Most Preterm Births in Wealthy Countries Defy Explanation, Despite Known Risk Factors

A multi-country analysis revealed that even when all known risk factors are combined, two-thirds of the preterm births in wealthy countries cannot be explained. The study highlights the urgent need for research into underlying biological causes of preterm births, which may lead to innovative and effective interventions.

The study, “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,” was published in journal PLOS ONE.

Preterm births (births occurring before 37 weeks of gestation) is a global public health challenge, with 15 million infants born preterm every year, and an estimated 35% of deaths in the first month of life directly attributable to prematurity. Babies who survive can have lifelong health problems, such as cerebral palsy, vision and hearing loss, and intellectual disabilities.

According to the authors, the risk factors associated with preterm birth remain poorly understood, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high-income countries.

“Preterm birth is the leading cause of death for children under age 5 around the world, but we can’t reliably prevent two-thirds with existing interventions,” said Joe Leigh Simpson, MD, the March of Dimes’ senior vice president for Research and Global Programs and the study’s senior author, in a news release. The March of Dimes works to end premature birth and other problems threatening the lives of babies.

In the analysis, researchers representing the March of Dimes/FIGO (International Federation of Gynecology and Obstetrics) Working Group for Preterm Birth Prevention analysed patient data on 4.1 million single pregnancies. This included 2.8 million pregnancies from four countries with a very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and 1.3 million from California as a comparator. The aim was to determine the specific contribution (adjusting for confounding effects) of 21 risk factors for preterm birth.

Results showed that a previous preterm birth and preeclampsia (high blood pressure in pregnancy) were the strongest individual risk factors of preterm birth worldwide (25%-50% of the risk). On a general population basis, nulliparity (mother who hasn’t previously given birth) and male sex in a baby were the two risk factors with the highest impact on preterm birth rates, accounting for 11%-16% of the risk.

According to Simpson, a woman’s increased risk of preterm birth caused by nulliparity and the baby’s sex is not as high as the risk from prior preterm birth or preeclampsia. Still, because many more pregnancies involve first babies or male sex, the impact is larger in the overall population. No biological reason for why nulliparity and male sex leads to this increased risk is known, he said.

“Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries,” the reserachers wrote.

Researchers found that more than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biological explanation, and 63% of the differences among countries cannot be explained with known risk factors.

“This finding confirms the wisdom of the March of Dimes decision to invest in 2010 in a network of five Prematurity Research Centers bringing together the brightest minds from many diverse disciplines of science to find the unknown causes of preterm birth,” said Simpson. “This complements the March of Dimes National Prematurity Campaign to improve delivery of the known and effective treatments and interventions.”

Researchers concluded that having a previous spontaneous preterm birth is still the No. 1 risk factor for preterm birth, although more biological justifications are yet to be found. They believe these are likely to be attributable to genetic, epigenetic, anatomical, microbiological, immunological or environmental factors.