Preterm labor is defined as the presence of uterine contractions accompanied by cervical change between 20 and 37 weeks gestation. It is the most common indication for hospital admission among pregnant women and the leading cause of neonatal morbidity and mortality. Neonatal consequences of preterm delivery include both immediate and long-term sequelae, notably respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and cerebral palsy. Healthcare costs for these complications are estimated to be at least $26 billion per year, or $51,000 per infant.¹

It is often difficult to predict whether preterm labor leads to preterm delivery; however, the implications and potential risks of long-term disability cannot be taken lightly. In recent years, 10% of all births in the United States were preterm, accounting for more than 400,000 infants.² It is important to acknowledge that this number includes both spontaneous and medically indicated deliveries. This chapter focuses on the diagnosis and management of spontaneous preterm labor with intact membranes.

Preterm labor can be described as a pathogenic onset of the physiological process of labor. Labor is multifactorial, encompassing a series of anatomical, biochemical, and endocrine changes in the uterus, cervix, and fetal membranes. This is regulated by the immunologic and endocrine systems, ultimately leading to the delivery of the fetus.

Activation of the myometrial component of labor occurs following the development of gap junctions among myometrial cells through increased expression of connexin 43. This causes transition from uterine contractures, characterized by low-intensity muscular activity lasting several minutes, to uterine contractions of high-intensity activity for brief but frequent episodes. At the histological level, these changes are the result of myometrial hyperplasia and hypertrophy from the increased production of extracellular matrix proteins, and eventually contractile modifications toward the end of gestation.

Another critical component of labor is cervical remodeling, defined as the softening, shortening, and dilation that occurs preceding uterine contractility. The hallmarks of cervical remodeling are changes in the production, modification, and subsequent degradation of components in the extracellular matrix, such as collagen fibers and glycosaminoglycans. The most prominent is cervical dilation, caused by an inflammatory process via a massive influx of neutrophils and macrophages that results in degradation of extracellular matrix components.

Following cervical remodeling and initiation of myometrial contractions, rupture of membranes occurs via a complex series of events in which fetal membranes in the lower uterine segment separate from the underlying decidua. Notably, fetal fibronectin is one of the extracellular matrix components present in the chorioamniotic-decidual interface. After its initial separation from the decidua or membrane activation, fibronectin can track downward and thus be detected in the cervical-vaginal fornices.

Spontaneous preterm labor is defined as a syndrome in which changes at the uterine, cervical, and membrane levels simultaneously yet inappropriately occur before 37 weeks gestation. Once the process begins, it can potentially (but not necessarily) culminate in preterm delivery. These changes may occur in an asynchronous manner, leading to distinct events such as threatened preterm labor, cervical insufficiency, or preterm premature rupture of membranes. Several prevalent etiologies implicated in the initiation of preterm labor will be discussed next.

Maternal infections, localized or systemic, are the most widely accepted cause of preterm labor. Infections such as pneumonia, pyelonephritis, and periodontal disease cause preterm labor, and treatment of these infections reduces the risk of preterm labor. Intrauterine infection, classified as clinical or subclinical chorioamnionitis, is defined as the pathogenic presence of microorganisms in the normally sterile environment of the amniotic cavity. These microbial agents elicit an inflammatory response, subsequently triggering the process of labor. The most commonly detected organism in amniotic fluid is genital mycoplasma ascending from the lower genital tract. Furthermore, microorganisms such as Enterococcus coli can gain entry through hematogenous and lymphatic routes, causing systemic infection.

Infection causes an inflammatory response, activating preterm labor through the release of pro-inflammatory cytokines such as interleukins 1, 6, and 8; tumor necrosis factor alpha; prostaglandins; and platelet-activating factor. Ultimately, intrauterine infection leads to fetal infection, developing a fetal inflammatory response and manifesting in a spectrum of abnormalities, including elevated C-reactive protein, leukocytosis, cardiac, pulmonary, and central nervous system (CNS) abnormalities. This pro-inflammatory status in the fetus then triggers the onset of labor.³

Uteroplacental bleeding is another pathological cause of preterm labor. More commonly in patients with intact membranes, abnormal remodeling of maternal spiral arteries causes defective hemostasis and bleeding at the decidual-chorionic interface. This defective hemostasis and bleeding generate the release of thrombin, causing the downstream activation of inflammatory pathways and initiation of preterm labor. A prime clinical example of this event is placental abruption, triggering preterm labor and disseminated intravascular activation.

In addition, myometrial stretch from uterine overdistension in cases of polyhydramnios, multiple gestations, and congenital uterine abnormalities can activate the labor process, contributing to cervical remodeling and rupture of membranes. These effects are mediated through a cascade of events and a number of mechanisms, such as prostaglandin release, oxytocin receptors, and increased expression of connexin 43.

The immune and endocrine systems play significant roles in the pathophysiology of preterm birth. The presence of immune-response effector cells within the maternal, fetal, and placental compartments suggests the possibility that a disregulated immunological mechanism such as allergy and hypersensitivity reaction can contribute to the process of preterm labor. Maternal stress has been associated with preterm labor. Stressors from work, social relationships, and mental illness may activate the hypothalamic-pituitary-adrenal axis, causing preterm labor.

Cervical insufficiency, a separate entity from preterm labor, can result in recurrent miscarriage, commonly in the second trimester. However, it also can be associated with certain subtypes of preterm labor, such as those with bulging membranes and painless cervical dilation. For more detail on this topic, see Chapter 23, on cervical insufficiency.

The differential diagnosis of preterm labor includes any underlying condition presenting with lower abdominal pain, uterine contractions, or vaginal bleeding. A system-based approach to consider these possibilities is shown in Table 45-1.