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What are steroids used for during pregnancy

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One of the central issues relating to the repeated administration of ANS is that the dose for repeated courses of antenatal steroids has not been empirically optimized. Some trials have simply repeated the initial treatment used by Liggins and Howie in Liggins and Howie, whereas others have used modified treatment schedules. This hospital-based study investigated the use of a single, weekly dose of The study reported reduced respiratory distress, and reduced severe lung injury with repeated doses of corticosteroids.

Interestingly, the significant reductions in weight, length and head circumference at birth in babies exposed to repeated corticosteroid treatment were not maintained at discharge Crowther et al. Of note is the authors' observation that there was no difference in perinatal mortality between the repeated steroid and placebo groups, and that the causes of death were p. This finding is a significant departure from the original trial conducted by Liggins and Howie, which demonstrated a significant reduction in perinatal mortality between a single ANS course infants and those receiving placebo control 3.

Assuming that repeated ANS administration does indeed convey a benefit to the preterm infant, the reasons for the similarity in risk of death between groups are unclear. Advances in neonatal care over the past four decades especially with regards ventilation and surfactant therapy contribute to increased survival and blunt any benefit from repeated corticosteroid therapy.

Whether or not this finding of equivalence would be replicated in a patient population drawn from mid and low-resource settings is of interest, given the high preterm birth and mortality burden in the developing world. In a 2-year follow-up to the ACTORDS study, the authors concluded that aside from an increase in treatment for attention problems, there were no statistically significant differences in body size, blood pressure or health service utilization between children exposed to repeated ANS and those exposed to placebo Crowther et al.

There is a strong body of epidemiological data demonstrating an association between low birthweight, accelerated neonatal growth and chronic diseases including type-2 diabetes, obesity, cardiovascular disease, hypertension and depression van Deutekom et al. Whilst noting the need for further, long-term follow-up, the authors concluded that the equivalence of 2-year survival free of major neurosensory disability supports consideration of administering a weekly treatment with a single dose of betamethasone in women who remain at risk of very preterm delivery 7 or more days after their initial corticosteroid treatment.

Additional reassurance is provided by data from a 6—8 year follow-up, suggesting no association between repeat antenatal corticosteroid exposure and cardio-metabolic disease risk in early school age McKinlay et al. However, an alternative view is that these rigorous clinical studies in fact support the adoption of a more conservative position. In light of ongoing concerns regarding administration of multiple courses of ANS discussed below, a demonstrated equivalence in perinatal morbidity and overall childhood wellbeing argues in favour of not administering repeated doses of ANS to women at continued risk of preterm delivery.

The multiple courses of antenatal corticosteroids for preterm birth study MACS evaluated the effect of repeated courses of ANS given at two weekly intervals in high-risk women who had failed to deliver 14—21 days after initial treatment Murphy et al.

The study involved women drawn, importantly, from a number of countries with differing levels of economic development and large differences in perinatal mortality rates. There was no difference in a composite primary outcome perinatal mortality and morbidities associated with prematurity including severe respiratory distress syndrome, neurological injury, haemorrhage and necrotising enterocolitis between the corticosteroid and placebo groups.

However, there were small but significant reductions in weight, length and head circumference at birth in infants exposed to repeated courses of antenatal corticosteroids. A pre-discharge study assessing the effect of repeated ANS exposure on auditory brainstem response in preterm infants found no difference in brain maturity or auditory function but did identify significant reductions in birthweight, length, and head circumference in association with repeated antenatal corticosteroid exposure Church et al.

The subsequent 5-year follow-up to the MACS study concluded that there were no significant differences in the risk of neurodevelopmental disability or death Asztalos et al. These conflicting data suggest that, if there are indeed changes in fetal neurodevelopment as a result of repeated antenatal corticosteroid exposure, then any adverse effects may be partially dependent on the gestational age at which the infant was born and also the post-natal age that neurosensory function is assessed.

Additionally, sex-dependent effects of antenatal corticosteroid exposure were observed in juvenile baboons Rodriguez et al. Long-term follow-up studies of children at risk of congenital adrenal hyperplasia and treated with dexamethasone in early pregnancy have suggested variable effects on brain function. Meyer-Bahlburg performed a questionnaire survey of children exposed prenatally to dexamethasone including 48 with congenital adrenal hyperplasia and unexposed children including with congenital adrenal hyperplasia between 1 month to 12 years of age Meyer-Bahlburg et al.

