OBJECTIVE:

To evaluate the neonatal morbidity and the growth in very low birth-weight (VLBW) infants after exposure to multiple courses of antenatal steroids.

STUDY DESIGN:

A total of 319 VLBW infants were placed in one of the two groups based on exposure to antenatal steroids: Group 1: less than two complete courses; Group 2: two complete courses or more. Anthropometric measurements at birth and discharge and neonatal morbidity were recorded. Composite morbidity was defined as presence of any of the following: death, chronic lung disease, major intraventricular hemorrhage and periventricular leukomalacia.

RESULTS:

The composite morbidity was not significantly different between the two groups (p=0.26). A significantly higher percentage of infants born after multiple courses of antenatal steroids had head circumference below 10th percentile at discharge (23 vs 9%, adjusted OR, 3.25, (95% CI, 1.4, 7.3); p=0.015).

CONCLUSIONS:

Multiple courses of antenatal steroids may predispose VLBW infants to impairment of postnatal somatic growth without providing any additional benefit for immediate neonatal outcome.

INTRODUCTION

Since Liggins first reported the beneficial pulmonary effects in fetus after maternal administration of corticosteroids, many subsequent studies have demonstrated that antenatal corticosteroids can reduce the morbidity and mortality of preterm human neonates.^{1, 2} Since these effects are known to be maximal at 48 hours after administration and are thought to wane after 7 to 10 days of administration, many clinicians routinely used repeated courses of antenatal steroids on a weekly basis when the risk of preterm birth persisted.³

Recent evidence from several sources has questioned the benefit and safety of repeated exposure of fetus to corticosteroids. After a meta-analysis of risks and benefits of multiple courses of antenatal steroids, Walfisch et al.⁴ reported that possible beneficial effects of multiple courses include lower rates of respiratory distress syndrome (RDS) and a decrease in oxygen use. But they also highlighted concerns including possibility of reduction in head circumference at birth and lower birth weights in exposed infants. Since then, Guinn et al.⁵ have reported that composite neonatal morbidity after weekly courses of antenatal steroids is not different when compared with a single course exposure. They also reported that birth weights and head circumferences at birth were similar in two groups of infants but anthropometric data at discharge was not reported. So far there is no consensus if exposure to multiple courses of antenatal corticosteroids is associated with adverse effects on fetal growth and no studies have evaluated if adverse effects of antenatal corticosteroids on somatic and brain growth, if any, persist after birth. Thus, the question of whether multiple courses of antenatal steroids have an adverse effect on somatic growth and neonatal outcome of exposed infants requires further study.

We conducted this retrospective analysis to determine the effect of maternal treatment with multiple courses of antenatal corticosteroids on antenatal and postnatal growth and neonatal outcome of exposed very low birth-weight (VLBW) infants.

MATERIALS AND METHODS

Using a perinatal database, all infants with gestational age at delivery between 24 and 34 weeks, birth weight 1500 g and whose mothers had received antenatal corticosteroids for fetal lung maturation were included in this analysis. Maternal demographic and obstetric data, including the use and frequency of antenatal corticosteroids, were obtained from the maternal medical records. Chorioamnionitis was defined by an elevated temperature (>100.4°F) and subsequent treatment with parenteral antibiotics.

The inpatient neonatal records were examined to determine presence and extent of neonatal morbidity and mortality, including RDS, necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP) and sepsis. These complications of prematurity were defined using the Vermont Oxford Network definitions. The duration of mechanical ventilation, need for supplemental oxygen at 28 days and 36 weeks postconception and need for postnatal corticosteroid use for treatment of chronic lung disease were also noted. Chronic lung disease was defined as need for supplemental oxygen at 36 weeks postconception. Composite morbidity was defined as presence of any of the following: death, chronic lung disease, major IVH (Grade III and IV IVH) and periventricular leukomalacia. Anthropometric measures, including weight, length and head circumferences were recorded at birth and at the time of discharge from the hospital.

To determine whether the use of multiple courses of antenatal corticosteroids in mother was associated with adverse effects on growth and neonatal outcome, patients were categorized into two groups based on the degree of maternal antenatal corticosteroid exposure. The groups were defined as Group 1 if women had received less than two full courses of antenatal corticosteroids and as Group 2 if they had received two full courses or more. Data are described using means and SD for continuous variables and frequency tabulations for categorical variables. Patient characteristics are compared using t-test for continuous variables and ² or Fisher's Exact tests for categorical variables. Effect of antenatal corticosteroid use on anthropometric measurements and individual and composite morbidity was investigated using logistic regression analysis, controlling for gestational age, multiple births, chorioamnionitis, neonatal morbidity and postnatal steroid use. Systematic data reduction was done using a threshold p-value of 0.2 on single predictor models. The final models for effect of antenatal steroids on outcomes also controlled for the effect of confounding risk factors, without saturating the model. Effect of antenatal steroid treatment on postnatal growth was analyzed after controlling for corresponding anthropometric measurements at birth. These models also account for the correlation between outcomes of infants from multiple births, using a generalized estimating equations approach, with the mother as a clustering variable. Adjusted odds ratios (OR) and 95% confidence intervals (CI) are presented with respect to primary predictors. All conclusions were made at 0.05 level of significance. Institutional Review Board of Northwestern University approved this study.

