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Obstetrics & Gynecology:
doi: 10.1097/AOG.0b013e3181a82b85
Original Research

Bone Metabolism in Fetuses of Pregnant Women Exposed to Single and Multiple Courses of Corticosteroids

Fonseca, Linda MD1; Ramin, Susan M. MD1; Mele, Lisa ScM2; Wapner, Ronald J. MD3; Johnson, Francee RN, BSN4; Peaceman, Alan M. MD5; Sorokin, Yoram MD6; Dudley, Donald J. MD7; Spong, Catherine Y. MD8; Leveno, Kenneth J. MD9; Caritis, Steve N. MD10; Miodovnik, Menachem MD11; Mercer, Brian MD12; Thorp, John M. MD13; O'Sullivan, Mary Jo MD14; Carpenter, Marshall W. MD15; Rouse, Dwight J. MD16; Sibai, Baha MD17; the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal Fetal Medicine Units Network (MFMU)

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From the 1Department of Obstetrics and Gynecology, University of Texas Health Science Center at Houston, Houston, Texas; 2Biostatistics Center, George Washington University Biostatistics Center, Rockville, Maryland; 3Department of Obstetrics and Gynecology, Drexel University College of Medicine, Philadelphia, Pennsylvania; 4Department of Obstetrics and Gynecology, Ohio State University, Columbus, Ohio; 5Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois; 6Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI; 7Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah; 8National Institute of Child Health and Human Development, Bethesda, Maryland; 9Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas; 10Department of Obstetrics and Gynecology, Magee Womens Hospital, Pittsburgh, Pennsylvania; 11Departments of Obstetrics and Gynecology, Columbia University, New York, New York, and University of Cincinnati, Cincinnati, Ohio; 12Department of Obstetrics and Gynecology, Case Western Reserve University, Cleveland Ohio; 13Department of Obstetrics and Gynecology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina; 14Department of Obstetrics and Gynecology, University of Miami, Miami, Florida; 15Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island; 16Department of Obstetrics and Gynecology, University of Alabama, Birmingham, Alabama; and 17Department of Obstetrics and Gynecology, University of Tennessee, Memphis, Tennessee.

*For the other members of the NICHD MFMU who participated in this study, see the Appendix online at http://links.lww.com/A1173.

Supported by grants from the National Institute of Child Health and Human Development (HD21410, HD21414, HD27869, HD27917, HD27905, HD27860, HD27861, HD27915, HD34122, HD34116, HD34208, HD34136, HD40500, HD40485, HD40544, HD40545, HD40560, HD40512, HD40485, HD36801) and M01-RR-000080 from the National Center for Research Resources.

The authors thank Michelle DiVito, MSN, for protocol development and coordination between clinical research centers and Elizabeth A. Thom, PhD, for protocol and data management and statistical analysis. The authors also thank Karen D. Bishop, BS, at the University of Texas Health Science Center at Houston for laboratory assistance.

Presented at the 54th Annual Meeting of the Society for Gynecologic Investigation, Reno, Nevada, March 14–17, 2007.

Dr. Spong, Associate Editor of Obstetrics & Gynecology, was not involved in the review or decision to publish this article.

Corresponding author: Linda Fonseca, MD, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston TX, 250 East Superior, Suite 05-2175, Chicago, IL 60611; e-mail: l-fonseca@northwestern.edu.

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

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Abstract

OBJECTIVE: To estimate the effect of single and recurrent doses of antenatal corticosteroids on fetal bone metabolism.

METHODS: This was a secondary analysis of a cohort of pregnant women from a previously reported randomized, placebo-controlled, multicenter trial of women at risk for preterm delivery who received weekly courses of betamethasone (active) or placebo after an initial course of corticosteroids. Umbilical cord serum levels of carboxy-terminal carboxy-terminal propeptide of type I procollagen and cross-linked carboxy-terminal telopeptide of type I procollagen were measured to assess the rate of fetal bone formation and resorption, respectively. Analysis was stratified according to number of repeat antenatal study courses of betamethasone or placebo (one to three compared with at least four courses, not including the initial course).

RESULTS: Of the 251 umbilical cord serum samples, the median serum carboxy-terminal telopeptide of type I procollagen levels, but not carboxy-terminal propeptide of type I procollagen levels, was significantly lower with repeat betamethasone exposure (55.0 compared with 57.9 micrograms/L, P=.01). In the fetuses exposed to at least four repeat study courses, there was a significant decrease in median carboxy-terminal telopeptide of type-I procollagen levels between repeat betamethasone exposure and placebo (53.4 compared with 58.6 micrograms/L, respectively, P=.04), but there was no difference between groups in the fetuses exposed to 1–3 repeat study courses (57.4 compared with 56.7 micrograms/L, respectively, P=.29).

