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Obstetrics & Gynecology:
doi: 10.1097/AOG.0b013e31825189dc
Original Research

Effect of Antenatal Corticosteroids on Fetal Growth and Gestational Age at Birth

Murphy, Kellie E. MD; Willan, Andrew R. PhD; Hannah, Mary E. MDCM; Ohlsson, Arne MD; Kelly, Edmond N. MB; Matthews, Stephen G. PhD; Saigal, Saroj MD; Asztalos, Elizabeth MD; Ross, Susan PhD; Delisle, Marie-France MD; Amankwah, Kofi MD; Guselle, Patricia MSc; Gafni, Amiram DSc; Lee, Shoo K. MB, BS; Armson, B. Anthony MD

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Author Information

From the Departments of Obstetrics and Gynaecology and Paediatrics, Mount Sinai Hospital, the Program in Child Health Evaluative Sciences, SickKids Research Institute and Division of Biostatistics, the Departments of Obstetrics and Gynaecology and Newborn & Developmental Paediatrics and the Centre for Mother, Infant and Child Research, Sunnybrook Health Sciences Centre, the Departments of Physiology, Obstetrics and Gynecology, and Medicine, and the Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; the Department of Paediatrics and the Centre for Health Economics and Policy Analysis, and the Department of Clinical Epidemiology and Biostatistics, McMaster University Medical Centre, Hamilton, Ontario, Canada; the Departments of Obstetrics and Gynaecology, University of Calgary, Calgary, Alberta, Canada, BC Women's Hospital, University of British Columbia, Vancouver, British Columbia, Canada, and IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada; the Department of Gynecology-Obstetrics, Women's and Children's Hospital, State University of New York at Buffalo, Buffalo, New York; and the Division of Neonatology, Hospital for Sick Children, Toronto, Ontario, Canada.

* For a list of other members of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study collaborative group, see the Appendix online at http://links.lww.com/AOG/A296.

Supported by Canadian Institutes of Health Research grant number MCT 38142.

Corresponding author: Kellie E. Murphy, MD, MSc, FRCSC, FACOG, Mount Sinai Hospital, Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Third Floor Room 3097, Ontario Power Generation Building, 700 University Ave., Toronto, Ontario, M5R 1X5, Canada; e-mail: kmurphy@mtsinai.on.ca.

Financial Disclosure The authors did not report any potential conflicts of interest.

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Abstract

OBJECTIVE: To estimate the effect of multiple courses of antenatal corticosteroids on neonatal size, controlling for gestational age at birth and other confounders, and to determine whether there was a dose–response relationship between number of courses of antenatal corticosteroids and neonatal size.

METHODS: This is a secondary analysis of the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, a double-blind randomized controlled trial of single compared with multiple courses of antenatal corticosteroids in women at risk for preterm birth and in which fetuses administered multiple courses of antenatal corticosteroids weighed less, were shorter, and had smaller head circumferences at birth. All women (n=1,858) and children (n=2,304) enrolled in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study were included in the current analysis. Multiple linear regression analyses were undertaken.

RESULTS: Compared with placebo, neonates in the antenatal corticosteroids group were born earlier (estimated difference and confidence interval [CI]: −0.428 weeks, CI −0.10264 to −0.75336; P=.01). Controlling for gestational age at birth and confounding factors, multiple courses of antenatal corticosteroids were associated with a decrease in birth weight (−33.50 g, CI −66.27120 to −0.72880; P=.045), length (−0.339 cm, CI −0.6212 to −0.05676]; P=.019), and head circumference (−0.296 cm, −0.45672 to −0.13528; P<.001). For each additional course of antenatal corticosteroids, there was a trend toward an incremental decrease in birth weight, length, and head circumference.

CONCLUSION: Fetuses exposed to multiple courses of antenatal corticosteroids were smaller at birth. The reduction in size was partially attributed to being born at an earlier gestational age but also was attributed to decreased fetal growth. Finally, a dose–response relationship exists between the number of corticosteroid courses and a decrease in fetal growth. The long-term effect of these findings is unknown.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00187382.

