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Effects of Antenatal Corticosteroid Administration on Mortality and Long-term Morbidity in Early Preterm, Growth-Restricted Infants

From the Departments of Obstetrics and Neonatology, Academic Medical Center, University of Amsterdam, Amsterdam; the Department of Obstetrics, University Medical Center, Utrecht; and the Department of Neonatology, Wilhelmina Children’s Hospital, Utrecht, The Netherlands.

Address reprint requests to: Arty H. Schaap, MD P.O. Box 22660 1100 DD Amsterdam The Netherlands E-mail: A.H.Schaap{at}amc.uva.nl

	Abstract

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Objective: To evaluate the effect of antenatal corticosteroids on mortality, morbidity, and disability or handicap rate in early preterm, growth-restricted infants.

Methods: This case-control study in two tertiary care centers included all live-born singleton infants with growth-restriction due to placental insufficiency, who were delivered by cesarean because of cardiotocographic signs of fetal distress before the beginning of labor at a gestational age of 26–32 weeks during the years 1984–1991. Infants who had been treated antenatally with corticosteroids more than 24 hours and less than 7 days before birth were matched by birth weight, sex, and year of birth with infants whose mothers had been admitted more than 24 hours before delivery but were not treated antenatally with steroids. The main outcome measure was survival without disability or handicap at 2 years corrected age. A sample of 60 case-control pairs would give 81% power to demonstrate 50% increase of this outcome [odds ratio (OR) 3.0] by corticosteroid treatment. Behavior and physical growth were evaluated at school age by questionnaire.

Results: The study group and control group consisted of 62 infants each. Survival without disability or handicap at 2 years’ corrected age was more frequent in the corticosteroid group [OR 3.2, confidence interval (CI) 1.1, 11.2]. In the long-term follow-up at school age there was a statistically significant negative effect on physical growth (OR 5.1, CI 1.4, 23.8), but no differences in behavior were detected.

Conclusion: Benefits from antenatal corticosteroids for early preterm, growth-restricted infants appear to outweigh possible adverse effects.

Antenatal corticosteroid therapy for the reduction of neonatal morbidity has been extensively reviewed in a meta-analysis.¹ Many randomized or controlled trials have demonstrated a reduction of respiratory morbidity, intracerebral hemorrhage, and mortality in the preterm newborn. However, most of the trials examined in this meta-analysis included only patients with spontaneous preterm labor or premature rupture of the membranes.¹ Data in the literature are insufficient to fully assess the effectiveness or risks of antenatal corticosteroid administration in maternal high-risk conditions, such as preeclampsia or fetal growth restriction (FGR).^2,3 The first randomized study in 1972 demonstrated a statistically significant higher fetal mortality in women with hypertensive disease who had been treated with corticosteroids.⁴ In a trial with long-term follow-up, the Amsterdam trial of Schutte et al,^5,6 FGR was an exclusion criterion. The 1994 report of the National Institutes of Health Consensus Development Conference on the use of corticosteroids for fetal maturation and their effect on perinatal outcomes acknowledged this lack of data.² Although the need for randomized trials was recognized, it was stated that it would be reasonable to treat patients as if they were at risk for preterm delivery. Recently, Elimian et al⁷ detected no benefit in neonatal morbidity from antenatal steroids in small for gestational age infants. Their results call into question the use of steroids in this specific obstetric population.

To evaluate the efficacy of antenatal corticosteroids on mortality, neonatal morbidity, and long-term outcome in early preterm, growth-restricted infants, we performed a case-control study.

	Materials and Methods

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Eligible for the study were all live-born singleton infants who were delivered by cesarean because of fetal distress before the onset of labor from 1984 through 1991 at a gestational age of 26 through 31 weeks in two tertiary care centers: the Academic Medical Center, University of Amsterdam and the University Medical Center of Utrecht. Part of this study population has been described previously.⁸

All mothers had been hospitalized before delivery for fetal surveillance because of FGR. Fetal growth restriction was diagnosed by fundal height measurement and by sonographic fetal biometry. The growth restriction was due to placental dysfunction, as confirmed by pathological examination of the placenta. All other causes of FGR were excluded. Fetal condition was surveyed by nonstress electronic monitoring. Eventually before the onset of labor, cardiotocographic signs of fetal distress were present because of placental dysfunction. All infants were therefore delivered by cesarean.