RESULTS

Patient Population

During the period of study, 319 infants met inclusion criteria. The corticosteroid given to all mothers in preterm labor for fetal lung maturation during the study period was betamethasone. A mother was considered to have received one complete course of treatment if two 12 mg intramuscular doses of betamethasone were given 24 hours apart prior to delivery. Mothers of 241 of these infants had received less than two full courses and 78 had received two full courses or more of antenatal steroids. In all, 37 of 78 mothers with multiple courses had received two courses; 26 had 2.5 to three courses; 10 had 3.5 to four courses, three had five courses and one each had received seven and eight courses, respectively. Maternal and neonatal characteristics categorized by corticosteroid exposure are shown in Table 1. There were no significant differences with respect to infant gender, mean birth weight, mode of delivery and ethnicity. Women who received at least two full courses of antenatal corticosteroids were older than their counterparts (31.77.0 years vs 29.96.0 years; p=0.04). Incidence of multiple births, chorioamnionitis and mean gestational age of infants were also different among the two groups (Table 1). All further analysis of neonatal morbidity and anthropometric measurements control for these differences.

Table 1 - Patient Characteristics.

Full table

Neonatal Morbidity

Table 2 summarizes the neonatal morbidity among infants in the two groups. Composite morbidity was not significantly different between the two groups (adjusted OR, 0.56, (95% CI, 0.2, 1.54); p=0.26). Use of surfactant and incidence of IVH was lower among infants exposed to multiple courses of antenatal steroids but these differences were not statistically significant after adjusting for the gestational age. The adjusted OR for surfactant use among infants in Group 1 was 1.09; (95% CI, 0.56, 2.12; p=0.8); similarly the adjusted odds ratio for IVH among infants in Group 1 was 1.31 (95% CI, 0.66, 2.57; p=0.4). There were no infants with major IVH among infants in Group 2 but this difference was not statistically significant after controlling for gestational age (p=0.7). The duration of mechanical ventilation (7.213.5 days in group 1 versus 611 days in Group 2; p=0.2) and need for supplemental oxygen at 28 days of life (13% in Group 1 vs 8% in Group 2; p=0.3) were similar in the two groups. The incidence of chronic lung disease and use of postnatal steroids for chronic lung disease were also comparable among infants in the two groups (Table 2). There were no other significant differences in other major neonatal morbidity as well as survival to discharge among infants in the two groups (Table 2).

Table 2 - Neonatal Morbidity.

Full table

Anthropometric Measurements at Birth and Discharge

The mean weight, length and head circumference were similar at birth in both groups of infants (Table 3). The number of infants with body weight and head circumference below 10th percentile at discharge were significantly higher among infants born after multiple courses of antenatal steroids (adjusted OR, 1.83; (95% CI, 1.03, 3.25); p=0.04 for birth weight and adjusted OR, 3.25; (95% CI, 1.44, 7.3); p=0.015 for head circumference respectively, Table 3). Post hoc power analyses were conducted for the outcomes of head circumference <10th percentile at discharge using two-sided ² tests at 0.05 level of significance, without accounting for any clustering. Based on current data, sample size was assumed to be in a 3:1 ratio of patients who received <2 courses (Group 1) vs 2 courses (Group 2) of antenatal steroids. With an observed incidence of 9 and 23% for the incidence of head circumference <10th percentile at discharge in Groups 1 and 2, respectively, the current sample size had a power of 80%.

Table 3 - Anthropometric Measurements at Birth and at Hospital Discharge for Discharged Patients.

Full table

DISCUSSION

Since Liggins and Howie's landmark report describing the beneficial effects of antenatal glucocorticoid treatment, various randomized clinical trials have confirmed a favorable benefit-to-risk ratio for a single course of antenatal corticosteroids in women at risk of premature delivery.^{1, 2} However, evidence for benefit and safety of multiple courses of antenatal steroids has been lacking and various animal studies as well as preliminary data from human trials have raised serious concerns about harmful effects of multiple courses of antenatal steroids on somatic and brain growth of growing fetus. In this retrospective analysis, we observed that the composite neonatal morbidity of VLBW infants born after multiple courses of antenatal steroids was not different when compared to infants born after a single course of antenatal steroids. However, it was concerning that higher proportion of infants born after exposure to multiple courses of antenatal steroids may have had impaired brain growth as suggested by head circumference at discharge when compared to infants born after a single course of antenatal steroids. These infants were also more likely to be below 10th percentile for weight at discharge from neonatal intensive care unit.

