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Figure. Overview of the Clinical Trial
Image description not available.
Asterisk indicates that patients withdrew for a variety of reasons and no patient withdrew because of adverse events; dagger, all 4 patients withdrawn by their physicians were withdrawn to allow for administration of known antenatal corticosteroids; and double dagger, denominators may vary slightly because of 2 cases of intrauterine fetal demise and incomplete data on neonates that were lost to follow-up.
Table 1. Demographic Data of Study Patients*
Image description not available.
Table 2. Pregnancy Outcomes*
Image description not available.
Table 3. Composite Morbidity and Individual Neonatal Outcomes*
Image description not available.
1.
National Institutes of Health Consensus Development Conference Statement.  Effects of corticosteroid for fetal maturation on perinatal outcomes, February 28–March 2, 1994.  JAMA.1995;273:413-417.
2.
Planer P, Ballard R, Ballard P.  et al.  Use of antenatal corticosteroids (ANCs) in the USA [abstract].  Am J Obstet Gynecol.1996;174:467A.
3.
Brocklehurst P, Gates S, McKenzie-McHarg K, Alfirevic Z, Chamberlain G. Are we prescribing multiple courses of antenatal corticosteroids? a survey of practice in the UK.  Br J Obstet Gynaecol.1999;106:977-979.
4.
Martin R, Fanaroff A. The respiratory distress syndrome and its management. In: Neonatal Perinatal Medicine. Vol 2. New York, NY: Mosby; 1992:811-820.
5.
Papile L, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm.  J Pediatr.1978;92:529-534.
6.
Bell M, Ternberg J, Feigin R.  et al.  Neonatal necrotizing enterocolitis: therapeutic decision based on clinical findings.  Ann Surg.1978;187:1-7.
7.
Dunlop S, Archer M, Quinlivan J, Beazley L, Newnham J. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system.  J Matern Fetal Med.1997;6:309-313.
8.
French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: behaviour outcomes in a regional population of very preterm infants [abstract].  Pediatr Res.1998;43:214A.
9.
French N, Hagan R, Evans S, Godfrey M, Newnham J. Repeated antenatal corticosteroids: size at birth and subsequent development.  Am J Obstet Gynecol.1999;180:114-121.
10.
Hack M, Breslau N, Weissman B, Aram D, Klein N, Borawski E. Effect of very low birthweight and subnormal head size on cognitive abilities at school age.  N Engl J Med.1991;325:231-237.
11.
Hagan R, French N, Evans S.  et al.  Repeated antenatal corticosteroids: growth and early childhood outcome.  Pediatr Res.1997;41:405.
12.
Skinner A, Battin M, Solimano A, Daaboul J, Kitson H. Growth and growth factors in premature infants receiving dexamethasone for bronchopulmonary dysplasia.  Am J Perinatol.1997;14:539-546.
13.
Stewart J, Gonzalez C, Christensen H, Rayburn W. Effects of multiple doses of betamethasone on the perinatal outcomes and growth of mice offspring.  Am J Obstet Gynecol.1997;176:676.
14.
Wu Y, Colford J. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis.  JAMA.2000;284:1417-1424.
15.
Yoon B, Romero R, Park J.  et al.  Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years.  Am J Obstet Gynecol.2000;182:675-681.
16.
Cooke R. Trends in incidence of cranial ultrasound lesions and cerebral palsy in very low birthweight infants 1982-93.  Arch Dis Child Fetal Neonatal Ed.1999;80:F115-F117.
17.
Doyle L, Betheras F, Ford G, Davis N, Callanan C. Survival, cranial ultrasound and cerebral palsy in very low birthweight infants: 1980's versus 1990's.  J Paediatr Child Health.2000;36:7-12.
18.
Vohr B, Allan W, Scott D.  et al.  Early-onset intraventricular hemorrhage in preterm neonates: incidence of neurodevelopmental handicap.  Semin Perinatol.1999;23:212-217.
19.
Smolders-de-Haas H, Neuvel J, Schmand B, Treffers P, Koppe J, Hoeks J. Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10-12 year follow-up.  Pediatrics.1990;86:65-70.
20.
MacArthur B, Howie M, Dezoete J, Elkins J. School progress and cognitive development of 6-year old children whose mothers were treated antenatally with betamethasone.  Pediatrics.1982;70:99-105.
21.
Esplin M, Fausett M, Smith S.  et al.  Multiple courses of antenatal steroids are associated with a delay in long-term psychomotor development in children with birth weights ≤1500 grams.  Am J Obstet Gynecol.2000;182:S24.
22.
Howard E, Granoff D. Increased voluntary running and decreased motor coordination in mice after neonatal corticosterone implantation.  Exp Neurol.1968;22:661-673.
23.
Carlos R, Seidler F, Slotkin T. Fetal dexamethasone exposure alters macromolecular characteristics of rat brain development: a critical period for regionally selective alterations?  Teratology.1992;46:45-59.
24.
Uno H, Lohmiller L, Thieme C.  et al.  Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques.  Brain Res Dev Brain Res.1990;53:157-167.
25.
Uno H, Eisele S, Sakai A.  et al.  Neurotoxicity of glucocorticoids in the primate brain.  Horm Behav.1994;28:336-348.
26.
Bohn M, Friedrich V. Recovery of myelination in rat optic nerve after developmental retardation by cortisol.  J Neurosci.1982;2:1292-1298.
27.
Roth S, Baudin J, McCormick D.  et al.  Relation between ultrasound appearance of the brain of very preterm infants and neurodevelopmental impairment at eight years.  Dev Med Child Neurol.1993;35:755-768.
28.
Chess P, Chess M, Manuli M, Guillet R. Screening head ultrasound to detect intraventricular hemorrhage in premature infants.  Pediatr Radiol.1997;27:305-308.
29.
DeFrance B, Brennan B. Single versus multiple courses of antenatal corticosteroids.  Evid Based Obstet Gynecol.2001;3:109-110.
Original Contribution
October 3, 2001

