exposed)
•No RSVpreF vaccination (unexposed)
Assignment
proceduresExposed women matched 1:1 to unexposed on:
•VSD site
•Propensity to be vaccinated*
•Gestational week
Follow -up period •Index date (vaccination or gestational day of vaccine for
unexposed match) through 2 weeks after pregnancy end
•Follow up censored at crossover to RSVpreF vaccinationRecreating a randomized experiment from observational data
*Covariates included: Maternal age, calendar week at pregnancy start, # of weeks with prenatal care,
race/ethnicity, comorbidities (i.e., HTN, DM, GHTN, GDM, obesity, substance use), history of preterm labor,
poor fetal growth, supervision of high -risk pregnancy, enrollment, and gestational week
© HealthPartners 6Analysis
•Estimated risk ratios with 95% Confidence Interval (CI) using Log
binomial model with robust variance with adjustment for nulliparity
•For small for gestational age at birth, matched set excluded if infant
weight not available for either infant in matched pair
•For hypertensive disorders of pregnancy, matched set excluded if onset
occurs before or on index date for either woman
© HealthPartners 7Balance plot before and after matching
•SMD = standardized mean differences for
variables included in the propensity score
before and after matching.
•Common way to assess covariate balance
after matching
•Interpretation: -0.2 to 0.2 = small difference
between groups
Notes:
•*Race/Ethnicity
•LMP = last menstrual period
•Enrollment = continuous health plan enrollment from 90
prior to LMP through index week
•ICD-10 codes for:
•High Risk = O09.* (Supervision of care for a high -
risk pregnancy)
•Poor fetal growth = O36.5
•Preterm labor history = O09.21, Z87.51
© HealthPartners 8Matched cohort* characteristics, N = 13,966
RSVpreF Vaccinated, n (%) Unvaccinated match, n (%)
Age group
•16–24 years 1405 (10.1) 1595 (11.4)
•25–29 years 3151 (22.6) 3439 (24.6)
•30–34 years 5461 (39.1) 5272 (37.7)
•35–39 years 3286 (23.5) 3020 (21.6)
•40–49 years 663 (4.7) 640 (4.6)
Race/Ethnicity
•Asian 3039 (21.8) 2635 (18.9)
•Black 862 (6.2) 991 (7.1)
•Hispanic 4459 (31.9) 4691 (33.6)
•White 4542 (32.5) 4541 (32.5)
•Other/Unknown 1064 (7.6) 1108 (7.9)
≥1 other vaccine during
pregnancy13758 (98.5) 11315 (81.0)
Nulliparity 5914 (46.4) 4853 (38.7)
*Not unique individuals due to crossover from unvaccinated to vaccinated
© HealthPartners 91–6 and 1 –21 day acute safety outcome risks among pregnant women
receiving RSVpreF vaccine and unvaccinated matches
© HealthPartners 101–42 day acute safety outcome risk among pregnant women
receiving RSVpreF vaccine and unvaccinated matches
© HealthPartners 11Preterm birtha risk among pregnant women receiving RSVpreF
vaccine and unvaccinated matches
Matched
pairs, NRSVpreF vaccinated Unvaccinated matchAdjusted Risk
Ratio (95% CI)b
N events* Preterm birth % N events* Preterm birth %
13,966 563 4.0 627 4.5 0.90 (0.80 –1.00)
aPreterm birth = birth <37 weeks gestational age
bAdjusted for nulliparity
*Events only included through date of censoring when unvaccinated pair crosses over to vaccinated
© HealthPartners 12SGAa at birth risk in infants born to RSVpreF vaccinated
pregnant person or unvaccinated pregnant matches
Matched
pairs, NRSVpreF vaccinated Unvaccinated matchAdjusted Risk
Ratio (95% CI)b
N events* SGA at birth % N events* SGA at birth %
11,822 799 6.8 774 6.5 0.99 (0.90 –1.09)
aSGA at birth = Small for gestational age at birth; birth weight <10th percentile for gestational age
compared with a U.S. reference population1
bAdjusted for nulliparity
*Events only included through date of censoring when unvaccinated pair crosses over to vaccinated