They found no significant effect of dexamethasone treatment on nine different social or developmental scales. These results conflict with those of a prospective follow-up study, of 40 children treated prenatally with dexamethasone and aged 7—17 years, which included neuropsychological testing as well as validated child and parental questionnaires Hirvikoski et al.

These studies suggest possible negative cognitive and behavioural effects resulting from steroids in early pregnancy. Although further long-term studies are needed, the potential long-term effects on brain function should be considered when weighing up the risks and benefits of early pregnancy steroid use. The intrauterine environment plays a key role in regulating fetal growth and development; data, predominantly from rodent studies, also suggest that it can also program health throughout life.

Corticosteroids are key mediators in this process, and excess exposure to antenatal corticosteroids is associated with adverse pregnancy outcomes, including reduced birthweight, and a host of persistent changes in hypothalamic—pituitary—adrenal HPA axis programming that manifest as elevated stress responses, hypertension and changes in glucose metabolism, behaviour and motivation Reynolds, ; Moisiadis and Matthews, Precisely how excess exposure to antenatal corticosteroids might affect pathological changes on the fetus remains unclear; however, several excellent reviews have recently highlighted the potential roles of the fetal HPA axis and the placenta Braun et al.

Impaired HPA axis function is associated with changes in behaviour and neurodevelopment along with an increased risk of chronic cardiovascular and metabolic diseases. Antenatal steroid exposure appears to differentially affect basal cortisol activity in neonates based on fetal sex, post-natal age at which studies are undertaken, and whether the infant was delivered preterm or at term Moisiadis and Matthews, Interestingly, a year follow-up of adults exposed to a single course of antenatal corticosteroids concluded that treatment did not adversely impact cardiovascular function but might cause insulin resistance Dalziel et al.

There are limited human data available on the long-term effects of repeated antenatal corticosteroid exposure on HPA axis function, although studies in sheep suggest that changes in HPA function associated with repeated antenatal corticosteroid exposure persist into adulthood Moisiadis and Matthews, Antenatal corticosteroids may also unbalance maturational effects in certain systems by selective stimulation of GR.

In contrast, synthetic corticosteroids selectively activate GR. In general, mineralocorticoid target tissues co-express 11 Beta-HSD-2, which converts cortisol to inactive cortisone to prevent unwanted stimulation of MR by cortisol Chapman et al. However, some of the functions of endogenous corticosteroids that mediate maturation of the developing fetus are signalled through MR not GR.

There is thus the potential that dexamethasone or betamethasone may perturb maturation in extra pulmonary systems by only stimulating GR Rog-Zielinska et al. Relative to late pregnancy, surprisingly little is known about the effects of GC exposure on the developing fetus in early pregnancy. Using a sheep model of pregnancy, Dodic and colleagues reported that transient 2 day exposure to dexamethasone at Day 27 of pregnancy resulted in hypertension, left ventricular hypertrophy, and reduced cardiac function in adult offspring Dodic et al.

The same group demonstrated changes in nephrogenesis in adult sheep exposed to corticosteroids in early pregnancy Wintour et al. Antenatal dexamethasone exposure in early pregnancy has been demonstrated to alter HPA axis function and maturation in fetal lambs Braun et al. If we are to understand how we might refine the use of antenatal corticosteroids then we must attempt to clarify how the maternal and fetal responses to such treatment might be modified by preterm birth-associated factors.

Factors including gestational age, maternal diet, the presence of intrauterine infection, and fetal sex have each been implicated as potential modulators of corticosteroid effects Fig. The scope for refining the use of ANS is highlighted by the observation that, under current obstetric protocols, a 60 kg women carrying a 33 week fetus would be given the exact same the same dose of ANS as a kg woman carrying a 24 week fetus in an attempt to improve neonatal outcomes. Factors that may influence the effectiveness of antenatal corticosteroids in reducing morbidity and mortality associated with prematurity.

T here are good data to suggest that GR density in target organs is critical in determining the level of response, or resistance, to corticosteroid stimulation. Accordingly, the ontology of GR receptor expression in the developing fetal lung should also be taken into account in future studies investigating gestation-specific antenatal steroid dosing.

