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

Abstract

BackgroundPreterm 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.MethodsWe 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.FindingsPrevious 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.ConclusionsWe 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 high...

The Impact of Kidney Development on the Life Course: A Consensus Document for Action

“…Weight loss before pregnancy has in some studies been associated with a reduced pregnancy risk in overweight women [264]. Preconception care has been shown to improve pregnancy outcomes [264,265,266], although it is important to recognize that up to 65% of preterm births remain unexplained [267]. Counseling and optimization of maternal weight and nutrition, and avoidance of alcohol, tobacco, and caffeine before pregnancy, all have a positive impact on pregnancy outcomes.…”

“…In a cross-country analysis of high human development index countries, the cause of preterm birth remained unknown in up to two thirds of cases [267]. Such data are not reported for LMIC, but it is known that over 60% of preterm babies globally are born in Asia and sub-Saharan Africa [33], possibly related to the high prevalence of maternal undernutrition in these regions [208].…”

Caesarean section increases risk of preterm birth in subsequent pregnancy

“…The aetiology of spontaneous preterm birth remains, despite many publications on the subject, largely indefinite 1. Studies focus on identification of risk factors for preterm birth in order to develop tailor-made care.…”

Induction of the apoptotic pathway by oxidative stress in spontaneous preterm birth: Single nucleotide polymorphisms, maternal lifestyle factors and health status

“…Although the normal duration of pregnancy is 40 weeks, 5-10% (mean average 8%) of births take place preterm in Europe, with prematurity constituting a main cause of perinatal morbidity and mortality (1). Pregnancy duration is primarily determined by a 'placental clock', which is activated in early stage pregnancy (2) and involves the triggering of several mechanisms including apoptotic events.…”