Obstetric Complications: Preterm Labor and Delivery, PROM, IUGR, Postterm Pregnancy, and IUFD

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. In the past 6 years there has been an increase in the incidence of poverty and obesity, which may contribute to the persistence of high levels of preterm birth.

Obstetric, Medical, and Environmental Factors

• 1

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

• 2

  Second-trimester abortions: The cause of second-trimester abortions when the fetus is normal is likely to have the same cause as preterm labor (PTL) after 20 weeks. Therefore, these early pregnancy losses are associated with 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, because they are more likely associated with malformed fetuses that may not have aborted spontaneously. However, if there are repeated first-trimester spontaneous abortions, there is an increased risk of spontaneous loss of a normal fetus because of immunological causes that are poorly understood. Other obstetric factors include multiple gestation and polyhydramnios.

• 3

  Medical factors: The major medical factors are hypertension, diabetes, obesity, and genital tract infection. Other factors include bleeding in the first trimester, urinary tract infections, uterine anomalies, and incompetent cervix.

• 4

  Environmental and behavior factors: Smoking during pregnancy is associated with an increased risk of preterm birth. Smoking cessation should be considered in any preventative program for preterm birth. Recently, attention has been directed toward maternal employment, physical activity, nutritional status stress, and anxiety as major risk factors for preterm birth. In addition, several papers have associated vitamin D deficiency with a greater risk of preterm birth, preeclampsia, and IUGR.

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. For many years, it has been known that treatment of asymptomatic and clinical cystitis is associated with a reduced incidence of PTB. 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 of 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, and/or in the presence of infection, shortening of the cervix can occur. In the presence of these changes, fibronectin (a protein substance) 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 of 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. Initially, there are important immunologic changes, with a switch from a Th-1 (helper cell) type of immunity, which may be embryotoxic, to a Th-2 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, assuring that a low resistance vascular connection is established. All three conditions associated with preterm delivery (spontaneous, PROM, and IUGR) are associated with failure of the trophoblast to properly invade the spinal arteries. Poor trophoblastic invasion may be caused by placental factors or maternal abnormalities secondary to atherosclerosis. 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.

The placenta is also an important source of progesterone production that plays an important role in the immune system and in the maintenance of uterine relaxation. The altered placental progesterone production in women at risk of preterm birth is thought to be secondary to placental hormonal dysregulation. Both 17-OH progesterone and vaginal progesterone play an important role in the prevention of preterm birth.

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. The biochemical response to stress is important for the maintenance of metabolic regulation. However, 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 and/or abnormal patterns of intake (fasting) are known stressors and have been associated with a significantly increased risk of 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. Thus, too much stress (chronic stress) is thought to be toxic and may cause preterm labor. Stress reduction and psychosocial support are the only current interventions that can be applied to this pathway. Meta-analyses have suggested that psychosocial support via networking between women's social groups can decrease the risk of preterm birth.

Uterine Stretch Pathway

Uterine stretch as a result of increasing volume during normal and abnormal gestations is an important physiological mechanism that facilitates the process of emptying the uterus. In normal pregnancy, the hormone parathyroid-related protein (PTrP) plays an important role in relaxing the myometrial tissues, but when stretch exceeds certain limits (e.g., multiple gestations, fetal macrosomia, and polyhydramnios), PTrP fails to keep the uterus relaxed and labor begins. This pathway is common in patients with polyhydramnios and those with multiple gestations, both of which have an increased risk of 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 have been reached. The drug should be continued at therapeutic levels until contractions cease unless the labor progresses. Because magnesium is excreted via the kidneys, adjustments must be made in patients with an abnormal creatinine clearance. Once successful tocolysis has been achieved, the infusion should be continued for at least 12 hours. The infusion rate may then be weaned over 2 to 4 hours and then discontinued. In very high risk patients (advanced cervical dilation or continued labor in very low birth weight cases), the infusion may be continued until the fetus has been exposed to glucocorticoids to enhance lung maturity.

A common minor side effect 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. Because vitamin D deficiency has been associated with the risk of premature labor, vitamin D supplementation should be considered because vitamin D is required for adequate mobilization of calcium from the skeleton.

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 thromboembolism-deterrent (TED) hose, to prevent pooling of blood in the lower extremities.

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 inhibit labor. These agents are used on a short-term basis in circumstances where prostaglandin production may be the inciting factor, as may occur in 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 of 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.

Combined therapy with nifedipine and prostaglandin synthetase inhibitors is currently being used in Australia, Canada, and Europe.

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 latter is the messenger that increases intracellular calcium, and causes myometrial contractions and up-regulation of prostaglandin production. These agents are not approved for use in the United States.

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 is under investigation, with the thought that the longer the fetus remains in utero the better the outcome.

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 remainder will have occult bacteria in the decidual cell space between the chorion and the myometrium. The use of prophylactic antibiotics in women with preterm labor may prevent progression from a subclinical infection to clinical amnionitis.