CONCLUSION: Levels of umbilical cord serum markers of bone resorption but not formation are reduced in fetuses exposed to repeat courses of antenatal betamethasone. Up to four courses of antenatal betamethasone do not seem to affect fetal bone metabolism.

LEVEL OF EVIDENCE: II

The clinical efficacy of antenatal corticosteroids in reducing the risk of respiratory distress syndrome, intraventricular hemorrhage, and infant mortality is well established.1 The 1994 and 2000 National Institutes of Health Consensus Development Conferences recommended routine administration of a single course of antenatal corticosteroids for those women at risk of preterm birth between 24–34 weeks gestational age. The use of repeat courses of antenatal corticosteroids, on the other hand, remains controversial, and insufficient data exist to support its practice.2,3

Despite the undisputed neonatal benefits of antenatal corticosteroids, there is also concern over potential maternal and fetal adverse effects on bone metabolism, particularly with repeat doses. Two biochemical markers of bone turnover have been used to study maternal and fetal bone metabolism patterns. Type I collagen is the main constituent of bone, accounting for approximately 90% of its organic matrix, with very little contribution from nonskeletal tissue to the circulating propeptide.4,5 Carboxy-terminal propeptide of type I procollagen and cross-linked carboxy-terminal telopeptide of type I collagen are specific and reliable serum markers of bone formation and resorption, respectively. Both serum markers are released in a 1:1 stoichiometric relationship with formation or resorption of type 1 collagen.4–8 The specificity of both markers to their respective bone changes has been confirmed by histomorphometry and calcium kinetic studies.4,6

Maternal and fetal bone metabolism patterns are independent of each, other making transplacental transport of carboxy-terminal propeptide of type I procollagen and cross-linked carboxy-terminal telopeptide of type I collagen unlikely.9–11 Single and repeat courses of antenatal corticosteroids have not been shown to have a persistent or cumulative effect on maternal bone metabolism as measured by carboxy-terminal propeptide of type I procollagen and cross-linked carboxy-terminal telopeptide of type I collagen.12–14 In one study, a transient decrease in maternal carboxy-terminal propeptide of type I procollagen levels was noted after 24 hours of administration of a single course of corticosteroids without any effect on cross-linked carboxy-terminal telopeptide of type I collagen levels.13 We identified two published studies evaluating the effects of antenatal corticosteroids on fetal bone metabolism (PubMed 1992 to 2008; MEDLINE 1992 to 2008 search terms: fetal bone metabolism, carboxy-terminal propeptide of type I procollagen, cross-linked carboxy-terminal telopeptide of type I collagen, antenatal corticosteroids; English publications). Both studies concluded that a single course of antenatal corticosteroids reduced umbilical cord levels of carboxy-terminal propeptide of type I procollagen without an effect on cross-linked carboxy-terminal telopeptide of type I collagen levels.15,16 Little is known about the effect of repeat courses of antenatal corticosteroids on fetal bone metabolism. Our study addresses the effects of single compared with repeat courses of antenatal corticosteroids on fetal bone metabolism as measured by umbilical cord blood biochemical markers, carboxy-terminal propeptide of type I procollagen and cross-linked carboxy-terminal telopeptide of type I collagen. The objective of this study was to estimate the effect of single and recurrent doses of antenatal corticosteroids on fetal bone metabolism. The null hypothesis is that there is no difference in fetal bone metabolism markers between those exposed to a single course of corticosteroids compared with those exposed to repeat courses.

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MATERIALS AND METHODS

This study was a secondary analysis of a cohort of pregnant women from a previously reported, randomized, double-masked, placebo-controlled, multicenter trial of single compared with repeat courses of antenatal corticosteroids, conducted between March 2000 and April 2003 at participating centers of the National Institute of Child Health and Human Development (NICHD), Maternal–Fetal Medicine Units (MFMU) Network.3 Our study of fetal bone metabolism markers was approved by the Committee for the Protection of Human Subjects Institutional Review Board at the University of Texas Health Science Center at Houston.

