Cross-Country Individual Participant Analysis of 4.1 Million Singleton Births in 5 Countries with Very High Human Development Index Confirms Known Associations but Provides No Biologic Explanation for 2/3 of All Preterm Births

PLoS One. 2016 Sep 13;11(9):e0162506. doi: 10.1371/journal.pone.0162506. eCollection 2016.

Abstract

Background: Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice.

Methods: We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and one comparator U.S. state (California) to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors.

Findings: Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6-6.0 and 2.8-5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25-50% and 11-16% of excess population attributable risk, respectively (p<0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted.

Conclusions: We have quantified the causes of variation in preterm birth rates among countries with very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions.

Publication types

  • Review

MeSH terms

  • California / epidemiology
  • Czech Republic / epidemiology
  • Databases, Factual
  • Developed Countries
  • Female
  • Humans
  • Infant, Newborn
  • Male
  • Multivariate Analysis
  • New Zealand / epidemiology
  • Pregnancy
  • Premature Birth / epidemiology*
  • Premature Birth / prevention & control
  • Regression Analysis
  • Risk Factors
  • Slovenia / epidemiology
  • Sweden / epidemiology

Grant support

This study was funded by the March of Dimes Foundation and the International Federation of Obstetrics and Gynecology (FIGO). Individuals from these organizations were involved in analyzing the data and writing the paper. Authors from the Boston Consulting Group (DMF, JL, SCS) contributed to this work under contract with the March of Dimes Foundation and FIGO. The sponsoring agencies’ financial management had no role in study design, data collection, data analysis, data interpretation, or writing of the report.