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PEDIATRICS Vol. 113 No. 2 February 2004, pp. 313-319

Effects of Three Courses of Maternally Administered Dexamethasone at 0.7, 0.75, and 0.8 of Gestation on Prenatal and Postnatal Growth in Sheep

Michelle A. Kutzler, DVM, PhD, Erin K Ruane, BS, Turhan Coksaygan, DVM, MS, Stella E. Vincent and Peter W. Nathanielsz, MD, PhD, ScD, FRCOG

From the Oregon State University College of Veterinary Medicine, Corvallis, Oregon


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 THE RICH ARE DIFFERENT
 REFERENCES
 
Objectives. To evaluate the effects of repeated low doses of maternally administered dexamethasone (DM) on growth in sheep during fetal life and the first 2 years of postnatal life.

Methods. Ewes received 3 courses of DM (1 course: four 2-mg intramuscular injections at 12-hour intervals) or saline beginning at 103, 110, and 117 days of gestation (dGA). At 119 dGA, fetal BW and organ weight were recorded. Total placentome number, weight, and morphologic distributions were recorded. Placentome glucocorticoid receptor expression was determined by immunocytochemistry. Newborn BW and organ weight were recorded within 12 hours of birth. Duration of gestation was recorded. Measurements were collected on body weight (BW), biparietal diameter (BPD), crown-to-rump length, thoracic girth circumference, abdominal girth circumference, and radial bone length for 2 months. Maternal estradiol and progesterone levels were measured daily from 135 dGA.

Results. At 119 dGA, DM significantly decreased BW. Placentome glucocorticoid receptor expression increased after DM exposure. DM did not significantly decrease BW at birth but did prolong gestation length. DM decreased maternal estradiol before lambing. DM decreased newborn brain weight and BPD. After 2 weeks of age, no effect of DM on postnatal growth could be found.

Conclusions. This study shows that repeated maternal DM treatment at doses threefold lower than what women in preterm labor receive results in decreased fetal BW, prolonged gestation length, decreased newborn brain weight, and BPD.

Key Words: biparietal diameter • estradiol • glucocorticoid receptor • glucocorticoids • placenta

Abbreviations: DM, dexamethasone • HPA, hypothalamic-pituitary-adrenal • GR, glucocorticoid receptor • dGA, days of gestation • BW, body weight • KPBS, potassium phosphate-buffered solution • BPD, biparietal diameter • CRL, crown-to-rump length • TGC, thoracic girth circumference • AGC, abdominal girth circumference • RBL, radial bone length • SEM, standard error of the mean

Betamethasone (2 doses of 12 mg at 24-hour intervals) or dexamethasone (DM) (4 doses of 6 mg at 12-hour intervals) are administered to women at risk of preterm labor from 24 to 34 weeks of gestation to reduce neonatal morbidity associated with respiratory distress syndrome and intraventricular hemorrhage.1,2 This prophylactic therapy is administered to nearly 10% of pregnant women;3 however, exogenous glucocorticoid administration has been associated with reduced birth weight and neonatal head circumference.4–6 Animal studies have shown that the severity of glucocorticoid-related fetal growth retardation is influenced by gestational age at exposure, number of exposures, timing and duration of exposure, dosage during exposure, and nature of the glucocorticoid administered.1,7–15 In addition, antenatal glucocorticoids alter both prenatal3,16,17 and postnatal hypothalamic-pituitary-adrenal (HPA) function18–20 as well as pituitary glucocorticoid receptor (GR) messenger RNA expression.17

In the ewe, parturition is initiated by the fetal HPA axis.19,21–23 The increased fetal cortisol secretion that occurs in the final 20 days of ovine gestation24 activates placental 17-hydroxylase and 17,20 lyase, resulting in increased conversion of progesterone to estrogen, and initiating parturition.25 Thus, in sheep, gestation length is determined by the level of fetal HPA activity.19,22 Antenatal glucocorticoid administration suppresses fetal adrenal activity and results in prolonged gestation length in rhesus macaques, sheep, and guinea pigs.26–28

GRs are widely expressed within the placenta. In humans29 and cattle,30 placental GR expression has been shown to increase with gestational age, which may be related to increasing concentrations of cortisol in late gestation. Maternal glucocorticoid administration alters placental growth and endocrine function in several species.6,31,32 Although the effects of antenatal DM on expression of GR in fetal tissues have been described,3,17,33–35 the effects on placental GR expression have not been investigated.

