Preterm birth (PTB) is one of the most important problems in obstetrics today as it complicates approximately 12% of all births in the United States and accounts for over 70% of perinatal morbidity and mortality. Approximately 45% to 50% of PTB is idiopathic or spontaneous, defined as regular uterine contractions leading to cervical change prior to 37 weeks of gestation, 30% is related to preterm rupture of membranes and the other 15% to 20% is attributed to medically indicated or elective preterm delivery, typically due to worsening maternal disease or fetal compromise. PTB is a complex disorder with heterogeneous risk factors, genetic and environmental susceptibilities, and pathophysiologic pathways. Risk factors for preterm labor are varied and include history of prior preterm labor, uterine anomalies, multiple gestation, maternal medical complications, low prepregnancy body mass index, gestational bleeding, low socioeconomic status, minority race, behavioral habits such as smoking, alcohol, drug abuse, stressful events, limited or no prenatal care, and infection. The pathophysiology of preterm labor is not well understood but may result from mechanical factors, hormonal changes, infection, or interruption of normal mechanisms responsible for sustaining uterine quiescence. Unfortunately the rate of PTBs continues to increase slightly each year. Despite this, survival rates have improved due to the use of antenatal corticosteroids and improvements in neonatal resuscitation and care.
There is a well-documented racial disparity in rates of PTB with African Americans at 17% versus only 11% in Caucasians. Further, the infant mortality rate for African American babies is 2.5 times higher than Caucasians. Population-based studies indicate that this disparity cannot be explained by socioeconomic status, maternal behavior, marital status, or education alone and likely point to true genetic differences.
Four major mechanistic pathways leading to PTB have been proposed: (1) stress or activation of maternal or fetal hypothalamic-pituitary-adrenal axis, (2) pathologic uterine distention, (3) inflammation/infection, and (4) decidual hemorrhage and coagulation. These are summarized in Figure 16–4. Each of these pathways has different epidemiologic, clinical, and biochemical features, but all are likely to initiate labor via prostaglandin production, myometrial activation, and degradation of extracellular matrix components leading to premature rupture of membranes and cervical dilation. The fetoplacental endocrine unit can trigger labor prematurely, activating CRH release in cases of a hostile intrauterine environment such as stress and chorioamnionitis.
Both exogenous and endogenous maternal stress, ranging from heavy workload to depression, is associated with PTB. The exact mechanism is not well understood, but CRH is thought to play an important role. Maternal CRH levels are elevated in both preterm and term labor and appear to activate the parturition pathway by increasing prostaglandins, inhibiting progesterone, and stimulating fetal cortisol and DHEA production.
Pathologic Uterine Distention
Myometrial stretching due to multiple gestations, polyhydramnios, and Mullerian anomalies has been associated with an increased risk of preterm labor. This is thought to occur as distension can induce myometrial contractility, prostaglandin release, collagenase activity, and increased oxytocin receptor expression.
Infection is the only pathologic process for which there is a clear causal link to preterm birth exhibited by the fact that: (1) intrauterine and extrauterine infections are associated with preterm birth; (2) antibiotics for intrauterine infection can prevent preterm birth; and (3) treatment of asymptomatic bacteruria prevents preterm birth. Microbiology studies suggest that infection may account for 25% to 40% of preterm births. Ascending infection is believed to be the most common source of microbial invasion of the amniotic cavity. Endotoxins from bacteria induce proinflammatory mediators such as IL-1 and TNF-alpha from the decidua, which stimulates prostaglandin production. Double knockout mice for IL-1 and TNF-alpha had decreased rates of PTB after administration of microorganisms. Other inflammatory cytokines and chemokines also have been implicated in infection-induced preterm labor.
Decidual Hemorrhage and Coagulation
Any vaginal bleeding during pregnancy is a known risk factor for preterm birth. Decidual hemorrhage and uteroplacental ischemia are thought to contribute to preterm labor via generation of thrombin. Thrombin stimulates myometrial contractility in a dose-dependent manner and also binds to protease-activated receptor type 1, which increases expression of metalloproteniases leading to cervical ripening and possible subsequent preterm delivery.
