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.

Boston Consulting Group Boston MA United States of America

Department of Genes and Environment Division of Epidemiology Norwegian Institute of Public Health Oslo Norway

Department of Obstetrics and Gynecology Columbia University College of Physicians and Surgeons New York NY United States of America

Department of Obstetrics and Gynecology Institute for the Health of Women and Children Sahlgrenska Academy University of Gothenburg Sahlgrenska University Hospital Gothenburg Sweden

Department of Obstetrics and Gynecology University of Perugia Perugia Italy

Department of Pediatrics Stanford University School of Medicine Palo Alto CA United States of America

Department of Perinatology Division of Obstetrics and Gynecology University Medical Centre Ljubljana Ljubljana Slovenia

Division of Maternal Fetal Medicine University of Mississippi Medical Center Jackson MS United States of America

Institute for the Care of Mother and Child Perinatal Centre Prague Czech Republic

International Federation of Gynecology and Obstetrics London United Kingdom

March of Dimes Foundation White Plains NY United States of America

Tommy's Centre for Fetal and Maternal Health Medical Research Council Centre for Reproductive Health Queen's Medical Research Institute The University of Edinburgh Edinburgh United Kingdom

Unit of Biostatistics IMM Karolinska Institutet Stockholm Sweden

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