Maternal Dexamethasone Administration Research Articles

Effects of Maternal Administration of Dexamethasone and Thyrotropin-Releasing Hormone on Fetal Rat Pulmonary Surfactant Synthesis

To determine the effects of maternal administration of dexamethasone (DEX) and thyrotropin-releasing hormone (TRH) on fetal lung maturation, 16 pregnant rats were divided into the following four groups: 20 micrograms/kg TRH twice a day was given intraperitoneally to the TRH group rats, 0.5 mg/kg/day DEX to the DEX group and both DEX and TRH to the DEX + TRH group for 3 consecutive days from gestational day 17. The control rats were given an equivalent volume of saline. The pregnant rats were sacrificed on gestational day 20 and the fetal lungs were removed. The relative amounts of surfactant protein A (SP-A), B (SP-B) and C (SP-C) mRNAs were analyzed by Northern blotting and the total lung disaturated phosphatidylcholine (DSPC) contents were determined using an enzymatic method. The SP-B and -C mRNA and DSPC contents in the DEX and DEX + TRH groups were significantly higher than those in the control group, whereas the SP-A mRNA levels did not differ significantly among the four groups. The SP-B and -C mRNA and DSPC contents in the DEX and DEX + TRH groups did not differ significantly. These findings suggest that TRH has no effects on the regulation of surfactant protein mRNAs or DSPC contents in the fetal rat lung and has no additive effects when combined with DEX.

Dexamethasone and fetal heart rate variation

To determine the effect of maternal administration of dexamethasone on fetal heart rate and its variation. Retrospective analysis of computerised data derived from cases studied over three years. High risk pregnancy unit, John Radcliffe Hospital, Oxford. Twenty-eight pregnant women, at 27 to 32 weeks of gestation, to whom dexamethasone was given to accelerate pulmonary maturation in the expectation of preterm delivery. Dexamethasone (two doses of 12 mg intramuscularly, 12 h apart) was given on 51 occasions at weekly intervals (one to four occasions per patient). Complete data were available for cardiotocograph analysis from computerised measurement of fetal heart rate variables for two days before and four days after dexamethasone and, in 19 women, measurements of umbilical arterial flow velocity waveforms before and after dexamethasone. In 10 pregnancies without fetal distress there was a highly significant (P < 0.01) transient rise in short term fetal heart rate variation after dexamethasone administration, from means (SE) 6.4 (0.28) to 9.8 (0.4) ms. In 18 pregnancies with subsequent delivery for fetal distress (abnormal fetal heart rate pattern) and high umbilical arterial resistance index [mean 0.93 (0.06 SE)], the rise in short term fetal heart rate variation was less (P < 0.01), from mean (SE) 5.4 (0.26) to 6.1 (0.48) ms. In a further case of discordant twin pregnancy, the larger twin continued to respond to dexamethasone administrations with a rise in fetal heart rate variation for five weeks; the smaller twin, with maintained tachycardia and reduced umbilical arterial end-diastolic flow velocity, failed to respond after the first two weeks. The results show that maternal dexamethasone administration normally causes a rise in fetal heart rate variation for up to a day. This rise is reduced in pre-eclampsia or intrauterine growth retardation, associated with a reduction in umbilical flow, perhaps because of a consequential lower concentration of steroid in the fetus. The results contrast with those for betamethasone which has been reported to reduce fetal heart rate variation.

Regulation of surfactant protein D expression by glucocorticoids in vitro and in vivo.

SP-D is a recently described lung-associated protein that is produced by alveolar type II cells and may function in pulmonary host defenses. Since little is known regarding the hormonal regulation of SP-D, and since the other surfactant proteins (SP-A, SP-B, and SP-C) are known to be regulated by glucocorticoids, we sought to determine the effects of glucocorticoids on SP-D mRNA and protein expression, both in vitro and in vivo, in the fetal rat lung. In vitro experiments were performed on lung explants from fetuses on gestational day 15 or 18. Explants were cultured in serum-free conditions with or without hydrocortisone for 3 days. SP-D mRNA expression was evaluated by Northern blot analysis. SP-D protein expression was analyzed using a polyclonal antibody against SP-D and standard immunohistochemical techniques. The expression of SP-D mRNA increased in fetal day 15 explants but remained unchanged in fetal day 18 explants cultured without the addition of hydrocortisone, compared with in vivo controls. The addition of hydrocortisone resulted in increases in SP-D mRNA expression at both gestational ages. This pattern of SP-D mRNA expression was compared with the expression of the other surfactant proteins and found to be most similar to that of SP-B. In vivo experiments were performed using maternal administration of dexamethasone (1 mg/kg) or an equal volume of saline on fetal days 15, 16, and 17 or on fetal day 17 with sacrifice on fetal day 18.(ABSTRACT TRUNCATED AT 250 WORDS)

