Pathways to preterm birth

Need for developing case definitions and guidelines for data collection, analysis, and presentation for pathways to preterm birth as an adverse event following immunization:

While immunizations confer protection against specific subtypes of infections, it is important to determine whether these interventions contribute to adverse maternal or neonatal outcomes in pregnancy. In particular, understanding the risk/benefit of immunizations with respect to pathways resulting in preterm birth is of particular interest. Preterm birth results from a variety of pathways ranging from idiopathic to spontaneous etiologies. Because there is a diverse spectrum of possible causes of preterm birth, it is important to determine whether some of the pathways to preterm birth can be activated by interventions, including immunizations.

The pathophysiology and pathways related to preterm birth represent diverse and complex processes. A critical principle is that spontaneous preterm births result from a spectrum of pathological processes that are initiated by specific molecular pathways, converging into a common pathway [1]. These molecular mechanisms are influenced by genetic, epigenetic, biological, behavioral, social, clinical, and environmental risk factors [1]. Different insults, such as stress, inflammation or infection, hemorrhage, uterine distention, and immune dysregulation can lead to uterine decidual and fetal membrane activation, which stimulate release of prostaglandins, cytokines, and matrix metalloproteinases that in turn lead to uterine contractions, cervical ripening, membrane rupture and subsequently, preterm birth [1]. In essence, it appears that the processes whereby term labor is initiated are implicated in preterm birth as well, with an important distinction being that term parturition results from physiologic activation of the components of the common pathway, while preterm labor arises from pathological processes that activate one or more of those components [1]. It is hypothesized that before 32 weeks gestation, the initiation of pathways to preterm birth requires a stronger stimulus than after 32 weeks, as later in the third trimester there is normal physiologic preparation of the uterus and cervix for delivery [1].

While preterm birth is being formally defined by another Brighton Collaboration working group and that definition will be incorporated into this document, the purpose of this exercise is to develop case definitions and guidelines for data collection, analysis, and presentation for the pathways to preterm birth. The etiologies of preterm birth can be grouped into four pathways that are considered the underlying events leading to preterm birth; they include: (1) premature preterm rupture of membranes (PPROM), (2) spontaneous preterm labor (PTL), (3) insufficient cervix (IC), and (4) provider-initiated preterm birth (PIPTB). Of note, the first three pathways are spontaneously occurring processes, while the fourth occurs when a decision is reached between a patient and her provider that iatrogenic initiation of labor is required for the health of the fetus, mother, or both. These four pathways are the adverse events of interest in this document, which will focus primarily on how researchers, in the context of vaccine trials, can determine that one of these four pathways has been activated, or an adverse event has occurred.

The diverse array of etiologies, coupled with obscured and/or overlapping clinical and scientific definitions has led to inconsistent definitions of pathways leading to preterm birth. Moving toward a consensus definition is critical for the purposes of monitoring adverse events in vaccine trials and to standardize terminology for improved data collection. Issues related to defining and classifying preterm birth include: relying on gestational age estimates based on a variety of approaches and validity, distinguishing between clinical versus etiologic phenotypes of preterm birth, considering whether to include or exclude multi-fetal gestations or stillborn infants, and deciding how to separate or combine different pathways to preterm birth [2]. Given that the term pathways to preterm birth has met with such difficulty in definition and classification previously, it is a crucial adverse outcome for the Brighton Collaboration to clarify for use in the context of vaccine related research.

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