Predictors/Prevention of Preterm Labor
Unfortunately, clinical symptoms to identify women at risk for PTB have been shown to be inaccurate and unreliable. Given the clinical, emotional, and financial gravity of preterm birth, multiple tests have been developed over the years to attempt to identify women at risk for preterm delivery. Home uterine activity monitors are not currently recommended as they have not been shown to improve outcome. The presence of bacterial vaginosis (BV) has been associated with preterm delivery independent of other known risk factors, however, there is insufficient data to support screening and treating women with positive cultures. Maternal estradiol and estriol levels have been used to predict activation of the fetal hypothalamic-pituitary-adrenal axis, but trials have failed to establish their clinical usefulness in accurately predicting preterm labor.
Numerous studies have confirmed the association between cervical shortening and subsequent preterm delivery. Transvaginal cervical ultrasonography has been shown to be a reliable and reproducible way to assess the length of the cervix. Despite the usefulness of cervical length determination as a predictor of preterm labor, routine use is not recommended because of the lack of proven treatments affecting outcome.
Fetal fibronectin (fFN) is a basement membrane protein of placental membranes and decidua. Numerous trials have shown that the risk of PTB is increased in the presence of fFN and decreased in its absence. The relationship among fFN, short cervix, BV, and traditional historical risk factors for spontaneous preterm birth suggest the highest associations of preterm birth with positive fFN, followed by cervical length less than 25 mm and a history of preterm birth. A negative fFN test indicates a 95% likelihood of not delivering within 14 days; therefore it is particularly useful in ruling out preterm delivery.
Supplemental progesterone therapy has been shown to reduce the rate of preterm delivery in high-risk populations. Weekly injections of 17α-hydroxyprogesterone caproate from 16 to 20 weeks until 36 weeks of gestation has been found to significantly reduce recurrent preterm birth in women with history of preterm delivery. A recent meta-analysis of 10 placebo-controlled trials found progesterone therapy to significantly reduce the frequency of recurrent preterm birth from 36% to 26%. Given the lack of other available treatments, many providers are using progesterone as preventative therapy in high-risk patients, but progesterone does not reverse established labor.
Management of Preterm Labor
Once preterm labor has been diagnosed, care should be taken to determine if patient warrants tocolysis, expectant management, or delivery. It is important to confirm an accurate gestational age because if less than 34 weeks, glucocorticoids should be administered as they clearly decrease neonatal morbidity and mortality in this population.
Tocolytic therapy is used to attempt to prolong pregnancy to allow time for corticosteroid administration. However, both tocolytic and steroid therapy may result in untoward maternal and fetal consequences and, therefore, their use should be limited to women in true preterm labor at high risk for spontaneous PTB.
In general, tocolytic drugs may prolong pregnancy for 2 to 7 days. There is no first-line tocolytic drug and the choices include beta-mimetics, magnesium sulfate, calcium channel blockers, and NSAIDs (nonsteroidal anti-inflammatory drugs). The tocolytic chosen should be based on maternal/fetal conditions, side effects, and gestational age. Prolonged use of any tocolytic drug is generally not indicated as it may increase maternal-fetal risk. Serious adverse events are rare but potentially life-threatening. Beta-mimetics, magnesium sulfate, and calcium channel blockers are all associated with an increased risk of pulmonary edema. Specifically, beta-mimetics are potent cardiovascular stimulants and can cause maternal myocardial ischemia, metabolic derangements (eg, hyperglycemia and hypokalemia), and fetal cardiac effects. Magnesium sulfate may cause maternal lethargy, drowsiness, double vision, nausea, and vomiting. NSAIDs can cause fetal oligohydramnios and premature closure of the ductus arteriosus. Calcium channel blockers used as a single agent appear to have a good maternal and fetal safety profile. Combining tocolytic drugs potentially increases maternal morbidity and should be used with caution.