Cause and Preventative Treatment of Most Preterm Births Remains Unknown Interview with:

Dr. Joseph Leigh Simpson

Dr. Joseph Leigh Simpson

Joseph Leigh Simpson, MD FACOG, FACMG
President at International Federation of Fertility Societies
March of Dimes Foundation
White Plains, NY What is the background for this study?

Response: Preterm birth (PTB) is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. A total of 1.1 million infants die each year. Preterm births and their complications are the leading cause of deaths in children under age 5.

The biological basis of preterm birth remains poorly understood, and for that reason, preventive interventions are often empiric and have only limited benefit. Large differences exist in preterm birth rates across high income countries: 5.5 percent in Sweden and at present 9.6 percent in the U.S. The International Federation of Gynecologists and Obstetricians (FIGO)/March of Dimes Working Group on Preterm Birth Prevention hypothesized that identifying the risk factors underlying these wide variations could lead to interventions that reduce preterm birth in countries having high rates. What are the main findings?

Response: We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries (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. (From Abstract)

We further stratified risk factors based on need for altering emphasis on research, policy and public health, or clinical practice. Two risk factors, previous preterm birth and preeclampsia, confer the highest odds ratios [4.6-6.0 and 2.8-5.7 respectively] to an individual for preterm birth. Odds ratios are less but still greater than 2 for diabetes or chronic hypertension. Odds ratios for other risk factors (e.g,, smoking, no prenatal care

On a population basis, nulliparity and male sex then become the two risk factors with the highest impact on preterm birth rates, accounting for 25-50 percent and 11-16 percent of excess population attributable risk respectively (p<0.001). That is, the relatively high prevalence of nulliparity and male sex (i.e., about 50 percent of deliveries) on population-attributable risk connotes a major role despite low odds ratios for a single individual. There is, then, no confirmed biological basis for preterm birth associated with nulliparity or male sex, just as there is none for prior preterm birth or preeclampsia. These four factors account for 65 percent of the total aggregated risk of preterm birth, meaning there is no plausible biologic explanation for two-thirds of preterm births. Likewise, 63 percent of differences among countries cannot be explained by known factors.

By contrast, only 5 percent of preterm birth is potentially amenable to altered clinical practices (e.g., avoiding multiple embryo transfer in ART; avoiding non-medically indicated deliveries before 39 completed weeks). Approximately 20-25 percent could potentially be amenable to changes in public health policy (e.g., reducing smoking and obesity, improved education), although even here the biological relationship to preterm birth may be unknown. Our conclusion is that the emphasis should be on research to elucidate the underlying mechanisms of preterm birth. What should readers take away from your report?

Response: Naturally we must utilize all those interventions accepted as effective, while still realizing this can only reduce preterm birth so far. The reason is that the biologic basis of human labor and, hence, preterm labor, is not known. Further research is needed, from which we can devise new therapies. What recommendations do you have for future research as a result of this study?

Response: Research needs to include fields not previously involved – such as genetics, immunology, infectious diseases, anatomic changes in cervix and uterus, placental-maternal signals between mother and fetus, and mitochondrial processes that convert diet into energy. Disturbances involving any or all of these areas are likely to play roles in preterm birth. All require collaborating scientists from many disciplines. Is there anything else you would like to add?

Response: 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. It complements the March of Dimes National Prematurity Campaign, begun in 2003, to improve delivery of the known and effective treatments and interventions. Thank you for your contribution to the community.


PLoS One. 2016 Sep 13;11(9):e0162506. doi: 10.1371/journal.pone.0162506. eCollection 2016.
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.
Ferrero DM1, Larson J1, Jacobsson B2,3, Di Renzo GC4,5, Norman JE6, Martin JN Jr7, D’Alton M8, Castelazo E4, Howson CP9, Sengpiel V2, Bottai M10, Mayo JA11, Shaw GM11, Verdenik I12, Tul N12, Velebil P13, Cairns-Smith S1, Rushwan H4, Arulkumaran S4, Howse JL9, Simpson JL9.

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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