Pathophysiology of Preterm Birth

Introduction

Although clinically managed as if it were a single disease, preterm birth is increasingly recognized as a syndrome secondary to multiple causative mechanisms and etiologies. In this chapter, we discuss the epidemiology of preterm birth, the endocrinology and physiology of parturition, and current practice in prediction and prevention of preterm labor (PTL).

Epidemiology of Preterm Birth

PTL is defined as the onset of labor before 37 completed weeks of gestation. Preterm birth may follow spontaneous or induced labor, or a planned cesarean section due to maternal or fetal complications. It is estimated that between 30% and 40% of all cases are induced or elective with remaining 60% to 70% occurring spontaneously. In most developed nations the rate of preterm birth is below 10%; the UK rate is around 7% and in the USA the rate fluctuates between 9% and 12% and varies by geographic location and ethnicity. Many low-income nations have preterm birth rates exceeding 15%. Preterm birth accounts for more than 75% of all perinatal deaths. Epidemiologic studies of PTL vary in terms of categorization. Generally, delivery prior to 23 to 24 weeks is considered pre-viable, although in the developed world survival after birth at 23 weeks is improving. “Viability” is often a legally defined limit, being, for example, 24 weeks in the United Kingdom but 20 weeks in the United States. The World Health Organization defines subcategories of preterm birth, based on gestational age as “extremely preterm” (<28 weeks), “very preterm” (28 to 32 weeks), and “moderate to late preterm” (32 to 37 weeks). The proportion of preterm births in each gestational age week epoque increases almost exponentially from approximately 32 weeks. The majority of preterm births are therefore at later gestational ages.

Preterm delivery is a major cause of neonatal morbidity and mortality, accounting for 65% of neonatal deaths and 50% of childhood neurologic disabilities. Prematurity is the biggest single cause of death within the first year of life. Survival rates are determined by gestation and birth weight. Intraventricular hemorrhages occur in 25% to 30% of very low-birth-weight neonates, compared to 3% to 4% of term babies. Those infants with higher grade hemorrhages are at risk to develop cerebral palsy, hydrocephalus, and seizures. The risks of major long-term morbidities following preterm birth after 34 weeks are considered to be comparable to those after 37 weeks’ gestation, although a significant risk of minor morbidities remains, and late preterm birth represents a much larger proportion of overall preterm births. ^, While a reduction in the rate of “extremely preterm” and “very preterm” births would significantly reduce the societal burden in the developed world, the greatest benefit in the developing world would be obtained by reducing the burden of “moderate-to-late preterm” births.

Although not identifiable in a significant proportion of women with preterm labor, risk factors include primigravida pregnancy, cervical incompetence or insufficiency, uterine distension (multiple pregnancy or polyhydramnios), infection, uterine and placental abnormalities, a previous history of preterm birth or second trimester pregnancy loss, advanced age, race, socioeconomic status, and body mass index (BMI). In the United Kingdom, the risk of preterm birth is 6% in white Europeans but 10% in Africans or Afro-Caribbeans. Similarly, African American women are overrepresented in rates of preterm birth in the United States. A poorer socioeconomic status in such groups and other minority groups adds environmental causes to probable genetic causes of preterm birth (i.e., polymorphisms in tumor necrosis factor α, TNF-α, a proinflammatory cytokine). Other environmental factors include poor nutrition, smoking, substance abuse, and psychosocial factors.

There are strong associations with preterm birth in women with diabetes, a low BMI, poor weight gain, or excess weight gain and obesity. ^, Alcohol consumption, smoking, and cocaine exposure all increase the risk of preterm birth. Dose-response effects have been described in alcohol consumption in various European studies, as well as increased risks from low-to-moderate and heavy smoking. Maternal stress is considered to increase the risk of preterm birth via a neuroendocrine pathway that activates the maternal-placental-fetal endocrine systems that promote parturition via immune and/or inflammatory pathway activation.

There is a clear role for genetics in the regulation of length of pregnancy and in the risk of preterm birth. The risk of a woman having a preterm delivery is increased if her mother, sisters, or maternal half-sisters have had preterm deliveries, but not if her paternal half-sisters or members of her partner’s family have preterm deliveries. Being a preterm baby increases a woman’s own risk of preterm delivery and having a previous preterm delivery confers an increased risk of recurrent preterm delivery. Therefore, the genetic traits linked to preterm birth are principally transmitted in a matrilineal manner. The candidate gene approach has suggested a potential association between preterm birth and polymorphisms in the β2-adrenergic receptor gene, which promotes smooth muscle relaxation in the uterus. Other commonly studied candidate genes are those involved in immunity and inflammation, such as tumor necrosis factor, interleukins, other cytokines, and their receptors. Although some studies have detected polymorphisms in these genes that alter the risk for preterm birth in either the mother or fetus in specific cohorts, the results have generally failed to be replicated or generalized across populations. The use of genome-wide association studies (GWAS) in preterm birth is affected by the heterogeneity of preterm birth etiology, by the arbitrary definition of the outcome and by limited availability of suitable cohorts. However, sample-size limitations have been to some extent overcome by using genomic data from a large cohort of women of European ancestry who had undergone commercial “recreational genetics.” This has identified maternal genomic loci associated with length of pregnancy linked to genes whose functions are consistent with a role in the timing of birth.

Maintenance of Human Pregnancy and the Onset of Parturition

Human pregnancy lasts for approximately 280 days (from last menstrual period, or 266 days from conception) with minor variations between ethnic groups. For the majority of pregnancy, the uterus remains quiescent yet expands to accommodate the growing fetus. At the same time, the cervix remains rigid and closed to retain the developing fetus within the uterus and to prevent ascending infection. Throughout pregnancy “pro-pregnancy” factors, such as progesterone and prostacyclin, inhibit myometrial contractility. At the end of pregnancy, “pro-labor” factors begin to mediate remodeling of the cervix and the uterus is stimulated to begin coordinated contractions. It has been suggested that labor results from the activation of a “cassette of contraction-associated proteins” (CAPs), which convert the myometrium from a quiescent to a contractile state. CAPs include gap junction proteins, oxytocin (OT) and prostanoid receptors, enzymes for prostaglandin synthesis, and cell signaling proteins. The latter mediate the uterine response to receptor activation. Activation of myometrial contractility, cervical remodeling, and fetal membrane rupture mark the initiation of parturition that culminates in the expulsion of the fetus and the placenta. It is thought that a combination of maternal and fetal signals contributes toward the timing of labor. ^,

Endocrinology of Parturition

An intricate interplay of endocrine, paracrine, and autocrine factors from both fetal and maternal origin has been proposed to play important modulatory roles in regulating the onset of human parturition. The most well characterized factors are considered here.