This secondary analysis included only a cohort of women with singleton gestations from the previously reported NICHD MFMU Network trial on antenatal corticosteroids.3 These women were at risk for preterm delivery with intact membranes between 23 0/7 weeks and 31 6/7 weeks who were randomly assigned to receive weekly courses of betamethasone or placebo, based on a previously described randomization design scheme, 1 week after receiving a single full course of corticosteroids (betamethasone or dexamethasone).3 In our secondary analysis we excluded patients with preterm premature rupture of membranes before randomization, confirmed fetal lung maturity, chorioamnionitis, major fetal anomaly, nonreassuring fetal status, systemic corticosteroid in pregnancy, and type 1 diabetes.

A subset of umbilical cord serum samples was received from the NICHD MFMU Network as deidentified, numbered serum aliquots. These umbilical cord serum samples had been stored at –20°C. Both carboxy-terminal propeptide of type I procollagen and carboxy-terminal telopeptide of type I procollagen are stable during storage at –20°C and after several freeze-thaw cycles, which we avoided as much as possible. We were blinded with respect to treatment group (corticosteroid compared with placebo) for each sample. All samples were run in duplicate for both the carboxy-terminal propeptide of type I procollagen and carboxy-terminal telopeptide of type I procollagen assays. If a greater than 15% discrepancy in calculated concentrations of the serum marker was noted between duplicate samples, the sample was rerun. If after three separate runs this discrepancy did not improve, the sample was excluded from the study. A standard curve was established for each microtiter plate, and serum marker concentrations were calculated from the standard curve for each plate, to minimize interplate variation.

Serum levels of type I procollagen C-peptide levels were determined by using the procollagen type I C-peptide enzyme immunoassay (EIA; Takara Bio Inc., Shiga Japan; www.takara-bio-co.jp) kit. This assay used a “sandwich” enzyme-linked immunosorbent assay technique. A microtiter plate coated with a mouse monoclonal anti-carboxy-terminal propeptide of type I procollagen antibody was simultaneously reacted with sample and peroxidase-labeled anti-carboxy-terminal propeptide of type I procollagen antibody. With incubation, carboxy-terminal propeptide of type I procollagen was bound to the anti-propeptide of type I procollagen (solid-phase) on one side, and tagged by peroxidase-labeled anti-propeptide of type I procollagen on the other. Reaction with peroxidase and substrate resulted in color development, with intensity proportional to carboxy-terminal propeptide of type I procollagen concentration. This concentration was quantified by specific absorbance using an EIA plate reader at optical density (OD) 450. Accurate sample concentrations were determined by comparison of specific absorbances to a standard curve run for each microtiter plate. Results were reported in micrograms per liter. The intraassay coefficient of variation was 4.5–7.4%, and that for interassay was 4.3–6%. The assay detection limit was reported as 10 micrograms/L.

Serum levels of type I carboxy-terminal telopeptide were determined using the UniQ cross-linked carboxy-terminal telopeptide of type I collagen EIA assay kit (Orion Diagnostica, Espoo, Finland; www.oriondiagnostica.fi). This is a competitive-inhibition enzyme-linked immunosorbent assay whereby the carboxy-terminal telopeptide of type I procollagen in the serum samples competes with high-affinity carboxy-terminal telopeptide of type I procollagen epitopes previously adsorbed onto microtiter plates for binding to a peroxidase-labeled goat-anti-rabbit antibody. This is followed by chromogenic development, subsequent determination of absorbance spectrophotometrically (OD450), and quantitation of carboxy-terminal telopeptide of type I procollagen concentration by comparison to a calibration standard for each microtiter plate. Results are reported in micrograms per liter. The intraassay coefficient of variation was 3.5–9.4% for analytes in the range of 1.0–50 micrograms/L and that for interassay precision was 6.4–9.8%. The assay detection limit was reported at 0.3 micrograms/L.

The primary outcomes of interest for this secondary analysis were the fetal bone metabolism markers. Because this was a secondary analysis of all available umbilical cord serum samples, the study was not “powered” to a particular level. However, we determined from the literature that a 10% change in carboxy-terminal telopeptide of type I procollagen or carboxy-terminal propeptide of type I procollagen between two groups corresponded to about one third of a standard deviation. To detect an effect size of one third standard deviation, we had 74% power with a sample size of 250. Data were analyzed at the Biostatistics Center, George Washington University, Rockville, MD. Categorical variables were compared using the χ2 or Fisher exact tests, where appropriate. Continuous variables were compared using the Wilcoxon rank sum test. Multivariable linear regression analyses included study group assignment, infant sex, ethnicity, and either gestational age at delivery, birth weight, or small for gestational age (SGA) status, which was based on a birth weight less than the 10th percentile of published standards.17 It was previously reported that birth weight was reduced in infants exposed to one to three courses of steroids, with significant reduction in those receiving four or more courses.3 Based on these results, we stratified our data according to number of repeat antenatal study courses of betamethasone or placebo (one to three compared with four or more courses, without including the initial course). A nominal two-tailed P value less than 0.05 was considered to indicate statistical significance; no adjustment was made for multiple comparisons. Box-and-whisker plots were used to provide graphic representation of the distribution of the serum markers and were generated using SAS statistical software (SAS Institute Inc., Cary, NC).