Only infants of women who had been admitted to the hospital more than 24 hours before delivery were included to exclude those cases who needed an emergency cesarean delivery directly after admission and therefore could not have been treated with corticosteroids. Fetal death or fetal distress at admission to the hospital, abruptio placentae, and neonates with lethal congenital anomalies or congenital infections were also exclusion criteria. Pregnancy-induced hypertension, preeclampsia, or hemolysis with elevated liver enzymes and low platelets (HELLP) syndrome were often present but not entry criteria. Preeclampsia was defined by a diastolic blood pressure 90 mmHg measured at least twice and proteinuria 0.3 g/24 hours. The HELLP syndrome was defined by hemolysis (serum lactate dehydrogenase 600 U/L or more), serum aspartate aminotransferase 50 U/L or more, and platelet count <100 x 10⁹/L.

Gestational age was calculated by the last menstrual period and early ultrasonographic examination if available. Birth weight percentile was calculated using the Amsterdam birth weight chart adjusted for parity and neonatal sex.⁹

During the time of the study the decision to administer betamethasone (two doses of 12.5 mg by IM injection with a 24-hour interval) depended on the attending obstetrician, because in both hospitals controversy existed about the benefit from this treatment in FGR.

The treated group consisted of all infants whose mothers had been given betamethasone more than 24 hours up to 7 days before birth. In the control group, were all remaining infants of mothers who did not receive betamethasone and who had been admitted more than 24 hours before delivery. Each case of the treated group was matched with one of the controls by random electronic selection based on birth weight (difference less than 175 g), sex of the infant, and year of birth (difference less than 2 years).

In both centers, the same definitions were used to assess neonatal morbidity. Respiratory distress syndrome (RDS) was defined as tachypnea, chest wall retractions, and oxygen requirement in the presence of a chest x-ray classified as RDS.¹⁰ Only a minority of the neonates with severe RDS received surfactant therapy, as this treatment was not standard during the first years of the study. Infants with transient tachypnea, pulmonary edema, and pneumonia were excluded from the RDS category. Bronchopulmonary dysplasia was defined as the presence of chronic respiratory distress and oxygen requirement beyond 28 days of life accompanied by a chest radiograph that showed persistent streaks of increased density in both lungs interspersed with normal or hyperlucent areas. Intracerebral hemorrhage was defined using Papile’s classification system.¹¹ Only grades 3 and 4 intracerebral hemorrhage were taken into account. Sepsis included (early and late onset) neonatal septicemia or meningitis. Only infants with sepsis confirmed by positive culture were included in this group. Survival was defined as survival at discharge home, irrespective of age. All infants who survived the initial hospital stay were included in the follow-up study.

At 2 years corrected age, infants were clinically screened for psychomotor development, neurological disorders, and speech, hearing, and visual function. The method was adapted from Egan et al.¹² They were classified as normal or having a disability, minor handicap, or major handicap according to the World Health Organization classification adapted for 2-year-old infants.^13,14

Long-term follow-up data (at school age) were obtained as described recently.¹³ The long-term outcomes of interest included physical growth and behavior. Physical growth was assessed by using standard deviation to adjust for discrepancies in age and sex.¹⁵ Behavior was assessed by the Diagnostic and Statistical Manual of Mental disorders criteria for attention-deficit hyperactivity disorder.¹⁶ As the prevalence of attention-deficit hyperactivity disorder symptoms is strongly related to age and gender, we used the DuPaul-score as described by Barkley,¹⁷ which distinguishes different cutoff points (two standard deviations above the mean) for age younger than 6 years versus 6–11 years, and for girls and boys. Parents were asked to score the 14 items of the questionnaire according to a 4-point scale (0 = not at all; 1 = sometimes; 2 = rather often; 3 = very frequently). Each item scoring 2 or more was assessed as positive (inappropriate). Behavior was defined as inappropriate for children aged younger than 6 years if 10 or more items were assessed as positive. For children aged 6 years or older, differentiation for sex was made: for boys ten and for girls eight positive items defined inappropriate behavior.¹⁸

Factors that might be associated with behavioral problems included maternal education, both parents at home, and number of siblings.¹⁹ Maternal education was measured on a 4-point scale, where 1 indicates less than high school graduate; 2, high school graduate; 3, postsecondary school; and 4, university degree.

Statistical analysis of case-control data was performed by paired-sample t tests for continuous variables and McNemar ² tests and calculation of Mantel–Haenszel matched odds ratios (OR) with 95% confidence intervals (CI) for discrete variables. For long-term follow-up, the case-control design had to be discarded because of the large number of incomplete pairs after neonatal death. These data were tested by two-sample t test or ² test as appropriate. Odds ratios were calculated from single table analysis with 95% CI. For all statistical tests P < .05 was considered statistically significant.

