Socioeconomic Factors

In the United States, the incidence of preterm deliveries in the black population is twice as high as that in the white population. This factor cannot be viewed as a single entity but probably encompasses other characteristics of the population, such as poor access to and procurement of antenatal care, high stress levels, poor nutritional status, and the possibility of genetic differences.

Medical and Obstetric Factors

When one preterm birth has occurred, the relative risk for preterm delivery in the next pregnancy is 3.9, and the risk increases to 6.5 with two previous preterm deliveries.

Second-trimester abortions seem to carry an increased risk for subsequent preterm delivery, especially if a previous preterm birth has also occurred. The risk associated with induced first-trimester abortions is controversial. Repeated spontaneous first-trimester abortions, however, do increase the risk.

Other medical and obstetrical factors include bleeding in the first trimester, urinary tract infections, multiple gestation, uterine anomalies, polyhydramnios, and incompetent cervix.

Recently, attention has been directed toward maternal employment, physical activity, nutritional status, genital tract infections, stress, and anxiety as major risk factors for preterm birth.

Infection-Cervical Pathway

Bacterial vaginosis has been shown to be associated with preterm delivery, independent of other recognized risk factors. Treatment of bacterial vaginosis has reduced the incidence of preterm delivery. In addition, treating women in preterm labor with antibiotics significantly prolongs the time from the onset of treatment to delivery, compared with that in patients who do not receive antibiotics. Thus, addressing the issue of these relatively asymptomatic infections is an important strategy for preventing preterm birth.

There is a link between vaginal-cervical infections and progressive changes in the cervical length, as measured by vaginal ultrasonography. The relative risk for preterm birth increases significantly from 2.4 for a cervical length of 3.5 cm (50th percentile) to 6.2 for a length of 2.5 cm (10th percentile). Short cervices appear to be more common in women who have had prior preterm births and pregnancy terminations.

The most recent test to be developed is cervical and vaginal fetal fibronectin. This substance is a basement membrane protein produced by the fetal membranes. When the fetal membranes are disrupted, as with repetitive uterine activity, shortening of the cervix, and in the presence of infection, fibronectin is secreted into the vagina and can be tested. A positive fetal fibronectin test at 22 to 24 weeks predicts more than half of the spontaneous preterm births that occur before 28 weeks. A positive test for fetal fibronectin is significantly associated with a short cervix, vaginal infections, and uterine activity. A negative test is the best predictor of a low risk for preterm delivery.

Placental-Vascular Pathway

The placental-vascular pathway begins early in pregnancy at the time of implantation, when there are important changes taking place at the placental-decidual-myometrial interface. First, there are important immunologic changes, with a switch from a T_H1 type of immunity, which may be embryotoxic, to T_H2 antibody profile, in which blocking antibody production is thought to prevent rejection. At the same time, the trophoblasts are invading the spiral arteries of the decidua and myometrium, thus assuring that a low-resistance vascular connection is established. Alterations in both of these early changes are thought to play an important role in the pathophysiology of poor fetal growth, an important component of preterm birth (indicated and spontaneous), fetal growth restriction, and preeclampsia.

Stress-Strain Pathway

Both mental (cognitive) and work-related stress and strain are postulated to initiate a stress response that increases release of cortisol and catecholamines. Cortisol from the adrenal gland initiates early placental corticotrophin-releasing hormone (CRH) gene expression, and elevated levels of CRH are known to initiate labor at term. Catecholamines released during the stress response not only affect blood flow to the uteroplacental unit but also cause uterine contractions (norepinephrine). Poor nutrition in the form of reduced calories or abnormal patterns of intake (fasting) are known stressors and have been associated with a significantly increased risk for preterm birth. In support of the stress pathway are the studies that have shown that the rate of change of CRH, a mediator of the stress response, increases significantly in the weeks before the onset of preterm labor. Stress reduction and improved nutrition are the only current interventions that can be applied to this pathway.

Uterine Stretch Pathway

Uterine stretch as a result of increasing volume during normal and abnormal gestations is an important physiologic mechanism that facilitates the process of emptying the uterus. This pathway is common in patients with polyhydramnios and those with multiple gestations, both of which have an increased risk for preterm birth.

Magnesium Sulfate

In the United States, magnesium sulfate is frequently the drug of choice for initiating tocolytic therapy. Magnesium acts at the cellular level by competing with calcium for entry into the cell at the time of depolarization. Successful competition results in an effective decrease of intracellular calcium ions, resulting in myometrial relaxation.