LEVEL OF EVIDENCE: II

The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study was an international, multicenter, double-blind, randomized controlled trial of single compared with multiple courses of antenatal corticosteroids in women at increased risk for preterm birth. Although newborns born to women in the antenatal corticosteroids group experienced similar composite morbidity (severe respiratory distress syndrome, intraventricular hemorrhage [grade III or IV], periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis) and mortality as compared with those in the placebo group (12.9% antenatal corticosteroids compared with 12.5% placebo, odds ratio 1.04, confidence interval [CI] 0.77–1.39; P=.83),1 a recent Cochrane review has found a reduced risk of composite serious neonatal outcome if antenatal corticosteroid courses are repeated.2 In the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, when compared with the placebo group, neonates in the antenatal corticosteroids group were smaller. They weighed less (2,216 g compared with 2,330 g; P<.003), were shorter (44.5 cm compared with 45.4 cm; P<.001), and had smaller head circumferences (31.1 cm compared with 31.7 cm; P<.001) at birth.1

The mean gestational age at birth was 34.5 weeks (standard deviation 3.6) for the antenatal corticosteroids group and 34.9 weeks (standard deviation 3.6) for the placebo group. It is possible that the neonates in the antenatal corticosteroids group were smaller partly because they were born earlier.

The primary objective of this secondary analysis was to determine whether the effect of multiple courses of antenatal corticosteroids on neonatal size was a direct effect of the corticosteroids on fetal growth, or whether it was attributable to a reduction in gestational age at birth, or both. The secondary objective was to determine whether there was a dose–response relationship between the number of courses of antenatal corticosteroids and decrease in fetal size.

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MATERIALS AND METHODS

After an initial course of antenatal corticosteroids, pregnant women 25 0/7 weeks of gestation or more and 32 6/7 weeks of gestation or less who remained at increased risk for preterm birth 14 to 21 days after an initial course of antenatal corticosteroids were eligible for the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study. Women were excluded if they had a contraindication to receiving corticosteroids, required chronic doses of corticosteroids, had evidence of chorioamnionitis, carried a fetus with a known lethal congenital anomaly, had the initial course of antenatal corticosteroids before 23 weeks of gestation, or previously participated in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study. Women carrying multiple gestations were considered eligible for the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study if a fetus died before 13 weeks of gestation; however, the fetus that died was not considered part of the pregnancy. Women were not eligible if fetal death occurred in one or more fetuses after 13 weeks of gestation.

After institutional approval at each site and informed consent, 1,858 women from 80 centers in 20 countries (see Appendix online at http://links.lww.com/AOG/A296) were randomized using a 24-hour telephone randomization service to receive multiple courses of antenatal corticosteroids compared with placebo every 14 days until 33 6/7 weeks of gestation or birth, whichever came first. Women randomized to a study treatment number corresponding to antenatal corticosteroids received multiple courses of betamethasone. A course consisted of two doses of betamethasone, 12 mg per dose intramuscularly administered 24 hours apart. Women randomized to a study treatment number corresponding to placebo received courses of a similar-appearing placebo.1 The first woman was randomized on April 9, 2001, and the last woman was randomized on August 31, 2006 (Fig. 1). The baseline characteristics were similar between the two groups, as were the number of courses of study drug administered1 (Table 1). Most women received one or two courses of study drug (74% in the antenatal corticosteroids group and 70% in the placebo group).

Fig. 1
Fig. 1
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Table 1
Table 1
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The outcome of interest in the secondary analyses was neonatal size (weight, length, and head circumference at birth) after controlling for gestational age at birth and other known confounding variables. The information from all children in the primary Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study analysis was included in these secondary analyses.1

To determine whether the effect of multiple courses of antenatal corticosteroids on neonatal size was a direct effect of the corticosteroids on fetal growth, whether it was attributable to a reduction in gestational age at birth, or both, we first compared randomized groups with respect to mean gestational age at birth. We then undertook multiple linear regression analyses to estimate, first, the effect of multiple courses of antenatal corticosteroids (antenatal corticosteroids compared with placebo groups) on birth weight, length, and head circumference, controlling for gestational age at birth and, second, the effect of multiple courses of antenatal corticosteroids (antenatal corticosteroids compared with placebo groups) on birth weight, length, and head circumference, controlling for gestational age at birth, as well as other known confounders (neonatal sex [male compared with female], parity [1 or more compared with 0], maternal smoking [smoker compared with nonsmoker], and number of fetuses).