Single vs Weekly Courses of Antenatal Corticosteroids for Women at Risk of Preterm DeliveryA Randomized Controlled Trial

Author Affiliations

Author Affiliations: Denver Health Medical Center and University of Colorado Health Sciences Center, Denver (Drs Guinn and Davies); University of Washington, Seattle (Dr Atkinson); Boston University, Boston, Mass (Dr Sullivan); New York University (Dr Lee), Columbia University (Dr Simpson), and Mount Sinai Medical Center (Dr Stone), New York, NY; Evanston Hospital, Evanston, Ill (Drs McGregor and Parilla); Northwestern University, Chicago, Ill (Dr Parilla); University of Michigan, Ann Arbor (Dr Hanlon-Lundberg); University of Southern California, Los Angeles (Dr Wing); Kapi'Olani Medical Center for Women and Children, Honolulu, Hawaii (Dr Ogasawara); and Loyola University, Maywood, Ill (Dr Muraskas).

JAMA. 2001;286(13):1581-1587. doi:10.1001/jama.286.13.1581
Context

Context The practice of administering weekly courses of antenatal corticosteroids to pregnant women at risk of preterm delivery is widespread, but no randomized trial has established the efficacy or safety of this practice.

Objectives To evaluate the efficacy of weekly administration of antenatal corticosteroids compared with a single course in reducing the incidence of neonatal morbidity and to evaluate potential complications of weekly treatment.

Design and Setting Randomized, double-blind, placebo-controlled intention-to-treat trial conducted in 13 academic centers in the United States from February 1996 through April 2000.

Participants A total of 502 pregnant women between 24 and 32 completed weeks' gestation who were at high risk of preterm delivery.

Intervention All patients received a complete single course of antenatal corticosteroids (either betamethasone, 12 mg intramuscularly repeated once in 24 hours for 2 doses, or dexamethasone, 6 mg intramuscularly repeated every 12 hours for 4 doses). Participants who had not delivered 1 week after receipt of the single course were randomly assigned to receive either betamethasone, 12 mg intramuscularly repeated once in 24 hours for 2 doses every week until 34 weeks' gestation or delivery, whichever came first (n = 256), or a similarly administered placebo (n = 246).

Main Outcome Measure Composite neonatal morbidity (including severe respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular hemorrhage, periventricular leukomalacia, proven sepsis, necrotizing enterocolitis, or perinatal death).

Results Composite morbidity occurred in 22.5% of the weekly-course group vs 28.0% of the single-course group (unadjusted relative risk, 0.80; 95% confidence interval, 0.59-1.10). Neither group assignment nor the number of treatment courses was associated with a reduction in composite morbidity.