The primary outcomes were defined by survival without disability or handicap at 2 years’ corrected age and by physical growth and behavior at school age. Stepwise logistic regression analysis was performed with the primary outcomes as dependent variables. Independent variables were gestational age, birth weight, sex of the infant, year of birth, center of birth, antenatal steroid administration, preeclampsia/HELLP, RDS, bronchopulmonary dysplasia, intracerebral hemorrhage, sepsis, and sociodemographic factors. The analysis was started with all variables included in the model. Terms were removed or re-entered at each step by maximum likelihood method. The convergence criterion for the likelihood function and for the parameters was set at 0.0001.

Statistical calculations were performed with BMDP statistical software (Los Angeles, CA). For sample size calculation, we assumed that the incidence of survival without disability or handicap without antenatal administration of corticosteroids was 50%²⁰ and that this outcome would increase 50% after corticosteroid treatment (OR 3.0).¹ A sample of 120 infants (60 cases and 60 matched controls) would provide a power of 81% to detect the increase for a two-sided test of significance at a critical level of 0.05 by a case-control study design.

The research ethics committees of the University Hospitals gave approval for the study.

	Results

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A total of 175 infants met the inclusion criteria. Sixty-two of these infants had been treated antenatally with corticosteroids. These infants were matched by birth weight, sex of the infant, and year of birth with 62 of the 113 infants who were not treated (the control group).

Table 1 shows the main perinatal details of the study and the control groups. Birth weight was on average 44 g less and gestational age at delivery on average 3 days less in the corticosteroid group. These differences reached statistical significance. Further differences between both groups were observed in center allocation and the incidence of preeclampsia and HELLP syndrome.

Fifty-three children in the steroid group and 47 children in the control group were discharged home alive. They were all followed at least until the corrected age of 2 years. Two infants in the treated group and seven infants in the control group had a disability or handicap (OR 0.2, CI 0.0, 1.3). Survival without disability or handicap was significantly higher in the steroid group (OR 3.2, CI 1.1, 11.2). Survival was higher in the study group, but this difference was not statistically significant (OR 2.5, CI 0.7, 10.9).

The causes of death in each group are summarized in Table 2. Death because of pulmonary dysfunction was equal in both groups. More infants in the control group died because of intracerebral hemorrhage and sepsis, although the incidence of these complications was comparable between the groups (Table 1).

All nine infants who received more than one course of steroids survived. However, two children had behavioral problems and one child showed physical growth below the tenth percentile.

The stepwise logistic analysis (Table 4) demonstrated that the odds of survival without disability or handicap increased by 1.7 for each additional 250 g of birth weight and by 3.1 for antenatal corticosteroids and decreased by 0.2 when intracerebral hemorrhage or bronchopulmonary dysplasia occurred. The odds of growth below the tenth percentile decreased by 0.5 for each additional 250 g of birth weight and increased by 4.9 for the use of antenatal steroids. None of the other variables mentioned in the Materials and Methods section contributed significantly to the model.

	Discussion

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We know of only two retrospective cohort studies that assessed the effectiveness of antenatal corticosteroids in preterm, growth-restricted infants.^7,22 In these studies, FGR was defined after delivery by a birth weight below the tenth percentile of a birth weight chart. This definition differs from that in our study group, which was defined antenatally by the sonographic diagnosis of FGR and by an abnormal nonstress test as a sign of fetal compromise necessitating a cesarean delivery. In this way, we could account for the functional aspect of the placenta and the dynamic aspect of fetal growth.

Spinillo et al²² studied a group of 424 infants with a gestational age less than 35 weeks. In this group, 96 children were growth restricted, of whom 32 received corticosteroids antenatally. In their study, the antenatal administration of corticosteroids significantly reduced the rate of grade 3 and 4 intracerebral hemorrhage (OR 0.17, CI 0.04, 0.80) but not of RDS (OR 0.5, CI 0.21, 1.26). Elimian et al⁷ described 1148 neonates below 1750 g of whom 28% were treated antenatally with corticosteroids. Antenatal steroids significantly decreased the incidence of major neonatal morbidity and mortality in appropriately grown neonates, whereas no benefit was detected in 240 small for gestational age infants, of whom 63 had been treated with corticosteroids antenatally. However, they did not demonstrate if gestational age at delivery was comparable between the growth-restricted infants who received steroids antenatally and those who did not.

In the above-mentioned studies^7,22 the control group was defined only by no-steroid treatment without further specification. It is conceivable that the fetal condition on hospitalization was different between cases and controls.

Similarly, in our study the possibility of selection bias cannot be excluded because of the retrospective design. The administration of corticosteroids was not randomized but determined by the belief of the attending obstetrician as to whether this treatment offered a benefit to the infant. These decisions were not founded on medical evidence at that time and, apparently, a difference of opinion between the two centers existed.

