Review

Preterm labor: One syndrome, many causes

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Science  15 Aug 2014:
Vol. 345, Issue 6198, pp. 760-765
DOI: 10.1126/science.1251816

Abstract

Preterm birth is associated with 5 to 18% of pregnancies and is a leading cause of infant morbidity and mortality. Spontaneous preterm labor, a syndrome caused by multiple pathologic processes, leads to 70% of preterm births. The prevention and the treatment of preterm labor have been long-standing challenges. We summarize the current understanding of the mechanisms of disease implicated in this condition and review advances relevant to intra-amniotic infection, decidual senescence, and breakdown of maternal-fetal tolerance. The success of progestogen treatment to prevent preterm birth in a subset of patients at risk is a cause for optimism. Solving the mystery of preterm labor, which compromises the health of future generations, is a formidable scientific challenge worthy of investment.

Looking forward

Progress in the understanding and prevention of preterm labor will require recognition that preterm parturition has multiple etiologies and further elucidation of the mechanisms underlying each. The definition of pathologic processes, identification of specific biomarkers, and implementation of therapeutic interventions within the unique complexity of pregnancy are particularly challenging. In pregnancy, two individuals with different genomes and exposomes coexist, largely with overlapping interests but occasionally in potential conflict. Inaccessibility of the human fetus also poses a formidable obstacle to elucidating the physiology of fetal development, maternal responses to this process, and the changes in both when pathologic processes arise.

High-throughput techniques and systems biology can be used to improve the understanding of the preterm labor syndrome. Early studies using unbiased genomic/epigenomic (6466), transcriptomic (67, 68), proteomic (69, 70), and metabolomic approaches (71) have been informative yet require verification and validation. Progress will also depend on the generation and availability of multidimensional data sets, with detailed phenotypic characterization of disaggregated patient groups according to the mechanisms of disease. Longitudinal studies are required to determine whether any of the discriminators, at molecular or pathway levels, can serve as biomarkers during the preclinical disease stage and enable risk assessment and/or noninvasive monitoring of fetal health and disease. In vivo monitoring of cell-free RNA during human pregnancy can provide information about fetal tissue-specific transcription is an exciting development (72, 73). Since a stereotypic blood transcriptome has been identified in fetuses with acute and chronic placental inflammatory lesions, there are opportunities to determine whether and when, during the course of pregnancy, these changes can be detected in maternal blood. This information could have enormous diagnostic and prognostic value to inform the selection of therapeutic interventions. Thus, we envision that the goal of reducing the rate of spontaneous preterm birth will be grounded in a deeper understanding of the mechanisms of disease responsible for this syndrome.

References and Notes

1. Acknowledgments: The authors regret that, because of page limitations, the contributions of many investigators to the study of parturition could not be credited in this article. The authors thank S. Curtis for editing the manuscript. The work of R.R. is supported by the Division of Intramural Research of the Eunice Kennedy Shriver NICHD, NIH/Department of Health and Human Services. Studies from S.K.D.’s lab were supported in part by grants from the NIH (HD068524 and DA06668) and March of Dimes (21-FY12-127 and 22-FY14-470). The work of S.F. is supported by R37 HD076253 and U54 HD055764. We thank M. Gormley for assistance preparing the figures.
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