Conclusions Weekly courses of antenatal corticosteroids did not reduce composite neonatal morbidity compared with a single course of treatment. Weekly courses of antenatal corticosteroids should not be routinely prescribed for women at risk of preterm delivery.

Maternal administration of antenatal corticosteroids reduces the incidence of respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and mortality in preterm neonates. The cumulative evidence is so compelling that the National Institutes of Health (NIH) in 1994 issued a consensus statement recommending administration of antenatal corticosteroids to all patients at risk of preterm delivery prior to 34 weeks' gestation.1

The NIH consensus statement also identified areas for future clinical research, including the short- and long-term benefits and risks of repeated administration of antenatal corticosteroids. Although a single completed course of antenatal corticosteroids (either betamethasone, 12 mg intramuscularly repeated once in 24 hours for 2 doses, or dexamethasone, 6 mg intramuscularly repeated every 12 hours for 4 doses) is clearly effective in both humans and animal models when administered 48 hours to 7 days before preterm birth, the duration of this benefit and the effects of repeated treatments if the neonate is not delivered are unknown. Despite limited data, many clinicians routinely repeat courses of antenatal corticosteroids weekly until 34 weeks' gestation.2,3

To date, no published randomized trial has established the efficacy or safety of single vs weekly courses of antenatal corticosteroids. Therefore, we performed a randomized, double-blind, placebo-controlled trial of single vs weekly courses of antenatal corticosteroids for women at high risk of preterm delivery. The objectives of this trial were (1) to determine the efficacy of this practice in reducing the incidence of composite neonatal morbidity beyond that achieved with a single course of therapy and (2) to evaluate potential maternal and early neonatal morbidities associated with weekly courses of antenatal corticosteroids.

METHODS

Pregnant women at high risk of preterm delivery were recruited from 13 academic centers in the United States from February 1996 through April 2000. Study procedures were conducted according to a common protocol at the participating centers. The investigational review board at each center approved the study protocol. Written informed consent was obtained from all participants.

Patients were eligible for this study if they were at high risk of preterm delivery between 24 weeks' and 32 weeks 6 days' gestation. Qualifying criteria included preterm labor with intact membranes (ie, either a history of regular uterine contractions associated with cervical dilation of ≥2 cm and effacement of ≥80% in a nulliparous patient or cervical dilation of ≥3 cm and ≥80% effacement in a multiparous patient at the time of presentation; or regular uterine contractions with documented cervical change); preterm premature rupture of membranes (rupture of membranes occurring >1 hour prior to onset of preterm labor); maternal medical illness (eg, preeclampsia, hypertension, diabetes, renal disease, systemic lupus erythematosus, trauma); or suspected fetal jeopardy (eg, intrauterine growth restriction [<10th percentile], oligohydramnios, abnormal antepartum testing, progression of a fetal anomaly compatible with life, twin-twin transfusion syndrome).

Exclusion criteria included a need for immediate delivery, fetal anomalies incompatible with life, documented fetal lung maturity, and maternal active tuberculosis or human immunodeficiency virus infection. Gestational age was determined by a reliable last menstrual period confirmed by ultrasonographic evaluation during the pregnancy in 387 women (77%). Patients with either an unreliable menstrual history or inadequate clinical estimators of gestational age were assigned an estimated date of confinement based on initial fetal biometry (115 [23%] by ultrasonography only). All patients received a complete single course of antenatal corticosteroids (either betamethasone, 12 mg intramuscularly repeated once in 24 hours for 2 doses, or dexamethasone, 6 mg intramuscularly repeated every 12 hours for 4 doses). If a patient had not delivered 1 week after her initial course of antenatal corticosteroids, she was invited to participate in the trial.

Computer-generated randomization logs were prepared centrally and distributed to the research pharmacist at each clinical site. The randomization was simple and stratified by center. Consenting patients were randomized on the day that the first course of study drug was due (ie, 7 days after the start of their initial course of antenatal corticosteroids). Participants were assigned by the pharmacy to receive either betamethasone, 12 mg intramuscularly repeated once in 24 hours for 2 doses every week until 34 weeks' gestation or delivery, whichever came first (weekly-course group), or a similarly administered placebo (single-course group). The placebo syringes were indistinguishable from the syringes containing betamethasone, and both patients and health care workers were blinded to study group.