Nuclear localization of labelled dexamethasone was also dependent on the cytoplasmic receptor. The lung is the human fetal tissue with the highest GR concentration and the GR is expressed from as early as 12 weeks gestation through to term. GR expression was also detected in the human fetal liver, kidney, heart, intestine, muscle and skin Ballard and Ballard, , GR mRNA expression was detected in the fetal rat brain from embryonic day Interestingly, Ballard and Ballard concluded that with regards the developing lung p.

This observation is supported by the findings of Labbe et al. More recently, Rajatapati and colleagues surveyed GR expression in human fetal lung samples collected at 16 pseudoglandular phase , Using immunohistochemistry, they identified nuclear GR reactivity in all samples analysed and, interestingly, that the GR mRNA concentration did not significantly differ with gestational age Rajatapiti et al.

Maternal nutrition is one factor that may warrant consideration in any future optimization of antenatal corticosteroid dosing regimens, both in low-resource settings with maternal nutrient restriction and in the increasingly obese developed world. Overweight or obese women are at an increased risk of gestational diabetes, potentially resulting a hyperglycaemic, hyperinsulaemic fetus. In sheep, maternal nutrient restriction did not impact lung growth but did result in small increases relative to animals maintained on normal diets in lung GR mRNA expression at 80 and days gestation in singleton lambs Gnanalingham et al.

Interestingly, studies in sheep have suggested that maternal undernutrition is associated with substantial changes in GR methylation and increased hypothalamic GR mRNA and protein expression in both male and female offspring Begum et al. In baboons, maternal nutrient restriction resulted in sex-dependent changes in GR mRNA, but not protein, expression. How sub-optimal maternal nutrition might impact the fetal maturational effects mediated by corticosteroids remains poorly understood.

However, the accumulating body of evidence suggests that maternal diet can influence the corticosteroid signalling machinery. Whether or not infection might alter fetal and maternal responses to antenatal corticosteroid therapy is another important consideration. Intrauterine infection and inflammation are strongly associated with preterm birth, especially those deliveries occurring at or below 32 weeks of gestation Goldenberg et al.

Histologic chorioamnionitis is the hallmark of intrauterine infection most commonly identified in early gestation deliveries Lahra and Jeffery, Intrauterine infection is frequently polymicrobial and access of organisms to the fetal environment has been suggested to occur following a discrete breach in the chorioamniotic membranes Jones et al. Ureaplasma species are commonly isolated from the gestational tissues in preterm birth Goldenberg et al.

In the sheep model of pregnancy, chronic Ureaplasma infection increased surfactant production and had a surfactant-independent additive effect on lung compliance following a single course of antenatal betamethasone Moss et al. Similar additive improvements in fetal ovine lung compliance in the absence of increased surfactant production were identified following the co-administration of maternal betamethasone with intraamniotic lipopolysaccharides from Escherichia coli Newnham et al.

Differential effects of infection and ANS on pulmonary growth factors may play a role in these observed differences. Fetal sex is known to influence the risk of adverse outcomes in response antenatal corticosteroid therapy. The underlying mechanisms remain poorly understood, although sex-specific differences in the placenta have been hypothesized as being important in determining fetal responses to antenatal insults and prematurity Clifton, Female premature infants respond more effectively to antenatal betamethasone exposure than their male counterparts, with lower rates of respiratory distress syndrome Papageorgiou et al.

This observation from clinical studies has been replicated in a sheep model of prematurity; a retrospective analysis of fetuses that received 0. The observed difference in corticosteroid responsiveness between male and female fetuses does not appear to derive from differences in lung structural development or surfactant production between the sexes Ishak et al.

Studies of the fetal programming of hypertension in sheep have shown that betamethasone exposure has a sex-dependent effect on endothelin-1 responsiveness Lee et al. Zuloaga et al. In baboons, repeated antenatal betamethasone exposure reduces motivation in both male and female offspring; interestingly, reductions in reversal task performance were more pronounced in female offspring compared with males Rodriguez et al.

The use of antenatal steroids has prevented the loss of thousands of pregnancies, and prevented significant morbidity in many more. However, it is also clear that ANS are not innocuous, and may have significant and long lasting effects on health. Maternal and fetal factors, as well as the healthcare setting, can influence the risk benefit ratio for ANS. There is surprisingly little data available to inform drug dosing and timing for early pregnancy complications such as recurrent miscarriage and congenital adrenal hyperplasia.

