Risk of Preterm or Small-for-Gestational-Age Birth After Influenza Vaccination During Pregnancy: Caveats When Conducting Retrospective Observational Studies

Am J Epidemiol. 2016 Aug 1;184(3):176-86. doi: 10.1093/aje/kww043. Epub 2016 Jul 22.


Vaccines are increasingly targeted toward women of reproductive age, and vaccines to prevent influenza and pertussis are recommended during pregnancy. Prelicensure clinical trials typically have not included pregnant women, and when they are included, trials cannot detect rare events. Thus, postmarketing vaccine safety assessments are necessary. However, analysis of observational data requires detailed assessment of potential biases. Using data from 8 Vaccine Safety Datalink sites in the United States, we analyzed the association of monovalent H1N1 influenza vaccine (MIV) during pregnancy with preterm birth (<37 weeks) and small-for-gestational-age birth (birth weight < 10th percentile). The cohort included 46,549 pregnancies during 2009-2010 (40% of participants received the MIV). We found potential biases in the vaccine-birth outcome association that might occur due to variable access to vaccines, the time-dependent nature of exposure to vaccination within pregnancy (immortal time bias), and confounding from baseline differences between vaccinated and unvaccinated women. We found a strong protective effect of vaccination on preterm birth (relative risk = 0.79, 95% confidence interval: 0.74, 0.85) when we ignored potential biases and no effect when accounted for them (relative risk = 0.91; 95% confidence interval: 0.83, 1.0). In contrast, we found no important biases in the association of MIV with small-for-gestational-age birth. Investigators conducting studies to evaluate birth outcomes after maternal vaccination should use statistical approaches to minimize potential biases.

Keywords: biases; birth outcomes; monovalent H1N1 influenza vaccine safety; pregnancy; preterm delivery; small for gestational age.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bias
  • Comorbidity
  • Databases, Factual
  • Female
  • Humans
  • Infant, Newborn
  • Infant, Small for Gestational Age*
  • Influenza A Virus, H1N1 Subtype / drug effects
  • Influenza A Virus, H1N1 Subtype / immunology
  • Influenza Vaccines / administration & dosage*
  • Influenza Vaccines / adverse effects
  • Influenza, Human / immunology
  • Influenza, Human / prevention & control*
  • Influenza, Human / virology
  • Maternal Age
  • Observational Studies as Topic / methods
  • Observational Studies as Topic / standards
  • Pregnancy
  • Pregnancy Complications, Infectious / immunology
  • Pregnancy Complications, Infectious / prevention & control*
  • Pregnancy Complications, Infectious / virology
  • Pregnancy Outcome / epidemiology*
  • Pregnancy Trimesters / drug effects
  • Pregnancy Trimesters / immunology
  • Premature Birth / epidemiology*
  • Premature Birth / immunology
  • Prevalence
  • Product Surveillance, Postmarketing / methods
  • Product Surveillance, Postmarketing / statistics & numerical data
  • Propensity Score
  • Retrospective Studies
  • Risk Assessment
  • Time Factors
  • United States / epidemiology
  • Young Adult


  • Influenza Vaccines