Note: 11,822 matched pairs with complete infant weight data (85%)
Talge NM, Mudd LM, Sikorskii A, Basso O. United States birth weight reference corrected for implausible gestational age estimates. Pediatrics . May
2014;133(5):844 -53. doi:10.1542/peds.2013 -3285
© HealthPartners 13Stillbirth risk in RSVpreF vaccinated pregnant women or
unvaccinated pregnant matches
Matched
pairs, NRSVpreF vaccinated Unvaccinated matchAdjusted Risk
Ratio (95% CI)a
N events*Stillbirths per
1000N events*Stillbirths per
1000
13,966 11 0.79 10 0.72 1.09 (0.46 –2.58)
aAdjusted for nulliparity
*Events only included through date of censoring when unvaccinated pair crosses over to vaccinated
© HealthPartners 14Hypertensive disorders of pregnancy (HDP) risk among pregnant women
receiving RSVpreF vaccine and unvaccinated matches, N = 13,474
Outcome RSVpreF vaccinated Unvaccinated matchAdjusted Risk
Ratio (95% CI)a
N events* % N events* %
Any HDP 2344 17.4 2056 15.3 1.09 (1.03 –1.15)
Eclampsia OR
HELLP40 0.3 50 0.4 0.77 (0.51 –1.16)
Preeclampsia 1198 8.9 1021 7.6 1.12 (1.03 –1.21)
Gestational
hypertensionb1069 8.8 939 7.8 1.10 (1.01 -1.19)
aAdjusted for nulliparity
bMatched pairs = 12104; excludes matched pairs with chronic hypertension
*Events only included through date of censoring when unvaccinated pair crosses over to vaccinated
© HealthPartners 15Evaluation of rates of cesarean delivery, admissions following birth
hospitalization, and lengths of stay for patients with hypertensive
disorders of pregnancy (HDP) by RSVpreF vaccination status
HDP Severity indicatorRSVpreF
vaccinated
N = 2344Unvaccinated
match
N = 2056
N (%) N (%)
Cesarean delivery 795 (33.9) 675 (32.8)
HDP admission ≤ 14 days following birth
hospitalization184 (7.8) 165 (8.1)
Length of stay >3 days for birth hospitalization
InfantaCesarean delivery 125 (17.8) 123 (21.4)
NSVD 93 (6.8) 70 (5.9)
MotherCesarean delivery 384 (49.0) 310 (46.0)
NSVD 277 (18.3) 245 (17.9)
NSVD = normal spontaneous vaginal delivery
aMissing : RSVpreF vaccinated = 282 ; Unvaccinated = 300
© HealthPartners 16
© HealthPartners 17
•Retrospective observational cohort study of patients who delivered at 32 0/7
weeks’ gestation or later at 2 NYC hospitals 9/22/23 – 1/31/24
•Stratified analyses by site and insurance status, association remained among
those with private insurance and at 1 of 2 sites
© HealthPartners 18❖RSVpreF vaccine not associated with increased risk for
•Acute safety outcomes
•Preterm birth
•SGA at birth
•Stillbirth
❖RSVpreF vaccine associated with small but statistically
increased risk for HDP
•Potential residual confounding or outcome misclassification
•Severity of HDP similar between vaccinated and unvaccinated women based on
rates of c -section, admission following birth hospitalization, and length of stay
❖2024 –2025 season analysis pendingConclusions from 2023 –2024 respiratory season findings
© HealthPartners 19HealthPartners
❖Malini DeSilva
❖Elyse Kharbanda
❖Jacob Haapala
❖Gabriela Vazquez -Benitez
❖Leslie Kuckler
❖Jingyi Zhu
❖Sunita Thapa
❖Nicole Trower
❖VSD site PIsOur Team
Weill Cornell Medicine
•Heather Lipkind
Kaiser Northwest
•Kimberly Vesco
CDC
•Eric Weintraub
•Elizabeth Quincer
© HealthPartners 20•Onset = 1st HDP diagnosis at or after 20+0 weeks GA
•Evaluate as combined outcome (any HDP) and individual outcomes
•For individual outcomes, only include most severe outcome:
Hypertensive disorders of pregnancy diagnoses
Patient GHTN Pre-eclampsia Eclampsia OR HELLP
1 X
2 X X
3 X X X
Count 0 2 1GHTN → preeclampsia → Eclampsia = HELLP
GHTN = gestational hypertension; HELLP = hemolysis, elevated liver enzymes, and low
