Maternal influenza vaccination appears safe overall, with small increases in gestational diabetes and postpartum hemorrhage, potential reductions in preterm/low birth weight and fetal growth restriction, and a very small rise in infant lower respiratory tract infections.

Background

Influenza during pregnancy increases maternal morbidity and adverse fetal outcomes. Despite recommendations and public funding in Korea since 2019, maternal influenza vaccine uptake remains suboptimal due to safety concerns, amplified during the COVID-19 era. This study evaluated real-world safety signals for mothers and offspring using a nationwide linked database in Korea.

Patients

• Maternal cohort: 493,925 eligible pregnancies (240,465 vaccinated during pregnancy); after 1:1 propensity score matching (PSM), 174,008 vaccinated–unvaccinated pairs.
• Neonatal cohort: 153,111 children (85,663 exposed via maternal vaccination); after PSM, 53,344 pairs.
• Key exclusions: Maternal cohort excluded women with outcomes of interest in the year before pregnancy; neonatal cohort excluded chromosomal abnormalities and first-trimester exposure to known teratogens.
• Setting: South Korea, National Health Insurance Service data linked to the national vaccination registry.

Intervention

Receipt of inactivated influenza vaccine (trivalent 2019–2020; quadrivalent 2020–2022) at any gestational age during pregnancy (time-varying exposure for relevant analyses).

Control

Pregnant women who did not receive influenza vaccination during the index pregnancy.

Outcome

• Maternal gestational outcomes: Preeclampsia, gestational diabetes mellitus (GDM), antenatal bleeding, postpartum hemorrhage (PPH).
• Maternal vaccine-related adverse events: Lymphadenitis, thrombocytopenia, anaphylaxis (14-day window), Guillain–Barré syndrome, neuritis/neuropathy, facial nerve palsy, thromboembolism, vasculitis.
• Other maternal health outcomes: Emergency department visits, ICU admission.
• Neonatal childbirth-related outcomes: Preterm or low birth weight (LBW), congenital malformations, fetal growth restriction, respiratory distress, all-cause mortality.
• Neonatal immune-related outcomes: Asthma, meningitis, upper and lower respiratory tract infection (URTI/LRTI), gastrointestinal infection, otitis media, urinary tract infection.

Study Design

• Retrospective, population-based mother–child linked cohort using nationwide claims and vaccination registry (2019–2022).
• 1:1 propensity score matching to balance extensive sociodemographic, clinical, medication, obstetric, and utilization covariates.
• Log-binomial models for cumulative outcomes (reporting relative risks, RRs) and Cox models for time-to-event outcomes (hazard ratios, HRs); robust SEs accounted for sibling clustering.
• Negative control outcome (all-cause injury requiring ED visit or hospitalization), multiple sensitivity analyses (single-dose only, nulliparous only, adjustment for SARS-CoV-2/RSV), and subgroup analyses by trimester and vaccine type.

Level of Evidence

Level 2b: Individual retrospective cohort study (Oxford hierarchy).

Follow up period

• Maternal: From estimated conception until outcome, death, or 90 days postpartum (minimum 3 months).
• Neonatal: From birth until outcome, death, or 365 days (minimum 1 year).

Results

Primary outcomes

• Gestational diabetes mellitus (GDM): RR 1.06 (95% CI 1.05–1.08); absolute risk difference (ARD) +1.10 per 100 pregnancies; NNTH ≈ 91.
• Postpartum hemorrhage (PPH): RR 1.05 (95% CI 1.01–1.08); ARD +0.19 per 100 pregnancies; NNTH ≈ 526.
• Preeclampsia, antenatal bleeding: No increased risk detected after adjustment.
• Preterm or low birth weight: RR 0.87 (95% CI 0.83–0.91); ARD −1.15 per 100 pregnancies; NNTB ≈ 87.
• Fetal growth restriction: RR 0.84 (95% CI 0.74–0.96); ARD −0.15 per 100 pregnancies; NNTB ≈ 667.
• Congenital malformations, respiratory distress, neonatal all-cause mortality: No increase observed.

Secondary outcomes

• Maternal vaccine-related adverse events: No meaningful increases detected (e.g., lymphadenitis ~null; thrombocytopenia ~null; facial nerve palsy ~null; thromboembolism ~null; vasculitis ~null). Anaphylaxis within 14 days had zero events among vaccinated, precluding effect estimation.
• Other maternal outcomes: Slightly lower healthcare utilization: ED visits HR 0.92 (95% CI 0.90–0.95); ICU admission HR 0.89 (95% CI 0.82–0.97).
• Infant immune-related outcomes (first year): Generally null except a small increase in LRTI: HR 1.06 (95% CI 1.007–1.12); ARD +0.85 per 100,000 person-years (very small absolute difference). URTI, asthma, meningitis, GI infection, otitis media, and UTI showed no meaningful increases.

Sensitivity and subgroup analyses

• Negative control outcome analyses were null, suggesting minimal residual confounding.
• Findings were consistent when restricted to single-dose recipients and to nulliparous women, and after additional adjustment for SARS-CoV-2 and RSV.
• No effect modification by trimester of vaccination or vaccine type.

Limitations

• Observational design with potential residual and unmeasured confounding.
• Study period overlapped with COVID-19, when respiratory virus circulation and healthcare-seeking patterns were atypical.
• Outcome misclassification possible in claims-based definitions.
• Limited ability to address familial/genetic confounding (small sibling cohort).
• Lack of data on COVID-19 vaccination during pregnancy.

Funding

• Government-wide R&D Fund for infectious disease research (HG18C0068).
• Ministry of Food and Drug Safety of South Korea (21153MFDS607).
• National Research Foundation of Korea (RS-2023-00208978).
• Funders had no role in design, analysis, interpretation, writing, or publication decisions.

Citation

Lee H, Yoon D, Kim JH, Noh Y, Joo E-J, Han JY, Choe YJ, Shin J-Y. Association of Influenza Vaccination During Pregnancy with Health Outcomes in Mothers and Children: A Population-Based Cohort Study. Clinical Pharmacology & Therapeutics. 2025 May;117(5):1381–1392. doi:10.1002/cpt.3565.