Document text
Gregg C. Sylvester, MD, MPH
ACIP Meeting Pregnancy Outcomes with ccIIV4
(Flucelvax); Post Marketing Study
October 25, 2023
2Study Overview
Purpose Post -marketing commitment
Main Objective Evaluate specific pregnancy and fetus/infant outcomes
Study Design Prospective, observational safety study
Study Population Patients immunized with ccIIV4 as part of routine obstetrical care
Scientific
Oversight
CommitteeTeratologist, blinded to exposure timing, reviewed and classified
reported malformations using the MACDP criteria
Independent experts in maternal -fetal medicine, pediatrics,
clinical research, infectious disease, epidemiology, and teratology
reviewed safety data and aligned on malformation classification(s)
MACDP, Metropolitan Atlanta Congenital Defects Program; OB/GYN, ccIIV4 , cell -based quadrivalent influenza vaccine (Flucelvax)
3Outcomes
Pregnancy Outcomes
•Live birth
•Stillbirth:
•Fetal death occurring ≥20 weeks’
gestation, or if gestational age was
unknown, a fetus that weighed 500 gm
or more
•Spontaneous abortion:
•Fetal death <20 weeks’ gestation,
including missed abortion, incomplete
abortion, and inevitable abortion
•Elective termination
•Voluntary interruption of pregnancy,
including pregnancy termination that
occurred electively, to preserve
maternal health, or due to fetal
abnormalitiesEvents of Interest
•Preterm birth :
•A live -born infant born at gestational
age <37 weeks
•Low birth weight :
•A live -born infant whose birth weight is
<2500 gm
•Major Congenital Malformation:
•Any major structural or chromosomal
defect or combination of three or more
conditional defects in live -or stillborn
infants, or fetal losses of any
gestational age, including outcomes
prior to 20 weeks’ gestation or
weighing <500 gm
4Eligibility/Ineligibility Criteria
Eligible Cases:
•Pregnant patients were enrolled prospectively
•Sufficient information to confirm that vaccination with ccIIV4
occurred during routine obstetrical care
•HCP’s contact information to allow for follow -up
•Subjects may have self -enrolled or may have been enrolled by a
participating OB/GYN clinic after providing informed consent
Ineligible Cases:
•Retrospective cases
•Persons who had prior knowledge of an adverse pregnancy
outcome
HCP -healthcare professional; OB/GYN -obstetrics and gynecology; ccIIV4 -cell-based quadrivalent influenza vaccine.
5Study Enrollment Over Three US Influenza Seasons
Persons Enrolled
2017/2018 10
2018/2019 268
2019/2020 415
Total Enrolled 693
Lost to Follow -up (27)
Ineligible (1)
Primary Analysis Population 665
6Demographics
Primary analysis population (PAP)
Maternal age at conception (years) N=665
Mean (SD) 28.0 (5.3)
Median 28.0
Min, max 17, 45
Paternal age at enrollment (years) N=612
Mean (SD) 30.4 (6.2)
Median 30.0
Min, max 17, 59
Ethnicity n (%) N=665
Hispanic or Latino 44 (6.6%)
Not Hispanic or Latino 437 (65.7%)
Missing* 184 (27.7%)
Race n (%) N=665
White 399 (60.0%)
Black or African American 194 (29.2%)
Asian 29 (4.4%)
American Indian or Alaskan Native 1 (0.2%)
Native Hawaiian or Other Pacific Islander 2 (0.3%)
Other 28 (4.2%)
Unknown 12 (1.8%)
SD, standard deviation *One clinic did not report ethnicity.
7Baseline Characteristics
Primary analysis population (PAP)
Pre-Pregnancy BMI (kg/m2) N=661
Mean (SD) 29.6 (8.2)
Median 28.1
Min, max 15.0, 64.8
Number of previous pregnancies, n (%) N=665
0 195 (29.3%)
1 186 (28.0%)
2 135 (20.3%)
≥3 149 (22.4%)
Family history of congenital malformations, n (%) N=665
Offspring 8 (1.2%)
Maternal history 40 (6.0%)
Paternal history 40 (6.0%)
Any family history 78 (11.7%)
Any concurrent condition, n (%) 527 (79.2%)
Any concomitant medications, n (%) 651 (97.9%)
Substance use, n (%)
Any tobacco use 84 (12.6%)
Any alcohol use 1 (0.2%)
Any illicit drug use N/A
BMI, body mass index; N/A, not applicable; SD, standard deviation
8Exposure by Gestational Age
051015202530354045
0 5 10 15 20 25 30 35 40 45Number of exposures
Gestational age at exposure (weeks)
First trimester Second trimester Third trimesterNumber of patients by gestational age at exposure to ccIIV4 (in weeks)
Among all subjects identified (N=693)
ccIIV4 , cell -based quadrivalent influenza vaccine.
