SHELTON, STUART D. MD; BOGGESS, KIM A. MD; MURTHA, AMY P. MD; GROFF, AMY O. MD; HERBERT, WILLIAM N. P. MD
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
Address reprint requests to: Stuart D. Shelton, MD, Darnall Loop, Department of Obstetrics and Gynecology, Darnall Army Community Hospital, Ft. Hood, TX 76544-5063. E-mail: email@example.com
The opinions and assertions contained herein are the private views of the authors and not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
Received May 9, 2000. Received in revised form August 8, 2000. Accepted October 5, 2000.
As reported by Liggins and Howie almost 30 years ago,1 corticosteroids enhance fetal lung maturity and thereby reduce both the incidence and severity of the neonatal respiratory distress syndrome. Additional benefits of corticosteroids include reductions in intraventricular hemorrhage, necrotizing enterocolitis, and neonatal mortality.2 Despite these benefits, controversy exists regarding management of the woman who is undelivered 7 days after steroid therapy but is still at risk for preterm delivery. In this instance, the risks and benefits of repeated dosing remain unsettled.
A 1994 ACOG Committee Opinion3 stated that further study was needed to establish the safety and benefit of repeated doses of corticosteroids in preterm patients. Although little human information was presented over the next 4 years, a 1998 revised committee opinion held that routine repeated dosing should be abandoned and replaced with rescue therapy on an as-needed basis.4 This recommendation was based on possible adverse fetal or maternal effects with repeated doses, as seen in animal studies. Johnson et al5 reported that repeated doses of betamethasone resulted in a 24% reduction in birth weight and a 15% reduction of brain size in preterm offspring of rhesus monkeys compared with controls. Ikegami et al6 administered repeated doses of betamethasone or saline to sheep and noted a progressive reduction in birth weight in the groups that received betamethasone. Both of these studies5,6 involved deliveries of preterm animals. Other studies of animal models have confirmed a reduction in neonatal birth weight7,8 or brain size9 in fetuses before or at term who were exposed to repeated doses of antenatal corticosteroids. Only one of these studies7 evaluated long-term postnatal growth and found no difference in subsequent body weight of mice exposed to multiple doses of betamethasone compared with controls.
In contrast to animal data, few studies are available on the effect of repeated doses of antenatal corticosteroids on human fetal growth,10–12 and the conclusions of these studies are not in agreement. Pratt et al10 found no significant effect of multiple doses of betamethasone on birth weight, whereas French et al11 and Banks et al12 noted a reduction in birth weight of infants exposed to multiple doses of antenatal betamethasone.
We sought to evaluate the effect of repeated doses of an antenatal corticosteroid, betamethasone, on birth weight and head circumference; the latter was chosen as an indirect index of brain size. We postulated that repeated doses of antenatal betamethasone would result in a reduction in neonatal birth weight and head circumference compared with single-dose therapy.
Materials and Methods
In accordance with our institutional review board guidelines, a historical cohort study was conducted by reviewing obstetric inpatient records for patients admitted between the gestational ages of 24 0/7 to 36 6/7 weeks to Duke University Medical Center from January 1991 through December 1995. We used a computer-generated list of women admitted before term that was based on International Classification of Diseases, Ninth Revision, codes to identify records for review. All patients receiving betamethasone were eligible for analysis. We excluded patients admitted before term in whom betamethasone was not used. Other exclusion criteria were fetal anomalies, multiple gestations, steroid use for other medical conditions, or insufficient data (ie, birth weight or head circumference not available). Maternal demographic information, number and timing of betamethasone doses, and clinical outcomes were recorded. Neonatal records were reviewed and neonatal birth weight, head circumference, and sex were noted.
Patients were divided into two groups for analysis according to whether they received one or multiple courses of therapy. A single course of betamethasone was defined as two 12-mg doses administered intramuscularly 24 hours apart. Administration of more than two doses qualified as multiple courses. Patients who received one of the two doses that made up a single course were analyzed in the single-course group.
Dichotomous variables were analyzed by using the χ2 or Fisher exact test, and continuous variables were analyzed by using the Student t-test. Multiple regression analysis controlling for gestational age at birth, race, sex, alcohol use, illicit drug use, and tobacco use was used to compare birth weights and head circumferences between groups. For all tests, statistical significance was set at P < .05 using a two-tailed test. Analyses were performed by using SAS software (SAS Institute, Cary, NC).
We identified 472 women with preterm admissions and reviewed their records. Of these, 320 were excluded: Two hundred fifty-one received no betamethasone, 38 had multiple gestations, 27 had insufficient data, 2 had fetal anomalies, and 2 had other steroid use. The most common reason that a woman delivering before term did not receive betamethasone was advanced preterm labor at time of admission.
After exclusion criteria were applied, 152 patients remained for study analysis; of these women, 107 received one course of betamethasone and 45 received multiple courses of therapy. Among patients receiving multiple courses, 28 received two courses, 4 received three courses, 5 received four courses, 2 received five courses, 5 received six courses, and 1 received seven courses.
The incidence of tobacco and alcohol use differed significantly between the groups. Patients receiving multiple courses of betamethasone were less likely to smoke tobacco or drink alcohol (Table 1). The groups did not differ with respect to pregnancy complications, such as diabetes or hypertensive disorders.