Finally, to determine whether there was a dose–response relationship between the number of courses of antenatal corticosteroids and decrease in birth weight, length, and head circumference, a multiple linear regression analysis was undertaken that included the number of courses of antenatal corticosteroids (2, 3, 4, or 5 each compared with 1), gestational age at birth, neonatal sex (male compared with female), parity (1 or more compared with 0), maternal smoking (smoker compared with nonsmoker), and number of fetuses.

All models included a random intercept to adjust for the dependence of multiple gestations within the pregnancy. In each model, the normally distributed error term consists of a between-pregnancy component and a within-pregnancy component.3 Because the effect of gestational age at birth on the outcomes was potentially nonlinear, we included this variable in the models with linear and quadratic terms. The multiple linear regression analyses were used to estimate the differences (and CIs) in birth weight, length, and head circumference between the compared groups. The level of statistical significance was two-tailed type I error of 0.05.

The Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study is funded by the Canadian Institutes of Health Research. Canadian Institutes of Health Research did not participate in the design, management, data collection, analysis, or interpretation of this study. Canadian Institutes of Health Research played no role in the writing of this manuscript or in the decision to submit for publication.

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RESULTS

Neonates in the antenatal corticosteroids group were born earlier as compared with those in the placebo group (34.51 compared with 34.94 weeks of gestation; estimated difference and CI: −0.428 weeks, CI −0.75336 to −0.10264; P<.001). After controlling for gestational age at birth, neonates in the antenatal corticosteroids group weighed less (estimated difference and CI for antenatal corticosteroids minus placebo groups: −35.30 g, CI −68.2868 to −2.3132]; P=.036), were shorter (estimated difference and CI for antenatal corticosteroids minus placebo groups: −0.352 cm, CI −0.63816 to −0.06584; P=.016), and had a smaller head circumferences (estimated difference and CI for antenatal corticosteroids minus placebo groups: −0.307 cm, CI −0.46968 to −0.14432; P<.001; Table 2). The highly significant positive linear coefficients for gestational age at birth indicate, as expected, that the growth factors increase with gestational age. However, the highly significant negative quadratic coefficients for length and head circumference indicate that for those factors, the incremental increase diminishes with gestational age. After controlling for gestational age at birth and the other known confounding factors, multiple courses of antenatal corticosteroids compared with placebo were associated with a decrease in weight (estimated difference and CI: −33.50 g, CI −66.27120 to −0.72880; P=.045), length (estimated difference and CI: −0.339 cm, CI−0.62124 to −0.05676; P=.019), and head circumference (estimated difference and CI: −0.296 cm, CI −0.45672 to −0.13528; P<.001 at birth; Table 3).

Table 2
Table 2
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Table 3
Table 3
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Last, controlling for gestational age at birth and other confounding factors, there was a general trend toward an incremental decrease in weight, length, and head circumference at birth for each additional course of antenatal corticosteroids (Table 4). The estimated difference and CI for two courses compared with one course was −26.58 g (CI −68.68080 to 15.52080; P=.22) for weight, −0.267 cm (CI −0.64528 to 0.11128; P=.17) for length, and −0.294 cm (CI −0.50900 to −0.07820; P=.008) for head circumference at birth. Whereas the estimated difference and CI for five courses compared with one course was −84.75 g (CI −164.73760 to −4.76240; P=.038) for weight, −0.467 cm (CI −0.97464 to 0.04064; P=.071) for length, and −0.527 cm (CI −0.82501 to −0.22799; P<.001) for head circumference at birth.

Table 4
Table 4
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DISCUSSION

Exposure to multiple courses of antenatal corticosteroids was associated with being born earlier. In 1969, Liggins4 reported that corticosteroid exposure, in sheep, could induce preterm birth. It was through this work that he observed that newborn sheep exposed to corticosteroids appeared more mature in comparison with those that did not. These observations led to the hypothesis that antenatal corticosteroid exposure could accelerate fetal lung maturation and, subsequently, to the hallmark randomized controlled trial of Liggins and Howie.5 Differences in gestational age at birth have not been previously described in any of the other randomized controlled trials investigating repeated courses of antenatal corticosteroids. In some trials there were nonstatistical differences in the gestational age at birth, with the women who were randomized to antenatal corticosteroids delivering before those in the placebo group.6,7 It is possible that other trials have not observed this finding secondary to smaller sample sizes (eg, Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD]) or because in other trials there was less overall cumulative corticosteroid exposure (eg, the Australasian Collaborative Trial of Repeat Doses of Steroids).