Even in obstetric medicine, which possesses the strongest empirical evidence base for ANS administration, there are still only two ANS dosing regimens, neither of which have been significantly refined to determine the optimal dose or treatment interval since their clinical introduction. In the era of personalized medicine, we must move away from a one-size fits all approach. There is a need to trial new formulations to maximize benefits and minimize unwanted side effects, provide better delivery systems and dosage, and tailor treatment to individual circumstances, ensuring delivery of the right ANS, to the right pregnancy and at the right time.

In this way, we can realize the full potential of this life saving, and morbidity sparing treatment. The authors declare no conflict of interest. The authors have no financial interest in the contents of this manuscript. Organizations funding the authors not have input to the drafting of this manuscript.

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The studies found that the mothers who received extra injections of the steroid betamethasone delivered babies that were not any different from normal in their body size measurements and had no significant differences in blood pressure or development at age 2 or 3. Conclusion: Overall topical corticosteroids appear to be safe during pregnancy. High-potency topical corticosteroids should be avoided if possible and when they must be used they should be used only for the shortest period possible.

Use of corticosteroids did not seem to increase the risk of congenital malformations, but the estimates are imprecise. Use of inhaled corticosteroids was associated with a slightly increased risk of miscarriage. For maternal disease, derivatives of cortisone and prednisone are suggested since they are more readily inactivated by the placenta, as opposed to dexamethasone and betamethasone, which are more likely to reach the fetus in the active state.

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Importantly, such studies should attempt, as best as possible, to control for differences in gestation, neonatal care and pregnancy-specific factors e. In humans, the corticosteroid cortisol is synthesized from cholesterol and released from the zona fasciculata of the adrenal cortex under the regulation of the hypothalamic—pituitary—adrenal axis.

Classically, corticosteroids are the essential regulators of metabolic processes and stress responses. Much of their contemporary pharmaceutical use derives from their marked anti-inflammatory and immunosuppressive activities. The maturational effects exerted by corticosteroids on multiple organs underpin the rationale for the use of corticosteroids in obstetric medicine Vandevyver et al.

Endogenous corticosteroids exert their effect predominantly through the glucocorticosteroid receptor GR , but other effects may result from mineralocorticoid receptor MR activation Funder, In contrast, synthetic corticosteroids such as dexamethasone and betamethasone exert their effects solely via the glucocorticosteroid receptor. The GR is ubiquitously expressed and is a member of the nuclear receptor superfamily of ligand-dependent transcription factors Hollenberg et al.

The human GR gene contains 9 exons exons 2—9 being responsible for encoding protein and spans a kb region on chromosome 5q31Y32 Oakley and Cidlowski, ; Turner et al. Structurally, the GR is comprised of three primary domains: i the N-terminal transactivation domain; ii the DNA-binding central domain; and iii the C-terminal ligand binding domain Oakley and Cidlowski, Nunez and colleagues demonstrated that three different promoter regions, 1A, 1B and 1C contribute to regulating GR gene expression Nunez and Vedeckis, Interestingly, a number of positive and negative corticosteroid response elements have been identified within the GR gene promotor region, suggesting that the GR has the ability to regulate its own expression Burnstein et al.

The GR is primarily an intracellular receptor; both active and inactive forms are thought to constantly shuttle between the cytoplasm and the nucleus Vandevyver et al. As summarized by Strehl and Buttgereit, mGR expression appears to be increased following vaccination, immunological stimulation and in patients with rheumatoid arthritis, although the function and clinical relevance of these observations is not well understood Strehl and Buttgereit, The ability of a single GR to exert precise biological regulation over a discursive array of targets may derive from the tissue-specific expression of a broad collection of GR subtypes originating from differential mRNA splicing and transcriptional isoforms.

Severe developmental abnormalities and perinatal lethality in GR knock-out mice demonstrate that GR receptor activity is essential for life. However, subsequent work by Reichardt and colleagues suggests that the GR's DNA-binding-independent activities are sufficient for survival in mice.

Homozygous mutant mice expressing dimerization impaired and thus DNA binding defective GR mutants induced by an AT mutation were viable, fertile and did not have the fatal lung atelectasis identified in homozygous GR-null mice Reichardt et al. Intriguingly, the ratios of isoform expression appear to influence a cell's responsiveness to corticosteroid stimulation, potentially through common and isoform-specific patterns of gene induction and repression Lu and Cidlowski, For example, cells expressing the GR-C3 isoform are more sensitive to corticosteroid killing, whereas GR-D expressing cells have reduced sensitivity Bender et al.

