Antenatal Hormonal Therapy for Prevention of Respiratory Distress Syndrome

Peripartum Role of Glucocorticoids

Fetal glucocorticoids play a key role in late gestation in preparing the fetus for extra-uterine life and achieving synchrony between maturation and parturition. In virtually all mammalian species, fetal adrenal activity increases exponentially towards term, and the resulting increase in circulating glucocorticoid concentrations—cortisol in humans—induces a wide range of proteins and enzymes that produce morphologic and functional maturation in most fetal tissues. Concurrently, this late gestation fetal glucocorticoid surge contributes to several feed-forward loops that ultimately lead to myometrial prostaglandin synthesis and the onset of labor.

A key target for endogenous fetal glucocorticoids is the lung, as there is high expression of glucocorticoid receptors in fetal lung tissue from mid-gestation. At birth, survival depends on lung aeration and maintenance of functional residual capacity, increased pulmonary blood flow, and initiation of gas exchange across the alveolar wall. Antenatal glucocorticoids support this postnatal transition by (1) upregulating epithelial sodium channels and the sodium-potassium adenosine triphosphatase (ATPase) to promote clearance of fetal lung fluid, (2) increasing lung surfactant content to reduce the alveolar surface tension when the lung is aerated, (3) increasing alveolar airspace volume and thus the surface area for gas exchange, (4) reducing the thickness of the alveolar septae to increase diffusion capacity for gas exchange, and (5) maturation of pulmonary vasculature to reduce alveolo–capillary permeability to plasma proteins.

The effects of glucocorticoids in the fetal lung have been studied most extensively for surfactant synthesis. Glucocorticoids increase the synthesis of surfactant proteins (SP) A, B, C, and D in type II pneumocytes, with lung tissue content increasing about 48 hours after glucocorticoid exposure. Glucocorticoids also increase the synthesis of phosphatidylcholine, but lung concentrations increase more slowly, as glucocorticoids act indirectly by inducing the lipogenic enzymes necessary for phospholipid synthesis (fatty acid synthetase, phosphatidyl acid phosphatase, lyso–phosphatidylcholine [PC]: acyl–coenzyme A [CoA] acyltransferase). The duration of physiologic effect depends on the half–life of the induced proteins and enzymes. SP–A and SP–B levels remain elevated in lung tissue and alveolar fluid for up to 2 weeks but return to control levels by about 3 weeks in the absence of ongoing glucocorticoid exposure. ^, Phosphatidylcholine levels remain elevated for slightly longer, determined by the half–life of the induced lipogenic enzymes.

Glucocorticoids also produce multiple changes in fetal lung structure, including differentiation of alveolar type I and II epithelial cells, decreased interstitial tissue in the alveolar wall, increased deposition of supportive connective tissue matrix (elastin and collagen), enlargement of alveolar airspaces, and maturation of alveolar capillary vessels. The net effect of these structural changes during postnatal transition is increased functional residual capacity, improved lung stability, reduced work of breathing, and enhanced gas exchange.

Glucocorticoids also promote maturation of several functional pathways in the fetal lung, the most important of which for birth transition is the clearance of fetal lung fluid. Glucocorticoids increase the synthesis of subunits of the epithelial sodium channel and basal sodium-potassium ATPase, which are critical for the movement of alveolar fluid from the alveolar airspace to the interstitium. Other pulmonary maturational effects of glucocorticoids include increased synthesis of antioxidant enzymes to reduce free radical injury (superoxide dismutase, catalase, glutathione peroxidase) and induction of glycogenolysis to provide substrates for phospholipid synthesis.

In addition to pulmonary maturation, glucocorticoids are responsible for a wide range of changes in other fetal tissues that support postnatal transition. In the liver, glucocorticoids increase the formation of bile canaliculi and induce multiple enzymes in metabolic pathways, including glycogenesis (glycogen synthetase) and gluconeogenesis (phospho–phenolpyruvate carboxykinase, glucose–6–phosphatase), fatty acid and protein synthesis (fatty acid synthetase, aminotransferases), and the conversion of thyroxine to triiodothyronine (5′–monodeiodinase). In the kidney, glucocorticoids increase renal blood flow and glomerular filtration rate and enhance tubular function. In the intestine, villus height and density are increased, as are brush border hydrolases, and secretion of gastric acid and pancreatic digestive enzymes is enhanced. Glucocorticoid-induced changes are also seen in the heart (myocyte differentiation), cerebral circulation (enhanced blood-brain barrier and maturation of microcirculation), endocrine pancreas (enhanced insulin response to glucose), skin (keratinization), bone marrow (hematopoiesis), and adrenal gland (enhanced catecholamine and cortisol secretion).

Glucocorticoid Mechanism of Action in the Fetus

Glucocorticoid action is mediated primarily by activation of the cytosolic glucocorticoid receptor with subsequent effects on transcription, messenger RNA (mRNA) stability, and post-translational processing. The activated glucocorticoid receptor induces a limited number of genes directly via nuclear response elements within the gene promoter, such as those encoding for SP–B, elastin, angiotensin, the β–1 subunit of the sodium–potassium ATPase, and the α subunit of the epithelial sodium channel. For these genes, maximal transcription rates are achieved within hours and are maintained with ongoing glucocorticoid exposure. However, for most genes, transcription is induced indirectly through interactions with nuclear transcription factors that coordinate the expression of multiple genes. Biphasic responses have been observed, such that with excessive glucocorticoid exposure, transcription of target genes may be suppressed.