Despite controlling for gestational age at birth, along with other factors known to be associated with a decrease in fetal anthropomorphic measurements (smoking, nulliparity compared with multiparity, multiple gestation compared with singleton), multiple courses of antenatal corticosteroids were negatively associated with fetal growth. Specifically, there was a negative dose–response relationship observed; higher corticosteroid exposure was associated with a progressively larger decrease in newborn weight, length, and head circumference at birth. This is biologically plausible and has been demonstrated in many animal models.8 Corticosteroids are known to force differentiation at the cost of cellular hyperplasia. Information from other randomized trials has suggested this association. Although the NICHD trial did not demonstrate an effect of multiple courses of antenatal corticosteroids on birth weight overall, possibly because of its smaller sample size, there was a lower birth weight in neonates exposed to four or more courses of antenatal corticosteroids compared with those who received placebo (2,400 g compared with 2,561 g; P=.01); in addition, more neonates in the antenatal corticosteroids group compared with placebo were in less than the 10th percentile (24% compared with 15%; P=.02).9 In the recent Cochrane systematic review, repeated doses of corticosteroids were associated with a reduction in mean birth weight (mean difference −75.79 g, 95% CI −117.63 to −33.96, nine trials, 5,626 neonates).2

Some of the differential effects of multiple courses of antenatal corticosteroids on fetal growth between the various antenatal corticosteroids trials may be attributable to the different corticosteroid exposure between studies. Most women in the Australasian Collaborative Trial of Repeat Doses of Steroids and the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study received only one or two courses of study drug (65.7% for the Australasian Collaborative Trial of Repeat Doses of Steroids; 72% for the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study)1,10; however, a repeated course of antenatal corticosteroids in the Australasian Collaborative Trial of Repeat Doses of Steroids consisted of only one dose of betamethasone,9 whereas in other trials (Guinn, NICHD, and the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study) a repeated course was two doses of betamethasone 24 hours apart.1,6,9 Women in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study received repeated courses of antenatal corticosteroids every 14 days, whereas in several other trials (Guinn, NICHD, and the Australasian Collaborative Trial of Repeat Doses of Steroids) they received repeated courses of antenatal corticosteroids every 7 days.

The long-term effect of weighing less or having a smaller head circumference at birth is not known. Therefore, it is critical that the children in these trials are followed-up long-term. The NICHD monitored the children in their study until age 2 to 3 years. At that assessment, the neurocognitive and physical measures did not differ between the antenatal corticosteroids and placebo groups; however, there was a nonsignificant increased risk of cerebral palsy in those exposed to weekly courses of antenatal corticosteroids (2.9% antenatal corticosteroids compared with 0.5% placebo).11 The investigators of the Australasian Collaborative Trial of Repeat Doses of Steroids reported on the outcome of their children at age 2 years.12 The primary outcome, the rate of survival free of major disability, was similar between the two groups. However, the children exposed to weekly courses of antenatal corticosteroids were more likely to warrant an assessment for attention problems than were those in the control group (P=.04).12 The follow-up assessment of death, neurologic impairment, and anthropomorphic measurements at 18 to 24 months for children in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study were similar between those in the antenatal corticosteroids and placebo groups.13 Although the results of these longer-term studies are reassuring, the studies are too small to rule out an adverse effect of multiple courses of antenatal corticosteroids on infrequent but serious outcomes. We are reminded of the randomized controlled trials of postnatal corticosteroid treatment that initially demonstrated short-term benefits and then over time, with the completion of long-term studies demonstrating the potential for adverse neurologic impairment.14 Regarding antenatal corticosteroids, longer-term follow-up studies to age 5 years and older are underway or planned, and these studies will provide additional information regarding the long-term effects, if any, of multiple courses of antenatal corticosteroids.15,16 Finally, an individual patient data meta-analysis is in progress.17 This meta-analysis will provide additional information regarding the relationship between antenatal corticosteroids and gestational age at birth and regarding the dose–response relationship between antenatal corticosteroids and neonatal anthropomorphic measurements.