9Results: Pregnancy Outcomes
OutcomeVaccine Exposure
Overall
First Trimester Second Trimester Third Trimester
Primary Analysis
Populationn=178 n= 277 n= 210 n=665
Live Birth, n
% (95% CI)172
96.6% (92.8 -98.8)277
100% (98.7 -100)210
100% (98.3 -100)659
99.1% (98.0 -99.7)
Stillbirth0
0 (0.0-2.1)0
0 (0.0-1.3)0
0 (0.0-1.7)0
0 (0.0-0.6)
Enrollment <20 weeks
gestationn=147 n= 64 N/A n=211
Spontaneous Abortion*4
2.7% (0.7-6.8)0
0 (0.0-5.6)N/A4
1.9% (0.5-4.8)
Elective Termination*1
0.7% (0.0-3.7)0
0 (0.0-5.6)N/A1
0.5% (0.0-2.6)
*Calculated using the population enrolled at <20 weeks of gestation (n = 211) as the denominator.
10Results: Events of Interest
10.2
8.3
2.89.2
5.8
1.9
024681012
Preterm birth Low birthweight Major Cong. MalformationsPercentage of events of interest (95% CI)US prevalence (%) Study prevalence (%)
CDC, Centers for Disease Control and Prevention; CI, confidence interval; MACDP, Metropolitan Atlanta Congenital Defects
Program; MCM, major congenital malformation ; NCHS, National Center for Health Statistics; NVSS, National Vital Statistics System.
1. Martin JA, et al. NCHS Data Brief. 2020;387:1 –8;2. Martin JA, et al. Natl Vital Stat Rep. 2019;68:1 –47; 3. Correa A, et al. Birth Defects
Res A Clin Mol Teratol . 2007;79:65 –93.
11Results: Major Congenital Malformations
Timing of Vaccine/
Weeks GAPreferred MACDP term Trimester of Vaccine
First5.4 Sex chromosome –XYY
10.7 Talipes equinovarusSecond16.1 Renal agenesis, right
16.1 Polycystic kidneys *
16.4Clubfoot, cardiomegaly, aorta malformation
(unknown), hypoplasia of upper or lower limb
18.1 Situs inversus abdominus
19.9 Hirschsprung’s Disease
23.0 Fluid around kidneys
24.9 Micropenis , microphthalmosThird30.3 Transposition of great vessels
32.1Trisomy 21, atrial septal defect, patent ductus
arteriosus
33.0 Absent foreskin
33.3 Hypospadias
33.4 Absent forearm
GA –Gestational Age, MACDP -Metropolitan Atlanta Congenital Defects Program
*One infant who died 24h after birth had polycystic kidneys and fetal anhydramnios reported during pregnancy. Key:
Defect with known cause
No temporal association
Unable to assess temporality
12Strengths and Limitations
Strengths
•>660 Subject enrolled across
multiple influenza seasons
•Diverse population which
included racial and ethnic groups
as well as a broad range of
maternal ages
•Enrollment occurred at five study
sites in four statesLimitations
•Effect of potential confounders
(previous pregnancy outcomes,
pregnancy complications, etc.)
•Potential for missing data or
limited level of detail collected as
part of routine care
•MACDP counts MCMs detected
up to the age of 6 years
MACDP -Metropolitan Atlanta Congenital Defects Program, MCM –Major Congenital Malformations
13Conclusion
•The findings are consistent with published data from various
databases and surveillance systems that monitor the safety of
influenza vaccines1–5
•The independent expert committee found no evidence of a safety
concern
•These data support the use of ccIIV4 for immunization against
influenza in this population
1. Chambers CD, et al. Vaccine. 2016;34(37):4443 –4449; 2. Zerbo O, et al. Vaccine. 2017;35(24):3186 –3190; 3. Donahue JG, et al.
Vaccine. 2019;37(44):6673 –6681; 4. Moro P, et al. Drug Saf.2017;40(2):145 –152; 5. Louik C, et al. Vaccine. 2016;34(37):4450 -4459.