| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From Regional Perinatal Center, Sacred Heart Women’s Hospital, Pensacola, Florida; Analytic Consultants of Lee’s Summit, Lee’s Summit, Missouri; Pediatrix Medical Group, Sunrise, Florida; and University of Minnesota Medical School, Minneapolis, Minnesota.
Address reprint requests to: J. A. Thorp, MD, 712 Jamestown Drive, Gulf Breeze, FL 32561; E-mail: jathorp{at}bellsouth.net.
 |
ABSTRACT |
|---|
TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: We conducted a retrospective analysis of non-anomalous newborns admitted to the neonatal intensive care unit from 23 to 34 6/7 weeks of gestation. Independent variables included maternal age, race, nulliparity, poor prenatal care, multiple gestation, obstetric complications, alcohol, tocolytic drugs, smoking, illicit drugs, gestational age at birth, presentation, method of delivery, 5-minute Apgar score < 7, surfactant use, severe intracranial hemorrhage, and length of stay.
RESULTS: Antenatal and postnatal corticosteroids were given in 62% and 14% of the newborns, respectively, and 10% of newborns received both. The mean (±SD) weight gain and head circumference growth in the nursery was 440 ± 582 g (n = 14,217) and 2.54 ± 3.42 cm (n = 12,808), respectively. After multivariable analysis, use of antenatal corticosteroids did not affect weight gain (3.6 ± 4.6 g) and head circumference growth (0.05 ± 0.04 cm) compared with no exposure to perinatal corticosteroids, but postnatal corticosteroids were associated with significant reductions in weight gain and head circumference growth (-120 ± 12.2 g and -0.53 ± 0.11 cm, respectively).
CONCLUSIONS: Antenatal corticosteroid therapy did not affect weight gain or head circumference growth in the nursery, even when used in conjunction with postnatal corticosteroid therapy.
In the 1990s, the sister subspecialties of maternal fetal medicine and neonatology embarked on strategies of aggressive and repeated corticosteroid therapies in hopes of improving outcomes in fetuses and newborns, respectively. Although well-intentioned, these strategies were based on little, if any, long-term outcome data. Two recent studies from experts in each of these subspecialties reviewed numerous publications alleging serious adverse consequences, including death, as a result of these strategies.1,2 The relationship of antenatal and postnatal corticosteroid therapy to outcomes has not been extensively studied. We investigated the associations of antenatal and postnatal corticosteroid therapies with weight gain and head circumference growth in the nursery.
|
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
We evaluated the following obstetric variables: maternal age; nulliparity; use of antenatal corticosteroid (yes or no); abruption; alcohol use; birth number (1, 2, or 
3); bleeding; diabetes; illicit drug use; smoking; gestational age; presence of group B streptococcus or herpes; antenatal use of indomethacin, magnesium, or nifedipine; poor prenatal care; preeclampsia; preterm premature rupture of membranes; premature labor; race (white, black, Hispanic, other); sex of the newborn; postnatal use of indomethacin; cesarean birth; gestational age at delivery, 5-minute Apgar score < 7, presentation (cephalic, breech, or other), surfactant use, use of postnatal corticosteroid (yes or no); severe intracranial hemorrhage; and length of stay. The Student t-test was used to compare continuous variables by antenatal steroid use, and 
2 tests were used to compare categorical variables.
Weight gain and head circumference growth were analyzed by using multivariable analysis of variance that controlled for all independent variables. Categorical variables were summarized by using least squares means. Continuous variables were classified into equally spaced ordinal categories to accommodate potential nonlinear trends; in each case, linear trend components were estimated. If variables had missing values, the entire observation was excluded from the analysis. Model adequacy was assessed by examination of plots of residuals versus fitted value. Preplanned comparisons of the corticosteroid exposure groups were tested by using Dunnett adjustment for multiple comparisons. Relative predictive strengths of the independent variables were compared by using the root mean square. The root mean square is an estimate of the SD in effect sizes across levels of the independent variable, expressed in the scale of the dependent variable, and is proportional to the mean difference between levels when the variable is dichotomous. Larger root mean square values indicate greater effects.