The purpose of this study was to investigate both intrauterine and postnatal growth effects of a relatively low dose of DM administered to pregnant sheep at 103, 110, and 117 days of gestation (dGA) (term: 149 dGA). Previous studies of the effects of glucocorticoids on growth in the perinatal period in sheep have used doses of betamethasone (500 µg/kg of maternal body weight [BW]) administered concomitantly with medroxyprogesterone acetate to prevent induction of preterm delivery.7,18,27 We have chosen to study a lower dose of glucocorticoids that does not require progesterone supplementation. We hypothesized that at a lower dose, the growth retardation reported with higher doses of glucocorticoids would be reduced, with only the most metabolically active tissues (eg, brain and placenta) being affected. To test this hypothesis, we determined the effect of three 48-hour exposures to maternal DM or saline at weekly intervals beginning at 103, 110, and 117 dGA on 1) fetal BW, organ weight, placental weight, and GR expression at 0.8 of gestation, 2) newborn BW, organ weight, and gestation length, and 3) postnatal weight and body measurements.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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Animals and DM Treatment
Rambouillet ewes bred only on a single occasion and carrying fetuses of known gestational age were used for this study. All experimental procedures were approved by the Cornell University Institutional Animal Care and Use Committee, and facilities were approved by the Association for Assessment and Accreditation of Laboratory Animal Care. A separate group of ewes was used for each experiment. All ewes received three 48-hour courses of DM (Azium, Schering-Plough Animal Health, Union, NJ) or saline at weekly intervals beginning at 103 dGA. Each treatment course consisted of 4 intramuscular injections of DM (2 mg per ewe per injection) or an equal volume of saline (1 mL) administered at 12-hour intervals. Individual ewe weight during the treatment period ranged from 60 to 70 kg. Thus, the dose of DM was equivalent to 29 to 33 µg/kg.

Experiment 1
Fetal and Placental Measurements
Twenty ewes were administered either DM (n = 9) or saline (n = 11). Within 12 hours of the last injection at 119 dGA, ewes received 1 g of ketamine (Ketaflo, Abbott Laboratories, North Chicago, IL) intramuscularly, and general anesthesia was induced with 4% isoflurane gas (Isoflo, Abbott Laboratories) administered by a face mask. The uterus was exteriorized through a ventral midline laparotomy. The uterus was isolated, and the fetus was delivered through an incision in the gravid horn. The umbilical cord was ligated, the fetus was towel-dried, and BW was recorded. Although still anesthetized, the fetus was euthanized by exsanguination, and the fetal brainstem was transected at the level of the first cervical vertebrae. The ewe was euthanized by an overdose (15 mL) of pentobarbital sodium (Fatal Plus, Vortech Pharmaceuticals, Dearborn, MI). The uterus was fully excised to facilitate placentome removal. Placentomes were dissected from the uterus and identified on the basis of morphology,36 and individual placentome weights were recorded. Fetal adrenal, kidney, liver, brain, and pituitary weights were recorded also.