Data were collected prospectively from the maternal and neonatal records and entered into precoded data forms by study personnel. Each instance of maternal and neonatal morbidity was defined prior to initiation of the trial. Respiratory distress syndrome4 was diagnosed when a neonate had evidence of respiratory difficulty (tachypnea, grunting respirations, and retraction) and associated radiographic findings (fine reticular pattern on chest radiograph) and laboratory findings (oxygen requirement) or respiratory insufficiency in the absence of other causes of respiratory failure. Severe RDS was diagnosed in neonates with RDS that required treatment with mechanical ventilation for a minimum of 24 hours and surfactant therapy. Bronchopulmonary dysplasia was diagnosed in neonates requiring oxygen (fraction of inspired oxygen >21%) and, usually, ventilatory therapy for at least 28 days of life. In instances in which oxygen was required to maintain an acceptable PO2 without additional ventilatory support, chest radiograph findings were consistent with bronchopulmonary dysplasia. In cases of neonatal death, bronchopulmonary dysplasia was diagnosed based on autopsy findings. Severe IVH was defined as intraventricular bleeding with dilation of the cerebral ventricles (grade III) or parenchymal hemorrhage (grade IV), as diagnosed with an imaging technique or autopsy. Cranial ultrasonographs were not mandated by the study protocol and were ordered if clinically indicated. All sites graded ultrasonographic findings using the criteria of Papile et al.5 For the purpose of analysis, we recorded the most severe intracranial finding. Periventricular leukomalacia was defined as the presence of more than 1 obvious hypoechoic cyst in the periventricular white matter. Follow-up cranial ultrasonographs or late ultrasonographs were not mandated by the study protocol. Proven necrotizing enterocolitis6 was defined as the presence of any of the following: (1) unequivocal intramural air in abdominal radiograph; (2) perforation on abdominal radiograph; (3) clinical evidence of perforation (erythema and induration of the abdominal wall or intra-abdominal abscess formation); (4) characteristic findings observed at surgery or autopsy; or (5) stricture formation after an episode of suspected necrotizing enterocolitis. Proven sepsis was defined as presence of a positive blood culture obtained in the first week of life in association with clinical findings suggesting illness for which the neonate received antibiotics. Finally, perinatal death was defined as death of a fetus or neonate at any time between randomization and nursery discharge.

The primary outcome measure for the trial was composite neonatal morbidity, defined as presence of any of the following complications: severe RDS, bronchopulmonary dysplasia, severe IVH, periventricular leukomalacia, necrotizing enterocolitis, proven sepsis, or death between randomization and nursery discharge.

We determined that a sample of 1000 women was required to have 90% power to detect a one-third reduction in composite morbidity from 25.0% to 16.5% (2-tailed α = .05) using a χ2 test for proportions. Two interim analyses were planned for efficacy and safety. To compensate for these, the overall α level for the trial was adjusted downward. At the first interim analysis, the significance level chosen to establish efficacy for composite morbidity was .005. An independent data and safety monitoring committee consisting of a perinatologist and a neonatologist reviewed the blinded results.

The primary statistical analysis of the trial was based on intention to treat, and the unit of analysis was the mother. In cases of multiple gestation, we randomly selected 1 of the infants for analysis. The latency interval was defined as the interval from the first unblinded corticosteroid injection to delivery.

Two independent sample t tests were used to compare continuous variables between treatments, and χ2 tests were used to compare discrete variables between treatments. We analyzed the primary and secondary outcomes using χ2 tests to compare the treatment groups with respect to composite morbidity (the primary outcome) and to each of the individual components within the composite outcome (secondary outcomes). These analyses were unadjusted. We used the Breslow Day test for homogeneity of effect across the multiple sites and the Mantel-Haenszel method to compute an adjusted χ2 test and estimates of adjusted relative risk, considering site as a potential confounder. In the final stage of analysis, we performed exploratory analyses on subgroups (eg, gestational age groups at randomization and delivery) to assess consistency of effect. Data were analyzed using SAS version 8.0 (SAS Institute, Cary, NC).