|
RESULTS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
shows selected demographic and clinical characteristics. Antenatal and postnatal corticosteroids were given in 62% and 14% of the newborns, respectively, and 10% of newborns received both antenatal and postnatal corticosteroids. Mean (± SD) gestational age and birth weight were 31.2 ± 2.9 weeks and 1671 ± 574 g, respectively. Weight gain from birth to discharge was 440 ± 582 g (n = 14,217), and length of stay was 29.5 ± 27.7 days. Table 2 shows the final multivariable model for weight gain; the R2 value was .86.
|
|
demonstrates the relationship between perinatal steroid exposure and weight gain from birth to discharge. Compared with no steroid use, use of antenatal steroids alone had no effect on weight gain (3.6 ± 4.6 g, P = .8), but postnatal steroid was associated with a significant reduction in weight gain (-120 ± 12.2 g, P < 0.001). A significant interaction was observed between antenatal and postnatal steroid use, with an effect size (± SE) of -39.8 ± 13.1 g (P = .002). Figure 2 shows the most important contributors in the model to prediction of weight gain from birth to discharge in order of decreasing significance by the root mean square.
|
|
shows the multivariable model for head circumference growth. The model R2 value was .71. Figure 3 demonstrates the relationship between perinatal steroid exposure and head circumference growth from birth to discharge. Compared with no steroid use, antenatal steroid use had no effect on head circumference growth (0.05 ± 0.04 cm, P = .51), but postnatal steroid was associated with a significant reduction in growth - 0.53 ± 0.11 cm, P < .001). No interaction was observed between antenatal and postnatal steroid use. Figure 4 shows the most important contributors in the model to prediction of head circumference from birth to discharge in order of decreasing significance by the root mean square.
|
|
|
|
DISCUSSION |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Finer and colleagues recently reviewed the emerging literature on use of postnatal steroids.2 Short-term comorbid conditions include gastrointestinal hemorrhage, intestinal perforation, nosocomial sepsis, meningitis, hyperglycemia, hyperinsulinemia, increased free fatty acid levels, and pituitary–adrenal suppression.2 Long-term adverse effects may include significant growth abnormalities, cerebral palsy, and other major abnormal neurodevelopmental outcomes.2 Finer and colleagues called for a moratorium on further studies of systemic or inhaled postnatal steroids in premature neonates unless they are well designed, adequately powered, and include evaluation of neurodevelopmental outcome as a primary end point.2 At least three studies suggested that postnatal corticosteroid therapy were associated with long-term adverse effects on neurologic function and growth with complications, including cerebral palsy.7–9
Our study shows that postnatal steroid use is associated with significant restrictions in brain and somatic growth in the intensive care nursery and that antenatal corticosteroid exposure was not associated with such effects. Administration of conventional corticosteroid regimens in the perinatal period results in levels approximately 5- to 10-fold greater in the newborn compared with the fetus; our findings are thus not unexpected.12 In an accompanying separate report of the same sample, we concluded that antenatal steroid was associated with significant reductions in birth weight and head circumference at birth.10 Although the clinical significance of our findings is unknown, these data are not reassuring. It is well known that corticosteroids increase protein catabolism and restrict growth; for this reason they should always be used cautiously before and after birth. Huang and colleagues, using betamethasone doses in pregnant sheep that were nearly identical to those used in humans, concluded that even one dose significantly retarded fetal brain growth.13 One dose of antenatal betamethasone produced a 10% reduction in brain weight at term, and brain weights were reduced by 21% with four doses.13
A major limitation of our study is that the severity of illness in the newborn period was not well controlled. The only independent variables in our analysis that reflected postnatal severity of illness were obstetric complications, gestational age at delivery, birth weight, 5-minute Apgar score < 7, use of surfactant, occurrence of severe intracranial hemorrhage, and length of stay. Thus, some selection bias may be associated with use of postnatal steroids: That is, more severely ill newborns received postnatal steroids, and the underlying illness rather than postnatal steroid use was responsible for the poor growth. However, our findings are consistent with randomized blinded trials that found similar effects of postnatal steroids. In contrast, it is much less likely that postnatal steroid use was associated with selection bias. We controlled for the major factors that obstetric care providers might use to select patients for antenatal steroid therapy, such as gestational age, preterm premature rupture of membranes, and preeclampsia. The multivariable analysis controlled for factors that might influence the clinician’s use of antenatal corticosteroids, such as gestational age, preterm premature rupture of membranes, preeclampsia, and diabetes. Another limitation of the study is that the exact timing and dosing of repeated corticosteroid administration is not available.
