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Effect of Antenatal and Postnatal Corticosteroid Therapy on Weight Gain and Head Circumference Growth in the Nursery

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

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OBJECTIVE: To assess the effect of antenatal and postnatal corticosteroids on head circumference growth and weight gain from birth to discharge.

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

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During the study, the Pediatrix Medical Group consisted of 100 neonatal intensive care units in North America. A computerized charting system allows prospective capture of relevant data in the neonatal intensive care units. Data were prospectively collected from the 100 neonatal intensive care units in five regions of the United States between May 1997 and January 2000, with the primary goals of medical record documentation and quality improvement. Data are collected on admission and daily until discharge. This database is much more accurate than a hospital administrative data set for several reasons. The primary care provider enters the data for the purpose of generating clinical progress notes for the medical record, and the database is frequently accessed and reviewed by the care providers during the hospitalization. At discharge, the collected data are sent to a common database. No unique patient identifiers appear in this common data set. On a monthly basis, a subset of the data (eg, mode of delivery, Apgar score, birth weight, or intraventricular hemorrhage) is monitored for accuracy. The data in the database are checked against a source document that is not related to the generation of the progress note: eg, head ultrasonography, radiography, or laboratory report in the clinical chart. A sample of 10% to 20% of the patients is reviewed, and accuracy is greater than 95% for the values checked. A subset of this data included nonanomalous live-born infants admitted to the neonatal intensive care unit from 23 to 34 6/7 weeks of gestation. Only inborns were included in this analysis. Data on antenatal corticosteroid use were classified according to the Vermont-Oxford Perinatal Database as none, incomplete, or complete.³ A complete course of antenatal corticosteroid therapy was defined as treatment for 48 hours or longer from the initial dose. During the study, the general obstetric practice was to give betamethasone as two 12-mg intramuscular injections 24 hours apart. The usual neonatal practice consisted of postnatal therapy with dexamethasone, 0.2 to 0.5 mg/kg daily, given intravenously over 7 to 14 days. Gestational age was the best estimate of the obstetric and neonatal care providers, based on menstrual and sonographic dating.

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

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Of 14,350 total cases in the database, 14,217 were available for analysis of weight gain from birth to discharge. Table 1 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.

View larger version (24K): [in this window] [in a new window]   Figure 1. Relationship between perinatal steroid exposure and weight gain from birth to discharge. Compared with no steroid use, antenatal steroid use had no effect on weight gain and postnatal steroid use was associated with a significant reduction in weight gain (P ± .001). A significant interaction was observed between antenatal and postnatal steroid, with an effect size (±SE) of -20 ± 6.5 g (P < .05). Thorp. Steroids and Growth in the Nursery. Obstet Gynecol 2002.

View larger version (25K): [in this window] [in a new window]   Figure 2. The most important predictors of weight gain from birth to discharge, in order of decreasing significance. Thorp. Steroids and Growth in the Nursery. Obstet Gynecol 2002.

View larger version (20K): [in this window] [in a new window]   Figure 3. Relationship between perinatal steroid exposure and head circumference growth from birth to discharge. Compared with no steroid use, antenatal steroid had no effect on head circumference growth and postnatal steroid was associated with a significant reduction in growth (P < .001). No interaction was observed between antenatal and postnatal steroid use. Thorp. Steroids and Growth in the Nursery. Obstet Gynecol 2002.

View larger version (24K): [in this window] [in a new window]   Figure 4. The most important predictors of head circumference from birth to discharge, in order of decreasing significance. Thorp. Steroids and Growth in the Nursery. Obstet Gynecol 2002.

	DISCUSSION

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Several reports suggest potentially serious side effects, including neonatal death, of antenatal^1,4,5 and postnatal corticosteroid therapies.^2,6–9 We assessed the association of antenatal and postnatal corticosteroid exposure with weight gain and head circumference growth. Our findings demonstrate that antenatal corticosteroid therapy did not affect weight gain and head circumference growth in the nursery, even when used in conjunction with postnatal corticosteroid therapy. Postnatal steroid therapy was associated with significant reductions in weight gain and head circumference growth from birth to discharge. Antenatal steroids have little if any association with reduced postnatal growth, and no adverse effects of antenatal and postnatal steroids on newborn growth were noted. Antenatal steroids tended to lessen the negative effect of postnatal steroids on weight gain (P < .05) and on head circumference growth (P > .10). Consistent with other studies, we found that antenatal steroids reduced fetal somatic and head circumference growth in utero.¹⁰ Poor prenatal care was associated with significant increases in weight gain and head circumference growth in the neonatal intensive care unit (P < .05). This may represent "catch-up growth" from inadequate prenatal nutrition, or selection bias reflecting "survival of the fittest." Papile and colleagues performed a multicenter double-blinded trial investigating two postnatal dexamethasone regimens (0.25 mg/kg twice daily, intravenously or orally) in ventilator-dependent premature newborns.⁶ They randomly assigned 182 infants at 2 weeks of life to receive dexamethasone for 2 weeks followed by placebo for 2 weeks and 189 infants to receive placebo for 2 weeks followed by dexamethasone for 2 weeks. Treatment at 2 weeks of life was more hazardous and no more beneficial than was treatment at 4 weeks of life. Growth was significantly impaired in the periods during which newborns received dexamethasone. Newborns who received dexamethasone from weeks 2 to 4 of life had significant and substantial reductions in weight gain (38 ± 101 g versus 122 ± 86 g, P < .001) and head circumference growth (0.8 ± 0.8 cm versus 1.2 ± 0.8 cm, P <.001) compared with newborns who received placebo at this age. Likewise, newborns who received dexamethasone from weeks 4 to 6 of life experienced significant and substantial reductions in weight gain (140 ± 99 g versus 225 ± 111 g, P < .001) and head circumference growth (1.4 ± 0.8 vs 1.8 ± 0.8 cm, P < .001) compared with those who received placebo at the same age. These findings are of concern because head circumference appears to be correlated with long-term outcome.¹¹

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

 
This study was supported by the Pediatrix Medical Group, Sunrise, Florida.

Received June 5, 2001. Received in revised form September 13, 2001. Accepted September 24, 2001.

	REFERENCES

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1. Antenatal corticosteroids revisited: Repeat courses. In: NIH Consensus Development Conference Statement, August 17–18, 2000; Vol 17, No. 7. Available at http://consensus.nih.gov.

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.[Abstract/Free Full Text]

7. Yeh TF, Lin YJ, Huang CC, et al. Early dexamethasone therapy in preterm infants: A follow-up study. Pediatrics 1998;101:1–8.[Abstract/Free Full Text]

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.[Abstract/Free Full Text]

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.[Abstract/Free Full Text]

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.[Abstract/Free Full Text]

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]

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