RESULTS
Interim Analysis

A planned, blinded interim analysis was conducted in March 1999 after 308 women had been randomized (161 in the weekly-course group and 147 in the single-course group). The groups were balanced at randomization for race, parity, gestational age, qualifying criteria, and center. Rates of composite morbidity in the 2 groups were similar at 24% (39/161) in the weekly-course group and 27% (40/147) in the single-course group (P = .54).

At the time of this analysis, there were increasing reports in the literature regarding the potential for long-term neurologic complications associated with weekly courses of antenatal corticosteroids in humans.713 Because of these safety concerns and our finding of only a marginal difference (3%) in short-term outcomes between the groups, the study statistician performed a conditional power analysis. If we recruited the planned 1000 women and the trends continued, then the probability that we would find a significant difference between the 2 treatment groups was less than 2%.

As a result of this analysis, the data and safety monitoring committee, the advisory board, and the principal investigator decided to revise our planned sample size and limit enrollment to 500 women. By continuing enrollment to this number, we could confirm that the current trends were continuing and increase our precision in estimating the effect of weekly- vs single-course therapy.

Final Results

A total of 502 patients were recruited from the 13 participating centers (Figure 1). Thirty-two women withdrew from the trial (15 [5.8%] of 256 in the weekly-course group and 17 [6.9%] of 246 in the single-course group; P = .63). The most common reason for withdrawal was a desire not to receive additional injections (regardless of whether they were receiving antenatal corticosteroids or placebo injections; n = 20). No patient withdrew because of adverse effects. In 4 additional cases, the managing obstetrician withdrew a patient from the study (n = 2 in each group) to administer known corticosteroid injections. Seven of these 36 patients received additional corticosteroids prior to delivery. Sixteen women and 1 neonate were lost to follow-up. Partial data are available for patients who were lost to follow-up. The investigators at each site attempted to contact patients who were lost to follow-up, their relatives, and their referring physicians using the information that was collected at the time of enrollment. In some cases, we were able to ascertain the birth date, weight, and health status of the neonate. All patients were evaluated in the intention-to-treat analysis, but because of missing data, the denominators presented may vary slightly from one variable to another.

Demographic data for the population are presented in Table 1. The patients recruited were racially and ethnically diverse. Most received government assistance in paying for health care. The most common indication for receiving antenatal corticosteroids was preterm labor.

Pregnancy outcomes are listed in Table 2. The interval from first unblinded corticosteroid injection to delivery (the latency interval) was significantly shorter in the weekly-course group (mean [SD], 5.0 [3.7] weeks vs 5.8 [3.8] weeks; P = .02), despite similar gestational ages at randomization. Consequently, patients in the weekly-course group received fewer treatment courses (2.8 [2.3] vs 3.3 [2.4] courses; P = .03). In the weekly-course group, 88 patients received 2 courses, 55 received 3 courses, 34 received 4 courses, 20 received 5 courses, and 48 received 6 or more courses of antenatal corticosteroids.

Birth weight and gestational age data are presented in Table 2. Overall, 275 neonates were male and 212 were female. The median Apgar score at 1 minute in both groups was 8 (interquartile range, 6-9; P = .47) and at 5 minutes in both groups was 9 (interquartile range, 8-9; P = .63). Ninety-nine neonates (20%) received 1 or more courses of surfactant (n = 40 cases in the weekly-course group and n = 59 in the single-course group; P = .01) and 37 (8.3%) received postnatal steroids for bronchopulmonary dysplasia (n = 20 cases in the weekly-course group and n = 17 in the single-course group; P = .75).

Neonatal outcomes are presented in Table 3. In the single-course group, the rate of composite morbidity was 28.0% compared with 22.5% of neonates in the weekly-course group (P = .16). To determine if a specific subgroup of neonates might have benefited from weekly courses of antenatal corticosteroids, the composite morbidity rates were stratified by gestational age groups at randomization and at delivery. In all of these planned subgroup analyses, the composite morbidity rates were lower in the weekly-course group compared with the corresponding single-course group, as shown in Table 3. However, this finding reached statistical significance only in neonates who were delivered prior to 28 weeks' gestation. Differences in the rate of severe RDS in neonates delivered before 28 weeks' gestation (21 [65.6%] of 32 women in the weekly-course group compared with 25 [89.3%] of 28 in the single-course group) accounted for the improvement in composite morbidity in the weekly-course group. Neither gestational age at randomization nor the number of courses of antenatal corticosteroids was related to the incidence of composite morbidity (P = .25) (data available from the author).