Hypertensive mothers were less often treated with corticosteroids (Table 1). It is unlikely that this pattern influenced results, as serious morbidity in infants of hypertensive mothers was demonstrated to be comparable to others.^23,24

Because all mothers had been admitted at least 24 hours before delivery, a difference in fetal condition on admission is unlikely. By matching the most important factors influencing survival without disability or handicap in early preterm, growth-restricted infants (birth weight, sex of the infants, and year of birth)¹³ we intended to minimize the influence of other factors besides the antenatal administration of corticosteroids on the outcome of the study. Notwithstanding the matching procedure, birth weight and gestational age were significantly lower in the corticosteroid group compared with the control group, although the quantity of this difference was small. Because this difference favors the control group, the observed effect of antenatal corticosteroid treatment may even be underestimated with regard to survival without disability or handicap. Furthermore, in the logistic analysis other factors that might influence outcome (differences between the participating centers, ethnic origin, parity, year of birth) did not contribute to the model predicting survival without disability or handicap, or growth below the tenth percentile.

Meta-analysis¹ of 15 randomized trials, conducted between 1972 and 1994, showed an overall reduction in approximately 50% in the incidence of RDS in preterm infants after antenatal administration of corticosteroids (OR 0.5; CI 0.4, 0.6). This effect has been demonstrated mainly for spontaneous preterm labor.^1,21 In our selected population the use of steroids, given between 24 hours and 7 days before delivery, was not associated with a reduction in RDS. This finding is comparable to that in two other studies evaluating the use of corticosteroids in FGR.^7,22

It has been reported that steroids can improve neonatal pulmonary function without reducing the overall rate of RDS.^25,26 In our population antenatal corticosteroids did not reduce the incidence of bronchopulmonary dysplasia, a finding that is in agreement with the influence of steroids on bronchopulmonary dysplasia from the meta-analysis.¹ Clinical trials of postnatal systemic corticosteroids in established chronic lung disease of prematurity have been reviewed thoroughly and show that this treatment facilitated weaning from mechanical ventilation.²⁷ In our population 16 (26%) children in the steroid group versus 19 (31%) in the control group had bronchopulmonary dysplasia. Ten of these infants with bronchopulmonary dysplasia in the steroid group compared with five in the control group received postnatal corticosteroids. Nevertheless, the mean number of days of mechanical ventilation was not different between the two groups.

Analysis of the literature showed a substantial reduction of the incidence of severe intracerebral hemorrhage (OR 0.5, CI 0.3, 0.9).^1,25,28 In our study antenatal steroid use was not associated with a reduction of severe intracerebral hemorrhage. This finding differs from the result of a previous investigation of preterm deliveries with different etiology,²² but is comparable to that of another study.⁷

Data in the literature on mortality (OR 0.6, CI 0.5, 0.8) mirror the data on the reduction of RDS.¹ In our study there was a lower mortality in the steroid group, although this difference was not statistically significant.

The group of infants who received more than one course of antenatal corticosteroids is very small (n = 9). Therefore, we cannot draw conclusions on this highly interesting item.

At 2 years’ corrected age, a statistically significant higher survival without disability or handicap in the steroid group was seen. This finding is consistent with a meta-analysis of follow-up studies, which suggested a protection of antenatal steroid administration against severe neurological disorders.¹

At school age there was no difference in behavioral problems between the steroid and the control group, which agrees with a follow-up study by MacArthur et al²⁹ in 4-year-old children and another by Schmand et al³⁰ in 10- to 12-year-old schoolchildren.

According to several studies, antenatal glucocorticoid treatment is safe for both mother and child.¹ Long-term follow-up studies in humans did not detect a negative effect of prenatal corticosteroid treatment on physical growth.^6,30,31 In our long-term evaluation, significantly less catch-up growth was seen in the steroid group. From studies in human neonates, it is known that somatic growth is impaired during high doses of dexamethasone treatment to prevent bronchopulmonary dysplasia.³² The body growth impairment induced by this treatment is temporary.^32,33 In our population, the number of cases with postnatal corticosteroid treatment in case of bronchopulmonary dysplasia was twice as high in the steroid group than in the control group. The stepwise logistic regression analysis demonstrated no significant influence of bronchopulmonary dysplasia on physical growth, eliminating a possible bias from bronchopulmonary dysplasia treatment.

Our study and data from literature did not show a significant difference in short-term morbidity after antenatal corticosteroid treatment. However, our (long-term) follow-up data demonstrated a significantly higher survival without disability or handicap, which far outweigh the negative effect of corticosteroid treatment on physical growth.

	Footnotes

 
PII S0029-7844(01)01343-6

Received September 13, 2000. Received in revised form January 5, 2001. Accepted January 31, 2001.

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