Materials and Methods
Beginning May 1, 1994, dexamethasone, 5 mg given intramuscularly every 12 hours for four doses (one course), was administered to all eligible women at risk for delivery between 24 and 34 weeks' gestation. This treatment was repeated at 7-day intervals until 34 weeks. Women with preterm ruptured membranes were eligible for treatment; however, dexamethasone was not given to those with hypertension, diabetes, or fever. Neither betamethasone nor thyrotropin-releasing hormone were used to promote fetal maturation at our hospital.
Selected obstetric and neonatal outcomes for all women delivering infants at Parkland Hospital (Dallas, TX) are routinely entered into a computerized database. Nurses attending each delivery complete an obstetric data sheet, and research nurses assess the data for consistency and completeness before electronic storage. Coinciding with the introduction of antenatal corticosteroids at our hospital, additional outcome information was collected and linked to the computerized database by a research nurse who prospectively followed dexamethasone-treated mothers during their antepartum course and their infants until discharge from the hospital.
The birth weights of the infants exposed to antenatal dexamethasone were compared with three groups: a reference obstetric population, a matched comparison group, and an historical cohort of infants delivered in the 12 months before the introduction of dexamethasone. The reference obstetric population comprised all singleton live-born infants without anomalies delivered at our hospital between January 1, 1988, and May 31, 1998, born to mothers without hypertension or diabetes and who did not receive antenatal dexamethasone. A similar birth weight distribution for this population has been reported previously.12 This birth weight distribution was constructed based on the obstetric estimate of gestational age that was used to manage women during the intrapartum period and the results of indicated obstetric ultrasonography performed during the pregnancy. The validity of this obstetric estimate of gestational age has been described previously.12
The pregnancies in the reference obstetric population were also used as a source of controls for frequency matching approximately 3:1 to the dexamethasone-treated infants. Infants were matched according to maternal race, infant sex, and gestational age at delivery. The third comparison group, the historical cohort, comprised infants delivered between 24 and 34 weeks' gestation in the 12 months preceding adoption of dexamethasone therapy as the standard of care at our hospital. These infants were not exposed to antenatal corticosteroids because our institutional protocol preempted such use. In addition, these pregnancies were not complicated by hypertension, diabetes, or fever.
For continuous measures, analyses of variance and covariance were used with the Student–Newman–Keuls method for post hoc multiple comparisons. Mantel–Haenszel methods were used to adjust relative risk (RR) estimates for covariates. Proportions are presented with 95% confidence intervals (CI) and means with standard errors. Computations were performed using SAS 8 statistical software (SAS Institute, Cary, NC).
Between May 1, 1994, and May 31, 1998, 961 singleton live-born infants without malformations were delivered of women given dexamethasone to stimulate fetal maturation. Fifty-two percent of the mothers were Hispanic; 38% were black; 8% were white, and the remainder were predominantly Asian. Approximately two-thirds of the women were parous and 45% of the infants were female. The distribution of these infants, in relation to the courses of dexamethasone received by the mother, is shown in Figure 1. One course of dexamethasone included four doses; a partial course included one to three doses.
Shown in Figure 2 is the birth weight distribution of dexamethasone-treated infants (n = 961) compared with the distribution of the reference obstetric population of untreated infants (n = 122,629) after adjustment for maternal race, parity, and infant gender. It was expected that if the birth weights for the dexamethasone-treated infants were normally distributed, 5% of these infants would fall into each of the birth weight percentile categories. There was, however, a significant shift in birth weights at both ends of the distribution. That is, there was a significant increase in dexamethasone-treated infants in the lower birth weight strata and fewer infants in the larger percentiles.
Shown in Figure 3 is the mean birth weight ± standard error of the mean for dexamethasone-treated infants compared with the reference obstetric population and matched controls (n = 2808). Mean birth weights from 24 to 40 weeks' gestation were not significantly different when the matched controls and reference obstetric population were compared (P = .27). However, dexamethasone-treated infants, when compared with either the matched controls or the reference group, were significantly smaller after adjustment for gestational age (P < .001).
