SummaryThe delivery of infants before 37 weeks gestation is a leading cause of perinatal mortality and morbidity in the United States. Traditional methods of predicting women at risk relying on obstetric history or premonitory symptoms (detected clinically or by tocodynamometry) are neither sensitive nor specific. Recent approaches to predicting preterm delivery have included sonographic measurement of cervical length and various biochemical assays. Although more sensitive than traditional methods, none of these alone exhibits sufficient accuracy to warrant widespread use. We contend that the failure of current approaches to predicting preterm delivery reflects an inadequate understanding of the underlying pathogenesis. Clinical and experimental evidence support the concept that most cases of preterm delivery reflect four pathogenic processes, which share a common final biological pathway leading to uterine contractions and cervical changes with or without premature rupture of membranes. These pathogeneses are: (1) activation of the maternal or fetal hypothalamic-pituitary-adrenal axis; (2) decidual-chorioamniotic or systemic inflammation; (3) decidual haemorrhage (i.e. abruption); and (4) pathological distention of the uterus. Our research seeks to combine the most useful biophysical and biochemical markers of such processes with optimal clinical and epidemiological predictors into a composite, easily applied risk tool. This integrated approach has the potential to identify at-risk asymptomatic patients with high sensitivity, specificity, and positive and negative predictive values, and also to ascertain underlying pathogenic processes that can lead to targeted therapy. To accomplish these goals, we employ logistic regression and artificial neural network models to assess and apply the appropriate weight to markers associated with each of the above pathogenic pathways, in addition to markers of the final common pathway leading to fetal membrane rupture, cervical extracellular matrix degradation, and myometrial activation.By combining these markers, we expect ultimately to produce a predictive model that is more robust than any existing method, and that identifies the relative contribution of each pathogenic process. Further analysis of this model using a neural network will enable us to identify asymptomatic patients destined to deliver preterm with high sensitivity, specificity, positive and negative predictive values, and to assess the relative contribution of each of the four distinct pathogeneses to this preterm delivery risk. 78

Clinical and experimental evidence indicate that PTD results from four primary pathogenic mechanisms: activation of the maternal or fetal HPA axis; amniochorionic-decidual or systemic inflammation; decidual hemorrhage; and, pathologic distention of the myometrium. Each of these four pathways has a distinct epidemiological and clinical profile, and unique biochemical and biophysical pathways initiating parturition, but shares a common final biochemical pathway involving myometrial activation and stimulation, and enhanced genital tract protease activity promoting PPROM and cervical change. Traditional methods of predicting women at risk relying on obstetrical history or symptoms and epidemiological risk factors are neither sensitive nor specific. Recent approaches to predicting PTD, including sonographic measurement of cervical length and biochemical assays for hCG, cytokines, fFN, MMPs, estrogens, and CRH, are more sensitive than traditional methods. Moreover, given the heterogeneous, interactive etiopathogeneses of PTD, multiple biochemical markers should not only increase sensitivity and specificity, but also permit the detection of the relative contribution of each pathogenesis to the overall risk of PTD.

Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.

Objective Preterm delivery has been shown to be associated with subsequent maternal cardiovascular morbidity. However, the impact of the severity and recurrence of preterm delivery on the risk of specific cardiovascular events and the metabolic syndrome in the mother, have not been investigated.Design National registry-based retrospective cohort study.Setting Women delivering in Denmark from 1978 to 2007.Population Women with a first singleton delivery (n = 782 287), and with a first and second singleton delivery (n = 536 419).Methods Cox proportional hazard models, with the gestational age stratified into four groups as primary exposure. We made adjustments for maternal age, year of delivery, hypertensive pregnancy disorders, fetal growth deviation, placental abruption and stillbirth.Main outcome measures Subsequent maternal hypertension, ischaemic heart diseases, thromboembolism and type-II diabetes.Results After a first delivery at 32-36 completed weeks of gestation, the adjusted risk of subsequent type-II diabetes increased 1.89-fold (1.69-2.10) and the risk of thromboembolism increased 1.42-fold (1.24-1.62). Women having a preterm delivery in the first pregnancy and a term delivery in the second had a 1.58-fold (1.34-1.86) increased risk of type-II diabetes and a 1.18-fold (0.96-1.44) increased risk of thromboembolism. Women having two preterm deliveries had a 2.30-fold (1.71-3.10) increased risk of type-II diabetes and a 1.80-fold (1.29-2.50) increased risk of thromboembolism.Conclusions Preterm delivery is independent of other pregnancy complications associated with subsequent maternal overt type-II diabetes and thromboembolism. The recurrence of preterm delivery will augment these risks.Keywords Cardiovascular morbidity, metabolic syndrome, preterm delivery, thromboembolism.Please cite this paper as: Lykke J, Paidas M, Damm P, Triche E, Kuczynski E, Langhoff-Roos J. Preterm delivery and risk of subsequent cardiovascular morbidity and type-II diabetes in the mother. BJOG 2010;117:274-281.

Second-trimester elevated plasma TAT concentrations are predictive of subsequent PPROM. These data provide further evidence that PPROM is associated with decidual thrombin activation.

Extrapolation of thrombin-enhanced MMP-1 expression in cultured endometrial stromal and decidual cells to the in vivo pregnant state provides an explanation for the strong association between placental abruption and preterm membrane rupture.

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