Proportions of neonates with individual morbidities are also listed in Table 3. The only statistically significant intergroup difference was in rates of severe RDS. Regardless of this difference, rates of bronchopulmonary dysplasia were similar. Cranial ultrasonography was performed in 221 neonates. There were more cases of severe IVH in the neonates exposed to weekly courses of antenatal corticosteroids (9 cases vs 2 cases in the single-course group), although the difference did not reach statistical significance (P = .06).

The rate of chorioamnionitis in the weekly-course group was 24.1% (60/249) compared with 17.8% (42/236) in the single-course group (P = .09). Twenty-seven additional patients developed postpartum endometritis (n = 13 in the weekly-course group and n = 14 in the single-course group; P = .73). There were no differences in wound infections (3 cases in the weekly-course group vs 4 cases in the single-course group; P = .71), hemorrhage (17 cases in the weekly-course group vs 27 cases in the single-course group; P = .08), or mean (SD) length of stay from delivery to discharge (2.6 [1.2] days in the weekly-course group vs 2.6 [1.3] days in the single-course group; P = .69). None of the patients developed clinical stigmata suggestive of Cushing syndrome.

COMMENT

Overall, weekly courses of antenatal corticosteroids did not significantly reduce composite morbidity compared with a single course. We chose composite morbidity as our primary outcome measure because it was conceivable that weekly antenatal corticosteroids might reduce certain morbidities (eg, severe RDS) while increasing others (eg, sepsis, necrotizing enterocolitis). We believe that combining these individual morbidities would be a better representation of the overall neonatal response to maternal treatment than the individual morbidities. In a secondary analysis, weekly courses of antenatal corticosteroids significantly reduced rates of severe RDS. However, there was no concomitant improvement in survival or reduction in rates of bronchopulmonary dysplasia or duration of neonatal hospital stays. There were also strong negative trends, including increased risk of severe IVH and chorioamnionitis. Both of these are independent risk factors for cerebral palsy.1418

Recently, the NIH convened a consensus development conference on repeat courses of antenatal corticosteroids. Panel members decided that the composite morbidity variable should be restricted to include variables that would be most predictive of long-term morbidity. The recommended composite morbidity included perinatal death, bronchopulmonary dysplasia, severe IVH, and periventricular leukomalacia. Applying this definition to our data, 36 neonates (14.5%) in the weekly-course group experienced significant morbidity compared with 34 (14.3%) in the single-course group (unadjusted relative risk, 1.01; 95% confidence interval, 0.65-1.55; P = .97).

Neonates who were delivered prior to 28 weeks' gestation appeared to benefit from weekly courses of antenatal corticosteroids by a significant reduction in our predetermined composite morbidity (unadjusted relative risk, 0.80; 95% confidence interval, 0.65-0.98). The benefit was largely due to fewer cases of severe RDS. However, after applying the composite morbidity variable of the NIH consensus panel, the outcomes in the neonates who were delivered at less than 28 weeks were not different (24 [77.4%] of 31 in the weekly-course group compared with 22 [78.5%] of 28 in the single-course group; P = .95). Furthermore, data from the North American Thyrotropin-Releasing Hormone Trial16 indicated that there was no improvement in RDS rates and a disproportionate increase in mortality among neonates born prior to 28 weeks' gestation with additional courses of antenatal corticosteroids.

We believe that we are justified in our decision to prematurely terminate the study. Continuing recruitment to 500 women ensured that we had sufficient precision to estimate the effect of weekly- vs single-course therapy. Using our predetermined composite morbidity outcome and our findings after recruitment of more than half of the planned sample, the probability that we would detect a difference in composite morbidity rates between the groups if we continued recruitment to 1000 women is estimated to be 7%. If we adopted the new composite morbidity of the NIH consensus panel, the probability would be considerably lower (0.3%).

