Drug Therapy During Labor and Delivery, Part 1

Gerald G. Briggs; Stephanie R. Wan

Disclosures

Am J Health Syst Pharm. 2006;63(11):1038-1047. 

In This Article

Fetal Lung Immaturity

In women at risk for preterm delivery (less than 37 weeks' gestation), antenatal corticosteroids are frequently administered to prevent fetal lung immaturity at birth. Two milliliters of betamethasone sodium phosphate-betamethasone acetate suspension (containing betamethasone 6 mg [as the sodium phosphate] and betamethasone acetate 6 mg) i.m. every 24 hours times two doses (single course) is the corticosteroid regimen of choice, but dexamethasone 6 mg (as the sodium phosphate salt) i.m. every 12 hours for four doses (single course) has also been used. The biological activity of the two agents is nearly identical, both lack mineralocorticoid activity, and the single-course therapy has weak immunosuppressive effects. The optimal benefits of this therapy begin within 24 hours of the first dose.[56]

Antenatal corticosteroids do not always prevent fetal lung immaturity. A 1990 meta-analysis of 12 randomized, controlled trials, conducted between 1972 and 1989, involved more than 3000 women in preterm labor.[57] Patients were randomized to receive corticosteroids, primarily betamethasone, or placebo. Steroids were associated with the reduction of about 50% in the risk of respiratory distress among infants born at less than 31 weeks' gestation. Moreover, the decrease in respiratory morbidity was associated with reductions in the risk of intraventricular hemorrhage, necrotizing enterocolitis, and neonatal death.[57] Women with PROM had a reduction in the risk of respiratory distress of 45%, a magnitude similar to those with intact membranes. In women with intact membranes, there was no increase in the risk of maternal, fetal, or neonatal adverse effects, such as death or infections. However, the data from five trials suggested that in women with PROM, the administration of corticosteroids was more likely to increase the incidence of neonatal infections (odds ratio, 1.61; 95% confidence interval, 0.87-2.98).[57]

The lungs are among the last of the fetal organs to mature, a process that involves the formation of surface-active phospholipids (surfactants) in the alveolar spaces.[58] In the mature fetal lung, the surfactants reduce the surface tension within the alveolar spaces after delivery, which allows the alveoli to stay open for gas exchange. Before delivery, the surfactants are released into the amniotic fluid and are a biological marker of fetal lung maturity.[58] Pre-term delivery, before the lungs mature, may result in respiratory distress syndrome of the newborn, a serious complication.

Tests for Fetal Lung Maturity

The most widely used test for fetal lung maturity is the lecithin-sphingomyelin ratio.[58] Amniocentesis is performed to obtain a sample of amniotic fluid to measure the concentration of these surfactants in amniotic fluid. Before 32-33 weeks' gestation, the concentrations of lecithin and sphingomyelin are similar, but lecithin concentrations markedly increase after this gestational age, whereas levels of sphingomyelin remain relatively constant. The ratio of these surfactants in the mature fetal lung is 2.0, but the absolute value may vary between laboratories.[58]

A second test of fetal lung maturity involves the detection of phosphatidylglycerol, a substance that enhances the spread of phospholipids on the alveolar surface.[58] This minor constituent of surfactant becomes detectable several weeks after the increase in lecithin concentration. Thus, its presence is an indication of more advanced fetal lung maturity.[58] The detection of phosphatidylglycerol is not inhibited by the presence of blood, meconium, or other contaminants, so vaginal pool samples, in patients with rupture of the membranes, can be used to determine if it is present.[58]

Corticosteroid Therapy

Corticosteroids stimulate the synthesis and release of surfactants into the alveolar spaces.[58] Although all corticosteroids can affect this change if therapeutic concentrations reach the fetus, only betamethasone and, to a lesser extent, dexamethasone are routinely used for this purpose. The placenta is a rich source of the enzyme 11ß-ol-dehydrogenase, which can convert corticosteroids to their inactive metabolites.[59] For example, the placenta converts up to 85% of hydrocortisone to inactive cortisol, whereas only about 50% of betamethasone and dexamethasone are metabolized.[60]

Single courses of antenatal corticosteroid treatment are recommended for women at risk for preterm delivery between 24 and 34 weeks' gestation if the fetal membranes are intact, or between 24 and 32 weeks' gestation if the membranes are ruptured.[56,61] Therapy after 34 weeks is recommended only if there is evidence of fetal pulmonary immaturity.[56] Betamethasone is the preferred corticosteroid. Dexamethasone is associated with increased risks of respiratory distress syndrome, intraventricular hemorrhage, fetal or neonatal infection, stillbirth, and neonatal death.[62] Furthermore, multiple courses of dexamethasone, compared to multiple courses of betamethasone, are associated with an increased risk of periventricular leukomalacia (PVL) and short-term (up to 24 months of age) neurologic impairment.[63]

In a 2001 study comparing pre-term neonates who had received, before birth, either betamethasone (n = 400; repeat courses given at weekly intervals up to 34 weeks' gestation or delivery) or no treatment (n = 761), significantly fewer steroid-exposed infants had isolated PVL or PVL with intraventricular hemorrhage.[64] Antenatal steroid treatment was associated with a 56% reduction in PVL with intraventricular hemorrhage and a 58% reduction in isolated PVL. A 2004 study found that among 541 very preterm infants (born before 32 weeks' gestation) alive at three years, increasing numbers of betamethasone courses were associated with significant reductions in cerebral palsy.[65] This outcome was associated with significant decreases in isolated PVL and PVL with intraventricular hemorrhage with increasing numbers of betamethasone courses. However, three or more steroid courses were associated with hyperactivity, but not with measures of internalizing behavior and intelligence quotient.[65]

Although a single course of betamethasone or dexamethasone is recommended, a 2004 editorial stated that the benefits of repeated courses have not been adequately studied.[66] Clinical trials are in progress to evaluate the potential benefits and risks of administering repeat courses at intervals longer than seven days. Such a clinical trial is being conducted at our institution. The editorial also reviewed studies demonstrating that multiple courses of corticosteroids resulted in lower birth weight and a reduction in head circumference.[66] However, these adverse effects on growth were no longer significant at three and six years of age, suggesting that the effects are transient.

Not surprisingly, multiple courses of betamethasone may be associated with maternal adrenal suppression.[67,68] Neonatal adrenal suppression also has been reported but was thought to be uncommon.[69,70] However, a 2006 study compared neonates exposed prenatally to repeat courses of betamethasone (n = 22) with those exposed to a single course (n = 29).[71] The study found that repeat courses suppressed adrenal response to a stressor (heel prick or nasopharyngeal suction). Poststress salivary cortisol concentrations were significantly reduced at age three days (11.9 versus 21.4 nmol/L; p = 0.02) and seven days (11.7 versus 18.2 nmol/L; p = 0.04) but not at age 14 days or later. The clinical significance of this finding remains to be determined.

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