Clinical Review

This simple and inexpensive treatment can cut neonatal

OBG Manag. 2002 September;14(9):50-58

This simple and inexpensive treatment can cut neonatal mortality rates in half, but not all common regimens are supported by evidence. The author reviews the literature and summarizes recommendations from the NIH.

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References

1. Creasy RK, Iams JD. Preterm labor and delivery. In: Creasy RK, Resnik R, eds. Maternal-Fetal Medicine. Philadelphia, Pa.: W.B. Saunders Co.; 1999.

2. Ballard PL. Hormones and lung maturation. Monogr Endocrinol. 1986;28:94-136-173-196.

3. Liggins GC. Premature delivery of fetal lambs infused with glucocorticoids. J Endocrinol. 1969;45:515-523.

4. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50:515-525.

5. The National Institutes of Health Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. NIH Consens Statement. Feb 28-Mar 2 1994;12(2):1-24.

6. Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol. 1990;97(1):11-25.

7. Crowley PA. Antenatal corticosteroid therapy: a meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol. 1995;173(1):322-335.

8. Ballard PL, Granberg JP, Ballard RA. Glucocorticoid levels in maternal and cord serum after prenatal betamethasone therapy to prevent respiratory distress syndrome. J Clin Invest. 1975;56:1548-1554.

9. Smolders-de Haas H, Neuvel J, Schmand B, et al. Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10- to 12-year follow-up. Pediatrics. 1990;86:65-70.

10. The National Institutes of Health Consensus Development Conference on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. Antenatal Corticosteroids Revisited: Repeat Courses. NIH Consens Statement. Aug 17-18 2000;17(2):1-18.

11. Ikegami M, Jobe AH, Newnham J, Polk DH, Willet KE, Sly P. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med. 1997;156:178-184.

12. Jobe AH, Wada N, Berry LM, Ikegami M, Ervin MG. Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep. Am J Obstet Gynecol. 1998;178:880-885.

13. Polk DH, Ikegami M, Jobe AH, Sly P, Kohan R, Newnham J. Preterm lung function after retreatment with antenatal betamethasone in preterm lambs. Am J Obstet Gynecol. 1997;176:308-315.

14. Quinlivan JA, Beazley LD, Evans SF, Newnham JP, Dunlop SA. Retinal maturation is delayed by repeated, but not single, maternal injections of betamethasone in sheep. Eye. 2000;14:93-98.

15. McEvoy C, Bowling S, Sontag B, Stewart M. Timely repetitive antenatal steroids (AS) versus single-course AS: effect on functional residual capacity (FRC) and respiratory compliance (CRS) in preterm infants. Pediatr Res. 1996;39:229A, abstract 1357.-

16. Guinn DA, Atkinson MW, Sullivan L, et al. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: a randomized controlled trial. JAMA. 2001;286(13):1581-1587.

KEY POINTS

Antepartum glucocorticoids are highly effective in reducing neonatal morbidity and mortality in prematurely born infants.
Single courses have shown no adverse effect on the mother or newborn.
Data on the risks and benefits of repeat courses are inconclusive.
Repeat courses should not be used.
Since optimal benefit occurs when the drug is given between 2 and 7 days before delivery, every attempt should be made to time administration accordingly.

Premature birth is the largest unsolved problem in obstetrics today and the single most significant cause of neonatal morbidity and mortality.¹ And although clinicians have been largely unable to reduce the incidence of preterm deliveries, the introduction of maternal antenatal glucocorticoid treatment to accelerate fetal lung maturity has allowed us to significantly reduce associated mortality and morbidity.

Research shows that this simple and inexpensive treatment can cut the neonatal mortality rate by about 50%, substantially lower the incidence of neonatal intracranial hemorrhage and diminish the cost of neonatal care. But following the first Consensus Development Conference on this therapy by the National Institutes of Health (NIH), held in 1994, many physicians became overly enthusiastic in their administration of antepartum steroids, often prescribing regimens and dose schedules not yet subjected to clinical trials.

Here, I review the literature on this therapy, looking at what we know and what is still being examined, and detail how clinicians should administer antepartum corti-costeroids based on current evidence.

The history

Glucocorticoids function as “switch” triggers in biology. In other words, they change cell behavior—often in dramatic ways. One effect is to “turn off” cell proliferation and initiate mature cell function. It is this mechanism that is believed to be instrumental in fetal pulmonary development. The agents stimulate the maturation of alveolar type 2 cells to begin surfactant production and trigger architectural maturation of the fetal lung, thereby reducing the thickness of the alveolar membrane as well as the diffusion distance between alveolar gas and pulmonary capillary.²

While studying the mechanism of parturition in sheep, Liggins observed that an intravenous injection of dexamethasone to a ewe’s fetus could induce labor at immature gestational ages. Delivery generally occurred about 50 hours after injection. Further, these lambs did not succumb to respiratory distress syndrome (RDS), while those delivered by cesarean section at comparable gestational ages died of respiratory immaturity.³

With Howie, Liggins later reported on a similar effect in humans treated with antepartum glucocorticoids.⁴ In their study, gravidas admitted in preterm labor were randomized to treatment with either placebo or 12 mg of a betamethasone phosphate/sulfate mixture. Patients received 2 doses intramuscularly (IM) 24 hours apart. Among women who received corticosteroids and delivered between 48 hours and 7 days after the first injection, there was a 50% reduction in neonatal mortality, compared with controls. In patients with hypertension, however, the authors noted an increased fetal death rate among treated patients compared with controls.

Other researchers sought to investigate this treatment further, and by 1994 a total of 17 prospective, randomized, controlled studies on antenatal glucocorticoids had been performed, most of which showed similar improvement in neonatal survival. Despite this overwhelming evidence, only an estimated 12% to 18% of infants born prematurely in the United States and United Kingdom received this treatment.⁵ This low utilization rate seemed to be due to general conservatism on the part of obstetricians, concern about potential long-term adverse effects, and specific risks in some circumstances (such as hypertension and premature rupture of membranes [PROM]). As a result, the NIH convened a Consensus Development Conference on the topic.

NIH Consensus Statement, 1994

The consensus panel reviewed the published literature and commissioned a study on the cost-effectiveness of antenatal glucocorticoids. It also asked Dr. Patricia Crowley to update a 1990 meta-analysis of 12 controlled trials on this therapy.⁶ Her revised report included all randomized trials published from 1972 to 1994.⁷ With this information in hand, the panel then held a conference at which experts and the public could comment on the topic.

The resulting report, published in November 1994, concluded that antenatal glucocorticoids significantly reduced the risk of mortality, RDS, and intraventricular hemorrhage in infants born between 24 and 34 weeks’ gestation.⁵ Maximum benefit was achieved when administration of the drug was initiated more than 48 hours prior to delivery. There appeared to be no difference in benefit based on the gender or race of the fetus.

Two drug regimens were tested in the various prospective trials: 12 mg of betamethasone, given IM in 2 doses 24 hours apart; and 6 mg of dexamethasone, given IM in 4 doses 12 hours apart (TABLE 1). While these doses were chosen arbitrarily, multiple clinical trials showed them to be effective. Studies of umbilical cord blood-drug levels also noted that these doses achieved steroid concentrations in the fetus comparable to that found during a neonatal stress response.⁸ No other drug or dose regimen has been studied as thoroughly or shown to be effective for preventing neonatal morbidity and mortality in premature infants.