GR Immunocytochemistry
From each animal, 1 placentome from the gravid uterine horn with a type A morphology was selected randomly. Placentomes were fixed in 10% buffered formalin and paraffin-embedded for immunocytochemistry. Because of the possible confounding variable of sex differences and an uneven proportion of female to male fetuses in each group, only placentomes from male fetuses were analyzed. Serial 5-µm sections were cut from paraffin blocks and mounted on poly-L-lysine-coated slides, deparaffinized in xylene, and rehydrated in a graded ethanol series (100%, 75%, 50%) to potassium phosphate-buffered solution (KPBS) (9 g of NaCl, 6.97 g of K2HPO4, and 1.36 of g KH2PO4 to 1000 mL of H20, pH 7.4). The action of tissue-specific endogenous peroxidases was inhibited by incubating slides in 30% hydrogen peroxide in methanol during hydration. Subsequent antigen retrieval was conducted by incubating the sections in 10 mM citrate buffer (pH 6.0) in a microwave oven for 7 x 2 minutes.38 Slides then were washed in KPBS 6 x 7 minutes, blocked for 10 minutes at room temperature with 10% normal horse serum in KPBS containing 0.4% Triton X-100, and incubated in a humidified chamber at 4°C with monoclonal antibodies for mouse anti-rat GR (Affinity Bioreagents, #MA1-510, Golden, CO) at 1:10 dilution in KPBS containing 0.4% Triton X-100 for 24 hours. Specificity of immunostaining was verified by replacement of the primary antibody with nonimmune mouse ascites fluid (Clone NS-1, Sigma Chemical Co, St Louis, MO) at the same dilution. Slides then were reacted with biotin-labeled horse anti-mouse immunoglobulin G and incubated with preformed avidin-biotin-peroxidase complex (ABC kit, Vector Laboratories, Burlingame, CA). Diaminobenzidine tetrahydrochloride chromogen was used as a substrate. Sections were counterstained (Light-Green SF Yellowish, no. C7902, Imelo, Inc, San Marcos, CA), dehydrated, and mounted.

Experiment 2
Hormone Analysis
Sixteen ewes were administered 3 courses of either DM (n = 8) or saline (n = 8). From 140 dGA until delivery, daily maternal blood samples were collected via jugular venipuncture into a heparinized container for measurement of estradiol and progesterone concentrations. Blood samples were centrifuged, and plasma was removed and stored at –20°C until processed. Ewes were allowed to spontaneously deliver, and gestation length at delivery was recorded. Progesterone was measured in maternal plasma by using a Coat-a-Count radioimmunoassay kit (Diagnostic Products Co, Los Angeles, CA). The cross-reactivities with 5{alpha}- and 5ß-pregnan-3,20-dione were 9.0% and 3.2%, respectively. The cross-reactivities of 17{alpha}-hydroxyprogesterone and 11-deoxy-corticosterone were 3.4% and 2.2%. Cross-reactivities to other steroids were <1%. The sensitivity of the assay (defined by 90% bound/free) was 0.1 ng/mL plasma. Inter- and intraassay coefficients of variations for the progesterone assay were 10.9% and 4.3%, respectively, for 9.1 ng/mL progesterone in control plasma.

Estradiol was measured in diethyl ether extracted maternal plasma using a Coat-a-Count radioimmunoassay kit. Plasma and control sera (500 µL) were double-extracted with 4.5 mL of diethyl ether and reconstituted in 250 µL of 0.01 M phosphate-buffered saline/0.5% bovine serum albumin. The cross-reactivities with ethinyl estradiol and d-equilenin were 1.8% and 4.4%, respectively. The cross-reactivities of estrone and estrone-ß-D-glucuronide were 10% and 1.8%. Cross-reactivities to other steroids were <1%. The sensitivity of the estradiol assay (defined by 90% bound/free) was 10 pg/mL estradiol in plasma. Inter- and intraassay coefficients of variations were 4.6% and 2.8%, respectively, for 141 pg/mL maternal control sera. Recovery of [3H]estradiol from control plasma was 88%.

Neonatal Measurements
Within 12 hours of delivery, 100 mg of ketamine (Ketaflo) was administered intramuscularly to fully dried newborn lambs, and general anesthesia was induced with 4% halothane (Halocarbon Laboratories, River Edge, NJ) inhalation via a face mask. BW was recorded. Euthanasia was accomplished by exsanguination under general anesthesia. The brainstem was transected at the level of the first cervical vertebrae. Newborn adrenal, kidney, gonad, liver, pancreas, heart, lung, thymus, thyroid, brain, pituitary, and eye weights were recorded.

Experiment 3
Postnatal Measurements
Twenty-six ewes were administered 3 courses of either DM (n = 13) or saline (n = 13). Ewes were allowed to deliver spontaneously, and duration of gestation at delivery was recorded. Within 24 hours of delivery, the following measurements were made on fully dried lambs and continued biweekly for 8 weeks: BW, biparietal diameter (BPD), crown-to-rump length (CRL), thoracic girth circumference (TGC), abdominal girth circumference (AGC), and radial bone length (RBL). All measurements were made with the animals standing. TGC and AGC were measured at the level of the axilla and umbilicus, respectively. The RBL was measured as the distance between the olecranon and the accessory carpal bone. BW and BPD measurements were repeated at 3, 4, 5, 6, 7, 8, 9, 12, 18, and 24 months of age.