The complexity of GR signalling in different organs has not yet been evaluated within the context of the effects of corticosteroids on the developing fetus. In the United States, recurrent miscarriage RM is defined as two or more consecutive miscarriages Anonymous, RM affects between 0. Th1 cells are important in host defence against intracellular pathogens. They are important for defence against extracellular infection, and express a range of immunomodulatory mediators including ILsa and 17f, both of which recruit and activate neutrophils.

In contrast to the co-inhibitory interaction between Th1 and Th2 cells, there appears to be a synergistic relationship between Th1 and Th17 cells Guerin et al. Treg cells have been shown to concentrate in the decidua and the lymph nodes draining the uterus after coitus Saito et al. Decreases in decidual and circulating Treg cells have been identified in women with RM. Similarly, the percentage of activated NK cells, and absolute number of NK cells has been shown to be increased in women with RM.

Due to the increasing body of evidence suggesting a T-helper cell imbalance in association with RM, a number of studies have attempted to use immunologic approaches to prevent RM in early pregnancy. A Cochrane Review of 20 randomized control trials of immunotherapies women; including paternal leukocyte transfusions and intravenous immunoglobulin for RM prevention concluded that there was no benefit over placebo to the live birth rate or a reduction in the future risk of RM.

Corticosteroids are also used as a treatment for RM, and are known to be able to exert immunosuppressive effects on T cells and NK cells Henderson et al. However, there is a shortage of data from large, randomized control trials to assist in the determination of therapy safety and efficacy.

And as with many corticosteroid applications in pregnancy, there is not a body of rigorous dose—response data to inform the optimal choice of agent, length of treatment, or dose. Confounding this situation is the observation that many studies employ corticosteroids, notably prednisolone, in combination with other agents including folate, aspirin and progesterone, making it difficult to determine the origin of any beneficial or adverse effects that might be observed.

Tempfer et al. Combination therapy including prednisolone significantly increased pregnancy success Several clinical reports describe beneficial effects of prednisolone therapy to pregnancy outcomes. Ogasarawa et al. Hasegawa and colleagues reported that combined use of prednisolone and low-dose asprin in women with anti-phospholipid antibodies significantly improved pregnancy success, relative to controls. Interestingly, combined treatment was also reported to ameliorate growth restriction identified in previous pregnancies Hasegawa et al.

These data are in contrast to that reported by Laskin et al. The primary outcome measure successful pregnancy was not statistically different from controls. Moreover, there was a statistically significant increase in hypertension, diabetes mellitus and an increased risk of preterm birth in the treatment group Laskin et al. As such, it is not clear if the NK cell reduction achieved by prednisolone therapy would improve pregnancy outcomes Quenby et al.

The safety of corticosteroid exposure in early pregnancy is yet to be conclusively determined. To date, prednisolone has been the corticosteroid of choice for RM treatment. A prospective controlled cohort study of pregnancies exposed to corticosteroids during at least the first trimester of pregnancy failed to identify an increased risk of birth defects, but did identify a 2-fold increase in preterm birth and reduction in birthweight Gur et al.

Interpreting these data is difficult due to substantial variation in the type of corticosteroids used e. In an attempt to answer the question of prednisolone efficacy, Tang and colleagues are presently undertaking a randomized, double-blind placebo controlled trial of prednisolone therapy for idiopathic RM Current Controlled Trials ISRCTN Tang et al.

Importantly, given concerns over the safety of early pregnancy ANS administration, secondary outcome measures will include ultrasound assessment of fetal growth at 28 and 34 weeks' gestation in addition to pregnancy complications, congenital abnormalities, and a 6-week follow-up. Congenital adrenal hyperplasia is a group of autosomal recessive disorders characterized by failure of cortisol synthesis by the adrenal cortex. It is traditionally classified as classical severe , which presents in the neonatal period, or non-classical mild , which has a later presentation.

The classical form has an incidence of 1 in 15 newborns Therrell, The pathophysiology relates to the enzymatic deficiency and disruption in cortisol biosynthesis. A lack of usual negative feedback leads to a compensatory increase in pituitary production of corticotropin and hypothalamic production of corticotropin-releasing hormone CRH and excess of cortisol precursors and adrenal androgens Merke and Bornstein, Intrauterine androgen excess and adrenal androgens cause virilization of the female fetus and ambiguous genitalia.