Gestational age dependence of 11β-hydroxysteroid dehydrogenase and its relationship to the enzymes of phosphatidylcholine synthesis in lung and liver of fetal rat

Increase in fetal surfactant synthesis and lung maturity is caused by the glucocorticoidal induction of enzymes required for phosphatidylcholine (PC) synthesis towards the end of gestation. The regulation of gestational age-dependent induction of PC synthesis by glucocorticoids is still unclear. Since 11-β-hydroxysteroid dehydrogenase (11β-HSD) activity and its metabolising capacity for glucocorticoids have been suggested to play a central role in this regulation, we measured the gestational age-dependent changes in 11β-HSD and PC synthesizing enzymes in lung and liver of fetal rat. The activity of cholinephosphate cytidyltransferase (CCT; key enzyme in PC synthesis), choline phosphotransferase (CPT) and lysolecithin acyltransferase (LAT) were found to increase gradually in the lung towards the end of gestation, reached peak values at term followed by a decrease of activity reaching finally adult levels. Only CK activity exhibited constant levels until term followed by a slight increase after the birth. In comparison with the lung, the liver enzymes followed a similar pattern, but at a higher rate of activity except for CCT which was higher in the lung. The activity of 11β-HSD in fetal lung microsomes was detectable from day 20 and increased towards the end of gestation in the lung and liver of the rat. Oxidase activity was always found to exceed the reductase activity. The activity of 11β-HSD continued to increase after delivery and reached peak levels in adult animals in both organs. In order to test the hypothesis, whether 11β-HSD activity and PC synthesis are induced by increasing endogenous glucocorticoidal levels, we examined on day 19 of gestation the effect of dexamethasone (DEXA) on enzymatic activities (11β-HSD, CCT) and on [ 14C]choline incorporation in phosphatidylcholine in fetal lung organoid cultures. Additionally, changes in CCT activity in fetal lungs after maternal administration of DEXA were measured. DEXA accelerated 11β-HSD and CCT activities as well as [ 14C]choline incorporation. We conclude, that endogenous glucocorticoids induce PC synthesis as well as 11β-HSD activity in lung and liver of the fetal rat. Fetal PC synthesis is not altered by increasing 11β-HSD levels, because the increase of free serum corticosterone levels apparently exceeds the metabolising capacity of 11β-HSD towards term.

Prenatal diagnosis and treatment of congenital adrenal hyperplasia.

Advances in technology have made possible the prenatal diagnosis and treatment of female fetuses with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hormonal measurement of 17-hydroxyprogesterone, androstenedione, testosterone and 21-deoxycortisol and HLA typing and DNA analysis for 21-OH/C4/HLA class I and II genes in chorionic villus cells and amniocytes are utilized for prenatal diagnosis. Maternal dexamethasone administration begun in the first trimester has prevented or ameliorated virilization in approximately three-fourths of infants. Maternal estriol levels appear to be the most accurate measure of fetal adrenal suppression. Maternal side effects are not infrequent and include excess weight gain, edema, glucose intolerance, hypertension and gastrointestinal problems. Severe permanent striae have been reported. Although no complications of prenatal treatment in the treated fetus or child have been reported long-term follow-up with careful neuropsychologic evaluation is not yet available and is necessary to fully evaluate possible long-term side-effects of prenatal dexamethasone treatment.

Ontogeny of Small Intestinal Glutaminase and Glutamine Synthetase in the Rat: Response to Dexamethasone

The ontogeny of small intestinal glutaminase (GA) and glutamine synthetase (GS) was studied with relation to the maternal administration of dexamethasone (DEX). Pregnant Sprague-Dawley rats were administered 0.2 mg/kg of DEX or saline twice daily on days 19 and 20 of gestation. Activity of GA did not increase from the fetus to the 10-day-old rat; however, GS activity increased 7-fold. DEX induced doubling of GA activity and mRNA, but only a slight increase is GS activity and mRNA was observed in the fetus. GA and GS activities appear to be regulated by different mechanisms.

The effect of prenatal administration of dexamethasone and ritodrine on cord blood cortisol and glucose concentrations in premature infants with respiratory distress syndrome.

The influence of maternal dexamethasone and ritodrine administration during pregnancy on cord blood cortisol and capillary serum glucose concentrations and on the incidence of respiratory distress syndrome (RDS) was studied in 30 premature infants (gestational age 27-36 weeks), and compared with a matched control group of 37 premature infants where no such medications were administered. RDS occurred less often in the treated group of infants (13.3%) than in the controls (35.1%, p < 0.01). The healthy treated infants had a significantly lower mean umbilical cord plasma cortisol concentration (5.5 +/- 1.8 ug/dl, mean +/- SD) than that observed in the controls (11.2 +/- 3.9 ug/dl, p < 0.01). Mean cord plasma cortisol concentrations increased with duration of pregnancy. No significant difference in the capillary serum glucose at 30 minutes post-delivery was found between the healthy, RDS, treated and non-treated infants. No adverse effects of steroid and ritodrine therapy were observed.