Although magnesium levels required for tocolysis have not been critically evaluated, it appears that the levels needed may be higher than those required for prevention of eclampsia. Levels from 5.5 to 7.0 mg/dL appear to be appropriate. These can be achieved using the dosage regimen outlined in Box 12-1. After the loading dose is given, a continuous infusion is maintained, and plasma levels should be determined until therapeutic levels are reached. The drug should be continued at therapeutic levels until contractions cease unless the labor progresses. Because magnesium is excreted by the kidneys, adjustments must be made in patients with an abnormal creatinine clearance. Once successful tocolysis has been achieved, the infusion is continued for at least 12 hours, and then the infusion rate is weaned over 2 to 4 hours and then discontinued. In high-risk patients (advanced cervical dilation or continued labor in very-low-birth-weight cases), the infusion can be continued until the fetus has been exposed to glucocorticoids to enhance lung maturity.

A common minor side effect of magnesium therapy is a feeling of warmth and flushing on first administration. Respiratory depression is seen at magnesium levels of 12 to 15 mg/dL, and cardiac conduction defects and arrest are seen at higher levels.

In the fetus, plasma magnesium levels approach those of the mother, and a low plasma calcium level may also be demonstrated. The neonate may show some loss of muscle tone and drowsiness, resulting in a lower Apgar score. These effects are prolonged in the preterm neonate because of the decrease in renal clearance.

Long-term parenteral magnesium therapy has been used for control of preterm labor in selected patients. An important side effect seems to be loss of calcium, and it may be important in such patients to institute calcium therapy on a prophylactic basis.

Nifedipine

Nifedipine as an oral agent is very effective in suppressing preterm labor with minimal maternal and fetal side effects. It works by inhibiting the slow, inward current of calcium ions during the second phase of the action potential of uterine smooth muscle cells and may gradually replace intravenous magnesium sulfate. The only side effects are headache, cutaneous flushing, hypotension, and tachycardia. The latter two side effects can be partially avoided by making certain the patient is well hydrated and by the use of support stockings, such as TED (antiembolism) hose.

Prostaglandin Synthetase Inhibitors

Prostaglandins induce myometrial contractions at all stages of gestation, both in vivo and in vitro. Because prostaglandins are locally synthesized and possess a relatively short half-life, prevention of their synthesis within the uterus could abort labor. These agents are used on a short-term basis in special circumstances when prostaglandin production may be the inciting factor in preterm labor, such as with the presence of uterine fibroids. In the United States, indomethacin is the most commonly used prostaglandin inhibitor; it can be administered both orally and rectally, with some slight delay in absorption from rectal administration as compared with the oral route. Peak serum levels of indomethacin occur 1.5 to 2 hours after oral administration. Excretion of the intact drug occurs in maternal urine. It can result in oligohydramnios and premature closure of the fetal ductus arteriosus, which in turn may lead to neonatal pulmonary hypertension and cardiac failure. In addition, indomethacin decreases fetal renal function, and indomethacin-exposed infants have a greater risk for necrotizing enterocolitis, intracranial hemorrhage, and patent ductus arteriosus. Short-term use may be acceptable, but if patients are given indomethacin, the fetus should be evaluated with ultrasonography for ductus arteriosus flow.

Oxytocin Receptor Antagonists

Atosiban was the first oxytocin receptor antagonist developed. It binds to receptors in the myometrium and other gestational tissues, preventing the oxytocin-induced increase in inositol triphosphate, the messenger that increases intracellular calcium and causes myometrial contractions and upregulation of prostaglandin production. These agents are not approved for use in the United States.

Combined Therapy

Combined therapy, using a combination of nifedipine and prostaglandin synthetase inhibitors, is being explored in countries such as Australia, Canada, and Europe.

Efficacy of Tocolytic Therapy

Although the advent of tocolytic agents has failed to decrease preterm births in large population studies, their use has improved neonatal survival, decreased respiratory distress syndrome (RDS), and increased the birth weight of infants. The benefit of measures to postpone delivery beyond 34 weeks’ gestational age is under investigation.

Antibiotic Therapy

A number of studies have advocated the use of antibiotic prophylaxis in patients with preterm labor. Such patients may have a higher incidence of subclinical chorioamnionitis than previously thought.

Diagnostic amniocentesis in patients with idiopathic preterm labor has identified about 15% whose amniotic cavity is colonized with pathogens. It is reasonable to assume that a proportion of the remaining cases will have bacteria in the decidual cell space between the chorion and the myometrium. Thus the use of prophylactic antibiotics in women with preterm labor may prevent the progression of a subclinical infection to clinical amnionitis.

Contraindications to Tocolytic Therapy

Contraindications include severe preeclampsia, severe bleeding from placenta previa or abruptio placentae, chorioamnionitis, intrauterine growth restriction, fetal anomalies incompatible with life, and fetal demise. Because of the low success rate, advanced cervical dilation may also preclude tocolytic therapy, although therapy may delay delivery sufficiently for glucocorticoid administration to accelerate fetal lung maturity. Management of patients should be individualized, and even if the patient’s cervix is dilated 6 cm and she is having infrequent contractions, it is advisable to employ tocolysis and administer glucocorticoid therapy.