In humans, a single course of antenatal corticosteroids has not been associated with detectable cognitive or motor deficits in long-term follow-up.19,20 In contrast, multiple courses of antenatal corticosteroids have been associated with deficits. French et al9 detected significant differences in head circumference at birth in very low-birth-weight neonates. Reductions in head circumference measurements were proportional to the number of courses administered. The differences in head circumference resolved by 3 years of age. However, an independent association between increased number of courses of antenatal corticosteroids and adverse behavior persisted. In addition, Esplin et al21 found that exposure to multiple courses of antenatal corticosteroids was independently associated with delayed psychomotor development. The preliminary findings of these 2 studies are based on small numbers of low-birth-weight neonates in highly selected patient populations. Nevertheless, their findings are consistent with similar observations in animal models.7,13,2226

Our trial was limited by the lack of standardization in obtaining cranial ultrasonographs. In general, all of the participating centers obtained at least 1 cranial ultrasonograph in the first week of life in neonates born at less than 32 weeks' gestation. None of the participating centers routinely performed ultrasonography in neonates who were delivered at more than 32 weeks' gestation. Follow-up scans were scheduled at the discretion of the clinicians. We recognized that we might fail to identify neonates who had grade I and II hemorrhages if cranial ultrasonographs were not routinely performed. However, these lesions are not predictive of adverse neurologic outcomes.1618,27 While it is possible to have asymptomatic periventricular leukomalacia, it is unlikely that severe IVH would occur without a change in clinical status that would prompt an evaluation of the central nervous system.28 Interestingly, the rate of severe IVH was higher in the neonates exposed to weekly courses compared with those who received a single course (9 vs 2; P = .06). This finding could simply be due to chance, or it could reflect a predisposition of neonates given weekly courses of antenatal corticosteroids to intracranial hemorrhage, perhaps by an alteration in cerebral blood flow.

Another limitation was the lack of standardized protocols for performing neonatal biometry. We believe that the recorded birth weights were accurate and obtained in a timely manner. There were no significant differences in mean birth weights between the 2 groups. This is reassuring, given the data demonstrating lower birth weights in animals and in humans exposed to repeated antenatal corticosteroids.7,9,2226 Similarly, we were unable to detect significant differences in head circumference. We acknowledge a potential lack of precision in the methods for obtaining these data as well as variability in timing of the measurements. Despite these limitations, because our trial was blinded, these data should not be preferentially biased in one way or another. In animal models, the dose of antenatal corticosteroids that affects the brain is lower than the dose that results in growth restriction.23 Long-term follow-up studies in humans are needed to determine the impact of weekly courses of antenatal corticosteroids on the nervous system.

In conclusion, in our randomized placebo-controlled trial, weekly courses of antenatal corticosteroids did not reduce composite morbidity compared with a single course in women at risk of preterm delivery. Given the apparent lack of efficacy and the potential for short- and long-term neurologic damage resulting from weekly administration, we elected to "do no harm" and stop the study prematurely. Our data strongly suggest that weekly courses of antenatal corticosteroids should not be prescribed routinely for women at risk of preterm delivery. Currently, a number of investigators have trials under way investigating the efficacy and safety of repeat courses of antenatal corticosteroids. These trials differ from our own in that the number of potential exposures to antenatal corticosteroids is limited and/or the interval between treatments is longer.29 We eagerly await their results and hope they will provide useful information on the optimal timing and frequency of antenatal corticosteroid therapy to allow maximal benefit to neonates while minimizing potential complications of therapy.