Maternal administration of dexamethasone stimulates choline-phosphate cytidylyltransferase in fetal type II cells.

Administration of dexamethasone to pregnant rats at 19 days gestation increased phosphatidylcholine synthesis (45%) from radioactive choline in type II cells. This enhanced synthesis of phosphatidylcholine was accompanied by an increased conversion of choline phosphate into CDP-choline. Similar results were obtained by incubating organotypic cultures of 19-day-fetal rat lung with cortisol. The increased conversion of choline phosphate into CDP-choline correlated with an enhanced choline-phosphate cytidylyltransferase activity (31% after dexamethasone treatment; 47% after cortisol exposure) in the cell homogenates. A similar increase (26% after dexamethasone treatment; 39% after cortisol exposure) was found in the microsomal-associated enzyme. No differences in cytosolic enzyme activity were observed. The specific activity of the microsomal enzyme was 3-4 times that of the cytosolic enzyme. Most of the enzyme activity was located in the microsomal fraction (58-65%). The treatments had no effect on the total amount of enzyme recovered from the cell homogenates. These results, taken collectively, are interpreted to indicate that the active form of cytidylyltransferase in type II cells is the membrane-bound enzyme and that cytidylyltransferase activation in type II cells from fetal rat lung after maternal glucocorticoid administration occurs by binding of inactive cytosolic enzyme to endoplasmic reticulum.

Unsuccessful treatment of fetal immunologic thrombocytopenia with dexamethasone

Corticosteroid therapy near term for mothers with immunologic thrombocytopenia has recently been suggested as a clinically useful method to prevent neonatal thrombocytopenia. The unreliability of this approach is illustrated by the case of an infant with a low platelet count delivered after the maternal administration of dexamethasone.

Maternal administration of dexamethasone in severe pregnancy-induced hypertension

Fourteen patients with severe pregnancy-induced hypertension and low lecithin/sphingomyelin (L/S) ratios were treated with 5 mg of dexamethasone phosphate intramuscularly every 12 hours for four doses to induce fetal pulmonary maturity. A comparison was made of the average gestational age, mean L/S ratio, method of delivery, Apgar scores, mean birth weight, and incidence of respiratory distress syndrome in these patients and in 16 patients with similar demographic backgrounds and clinical presentations who did not receive corticosteroid therapy. There was no significant difference between the two groups except that the time or treatment (or nontreatment) to delivery was longer in the steroid group. There were two cases of neonatal respiratory distress syndrome in the treatment group, and one of these infants died. In the control group, there were two neonatal deaths among four cases of respiratory distress syndrome. There was no clinical evidence of intraventricular hemorrhage in any neonate nor was there aggravation of hypertension in the parturient patients. The administration of corticosteroids to induce fetal pulmonary maturity in patients with severe pregnancy-induced hypertension who are carefully selected and monitored does not appear to be contraindicated.

Suppression of adrenal cortical growth and differentiation in fetal rats exposed to dexamethasone.

AbstractThe effects of maternal dexamethasone (DEXA) administration during the last days of gestation on fetal adrenal growth and differentiation were studied. Timed pregnant rats were divided into three groups: (a) 21d DEXA‐3 received DEXA in drinking water (5 μg/ml) from days 18 to 21 of gestation; (b) 21d DEXA‐6 received the same dosage of DEXA from days 15 to 21 of gestation; and (c) 21d control received tap water throughout gestation. On gestation day 21, pregnant rats were decapitated and ble into heparinized tubes; their fetuses were excised, weighed, decapitated, and bled. Fetal adrenals were prepared for electron microscopy or weighed and frozen until assayed for corticosterone. Control adrenals were also collected on day 15 of gestation and processed for electron microscopy only. Fetal adrenals were fixed in 2.5% glutaraldehyde in 0.5 M cacodylate buffer, postfixed in 2% osmium tetroxide (OsO4), dehydrated, and embedded in Epon 812. Twenty‐one day (21d) fetal adrenal weights were 44% and 68% lower than control values for DEXA‐3 and ‐6, respectively. Fetal adrenal corticosterone levels were decreased by 70% and 89% for the respective groups. These observations correlated with ultrastructural findings of decreased mitochondrial number and size, altered orientation of the inner mitochondrial membrane, decreased lipid, and dilation of smooth endoplasmic reticulum (SER) in cortical fascicular cells of DEXA‐exposed fetuses. Ultrastructural changes in the 21d DEXA fetal adrenals resembled 15d day control fetal adrenals. The results suggest suppressed adrenocortical differentiation probably due to DEXA inhibition of the steroidogenic influence of the fetal pituitary on the developing adrenal gland in DEXA‐exposed fetuses.