The groups did not differ significantly with respect to gestational age at delivery, birth weight, or head circumference; in contrast, gestational age at the time of the initial treatment with betamethasone differed significantly (Table 2). After multiple regression analysis controlling for gestational age at birth, sex, race, tobacco use, alcohol use, and illicit drug use, the groups still did not differ significantly.
Our retrospective analysis demonstrated that birth weight and head circumference in fetuses exposed to multiple courses of betamethasone did not differ significantly from those in fetuses exposed to a single course. Our results are consistent with those of Pratt et al,10 who found no significant difference in birth weights of infants exposed to one or multiple courses of betamethasone. Their analysis, like ours, was retrospective and therefore subject to the same potential problems.
In contrast to our results and the findings of Pratt et al,10 other investigators noted decreased birth weights of human fetuses exposed to multiple doses of betamethasone.11,12 However, in the study by Banks et al,12 the difference in birth weights between the single-course group and the multiple-course group was only 39 g. French et al11 found a 9% reduction in birth weight with multiple doses, but this translated into only a 122-g difference. The clinical significance of such small reductions in birth weight depends on the gestational age at which it was detected, and they are not likely to impact neonatal outcome, except in extremely low birth weight infants.
We recommend caution in interpreting the results of all these studies, since retrospective investigations are inherently subject to data collection bias. The persons who performed the chart reviews for our study were not blinded to the study objective and were therefore potentially subject to ascertainment bias. Although we used regression analysis to control for possible confounding variables, the multiple factors affecting growth make comparison of groups difficult. Additional factors that affect neonatal birth weight may exist but were not included in our regression model.
Several possible explanations account for our finding of no difference in birth weights or head circumferences between groups. First, a type II error may have occurred; that is, a difference actually existed, but we did not find it because of the small sample. Retrospectively, we determined that we had 80% power to detect a 20% difference in birth weights between the groups at an α level of 0.05. Therefore, a smaller difference in birth weight may be present that was not detected by our analysis. Sufficient power to detect a 10% difference in birth weights between groups would require quadrupling the size of each group. This would not be possible using patients from our institution, since we began to decrease our use of multiple steroid courses in the years after this study. In addition, a 10% reduction in birth weight is unlikely to have clinical significance, except perhaps at birth weights less than 750 g. A second reason for lack of difference in birth weight and head circumference between the single-course and multiple-course groups may be that the reduction seen in animal models was due to differences in steroid doses or in animal versus human response to steroids. Finally, we may not have found a difference because repeated courses of antenatal betamethasone do not adversely affect fetal growth.
The conclusions drawn from our study must be limited to effects on growth outcomes. We did not examine possible beneficial effects of multiple courses of betamethasone. We also did not address other potential deleterious effects of multiple courses of betamethasone, such as fetal adrenal suppression or increased risk of maternal or fetal infection. Finally, our study examined only short-term effects of betamethasone on fetal growth and not potential long-term effects of multiple steroid courses on growth and development.
Although we did not find a reduction in birth weight or head circumference in fetuses exposed to multiple courses of betamethasone, we believe that concern about possible adverse effects of repeated courses of corticosteroids is legitimate. In the absence of clear evidence to show that repeated doses provide benefits above those of single-course therapy, we feel that is incumbent on the provider to prove that multiple doses are not harmful.
Consideration of repeated administration of corticosteroids to women who are undelivered but remain at risk for preterm delivery 7 days after a course of antenatal corticosteroids should take into account the risks as well as the benefits of such therapy. Until prospective studies specifically designed to evaluate the risks and benefits of multiple courses of antenatal corticosteroids are performed, we are limited to animal and retrospective human analyses. Although our study results provide some reassurance about the safety of repeated courses of antenatal betamethasone, until clinical benefit for repeated doses can be shown or no other possible adverse effects are found, caution should be exercised when considering repeated dosing of corticosteroids.
1. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515–25.
2. NIH Consensus Development Panel. Effect of corticosteroids for fetal maturation on perinatal outcomes. JAMA 1995;273:413–7.
3. American College of Obstetricians and Gynecologists. Antenatal corticosteroid therapy for fetal maturation. Committee opinion no. 147. Washington, D.C.: The College; 1994:1–2.
4. American College of Obstetricians and Gynecologists. Antenatal corticosteroid therapy for fetal maturation. Committee opinion no. 210. Washington, D.C.: The College; 1998:1–2.
5. 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;141:1053–63.
6. 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.
7. Stewart JD, Sienko AE, Gonzalez CL, Christensen HD, Rayburn WF. Placebo-controlled comparison between a single dose and a multidose of betamethasone in accelerating lung maturation of mice offspring. Am J Obstet Gynecol 1998;179:1241–7.
8. 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;178:880–5.
9. 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.
10. Pratt L, Waschbusch L, Ladd W, Gangnon R, Hendricks SK. Multiple vs. single betamethasone therapy: Neonatal and maternal effects. J Reprod Med 1999;44:257–64.
11. 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.
12. Banks BA, Cnaan A, Morgan MA, Parer JT, Merrill JD, Ballard PL, et al. Multiple courses of antenatal corticosteroids and outcome of premature neonates. North American Thyrotropin-Releasing Hormone Study Group. Am J Obstet Gynecol 1999;181:709–17.