Figure 4 shows the differences in birth weights between the dexamethasone-treated infants and the historical cohort of infants (n = 444) with an indication for antenatal dexamethasone therapy but delivered in the 12 months before the introduction of corticosteroids at our hospital. The median birth weight for each week of gestation for the reference population was calculated and served as a standard weight. The decrement in birth weight from this standard was calculated for the dexamethasone-treated infants and the historical controls after adjusting for gestational age, maternal race, parity, and infant gender. Dexamethasone-treated infants were significantly smaller compared with either the reference obstetric population (P < .001) or the historical controls (P < .001). Compared with the historical controls, the average birth weight of dexamethasone-treated infants was smaller by 12 g at 24–26 weeks, 63 g at 27–29 weeks, 161 g at 30–32 weeks, and 80 g at 33–34 weeks' gestation. The birth weights of the reference obstetric population and historical controls were similar (P = .897).
A total of 18 neonatal deaths occurred in women given dexamethasone; 15 occurred in women treated with one or fewer courses and three occurred in those given two courses. There were no deaths in women given three or more courses of dexamethasone. The RR (and 95% CI) for neonatal death comparing the historical cohort with the dexamethasone-treated infants was 2.1 (0.87, 5.08) after adjusting for gestational age and year of delivery (P = .098). Thus, although smaller, dexamethasone-treated infants were not at a significantly increased risk for neonatal death.
Birth weight curves were computed for the 961 dexamethasone-treated infants according to the dosage administered to the mother (Figure 5). Birth weight for gestational age was not significantly related to the dexamethasone dosage (P = .18).
Our results, using three separate analyses, imply that dexamethasone given to the mother to promote fetal maturation negatively impacts birth weight. First, when compared with the birth weights in the overall obstetric population for our hospital, the birth weights of dexamethasone-treated infants were more frequently in the lower percentiles than expected. Second, the mean birth weight of dexamethasone-treated infants was significantly less than that in the reference obstetric population and matched controls. Third, mean birth weights of dexamethasone-treated infants were also significantly less than those infants with indications for dexamethasone therapy but delivered in the 12 months before implementation of such treatment at our hospital. These birth weight effects were not related to the number of doses of dexamethasone administered to the mother. One possible explanation for this result is the observation in experimental animals of a threshold effect of corticosteroids to reduce birth weight after one course of treatment.4
It was observed very early (1940) in the history of the development of corticosteroids that small doses promptly suppressed growth in the rat.13 Similar effects have been subsequently observed in fetal rabbits,6 lambs,3–5 and rhesus monkeys.2 For example, Newnham et al4 randomized betamethasone and saline injections in pregnent ewes and found that the lambs exposed to betamethasone were on average 550 g smaller after a single dose (typical birth weights for these lambs were approximately 2900 g). The mechanism of growth impairment associated with corticosteroid therapy is thought to be related to reduced biosynthesis of DNA and RNA as well as prolonged inhibition of mitosis and cellular synthetic activity. These effects, in turn, lead to impaired growth particularly in the brain, lung, heart, kidney, adrenal gland, and skeletal muscles.7 However, investigators studying neurodevelopmental growth in humans up to 12 years of age have failed to reveal an adverse effect of corticosteroids given to pregnant women to enhance fetal lung maturation.14,15
Although the somatic growth inhibition associated with glucocorticoid hormones is conspicuous in immature animals, the effects in human fetuses are not as clear. Impaired fetal growth was not identified in the original randomized trials9,16 of glucocorticoids given for acceleration of fetal lung maturity. Similar to our findings, however, French et al10 recently demonstrated an independent association between repeated administration of antenatal corticosteroids and impaired fetal growth in 166 steroid-treated infants delivered at less than 33 weeks' gestation. We found, in addition, that dexamethasone-treated infants delivered later than 33 weeks' gestation were also at significant risk for decreased birth weight. This increasing birth weight decrement with advancing gestational age further supports a corticosteroid-related effect. Interestingly, French et al10 found a significant decrease in birth weight in relation to an increased number of corticosteroid courses. Their finding, involving 43 infants, contrasts with the absence of a dose-related effect in the 235 infants treated with multiple courses in our analysis. Banks et al11 also reported an association between antenatal corticosteroid treatment and diminished fetal growth. In a retrospective analysis of 710 preterm births, they observed that expected birth weight was decreased by 39 g in neonates of the same gestational age if they received more than one course of antenatal corticosteroids.