Although molecular mechanisms have been well established for some glucocorticoid–induced effects, such as increased synthesis of surfactant components, mechanisms are less well established for others. For example, it is not entirely clear how glucocorticoids change lung architecture. This may result from effects on the cell cycle, induction of various growth factors, and antagonism of lung retinoids that promote alveolarization. Glucocorticoids also have a variety of non-genomic effects, including altered cell membrane permeability, mitochondrial function, and intracellular signaling, although the extent to which this occurs in the fetus is not known.

Synthetic Glucocorticoids for Preterm Birth

Betamethasone and dexamethasone are the only parenterally administered glucocorticoids that reliably cross the placenta due to their limited affinity for 11–hydroxysteroid dehydrogenase (HSD)–2, a placental enzyme that metabolizes cortisol into inactive cortisone, thereby creating a functional barrier to the passage of maternal cortisol to the fetus. Hydrocortisone and prednisone do reach the fetus if given in sufficient amounts but are rapidly cleared from the fetal circulation and thus have limited effect on fetal maturation.

Betamethasone and dexamethasone are optical isomers of the same fluorinated synthetic steroid, differing in the orientation of a single methyl substituent at position C16. The pharmacokinetic properties of these drugs are similar, with fetal plasma concentrations being approximately one-third that of maternal. However, dexamethasone has a slightly greater affinity for the glucocorticoid receptor than betamethasone and a slightly longer duration of biologic activity with current antenatal dosing regimens. Dexamethasone also appears to have greater potency for non-genomic effects.

The success of antenatal glucocorticoid therapy is due in large part to the fact that synthetic glucocorticoids accelerate a similar sequence of coordinated organ development in the preterm fetus as occurs typically with the increase in endogenous cortisol at term. Although the underlying developmental state of fetal tissues influences the maturation response, studies in preterm lambs and human lung explants have shown that glucocorticoids can induce marked increases in surfactant and changes to tissue architecture even during the early saccular phase of fetal lung development. While surfactant deficiency is central to the pathophysiology of RDS, immature lung structure underlies the acute respiratory distress seen in preterm infants. Thus, the clinical effect of synthetic glucocorticoids on the incidence and severity of RDS is due not only to increased lung surfactant but also wider maturational effects in the preterm fetus on lung structure and other functional pathways, which may occur more rapidly. This may explain why antenatal glucocorticoids are of benefit even with a short duration of exposure (<48 hours), before appreciable amounts of surfactant have been produced, and the synergism that has been observed between antenatal glucocorticoid and postnatal surfactant therapies.

In vitro studies have shown that the glucocorticoid receptor is saturated at low nanomolar concentrations of betamethasone and dexamethasone, and thus the fetal concentrations achieved with current clinical dosing regimens are likely in excess of that needed to induce gene transcription. Indeed, in sheep, a single maternal injection of the slowly absorbed betamethasone acetate was as effective as serial bolus dosing with betamethasone phosphate, despite considerably lower fetal plasma concentrations. However, with the commercial formulations available, current dosing regimens of dexamethasone and betamethasone are required to increase circulating fetal glucocorticoid concentrations for a sufficient duration (up to 60 to 72 hours).

Role of Other Hormones in Respiratory Distress Syndrome

In addition to glucocorticoids, the fetal lung is also responsive to thyroid hormones and catecholamines. Triiodothyronine (T ₃ ) directly stimulates phospholipid synthesis in type II epithelial cells, and in animal studies, T ₃ and glucocorticoids were shown to act synergistically to increase the surfactant content of the fetal lung. Indeed, glucocorticoids upregulate the deiodination of thyroxine in the fetal liver, and preterm babies with low cord blood T ₃ concentrations have increased incidence and severity of RDS. Because T ₃ does not readily cross the placenta, clinical trials have investigated co-administration of thyrotropin-releasing hormone (TRH) with betamethasone to women for prevention of RDS, but the addition of TRH did not offer any clinical advantage compared to betamethasone alone and maternal side effects were increased.

Catecholamines stimulate surfactant release from type II epithelial cells and promote clearance of fetal lung fluid. Catecholamine action is facilitated by glucocorticoids, which induce β–adrenergic receptors throughout the fetal lung. Although not given directly for prevention of RDS, use of β–agonists for tocolysis has not been associated with a reduced incidence of RDS.

Long-Term Effects of Fetal Glucocorticoid Exposure

In promoting tissue differentiation, antenatal glucocorticoids cause a shift in the cell cycle leading to decreased DNA synthesis and cell division. Although these genomic effects appear to be fully reversible, this has raised concern that excess fetal glucocorticoid exposure could permanently reduce the number of functional units in metabolic tissues, with effects on long–term health. For example, reduced nephrogenesis could contribute to later hypertension, and decreased alveolarization to emphysema in adulthood. Further, in some animal studies, fetal glucocorticoid exposure has been associated with altered homeostasis, including the hypothalamic-pituitary-adrenal and insulin-glucose axes, with long-term effects on stress responses and insulin sensitivity.

Consequently, fetal overexposure to glucocorticoids has been postulated as a potential mechanism to explain the known associations between fetal growth restriction and adult cardiometabolic diseases, such as diabetes, hypertension, stroke, and ischemic heart disease. This is supported by experimental evidence showing that manipulations that inhibit placental 11–β–HSD–2 activity, and thereby increase the transfer of maternal cortisol to the fetus, are associated with both fetal growth restriction and components of the metabolic syndrome, effects that can be prevented by blockade of maternal glucocorticoid synthesis.