Characteristically there is enlargement of the clitoris, partially fused labia with rugae, and a common urogenital sinus rather than separate vagina and urethra, but normal internal female organs Merke and Bornstein, Complex surgery is required for feminization of the genitalia, and this is frequently carried out in the neonatal period Clayton et al. Supraphysiological doses of exogenous steroids are required to supress androgen excess, and in the s, it was shown that prenatal dexamethasone treatment of fetuses at risk of congenital adrenal hyperplasia can prevent masculinization of a female fetus New et al.

This treatment has since been offered to avoid the need for surgery and the risk of complications, and remains controversial. As masculinization starts as early as 6 weeks post-conception, to prevent development of ambiguous genitalia prophylactic, dexamethasone must be given to all at-risk fetuses as soon as pregnancy is recognized.

Chorionic villus sampling should be performed as soon as possible to confirm gender and whether the fetus carries a hydroxylase gene mutation, and treatment should be stopped in unaffected and male fetuses. As the chance of an affected female fetus is only 1 in 8 pregnancies, 7 out of 8 fetuses receive unnecessary dexamethasone. As discussed below, the long-term effects of steroids in early pregnancy remain unclear, with potential detrimental effects on fetal programming, brain function and congenital anomalies.

Therapy should therefore be only offered at specialist centres, with full counselling about the risks and benefits of antenatal treatment. Our inability to effectively diagnose and prevent preterm birth places increased importance on treatments to maximize survival and optimize short- and long-term outcomes for preterm infants. In developed countries, antenatal corticosteroids are recommended for women at risk of preterm labour when the fetus is considered viable, i.

Fetal maturational responses to corticosteroids occur in animal models of extremely preterm gestations Bunton and Plopper, Observational studies have also suggested a reduction in adverse outcomes in babies born at extreme preterm gestations Costeloe et al. However, there is little evidence of benefit from randomized control trials. Roberts and Daziel Roberts and Dalziel, performed a post hoc analysis of clinical trials of corticosteroids on the effect of the gestational age at trial entry.

They found no differences for women who received ANS and delivered before 28 weeks gestation compared with those receiving placebo or no treatment with regards to neonatal death RR 1. However only one trial was included in the analysis, and the lack of significant findings may reflect inadequate power to detect benefit. In addition, ANS at extreme preterm gestations may decrease, but not prevent, complications of prematurity.

In a trial of steroids at 24—28 weeks, although there was no difference in the incidence of respiratory distress syndrome RDS , it was less severe Garite et al. There is conflicting evidence regarding a putative link between synthetic corticosteroids use in early pregnancy and teratogenicity.

Only three studies have included more than ten women exposed to any formulation of corticosteroids, and even in these studies, there are few women exposed to systemic corticosteroids. Pradat et al. They included 11 women with babies with congenital abnormalities, of whom had babies with cleft palate or cleft lip. Single formulation systemic corticosteroid exposure was not associated with increased odds of cleft palate or lip compared with other congenital anomaly odds ratio 1.

In total there were births in the period, and infants with clefts. The authors compared observed and expected frequencies of clefts in women exposed to glucocorticoids in early pregnancy. No significant increase of clefting was found in association with systemic corticosteroid use relative risk 1. The National Birth Defects Prevention Study is a population based case—control study, which included mothers of children with cleft lip with or without cleft palate, mothers of children with isolate cleft palate, and controls.

Carmichael et al. The odds ratio for cleft lift and palate with any steroid exposure was 1. Corticosteroid exposure only during Weeks 1—4 and 5—8 after conception were associated with the highest increase in risk of cleft lip and palate with an OR of 7. In summary, the evidence suggests there may be a small, but significant association between systemic corticosteroid use and cleft lip and palate, but the absolute risk is small. Antenatal corticosteroids ANS are perhaps the most effective therapy for improving short- and long-term outcomes in preterm infants Jobe and Soll, Drawing on experimental and clinical data, the National Institutes of Health consensus statement concluded that ANS therapy reduces mortality, respiratory distress syndrome RDS and cerebral haemorrhage in preterm infants born between 24 and 34 weeks' gestation Health, Subsequent analyses of clinical trials, conducted predominantly in high- and middle-income countries, confirmed that the use of maternally administered ANS in cases of threatened preterm delivery improves neonatal outcomes with reductions in neonatal death, respiratory distress syndrome, cerebral haemorrhage and necrotising enterocolitis, without risk to maternal wellbeing Roberts and Dalziel, A key feature of PTB is its heterogeneity, both in terms of underlying cause, and effects on the mother and baby Romero et al.

