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Multinational study finds no known cause for most preterm births

A multinational study published on Tuesday found that 2/3 of preterm births have no known biological cause.

“It's embarrassing but we don't know,” said Dr. Joe Leigh Simpson, March of Dimes senior VP for research and global programs. “We can’t treat if we don’t know.”

About 15 million babies are born preterm around the world each year, according to the World Health Organization. Complications from preterm birth - defined as delivery before 37 weeks of gestation - are the leading cause of death among children under 5.

In the United States, one in 10 infants is born preterm, according to the Centers for Disease Control. Babies born preterm can suffer from neurological disabilities, cerebral palsy, developmental delays, vision and hearing problems as well as breathing and eating challenges.

The study, which was published in the journal PLOS ONE, was a collaboration between the March of Dimes and the International Federation of Gynecology and Obstetrics. It was the first study to take an international view of preterm birth by comparing individual patient-level data sets for mothers in Sweden, Czech Republic, Slovenia, New Zealand and the state of California to determine how multiple risk factors might affect a patient’s risk of delivering a preterm baby.

The study was also unique in terms of factors considered. For instance, it looked at the full range of known risk factors and how they might interact, rather than focusing on a single potential risk factor and measuring its isolated impact.

“It was a much more robust study design that allowed us to take into account the fact that multiple risk factors were sometimes occurring in the same individual and the same sub set,” Simpson said.    

By contrast, other studies have looked at individual risk factors. A study published in August, for example, found that pre-pregnancy body mass index, pregnancy weight gain and a short time between pregnancies could impact preterm birth. Studies like the August one do not take into account other risk factors, but instead seek to determine the impact of a specific factor or set of related factors. 

Doctors know that the two greatest risk factors for preterm birth are a prior preterm birth and preeclampsia, a condition that causes high blood pressure, protein in the urine and, sometimes, swelling in the extremities.

“If you are a woman and you've had pre-eclampsia, or you've had a prior preterm birth, you are in the highest category,” Simpson said. “It turns out if you had any other risk factors other than both together, that only increases your risk by a very small amount.”

Other factors present a lower risk, but affect a huge portion of the population. Women having their first baby and women carrying a male baby both have slightly elevated risk.

“Half of the babies in the pop[ulation] are male, so if you look at the pop[ulation] impact, a lower-odds ratio is going to have an enormous impact on the entire population,” Simpson said. “In terms of what it makes in terms of the global perspective, it's much higher.”

The new study identified some areas where increased patient education or proactive clinical intervention could have improved outcomes, but this could have helped in only about one-third of the cases. After accounting for all known causes of preterm birth, the researchers still had no explanation for about two-thirds of the cases.

“We just don't have any clue. We don’t know the causes of pre-eclampsia, we don't know the causes of prior preterm birth, we certainly don’t know why having a male baby increases the risk,” Simpson said. “We've got some ideas and certainly in some cases we know information, but by and large we don't know it in the way we might know the causes of diabetes or some cancers for example.”

The March of Dimes is working toward answers to those questions. In 2012, the organization founded its Premature Research Centers program, funded by donations. Between 2012 and 2015, five research centers were selected to explore genetic indicators, signals between mother and fetus, the array of microorganisms found in healthy and diseased human bodies, and other indicators that might yield insight into the causes of preterm birth.  
All of the studies conducted by the Premature Research Centers are still in progress. Once the results are in, they will need to be replicated and validated by the scientific community.
Preterm birth is sometimes necessary, due to illness in the mother or baby, or other circumstances, so the pre-term birth rate will never be zero.
“But we believe, based upon elucidation of what we do, it certainly should be 5 percent in about 2030,” Simpson said. “I think the March of Dimes and the public will achieve that.”