platelet syndrome; GA = gestational ageHypertensive Disorders of Pregnancy (HDP)
© HealthPartners 21Acute outcomes
Outcome Risk window(s)
(days)Background
rate/10,000*RSVpreF clinical trial,
N=3682, n (%)**
Anaphylaxis 0–1 n/a n/a
Fever 1–7 3.3 3%
Malaise / fatigue 1–7 11.4 46%
Skin and soft tissue or local allergic reactions 1–7 7.0 41%
Acute disseminated encephalomyelitis 1–21, 1 –42 0 n/a
Acute myocardial infarction 1–21, 1 –42 0.3 n/a
Appendicitis 1–21, 1–42 0.6 n/a
Bell's Palsy 1–21, 1–42 0.8 n/a
Disseminated intravascular coagulation (DIC) 1–21, 1–42 0.3 n/a
Guillain -Barré syndrome 1–21, 1–42 0 n/a
Immune thrombocytopenic purpura (ITP) 1–21, 1–42 7.6 n/a
Lymphadenopathy / lymphadenitis 1–21, 1–42 4.6 <0.1%
*Identified from unvaccinated pregnant persons, COVID -19 medically attended acute outcomes 1 –7 or 1 –21 day evaluation
**RSVPreF Phase 3 clinical trial electronic diary for 7 days after vaccination
n/a = not available
© HealthPartners 22Acute outcomes, continued
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 0/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
© HealthPartners 23Previous VSD studies evaluation HDP
Vaccine IIV Tdap COVID -19 IIV in successive
pregnancies
Time period* 6/1/2022 –7/31/2009 1/1/2010 –11/15/2012 6/1/21 – 1/31/22 1/1/2004 –
12/31/2018
Age of
participants14–49 14–49 16–49 any
GA at exposure any <20 weeks <20 weeks any
HDP outcomes ICD-9 codes:
•GHTN (642.3,
642.9); vax ≥ 20
weeks GA
•Mild preeclampsia
(642.4)
•Severe
preeclampsia or
eclampsia (642.5 -
642.7)ICD-9 codes
occurring ≥20 weeks
GA:
•GHTN (642.3x,
642.9x)a
•Preeclampsia
(642.4x -642.8x )bICD-10 codes ≥20
weeks GA –2 wks
postpartum :
•Gestational HTN
(O13.x)
•Preeclampsia -
eclampsia -HELLP
syndrome ( O14.x,
O15.x, and O16.x)•Preeclampsia
(642.4x, 642.5x,
642.7x; O11.x,
O14.x )
•Eclampsia (642.6x;
O15.x)
*may refer to vaccine administration dates, pregnancy end date, or pregnancy start date
a 642.3x, 642.4x, 642.9x = 2 outpatient or 1 inpatient diagnosis
b 642.5x -642.7x = inpatient diagnosis
© HealthPartners 24Inactivated Influenza Vaccine
Citation: Kharbanda EO, Vazquez -Benitez G, Lipkind H, Naleway A, Lee G, Nordin JD; Vaccine Safety Datalink Team. Inactivated inf luenza vaccine during
pregnancy and risks for adverse obstetric events. Obstet Gynecol. 2013 Sep;122(3):659 -67. doi: 10.1097/AOG.0b013e3182a1118a. PMID: 23921876.
© HealthPartners 25Tdap
Kharbanda EO, Vazquez -Benitez G, Lipkind HS, Klein NP, Cheetham TC, Naleway A, Omer SB, Hambidge SJ, Lee GM, Jackson ML, McCarth y NL,
DeStefano F, Nordin JD. Evaluation of the association of maternal pertussis vaccination with obstetric events and birth outco mes. JAMA. 2014 Nov
12;312(18):1897 -904. doi: 10.1001/jama.2014.14825. PMID: 25387187; PMCID: PMC6599584.
© HealthPartners 26COVID -19
Vesco KK, Denoble AE, Lipkind HS, Kharbanda EO, DeSilva MB, Daley MF, Getahun D, Zerbo O, Naleway AL, Jackson L, Williams JTB , Boyce TG, Fuller CC, Weintraub
ES, Vazquez -Benitez G. Obstetric Complications and Birth Outcomes After Antenatal Coronavirus Disease 2019 (COVID -19) Vaccinatio n. Obstet Gynecol. 2024 Jun
1;143(6):794 -802. doi: 10.1097/AOG.0000000000005583. Epub 2024 Apr 17. PMID: 38626447; PMCID: PMC11090513.
© HealthPartners 27IIV in successive pregnancies
•At least 2
successive,
singleton births
between 1/1/2004 –
12/31/2018
Getahun D, Liu IA, Sy LS, Glanz JM, Zerbo O, Vazquez -Benitez G, Nelson JC, Williams JT, Hambidge SJ,
McLean HQ, Irving SA, Weintraub ES, Qian L. Safety of the Seasonal Influenza Vaccine in 2 Successive
Pregnancies. JAMA Netw Open. 2024 Sep 3;7(9):e2434857. doi: 10.1001/jamanetworkopen.2024.34857.
PMID: 39298167; PMCID: PMC11413712.