PTB spans a wide spectrum of fetal development, varying by as much as 15 weeks depending on how the lower limit of prematurity is defined by individual jurisdictions Kramer et al. PTB is associated with lifestyle, social, environmental, and genetic factors, many of which stratify against gestational age at delivery in both high- and low-income countries Blencowe et al.

Yet in stark contrast to the complex clinical picture of PTB, only two standardized treatment regimens for ANS delivery are recommended to improve outcomes Jobe and Soll, Although these regimens were initially used as single-course treatments, they have been used for multiple-course treatments when anticipated PTB does not occur within 7 days of the initial treatment Murphy et al.

Despite the extensive research on ANS use, a number of controversies remain regarding their use. In particular, there is a contention with regards to the administration of multiple courses of ANS to women at risk of preterm birth, the long-term effects of synthetic corticosteroid exposure on the developing fetus, and their use in resource-poor settings Crowther and Harding, ; Murphy et al.

Of late, potential limitations of ANS for anticipated PTB in a low-resource setting has been highlighted by Althabe and colleagues' report of an excess of 3. The administration of synthetic corticosteroids mimics the surge in endogenous corticosteroids seen in late gestation that is essential for normal development of many organs systems and prepares the fetus for ex-utero life. Corticosteroids have well described effects on fetal lung maturation.

Alveolar structure, vascularization, surfactant production and airspace fluid clearance have all been implicated in improvements to preterm lung function observed following antenatal corticosteroid therapy Whitsett and Matsuzaki, Corticosteroids also have important effects on other organ systems, including heart, brain, circulation hypothalamus, kidneys and thyroid, that support post-natal adaptation.

In key studies, homozygous GR-null mice had normal lung morphogenesis until embryonic day The activity of selected populations of GRs might be essential and sufficient for late-gestation lung development. In elegant work using germ layer targeted GR knockout mice, Bird and colleagues reported that isolated mesenchymal GR activity was critical for fetal lung maturation and post-natal survival Bird et al.

Jobe and Ikegami suggest that the early lung maturation driven by antenatal corticosteroid exposure results initially from thinning of the alveolar walls, which in turn increases the lung volume available for gas exchange prior to an increase in surfactant production Jobe and Ikegami, Subsequent work in preterm lambs demonstrated that relative to a saline control, alveolar thinning, higher alveolar volumes and an increased proportion of alveolar ducts followed repeated maternal and intraamniotic antenatal betamethasone administration in sheep Polglase et al.

Improved neonatal respiratory function from induced surfactant production by the preterm lung is an important physiological response to the administration of ANS therapy. Phospholipids are the primary surface tension-lowering component of pulmonary surfactant Gunasekara et al. SP-A and SP-D are multifunctional collections, innate host defence proteins that participate in surfactant homeostasis and the regulation of pulmonary inflammation.

Both SP-A and SP-D recognize a broad range of conserved pathogen-associated molecular patterns, including lipopolysaccharide and lipoteichoic acid Kingma and Whitsett, ; Nayak et al. Surfactant protein A, for example, binds a number of PTB-associated pathogens including members of the Pseudomonas, Mycoplasma, Escherichia and Candida species Piboonpocanun et al. Corticosteroids appear to increase surfactant production by both transcription and post-transcriptional mechanisms, enhancing the rate of phosphatidylcholine and fatty acid biosynthesis in the fetal lung Bolt et al.

Interestingly, corticosteroids have been suggested to have differential effects on surfactant protein expression; SP-B, SP-C and SP-D expression is increased at the expense of SP-A, with effects mediated by changes in the rate of absolute transcription and the stability of the mRNA transcripts Rooney et al.

The dynamic nature of SP-expression may contribute to the loss of antenatal corticosteroid efficacy 7 days after treatment Jobe and Ikegami, Studies investigating a potential link between genetic variation in surfactant protein genes and neonatal lung disease have demonstrated an association between SP-A, SP-B and respiratory distress syndrome Hallman et al.

Allelic variants of SP-B have also been linked to an increased risk of bronchopulmonary dysplasia Pavlovic et al. Surfactant increases compliance and protects the lung from atelectasis. Not all the effects of antenatal corticosteroids on preventing respiratory distress are mediated through surfactant production. Rapid removal of fluid from the lung to allow efficient gas exchange at the alveolar surface is key to the fetus' transition to ex-utero life.