In summary, fetuses exposed to multiple courses of antenatal corticosteroids were delivered earlier as compared with those who received placebo. In addition, a dose–response relationship was noted between increasing number of courses of antenatal corticosteroids and a decrease in weight, length, and head circumference at birth. The clinical importance of being born smaller is not yet known.

Until further evidence is available, the short-term neonatal benefits from repeat courses of antenatal corticosteroids, as found in the recent Cochrane review,2 must be weighed against the possible risk of harm that might come from a lower birth weight, length, and head circumference. Because no benefit was observed from multiple courses of antenatal corticosteroids in the Multiple Courses of Antenatal Corticosteroids for Preterm Birth Study, multiple courses of antenatal corticosteroids every 14 days are not recommended.

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REFERENCES

1. Murphy KE, Hannah ME, Willan AR, Hewson SA, Ohlsson A, Kelly EN, et al.. Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial. Lancet 2008;372:2143–51.

2. Crowther CA, McKinlay CJD, Middleton P, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease. Cochrane Database Syst Rev 2011;6.

3. West BT, Welch KB, Galecki AT. Linear mixed models: A practical guide to using statistical software. New York (NY): Chapman & Hall/CRC; 2007.

4. Liggins GC. Premature delivery of foetal lambs infused with glucocorticoids. J Endocrinol 1969;45:515–23.

5. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics 1972;50:515–25.

6. Guinn DA, Atkinson MW, Sullivan L, Lee M, MacGregor S, Parilla BV, et al.. Single vs weekly courses of antenatal corticosteroids for women at risk of preterm delivery: A randomized controlled trial. JAMA 2001;286:1581–7.

7. Peltoniemi OM, Kari MA, Tammela O, Lehtonen L, Marttila R, Halmesmaki E, et al.. Randomized trial of a single repeat dose of prenatal betamethasone treatment in imminent preterm birth. Pediatrics 2007;119:290–8.

8. Aghajafari F, Murphy K, Matthews S, Ohlsson A, Amankwah K, Hannah M. Repeated doses of antenatal corticosteroids in animals: a systematic review. Am J Obstet Gynecol 2002;186:843–9.

9. Crowther CA, Haslam RR, Hiller JE, Doyle LW, Robinson JS, Australasian Collaborative Trial of Repeat Doses of Steroids (ACTORDS) Study Group. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Lancet 2006;367:1913–9.

10. Wapner RJ, Sorokin Y, Thom EA, Johnson F, Dudley DJ, Spong CY, et al.. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol 2006;195:633–42.

11. Wapner RJ, Sorokin Y, Mele L, Johnson F, Dudley DJ, Spong CY, et al.. Long-term outcomes after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357:1190–8.

12. Crowther CA, Doyle L, Haslam RR, Hiller JE, Harding JE, Robinson JS, et al.. Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 2007;357:1179–89.

13. Asztalos EV, Murphy KE, Hannah ME, Willan AR, Matthews SG, Ohlsson A, et al.. Multiple courses of antenatal corticosteroids for preterm birth study: 2-year outcomes. Pediatrics 2010;126:e1045–55.

14. Halliday HL, Ehrenkranz RA, Doyle LW. Early (<8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochran Database of Sys Rev 2010;5.

15. Sunnybrook Research Institute. Centre for Mother, Infant, & Child Research. Available at: http://sunnybrook.ca/research/content/?page=sri_proj_cmicr_trial_macs5_home. Retrieved March 25, 2012.

16. The University of Adelaide. Available at: http://www.adelaide.edu.au/arch/research/clinical_trials/actords.html.Retrieved March 25, 2012.

17. The University of Adelaide. The Robinson Institute. ARCH: Women & Babies Health. Available at: http://www.adelaide.edu.au/arch/research/res_synthesis/#IPD. Retrieved March 25, 2012.

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© 2012 The American College of Obstetricians and Gynecologists

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