Epidemiologic studies in Europe, Asia, Australia, Caribbean, and the United States demonstrate that lower birth weight is associated with an increased risk of adult cardiovascular and metabolic disorders, including hypertension, hyperlipidemia, type 2 diabetes, and death from ischemic heart disease.14,15 Welberg and Seckl suggest that this association could be caused by fetal brain imprinting or programming mediated by high levels of glucocorticoids.16 The potential long-term risks of antenatal betamethasone therapy, in terms of fetal brain imprinting or programming or other adverse events, have not been excluded and require further consideration in clinical practice. From the obstetric perspective, the dramatic effects of postnatal corticosteroid use should cause even more concern about the casual use of repeated betamethasone treatment during pregnancy. As our neonatologist colleagues have done,2 it may be timely for obstetricians to consider a moratorium on the use of repeated antenatal corticosteroid therapy outside of a randomized controlled clinical trial that includes long-term follow-up.
|
Footnotes |
|---|
Received June 5, 2001. Received in revised form September 13, 2001. Accepted September 24, 2001.
|
REFERENCES |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2. Finer NN, Craft A, Vaueber E, Clark RH. Postnatal steroids: Short-term gain, long-term pain? J Pediatr 2000; 137:9–13.[Medline]
3. Crowley PA. Antenatal corticosteroid therapy: A meta-analysis of the randomized trials, 1972 to 1994. Am J Obstet Gynecol 1995;173:322–34.[Medline]
4. Banks BA, Merrill JD, Cnaan A, et al, and the North American Thyrotropin-Releasing Hormone Study Group. Multiple courses of antenatal corticosteroids and outcome of premature neonates. Am J Obstet Gynecol 1999;181: 709–17.[Medline]
5. Vermillion ST, Soper DE, Newman RB. Neonatal sepsis and death after multiple courses of antenatal betamethasone therapy. Am J Obstet Gynecol 2000;83:810–4.
6. Papile LA, Tyson JE, Stoll BJ, et al. A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants. N Engl J Med 1998;338:1112–8.
7. Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy in preterm infants: A follow-up study. Pediatrics 1998;101:1–8.
8. O’Shea MT, Kothadia JM, Klinepeter KL, et al. Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age. Pediatrics 1999;104: 15–21.
9. Shinwell ES, Karplus M, Reich D, et al. Early postnatal dexamethasone treatment and increased incidence of cerebral palsy. Arch Dis Child Fetal Neonatal Ed 2000;83: F177–81.
10. Thorp JA, Jones PG, Knox E, Clark RH. Does antenatal corticosteroid therapy affect birth weight and head circumference? Obstet Gynecol 2002;99:101–8.
11. Stathis SL, O’Callaghan M, Harvey J, Rogers Y. Head circumference in ELBW babies is associated with learning difficulties and cognition but not ADHD in the school-aged child. Dev Med Child Neurol 1999 Jun;41:375–80.[Medline]
12. Whitelaw A, Thoresen M. Antenatal steroids and the developing brain. Arch Dis Child Fetal Neonatal Ed 2000; 83:F154–7.
13. Huang WL, Beazley LD, Quinlivan JA, Evans SF, Newnham JP, Dunlop SA. Effect of corticosteroids on brain growth in fetal sheep. Obstet Gynecol 1999;94:213–18.
14. Barker DJP, Osmond C, Goldings J, Kuh K, Wadsworth MEJ. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. Br Med J 1989;298;564–7.
15. Barker DJP, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989;2;577–80.[Medline]
16. Welberg LA, Seckl JR. Review article: Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 2001;13:113–28.[Medline]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
