In pregnant women, is the quadrivalent inactivated influenza vaccine superior to the trivalent influenza vaccine?

Quadrivalent vs. Trivalent Influenza Vaccine in Pregnancy

Both quadrivalent (IIV4) and trivalent (IIV3) inactivated influenza vaccines are equally safe and effective for use during pregnancy, and either formulation is appropriate. Current guidelines recommend any licensed, age-appropriate inactivated influenza vaccine without preference between trivalent and quadrivalent formulations 1, 2.

Guideline Recommendations

• Any licensed inactivated influenza vaccine (IIV)—whether trivalent or quadrivalent—may be administered safely during any trimester of pregnancy 1, 2.
• The CDC's Advisory Committee on Immunization Practices (ACIP) and the American College of Obstetricians and Gynecologists explicitly state that any licensed, recommended, and age-appropriate IIV4 or recombinant influenza vaccine (RIV4) may be used, without expressing preference for quadrivalent over trivalent 1.
• Live attenuated influenza vaccine (LAIV) remains contraindicated during pregnancy but may be used postpartum 1.

Comparative Safety Evidence

The safety profiles of trivalent and quadrivalent vaccines in pregnancy are equivalent:

• Substantially less clinical experience exists with quadrivalent vaccines during pregnancy compared to trivalent formulations, as quadrivalent vaccines are more recently licensed 1.
• The FDA drug label for Fluzone notes that developmental toxicity studies in rabbits using Fluzone Quadrivalent revealed no vaccine-related fetal malformations, no adverse effects on pre-weaning development, and no impairment of female fertility 3.
• A randomized phase IV trial directly comparing IIV4 versus IIV3 in 346 pregnant women found rates of solicited and unsolicited vaccine-related adverse events were similar between groups, with all participants achieving live births and no vaccine-related adverse events in newborns 4.

Comparative Immunogenicity

The primary difference between formulations is breadth of coverage, not safety or maternal/infant outcomes:

• IIV4 provides protection against an additional influenza B lineage (four strains total: two influenza A and two influenza B) compared to IIV3 (three strains: two influenza A and one influenza B) 4.
• In the randomized trial, HAI antibody titers increased similarly for the shared strains between IIV4 and IIV3, while the additional B strain in IIV4 generated higher titers in IIV4 recipients (geometric mean titer ratio 6.3 vs. 3.4) 4.
• Transplacental antibody transfer was equivalent between formulations, with umbilical cord blood HAI titers 1.5–1.9-fold higher than maternal blood for all strains in both groups 4.

Effectiveness Data

Real-world effectiveness studies demonstrate benefit for both formulations:

• Quadrivalent vaccine effectiveness against laboratory-confirmed influenza in pregnant women ranged from 43.5% to 72% across two prospective cohort studies 5, 6.
• Trivalent vaccine effectiveness in pregnant women was 63.9% (95% CI 29.1–81.6%) in a Danish test-negative case-control study 7.
• For infant protection, quadrivalent vaccine effectiveness ranged from 31.4% to 64.5% 5, 6, while trivalent vaccine effectiveness was 56.8% (95% CI 25.0–75.1%) 7.

These effectiveness estimates overlap substantially and do not demonstrate clear superiority of one formulation over the other.

Practical Considerations

• The 2025-26 influenza season marks a transition from quadrivalent to trivalent vaccines due to apparent elimination of the B/Yamagata lineage from circulation and WHO guidance to remove this antigen 8, 9.
• This shift does not diminish vaccine value—it reflects dynamic strain surveillance and targeting of vaccines against circulating strains 8.
• For the 2025-26 season, ACIP recommends that pregnant women receive seasonal influenza vaccines only in single-dose, thimerosal-free formulations 9.

Clinical Algorithm

When selecting an influenza vaccine for a pregnant patient:

1. Confirm the vaccine is inactivated (IIV or RIV)—never administer LAIV during pregnancy 1, 2.
2. Choose any available licensed, age-appropriate inactivated influenza vaccine without preference for trivalent versus quadrivalent 1.
3. Administer during any trimester without delaying for a specific gestational age 1, 2.
4. Prioritize single-dose, thimerosal-free formulations per updated 2025-26 ACIP guidance 9.
5. Do not postpone vaccination due to concerns about first-trimester safety—evidence robustly supports safety across all trimesters 2.

Key Caveats

• While quadrivalent vaccines theoretically offer broader B-lineage coverage, this advantage is now moot given the elimination of B/Yamagata from circulation and the shift back to trivalent formulations 8, 9.
• Pregnant women have substantially less clinical experience documented with quadrivalent formulations compared to the extensive safety database for trivalent vaccines 1.
• The most important clinical priority is ensuring pregnant women receive any inactivated influenza vaccine, as vaccination coverage remains unacceptably low at only 38.1% in the 2023-2024 season 2.