References
1.
National Institutes of Health Consensus Development Conference Statement.  Effects of corticosteroid for fetal maturation on perinatal outcomes, February 28–March 2, 1994.  JAMA.1995;273:413-417.
2.
Planer P, Ballard R, Ballard P.  et al.  Use of antenatal corticosteroids (ANCs) in the USA [abstract].  Am J Obstet Gynecol.1996;174:467A.
3.
Brocklehurst P, Gates S, McKenzie-McHarg K, Alfirevic Z, Chamberlain G. Are we prescribing multiple courses of antenatal corticosteroids? a survey of practice in the UK.  Br J Obstet Gynaecol.1999;106:977-979.
4.
Martin R, Fanaroff A. The respiratory distress syndrome and its management. In: Neonatal Perinatal Medicine. Vol 2. New York, NY: Mosby; 1992:811-820.
5.
Papile L, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm.  J Pediatr.1978;92:529-534.
6.
Bell M, Ternberg J, Feigin R.  et al.  Neonatal necrotizing enterocolitis: therapeutic decision based on clinical findings.  Ann Surg.1978;187:1-7.
7.
Dunlop S, Archer M, Quinlivan J, Beazley L, Newnham J. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system.  J Matern Fetal Med.1997;6:309-313.
8.
French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: behaviour outcomes in a regional population of very preterm infants [abstract].  Pediatr Res.1998;43:214A.
9.
French N, Hagan R, Evans S, Godfrey M, Newnham J. Repeated antenatal corticosteroids: size at birth and subsequent development.  Am J Obstet Gynecol.1999;180:114-121.
10.
Hack M, Breslau N, Weissman B, Aram D, Klein N, Borawski E. Effect of very low birthweight and subnormal head size on cognitive abilities at school age.  N Engl J Med.1991;325:231-237.
11.
Hagan R, French N, Evans S.  et al.  Repeated antenatal corticosteroids: growth and early childhood outcome.  Pediatr Res.1997;41:405.
12.
Skinner A, Battin M, Solimano A, Daaboul J, Kitson H. Growth and growth factors in premature infants receiving dexamethasone for bronchopulmonary dysplasia.  Am J Perinatol.1997;14:539-546.
13.
Stewart J, Gonzalez C, Christensen H, Rayburn W. Effects of multiple doses of betamethasone on the perinatal outcomes and growth of mice offspring.  Am J Obstet Gynecol.1997;176:676.
14.
Wu Y, Colford J. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis.  JAMA.2000;284:1417-1424.
15.
Yoon B, Romero R, Park J.  et al.  Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years.  Am J Obstet Gynecol.2000;182:675-681.
16.
Cooke R. Trends in incidence of cranial ultrasound lesions and cerebral palsy in very low birthweight infants 1982-93.  Arch Dis Child Fetal Neonatal Ed.1999;80:F115-F117.
17.
Doyle L, Betheras F, Ford G, Davis N, Callanan C. Survival, cranial ultrasound and cerebral palsy in very low birthweight infants: 1980's versus 1990's.  J Paediatr Child Health.2000;36:7-12.
18.
Vohr B, Allan W, Scott D.  et al.  Early-onset intraventricular hemorrhage in preterm neonates: incidence of neurodevelopmental handicap.  Semin Perinatol.1999;23:212-217.
19.
Smolders-de-Haas H, Neuvel J, Schmand B, Treffers P, Koppe J, Hoeks J. Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10-12 year follow-up.  Pediatrics.1990;86:65-70.
20.
MacArthur B, Howie M, Dezoete J, Elkins J. School progress and cognitive development of 6-year old children whose mothers were treated antenatally with betamethasone.  Pediatrics.1982;70:99-105.
21.
Esplin M, Fausett M, Smith S.  et al.  Multiple courses of antenatal steroids are associated with a delay in long-term psychomotor development in children with birth weights ≤1500 grams.  Am J Obstet Gynecol.2000;182:S24.
22.
Howard E, Granoff D. Increased voluntary running and decreased motor coordination in mice after neonatal corticosterone implantation.  Exp Neurol.1968;22:661-673.
23.
Carlos R, Seidler F, Slotkin T. Fetal dexamethasone exposure alters macromolecular characteristics of rat brain development: a critical period for regionally selective alterations?  Teratology.1992;46:45-59.
24.
Uno H, Lohmiller L, Thieme C.  et al.  Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques.  Brain Res Dev Brain Res.1990;53:157-167.
25.
Uno H, Eisele S, Sakai A.  et al.  Neurotoxicity of glucocorticoids in the primate brain.  Horm Behav.1994;28:336-348.
26.
Bohn M, Friedrich V. Recovery of myelination in rat optic nerve after developmental retardation by cortisol.  J Neurosci.1982;2:1292-1298.
27.
Roth S, Baudin J, McCormick D.  et al.  Relation between ultrasound appearance of the brain of very preterm infants and neurodevelopmental impairment at eight years.  Dev Med Child Neurol.1993;35:755-768.
28.
Chess P, Chess M, Manuli M, Guillet R. Screening head ultrasound to detect intraventricular hemorrhage in premature infants.  Pediatr Radiol.1997;27:305-308.
29.
DeFrance B, Brennan B. Single versus multiple courses of antenatal corticosteroids.  Evid Based Obstet Gynecol.2001;3:109-110.
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