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RESULTS

There were 285 umbilical cord serum samples that were assayed for carboxy-terminal propeptide of type I procollagen and carboxy-terminal telopeptide of type I procollagen concentrations. Thirty-four samples were excluded because of a greater than 15% discrepancy in duplicated samples after three separate runs. Thus, the umbilical cord serum samples from 114 women assigned to receive repeat placebo study courses and 137 women assigned to receive repeat betamethasone study courses from the Network trial were included (n=251). Forty-one women in the placebo group and 46 women in the betamethasone group received one to three repeat courses, whereas 73 women in the placebo group and 91 women in the treated group, respectively, received four or more repeat study courses. There were no significant differences between placebo and active group with respect to maternal and infant characteristics (Table 1).

Table 1
Table 1
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Mean time from randomization to delivery was not significantly different between groups (Table 1). Mean±standard deviation gestational age at delivery for the one to three study course group was 33.8±4.5 weeks for the placebo group and 32.7±4.5 weeks for the active group (P=.27). In the four or more study course group the mean gestational age at delivery was 36.1±2.8 weeks for the placebo group and 36.3±2.9 weeks for the active group (P=.61). Mean birth weight in the placebo group was 2528.4±784.5 g and 2376.1±799.3 g in the active group (P=.15). There were 31 SGA infants overall.

Table 2 summarizes the median values of carboxy-terminal propeptide of type I procollagen and carboxy-terminal telopeptide of type I procollagen levels in each group. When comparing all samples, there was no difference in median serum carboxy-terminal propeptide of type I procollagen levels, but carboxy-terminal telopeptide of type I procollagen concentrations were significantly lower in the betamethasone group compared with placebo (55.0 compared with 57.9 micrograms/L, respectively P=.01). There was no significant difference in carboxy-terminal propeptide of type I procollagen levels (422.0 compared with 478.0 micrograms/L, P=.37) or carboxy-terminal telopeptide of type I procollagen levels (57.4 compared with 56.7 micrograms/L respectively, P=.29) among those receiving one to three courses when comparing betamethasone with placebo. Fetuses exposed to four or more repeat study courses did not have significantly increased carboxy-terminal propeptide of type I procollagen levels compared with placebo (P=.17) but did have decreased median serum carboxy-terminal telopeptide of type I procollagen levels compared with placebo (53.4 compared with 58.6 micrograms/L, respectively, P=.04). Graphical representation of the median fetal serum carboxy-terminal propeptide of type I procollagen and carboxy-terminal telopeptide of type I procollagen concentrations according to the number of study courses are presented in Figures 1 and 2, respectively. Multivariable analysis, controlling for infant sex, ethnicity (African American compared with other), and either gestational age at delivery, birth weight, or SGA infants showed that the repeated steroid group was significantly associated with lower carboxy-terminal telopeptide of type I procollagen levels. Although carboxy-terminal telopeptide of type I procollagen levels were decreased in the univariable analysis in the overall group (single compared with repeat corticosteroid group) and within those who received four or more courses, there was no difference in effect between those who received one to three courses and those who received four or more courses in the multivariable analysis.

Table 2
Table 2
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Fig. 1
Fig. 1
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Fig. 2
Fig. 2
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DISCUSSION

The results of our study demonstrate that repeat courses of betamethasone are associated with reduced umbilical cord serum levels of carboxy-terminal telopeptide of type I procollagen, the marker for fetal bone resorption. Our data are consistent with prior studies in adults (Hansen M, Horslev-Peterson K, Stoltenberg M, Lorenzen I, Risteli L, Ristel J. Type I collagen metabolism in rheumatoid arthritis. Effects of a single pulse of methylprednisolone [abstract]. Br J Rheumatol 1992;31:129)8 and children,18 which also showed that corticosteroid treatment resulted in reduced serum concentration of carboxy-terminal telopeptide of type I procollagen. Based on the available studies, there is no conclusive data on the effects of corticosteroids on fetal bone metabolism.15,16

We found that carboxy-terminal telopeptide of type I procollagen levels were decreased in the univariable analysis in the overall group (single compared with repeat corticosteroid group) and within those who received at least four corticosteroid courses but not those in the one to three course group. However, we did not see a dose effect by the number of corticosteroid courses in the multivariable analysis. This may have been due to a lack of power or the effect of other confounding variables. Based on previous studies, suppression of bone formation is evident within 2–4 days of treatment followed by recovery to pretreatment levels within 1–2 weeks in adults.19,20 When we controlled for time from last corticosteroid dose (data not shown), our results were unchanged.