Amniotic fluid phospholipids after maternal administration of dexamethasone

The administration of corticosteroids to pregnant women in premature labor can accelerate fetal lung development and potentially prevent neonatal respiratory distress syndrome (RDS). Controversy exists, however, as to whether amniotic fluid phospholipid indices of lung maturation are influenced by such treatment. Without a suitable test for evaluating the fetal response to corticosteroids, there is no method of recognizing whether and when lung development has been stimulated. In an attempt to resolve this issue, we carried out a study of amniotic fluid phospholipids as part of the National Institutes of Health multicenter trial of prenatal corticosteroids. Amniocenteses were performed before the administration of either steroid hormone or placebo and approximately 1 week after a series of four injections was initiated. Analysis of the ratio of lecithin (phosphatidylcholine) to sphingomyelin (L/S ratio) revealed nearly identical values initially and no significant difference in the posttreatment means when 25 steroid-treated pregnancies were compared to 20 control pregnancies. Although there were significant increases in both groups during the interval between amniocenteses, no statistical difference was found in the extent of change in L/S ratios between the two groups, when pretreatment values were compared with those obtained an average of 1 week later. In addition to evaluating L/S ratios, we performed an assessment of phospholipid concentrations in 17 pregnancies before and after administration of dexamethasone. This revealed no detectable phosphatidylglycerol. There were increases in the absolute concentrations of phosphatidylcholine and disaturated phosphatidylcholine, but these changes were relatively modest in magnitude and could be attributable to either advanced gestational age or dexamethasone. Our results demonstrate that current tests of fetal lung maturity do not provide a routine means for prenatal detection of pulmonary maturational responses to corticosteroids.

Neonatal Leukocytosis Associated with Prenatal Administration of Dexamethasone

Prophylactic induction of fetal surfactant through maternal steroid administration in early premature labor is becoming accepted clinical practice. This article describes an 840-gm, 27 weeks' gestation male infant, who had a profound, apparently benign, leukocytosis persisting throughout the first week of life following maternal dexamethasone administration.

Phosphatidylcholine synthesis and glycogen depletion in fetal mouse lung: developmental changes and the effects of dexamethasone.

We measured the rate of choline incorporation into phosphatidylcholine in lung slices; the glucogen content of the lung; and the activities of pulmonary cholinephosphate cytidylyltransferase, cholinephosphotransferase and phosphatidate phosphatase in the mouse during late fetal and early postnatal development. We also examined the effect of maternal dexamethasone administration on these parameters of fetal lung maturation. There was a development increase in the rate of choline incorporation between 17 days gestation (term is 19 days) and the immediate newborn period. There was also a developmental decrease in the glycogen content of the lung but this did not occur until 18 days. There was a developmental increase in the activities of cholinephosphate cytidylytransferase and phosphatidate phosphatase but little change in the activity of cholinephosphotransferase. Dexamethasone doubled the rate of choline incorporation into phosphatidylcholine at 17 and 18 days gestation. It decreased the glycogen content of the fetal lung by 74% at 18 and 19 days, but had no effect at 16 and 17 days. Dexamethasone increased the activity of pulmonary cholinephosphate cytidylyltransferase by 37% and that of cholinephosphotransferase by 27% at 17 days. It increased the activity of phosphatidate phosphatase by 25% at 16 days and by 32% at 19 days. These data show that the normal development profile of these parameters of fetal lung maturation in the mouse, as well as the effects of glucocorticoids thereon, are generally similar to those in the rabbit and rat. However, stimulation of cholinephosphotransferase by glucocorticoids has not been generally observed in other species. Furthermore, since the changes in the rate of choline incorporation precede those in glycogen depletion, the data suggest that the relationship between phospholipid synthesis and glycogen degradation is not simply that of precursor to product.

Changes in amniotic fluid lecithin-sphingomyelin ratio following maternal dexamethasone administration

The effect of dexamethasone on amniotic fluid lecithin-sphingomyelin (L/S) ratio was measured in 15 fetuses of 34 weeks or less of gestation. Six of the patients presented with premature rupture of the membranes. A rise in the L/S ratio to mature levels (two or more) was observed 24 hours to 11 days after the start of treatment in 12 patients. In 2 patients (one second twin and one anencephalic fetus), no rise in L/S ratio occurred. Of 12 cases which ended in premature delivery (29 to 35 weeks) only one infant, a second twin delivered at the thirtieth week with a posttreatment L/S ratio of 1.4 weighing 1,240 grams, developed severe respiratory distress syndrome and died. It is suggested that dexamethasone accelerates fetal lung maturation by increasing surfactant synthesis or release, and this may be achieved as early as the twenty-eighth week of pregnancy.