We were curious about our finding that infants with only a brief exposure to dexamethasone had lower than expected birth weights. This observation raises the possibility that the receipt of dexamethasone may be a marker for other factors that are themselves associated with reduced birth weight. Stated differently, when compared with fetuses born at term, those destined to be born preterm may be smaller even before the event precipitating the preterm delivery is identified. Smith et al17 for example, recently reported that diminished growth during the first trimester is associated with a subsequent risk for low birth weight and preterm birth. We cannot preclude such an effect in our analysis.
Our results suggest that although dexamethasone-treated infants are smaller, they are not at increased risk for neonatal death. Similarly, we found no association between the number of courses of dexamethasone and neonatal death. Thus, while appearing to interfere with birth weight, corticosteroids given to enhance fetal maturation do not appear to be detrimental when this effect is balanced against the reported benefits.1
1. National Institutes of Health Consensus Development Conference Statement. Effect of corticosteroids for fetal maturation on perinatal outcomes, February 28–March 2, 1994. Am J Obstet Gynecol 1995;173:246–52.
2. Johnson JWC, Mitzner W, Beck JC, London WT, Sly DL, Lee PA, et al. Long-term effects of betamethasone on fetal development. Am J Obstet Gynecol 1981;141:1053–64.
3. 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;156:178–84.
4. Newnham JP, Evans SF, Godfrey ME, Huang WL, Ikegami M, Jobe A. Maternal, but not fetal, administration of corticosteroids restricts fetal growth. J Matern Fetal Med 1999;8:81–7.
5. Huang WL, Beazley LD, Quinlivan JA, Evans SF, Newnham JP, Dunlop SA. Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol 1999;94:213–8.
6. Tabor BL, Rider ED, Ikegami M, Jobe AH, Lewis JF. Dose effects of antenatal corticosteroids for induction of lung maturation in preterm rabbits. Am J Obstet Gynecol 1991;164:675–81.
7. Wu FF, Momma K, Takao A. Cardiovascular and pulmonary effects of betamethasone during midtrimester on fetal rats. Fetal Diagn Ther 1993;8:89–94.
8. DeSouza SW, Adlard BPF. Growth of suckling rats after treatment with dexamethasone or cortisol. Arch Dis Child 1973;48:519–22.
9. Collaborative Group on Antenatal Steroid Therapy. Effects of antenatal dexamethasone administration in the infant: Long-term follow-up. J Pediatr 1984;104:259–67.
10. French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: Size at birth and subsequent development. Am J Obstet Gynecol 1999;180:114–21.
11. Banks BA, Cnaan A, Morgan MA, Parer JT, Merrill JD, Ballard PL, et al. Multiple courses of antenatal corticosteroids and outcome of premature neonates. Am J Obstet Gynecol 1999;181:709–17.
12. McIntire DD, Bloom SL, Casey BM, Leveno KJ. Fetal growth: The relationship between birthweight and morbidity and mortality in newborn infants. N Engl J Med 1999;340:1234–8.
13. Wells BB, Kendall EC. The influence of corticosterone and C
17 hydroxydehydrocorticosterone (compound E) on somatic growth. Proc Staff Meet Mayo Clin 1940;15:324–8.
14. Salokorpi T, Sajaniemi N, Hallback H, Kari A, Rita H, Von Wendt L. Randomized study of the effect of antenatal dexamethasone on growth and development of premature children at the corrected age of 2 years. Acta Pediatr 1997;86:294–8.
15. Smolders-deHaas H, Neuvel J, Schmand B, Treffers PE, Koppe JG, Hoeks J. 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.
16. Howie RN, Liggins GC. The New Zealand study of antepartum glucocorticoid treatment. In: Farrel PM, ed. Lung development: Biological and clinical perspectives, II. New York: Academic Press, 1982:255–65.
17. Smith GCS, Smith MFS, McNay MB, Fleming JEE. First-trimester growth and the risk of low birth weight. N Engl J Med 1998;339:1817–22.