Data Analysis
An investigator who was unacquainted with the treatment status (either saline or glucocorticoid-exposed) made all measurements. For the analysis of GR expression, a blinded observer randomly selected 3 fields equidistant from the maternal and fetal surfaces of the placentome (labyrinth region) under x10 magnification. The number of cells with GR immunoreactivity per field as well as the intensity of staining was evaluated blindly by using image-analysis software (Simple PCI, Compix Inc Imaging Systems, Cranberry Township, PA). Comparisons between groups, times, and sexes were made by using a 2-tailed Student’s t test, 2-way analysis of variance, or exponential regression analysis as appropriate. Differences were considered statistically significant at P < .05. All the results are presented at means ± standard error of the mean (SEM), and n refers to the number of animals studied.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 THE RICH ARE DIFFERENT
 REFERENCES
 
Experiment 1
Effects of DM Treatment on Fetal Growth
Three female and 8 male lambs were delivered from ewes treated with DM, whereas 3 female and 6 male lambs were delivered from ewes treated with saline. All ewes had singleton pregnancies. Fetal BW did not differ by gender (Table 1). Maternal DM treatment reduced fetal BW and renal weight in both sexes. However, when examined as a proportion of BW, the difference in renal weight between treatment groups was not significant (data not shown).


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  		TABLE 1. Effects of 3 48-Hour Courses of Maternally Administered Saline or DM on Fetal BW and Organ Weight at 119 dGA

 
Effects of DM Treatment on Placental Growth and GR Expression
Total number of placentomes, total placentome weights, and fetal/placental weight ratios did not differ between treatment groups (Table 2). The weight of the different morphologic types of placentomes did not differ between treatment groups, but the distribution of type C placentomes was increased after DM exposure. In placentomes from male fetuses, the intensity of immunostaining for GR and the number of immunopositive staining cells per field within the labyrinth region of placentomes was increased in DM-treated compared with the saline-treated animals (Fig 1 and Table 2).


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  		TABLE 2. Effects of 3 48-Hour Courses of Maternally Administered Saline or DM at 0.7, 0.75, and 0.8 of Gestation on Total Weight, Number, and Morphologic Distribution as Well as GR Immunostaining Intensity and Number of Immunopositive Staining Cells at 119 dGA

 

Figure 1
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  		Fig 1. Immunocytochemical staining (x40) for GR in paraffin-embedded ovine placentome sections from ewes treated with three 48-hour courses of saline (A) or DM (B) at 0.7, 0.75, and 0.8 of gestation. DM increased the number of immunopositive staining nuclei within the labyrinth region of the placentome (P < .05).

 
Experiment 2
Effects of DM Treatment on Birth Weight and Gestation Length
Of the 16 ewes, 5 ewes from each treatment group delivered sets of twin male lambs. To eliminate the confounding factors of comparing twins versus singles and males versus females, only the ewes with the twin male lambs were used in experiment 2. Three courses of maternally administered DM did not reduce newborn BW (P = .16) compared with the saline-treated group but did prolong gestation length (Table 3). Newborn brain weights were reduced after exposure to DM in utero (55.8 ± 1.48 g) when compared with saline controls (61.8 ± 0.8 g), whereas other organ weights were not different (Table 3). Similar results were found when organ weights were compared as a percent of BW.


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  		TABLE 3. Effects of 3 48-Hour Courses of Maternally Administered Saline or DM at 0.7, 0.75, and 0.8 of Gestation on Newborn BW and Organ Weight Within 12 Hours of Delivery

 
Effect of DM Treatment on Maternal Estradiol and Progesterone Concentrations
Maternal plasma estradiol concentrations were increased in both treatment groups on the day before delivery when compared with previous days (Fig 2). Three courses of maternally administered DM reduced prepartum estradiol levels compared with the saline-treated group. Progesterone concentrations were decreased from the days before delivery within each group but did not differ significantly between treatment groups (Fig 2).