The results of prior studies evaluating the benefit of repeated courses of antenatal steroids in reducing the incidence of neonatal morbidity have been inconsistent so far. Abbasi et al.⁶ and Elimian et al.⁷ reported lower incidence of RDS among infants born after multiple courses of antenatal steroids but a higher incidence was reported by Vermillion et al.⁸ and no differences were reported by Guinn et al.⁵ and Bank et al.⁹ Some of this variability is related to the lack of a consistent definition of RDS used in different studies. In our cohort of infants, we assessed respiratory morbidity by need for surfactant, duration of mechanical ventilation, use of postnatal steroids for chronic lung disease and need for supplemental oxygen at 28 days and 36 weeks postconception and there were no differences in the two groups.

The beneficial effects of a single course of antenatal steroids on the incidence of major IVH have been well documented.^{10, 11, 12} However, effect of multiple courses of antenatal steroids on the rate of major IVH remains unclear. Abbasi et al.⁶ and Elimian et al.⁷ did not observe any difference but Vermillion et al.⁸ and Guinn et al.⁵ reported a trend toward increase in major IVH after repeated courses of antenatal corticosteroids. In our study, none of the infants born to mothers after two or more courses of antenatal corticosteroids had major IVH as compared to 7% incidence among infants born after less than two complete courses but this difference did not reach statistical significance after adjusting for gestational age. However, the composite morbidity in our study was also not different among infants born to mothers after less than two and two or more courses of antenatal corticosteroids. This observation is consistent with the results reported by Guinn et al.⁵

Impairment in fetal growth after exposure to multiple courses of antenatal corticosteroids has been reported earlier.^{9, 13, 14, 15, 16} However, to the best of our knowledge, this is the first report evaluating the effect of multiple courses of antenatal steroids on early postnatal growth. Repeated doses of antenatal corticosteroids have been found to cause growth restriction in different animal species as well as in human fetus. Stewart et al.¹³ randomized pregnant mice to receive two, four or eight doses of betamethasone or placebo. They found that the group exposed to eight doses of betamethasone had significantly lower birth weight, shorter body length and narrower head width compared with the placebo exposed group. Pratt et al.¹⁴ and Sun et al.¹⁵ also reported a significant reduction in birth weight after antenatal betamethasone exposure in rabbits. Other investigators have also reported a reduction in fetal weight in sheep that was inversely proportional to the number of antenatal corticosteroid courses.¹⁶

Banks et al.⁹ performed a post hoc nonrandomized analysis of preterm infants born to mothers who had received 1, 2, or 3 courses of antenatal corticosteroids and reported that neonates born after two or more courses had lower birth weights compared with those born after a single course of antenatal corticosteroids. They did not report any differences in head circumferences and length of these infants. Recently, Guinn et al.⁵ compared outcome of infants born after single versus weekly courses of antenatal corticosteroids and found no differences in head circumference and weight at birth. Anthropometric data at discharge was not reported in either of these two studies. In an observational study from Australia, French et al.¹⁷ reported that birth weight ratio decreased with increasing number of corticosteroid courses. They reported a 9% reduction in birth weight and as much as 4% reduction in head circumference at birth after three or more courses of antenatal corticosteroids. Analysis of birth length showed a trend toward an independent association with repeated courses of antenatal corticosteroids but did not reach statistical significance (p=0.06). However, they also did not collect anthropometric measurement data at discharge in these infants. In our study, weight, length and head circumference at birth as well as percentage of infants with these measurements at birth below 10th percentile for their gestational age were similar among infants in the two groups. We speculate that observed lack of difference in anthropometric measurements at birth in our study as well as other reports could be related to short interval between exposure and delivery in some of the study infants. This speculation is supported by the observation of French et al.¹⁷ who reported no effect on growth until a 14 day interval, with a 150 g drop in birth weight only after larger periods of exposure. However, in our cohort of infants, it is concerning that despite no statistically significant differences in all neonatal morbidity categories, infants born after multiple courses of antenatal corticosteroids were more likely to have body weight and head circumference below 10th percentile at discharge. We feel that comparison of number of infants below10th percentile is more appropriate as compared to mean values because it adjusts for differences in the duration of hospital stay and gestational ages of infants and is probably more useful in identifying infants at risk of subsequent handicap. This study was a retrospective study of a nonrandomized population, and as such, has the potential to contain hidden sources of bias. For example, infants who received only one course of steroids may be fundamentally different from their counterparts who received more courses. However, other factors associated with poor postnatal growth such as chronic lung disease, late sepsis, NEC and postnatal steroid use were similar among the two groups and could not account for these differences. To the best of our knowledge, this is, the first report documenting that adverse effects of antenatal corticosteroids on growth may persist during early postnatal period. However, the long-term significance of these findings remains unclear.

In conclusion, the results of this study suggest that multiple courses of antenatal steroids may predispose VLBW infants to impairment of somatic growth in immediate postnatal period without providing any additional benefit for reduction in their composite or individual neonatal morbidity. Future prospective trials of infants born after exposure to multiple courses of antenatal steroids should include long-term somatic growth and neuro-developmental assessment as outcome measures.

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