Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder
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Abstract
Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. Although the severity of neonatal outcomes is inversely correlated with gestational age, all PTBs can lead to potentially life-threatening neonatal outcomes and major lifelong health complications. Because advances in neonatal care have substantially decreased neonatal mortality, the incidence of PTB and its complications is unabatedly rising. PTB currently affects more than 10% of births worldwide, with similar numbers in developed countries. Correspondingly, improving neonatal outcome is a key objective of the World Health Organization. The recently approved (in Europe) tocolytics drug, Atosiban, used to prolong preterm gestation, has not been shown to improve neonatal outcome, nor have other tocolytic agents used in clinic. Thus, PTB remains an unmet medical need. Recent evidence shows that most, if not all, PTBs are associated with (overt or occult) inflammatory processes in gestational tissues, independent of infection. Pro- inflammatory cytokines are produced from maternal and fetal cells in response to sterile or infectious stressors. These seem to orchestrate a multi-tissue response including myometrial contractility, cervical ripening, and weakening/rupture of fetal membranes, leading to the onset of preterm labor. This integrated system might have been conserved through mammalian evolution due to increased maternal and/or fetal survival when gestation is terminated in specific settings, such as infection. Hence, inflammation may be a common pathway to the numerous aetiologies of PTB. Most importantly, recent evidence suggests that inflammation is transmitted to the fetus, thereby inducing organ injuries that may underlie the development of major neonatal diseases. Targeting inflammation prenatally instead of myometrial contraction could be a more successful and safe approach for the management of PTB, as suggested by recent animal studies.
Résumé
La naissance prématurée est la principale cause de mortalité et de morbidité néonatale. Bien que la sévérité des issus néonataux soit inversement corrélée avec l’âge gestationnel à la naissance, toutes les naissances prématurées peuvent mener à des issus néonataux potentiellement mortels et à des complications avec répercussions s’échelonnant sur toute la vie. Étant donné que la mortalité néonatale a considérablement diminuée avec les récentes avancées en néonatalogie, l’incidence de la naissance prématurée et de ses complications sont en hausse. La naissance prématurée affecte présentement plus de 10% des naissances à travers le monde, avec des taux similaires dans les pays développés. Conséquemment, d’améliorer l’issu néonatal est un objectif clé de l’Organisation Mondiale de la Santé. Le tocolytique Atosiban récemment approuvé (en Europe) pour prolonger les gestations pré- maturées n’a pas démontré d’efficacité pour améliorer les issus néonataux, tout comme les autres tocolytiques utilisés en clinique, et la naissance prématurée demeure un besoin médical non-atteint. Des données récentes démontrent que la plupart, sinon toutes les naissances prématurées sont associées avec des processus inflammatoires (francs ou silencieux) dans les tissus gestationnels, indépendamment de l’infection. Les cytokines pro-inflammatoires sont produites dans les cellules maternelles et fœtales en réponse à des stresseurs stériles ou infectieux, et semblent orchestrer une réponse multi-tissulaire incluant la contractilité myométriale, la préparation cervicale, et l’affaiblissement/rupture des membranes fœtales, menant au commencement du travail préterme. Ce système intégré pourrait avoir été conservé durant l’évolution mammifère à cause d’une survie accrue de la mère et/ou du fœtus lorsque la gestation est terminée dans un contexte spécifique, comme l’infection. Donc, l’inflammation pourrait constituer une voie commune finale pour les nombreuses causes de la naissance prématurée. De façon importante, des données récentes sug- gèrent que cette inflammation est transmise au fœtus et en retour induit des dommages aux organes qui pourraient sous-tendre le développement de maladies néonatales majeures. De cibler l’inflammation en prénatal plutôt que les contractions myométriales pourrait constituer une approche sécuritaire et plus efficace, comme suggéré par de récentes études animales.
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