Figure 2
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  		Fig 2. Maternal plasma estradiol (A) and progesterone (B) concentrations over the last 7 days before delivery in ewes treated with three 48-hour courses of saline (open bars, n = 5) or DM (solid bars, n = 5) beginning at 0.7, 0.75, and 0.8 of gestation. Mean ± SEM: *P < .05 compared with the saline-treated group; {dagger}P < .05 compared with previous day.

 
Experiment 3
Effects of DM Treatment on Birth Weight and Gestation Length
Seven female and 6 male singleton lambs were born to ewes treated with DM, and 5 female and 8 male singleton lambs were born to ewes treated with saline. As observed in experiment 2, 3 courses of maternally administered DM did not reduce birth weight (P = .18) compared with the saline-treated group but did prolong gestation length (Table 4). Males weighed more than females in both treatment groups (Table 4).


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  		TABLE 4. Effects of 3 48-Hour Courses of Maternally Administered DM or Saline at 0.7, 0.75, and 0.8 of Gestation on Weight and Body Measurements at Birth

 
Effects of DM Treatment on Postnatal Body Measurements
At birth, TGC, AGC, CRL, and RBL were not different between groups. However, BPD was reduced in both male and female lambs after this exposure to DM in utero (Table 4). Males had a larger BPD than females in both treatment groups after 16 weeks of age (Fig 3). Males also weighed more than females in both treatment groups after 32 weeks of age (Fig 3). Body measurements were similar between treatment groups at every time point after 2 weeks of age (Fig 3).


Figure 3
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  		Fig 3. Effects of three 48-hour courses of maternally administered saline (open symbols, n = 5–8) or DM (filled symbols, n = 6–7) at 0.7, 0.75, and 0.8 of gestation on weight and body measurements postnatally (postnatal age in weeks on y axis). Mean ± SEM: *P < .05 females (circles) compared with males (squares).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
THE RICH ARE DIFFERENT
 REFERENCES
 
The recommended dose of DM (6 mg twice a day for 2 days) or betamethasone (12 mg once a day for 2 days) used in the clinical management of women in preterm labor, surprisingly, is not weight adjusted. On the usual dosing regimen, a 60-kg woman receives 100 µg/kg per injection. In the current study, we examined effects of a relatively low dose (28–32 µg/kg) of DM on prenatal and postnatal growth. Critically, we observed marked differences from other reports in sheep using weekly doses of a single injection of betamethasone (500 µg/kg), a dose fivefold higher than used in obstetric medicine.7,17,27,37, 38 We observed a DM-induced reduction in BW of 15% at 119 dGA, in contrast to 23% to 25% reduction in fetal growth at 125 dGA after 3 weekly maternal betamethasone treatments.7,39 A single high dose of betamethasone at 121 dGA reduces fetal BW at 135 dGA (25%–26% reduction) as much as 3 high doses of betamethasone administered at 114, 121, and 128 dGA.39 The same investigators found an 11%7 or 20%39 reduction in fetal weight after a single dose of betamethasone at 104 dGA, when the fetuses were delivered at 125 dGA but no difference in fetal weight after a single dose of betamethasone at 114 dGA when lambs were delivered at 135 dGA.39

The 9%, 2%, and 6% reductions in weight after low-dose DM treatment in singleton females, singleton males, and twin males, respectively, in our study were not significant. In contrast, previous studies using higher doses of betamethasone (500 µg/kg) reported reduced weight after elective delivery at 145 to 146 dGA and spontaneous delivery. At 145 to 146 dGA, 1 injection of betamethasone at 104 dGA resulted in a 14% reduction in birth weight7 compared with a 19%7 or 30%38 reduction in birth weight after 3 betamethasone injections at weekly intervals beginning at 104, 111, and 118 dGA. After spontaneous delivery, 4 betamethasone injections administered at weekly intervals beginning at 104, 111, 118, and 125 dGA resulted in a 36% reduction in BW.27 Single or repeated fetal betamethasone treatment did not decrease weight after elective delivery at 146 dGA38 or spontaneous delivery.27 The lack of a difference in birth weight in the current study may have resulted from the lower dose of DM used or the prolonged gestation length after DM treatment. As stated before, increased gestation length after antenatal glucocorticoid administration has been reported in guinea pigs,26 sheep,27 and rhesus macaques28 after long-term DM or repetitive betamethasone exposure.