Normally, maternal serum carboxy-terminal propeptide of type I procollagen and carboxy-terminal telopeptide of type I procollagen levels steadily increase with advancing gestational age, reaching peak levels at term.21 On the other hand, data on the normal physiologic pattern of bone metabolism in the fetus is limited. Some studies have suggested that fetal bone metabolism serum markers decrease with advancing gestational age.10,22 Ogueh and colleagues10 found in normal pregnancies without antenatal corticosteroid exposure that umbilical cord blood levels of carboxy-terminal propeptide of type I procollagen and carboxy-terminal telopeptide of type I procollagen were higher than maternal levels and concluded that fetal and maternal bone metabolism are independent of each other. Carroll and colleagues12 also examined maternal bone metabolism markers in women from the NICHD MFMU Network trial. The maternal serum carboxy-terminal propeptide of type I procollagen and carboxy-terminal telopeptide of type I procollagen levels at delivery in their study were higher than the umbilical cord serum levels in our study in both the single and repeat corticosteroid groups, suggesting that maternal and fetal bone metabolism markers are independent of each other, which is consistent with Ogueh's findings.

Furthermore, it is certainly possible that the decrease in carboxy-terminal telopeptide of type I procollagen levels we observed in the repeat corticosteroid group may not only have been influenced by in utero exposure to corticosteroids but also by the physiologic effect of advancing gestational age on the fetal bone metabolism profile. However, when controlling for gestational age at delivery and multiple variables, our results of decreased carboxy-terminal telopeptide of type I procollagen levels were confirmed. An association between fetal bone metabolism markers and birth weight has also been studied. Small for gestational age infants have been shown to have decreased markers of bone formation at all gestational ages and decreased markers of bone resorption before 36 weeks of gestation.22 Our study only included 31 SGA infants, which is insufficient for evaluating the effect of antenatal corticosteroids on bone metabolism patterns in these infants.

Our study estimated the effects of multiple courses of antenatal corticosteroids on fetal bone metabolism. Umbilical cord serum levels of carboxy-terminal telopeptide of type I procollagen are reduced in fetuses exposed to repeat courses of antenatal betamethasone.

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REFERENCES

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15. Saarela T, Risteli J, Kauppila A, Koivisto M. Effect of short term antenatal dexamethasone administration on type I collagen synthesis and degradation in preterm infants at birth. Acta Paediatr 2001;90:921–5.

16. Korakaki E, Gourgiotis D, Aligizakis A, Manoura A, Hatzidaki E, Giahnakis E, et al. Levels of bone collagen markers in preterm infants: relation to antenatal glucocorticoid treatment. J Bone Miner Metab 2007;25:172–8.

17. Alexander GR, Kogan MD, Himes JH. 1994–1996 U.S. singleton birth weight percentiles for gestational age by race, Hispanic origin, and gender. Matern Child Health J 1999;3:225–31.

18. Wolthers OD, Juul A, Hansen M, Muller J, Pedersen S. The insulin-like growth factor axis and collagen turnover during prednisolone treatment. Arch Dis Child 1994;71:409–13.

19. Oikarinen A, Autio P, Vuori J, Vaananen K, Risteli L, Kiistala U, et al. Systemic glucocorticoid treatment decreases serum concentrations of carboxyterminal propeptide of type I procollagen and aminoterminal propeptide of type III procollagen, Br J Dermatol 1992;126:172–8.

20. Ogueh O, Johnson MR. The metabolic effect of antenatal corticosteroid therapy. Hum Reprod Update 2000;6:169–76.

21. Naylor KE, Iqbal P, Fledelius C, Fraser RB, Eastell R. The effect of pregnancy on bone density and bone turnover. J Bone Miner Res 2000;15:129–37.

22. Saarela T, Risteli J, Kauppila A, Koivisto M. Type I collagen markers in cord serum of appropriate vs. small for gestational age infants born during the second half of pregnancy. Eur J Clin Invest 2001;31:438–43.

Figure. No Caption available.


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