Individual-based versus aggregate meta-analysis in multi-database studies of pregnancy outcomes: the Nordic example of selective serotonin reuptake inhibitors and venlafaxine in pregnancy

Pharmacoepidemiol Drug Saf. 2016 Oct;25(10):1160-1169. doi: 10.1002/pds.4033. Epub 2016 May 19.


Purpose: Compare analyses of a pooled data set on the individual level with aggregate meta-analysis in a multi-database study.

Methods: We reanalysed data on 2.3 million births in a Nordic register based cohort study. We compared estimated odds ratios (OR) for the effect of selective serotonin reuptake inhibitors (SSRI) and venlafaxine use in pregnancy on any cardiovascular birth defect and the rare outcome right ventricular outflow tract obstructions (RVOTO). Common covariates included maternal age, calendar year, birth order, maternal diabetes, and co-medication. Additional covariates were added in analyses with country-optimized adjustment.

Results: Country adjusted OR (95%CI) for any cardiovascular birth defect in the individual-based pooled analysis was 1.27 (1.17-1.39), 1.17 (1.07-1.27) adjusted for common covariates and 1.15 (1.05-1.26) adjusted for all covariates. In fixed effects meta-analyses pooled OR was 1.29 (1.19-1.41) based on crude country specific ORs, 1.19 (1.09-1.29) adjusted for common covariates, and 1.16 (1.06-1.27) for country-optimized adjustment. In a random effects model the adjusted OR was 1.07 (0.87-1.32). For RVOTO, OR was 1.48 (1.15-1.89) adjusted for all covariates in the pooled data set, and 1.53 (1.19-1.96) after country-optimized adjustment. Country-specific adjusted analyses at the substance level were not possible for RVOTO.

Conclusion: Results of fixed effects meta-analysis and individual-based analyses of a pooled dataset were similar in this study on the association of SSRI/venlafaxine and cardiovascular birth defects. Country-optimized adjustment attenuated the estimates more than adjustment for common covariates only. When data are sparse pooled data on the individual level are needed for adjusted analyses. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: meta-analysis; methods of analysis; multi-database; pharmacoepidemiology.

Publication types

  • Comparative Study
  • Meta-Analysis

MeSH terms

  • Adult
  • Cohort Studies
  • Databases, Factual
  • Female
  • Heart Defects, Congenital / chemically induced*
  • Heart Defects, Congenital / epidemiology
  • Humans
  • Middle Aged
  • Pregnancy
  • Pregnancy Outcome
  • Registries
  • Research Design
  • Risk Factors
  • Scandinavian and Nordic Countries / epidemiology
  • Selective Serotonin Reuptake Inhibitors / administration & dosage
  • Selective Serotonin Reuptake Inhibitors / adverse effects*
  • Serotonin and Noradrenaline Reuptake Inhibitors / administration & dosage
  • Serotonin and Noradrenaline Reuptake Inhibitors / adverse effects
  • Venlafaxine Hydrochloride / administration & dosage
  • Venlafaxine Hydrochloride / adverse effects*
  • Ventricular Outflow Obstruction / chemically induced*
  • Ventricular Outflow Obstruction / epidemiology
  • Young Adult


  • Serotonin Uptake Inhibitors
  • Serotonin and Noradrenaline Reuptake Inhibitors
  • Venlafaxine Hydrochloride