We have shown that DM decreased basal levels of maternal estradiol, but not progesterone, and diminished the prepartum estrogen surge. Administration of glucocorticoids to pregnant women in late gestation has similar effects; it decreases estriol concentrations without changes in progesterone concentrations.39 Additional studies demonstrated that a single dose of maternally administered betamethasone rapidly decreases maternal estriol levels.40 Because the fetal HPA function can be estimated indirectly by estriol concentrations,41 our findings support decreased fetal HPA activity.

The dose of corticosteroids needed to reduce brain weight is lower than the dose needed to reduce BW.12 Our finding of reduced newborn brain weight and male and female BPD in the presence of normal birth weight is similar to results in fetal guinea pigs3 and rhesus monkeys.42 In fetal sheep, betamethasone infusion (10 µg/hour for 48 hours beginning at 128 dGA) reduces brain blood flow43 and results in a reduction in microtubular-associated proteins and synaptophysin at many locations in the brain,44,45 both of which may contribute to decreased brain weight. It is of interest to note that there is evidence from prenatal and postnatal clinical studies as well as experiments in pregnant mice indicating that, although there are side effects associated with both isomers, betamethasone is safer and more protective to the developing brain than DM.46 Differences related to head circumference size in children after exposure to antenatal glucocorticoids were no longer evident at 3 years of age.5 This finding supports our results in that differences from 3 courses of maternally administered DM in BPD at birth are no longer present at subsequent postnatal time points (>2 weeks of age).

It has been reported that maternal DM infusion (0.76 mg/hour for 72 hours; equivalent to 180 µg/kg twice a day for a 50-kg ewe) significantly alters the composition of the fetal fluids at 0.6 of gestation without affecting fetal BW and organ and placental weight.47 The authors reported that DM treatment increased the number of placentomes >5 g as well as induced a change in placentome morphology, such that 3% of the DM-treated animals had placentomes that were of the "bovine" type in morphology.47 Although there was a trend toward a placenta of reduced weight from DM treatment in the present study, this difference was not significant. However, we did find an increase in the percentage of everted (type C) placentomes after DM exposure. We also observed that maternal DM treatment increased placental GR expression at 119 dGA in agreement with the observations that immunoreactive GR and GR{alpha} protein increase in ovine trophoblast cells after cortisol infusion48 and with gestational age, presumably from increasing endogenous fetal cortisol.29,30

In summary, the effects on fetal growth obtained by the low dose of DM we used are much lower than those reported previously with other dosing regimens. It is undisputed that antenatal glucocorticoids improve the immediate problems associated with being born prematurely. Additional studies are needed to determine therapeutic regimens that enhance the beneficial effects of prenatal steroid therapy while minimizing unwanted side effects on whole-body and organ development.


   THE RICH ARE DIFFERENT
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 THE RICH ARE DIFFERENT
REFERENCES
 
"The Chronicle of Philanthropy reports that Americans making $70 000 or more dispensed a paltry 3.3% of their earnings to charitable causes; in contrast, those making $50 000 to $69 999 gave 5.6%, and those making $30 000 to $49 999 gave 8.9%."

Atlantic Monthly. October 2003

Submitted by Student


   ACKNOWLEDGMENTS
 
This investigation was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute National Research Service Award F32 HL68393 and grants R01 HL055416 and P01 HD21350.

We thank Sue Jenkins for assistance with data analysis and A. Damon Fergason and Steve Elser for animal support.


   FOOTNOTES
 
Received for publication Feb 5, 2003; Accepted May 19, 2003.

Reprint requests to (M.A.K.) Oregon State University College of Veterinary Medicine, Magruder Hall, Corvallis, OR 97331. E-mail: michelle.kutzler{at}oregonstate.edu


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 METHODS
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 DISCUSSION
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