In primary rat lung cells, a 10 hour treatment with 0. There is high-level evidence from systematic reviews and meta-analysis of clinical trials that babies who are born preterm benefit from a single course of maternal ANS. In the most recent Cochrane review, Roberts and Dalzeil concluded that ANS administration to women at risk of preterm birth was associated with a reduction in neonatal death RR 0.

ANS are one of 13 commodities identified by the UN that could save the lives of more than six million women and children worldwide if more widely accessed and properly used. Appropriate administration of ANS is frequently used as a marker of the quality of antenatal care Henderson et al.

The majority of ANS trials included women with singleton pregnancy and moderate prematurity 28—34 weeks , and therefore, the evidence of benefits relate to this group of women. Nevertheless, as discussed below, the benefits of ANS administration to other groups of pregnant women have been extrapolated to a wide range of cases without clear evidence of benefit.

Although it seems reasonable to give ANS in most of these cases, the potential for long-term harms must be remembered. Relatively few follow-up studies of infants who have received ANS have been carried out. A salient reminder of the potential harms of ANS is provided by the use of post-natal dexamethasone to prevent and treat bronchopulmonary dysplasia, a chronic lung disease of preterm neonates. Widespread use of dexamethasone was implemented after reports of short-term benefits to reduce the incidence of bronchopulmonary dysplasia, facilitate extubation and reduce the incidence of other complications such as retinopathy of prematurity in neonates requiring ventilation Doyle et al.

The routine administration of post-natal corticosteroids to ventilated neonates is, however, not recommended due to the excess long-term neurological morbidity that may result Watterberg, American Academy of Pediatrics. Committee on, and Newborn, Placental insufficiency is the term used to describe the condition where the placenta fails to meet the oxygen or nutrient demands of the developing fetus. It can be recognized by progressive alterations in the pattern of fetal growth fetal growth restriction , followed by changes in cardiovascular, metabolic and behavioural indices, representing increasing hypoxaemia and acidosis.

As there are currently no effective interventions to prevent or treat placental insufficiency, the mainstay of management is based on monitoring progression of resulting fetal restriction, and delivering the baby at a time that is thought to minimize risk to the infant Stock et al.

This means that affected pregnancies are frequently delivered preterm. However, there is conflicting evidence regarding the benefits of antenatal steroid administration in women with suspected fetal growth restriction. It has been hypothesized that placental insufficiency and fetal growth restriction accelerate fetal lung maturation, based on observations that small for gestational age infants have lower rates of respiratory complications at delivery when compared with appropriately grown infants born at the same gestation Procianoy et al.

Increased exposure to endogenous steroids may mediate lung maturation, as higher cortisol and lower ACTH is seen in the blood of growth-restricted fetuses, when compared with appropriately grown fetuses at similar gestations Economides et al.

Fetal growth restriction is associated with a reduction in placental beta-hydroxysteroid dehydrogenase type 2, thus more maternal cortisol may be able to cross to the fetus McTernan et al. The potential benefits of exogenous steroids in already stressed, growth restricted fetuses have been questioned, particularly in view of potential effects on fetal programming and brain development associated with elevated steroid levels.

There are no randomized control trials of the use of antenatal corticosteroids in women with suspected growth restriction that have examined neonatal or longer-term outcomes. Torrance et al. In total, fetuses were exposed to corticosteroids and were not exposed to corticosteroids Torrance et al.

There were no significant differences in incidence of respiratory distress syndrome, brain injury intraventricular haemorrhage, periventricular leukomalacia, intracranial haemorrhage or necrotizing enterocolitis between the steroid exposed and non-exposed infants odds ratios 0. The authors concluded that, on the basis of this evidence, there is no benefit of antenatal corticosteroid administration in women with suspected fetal growth restriction. Most of the studies in the Torrance review were retrospective, but one was a carefully designed case—control study of 62 growth-restricted infants who received antenatal corticosteroids between 24 h and 7 days prior to delivery, matched by birthweight, sex and year of birth to 62 infants who did not receive antenatal steroids Schaap et al.

Infants were prospectively followed up to determine disability. The odds of survival without disability or handicap at 2 years corrected age were higher in the corticosteroid group compared with the control group OR 3. At school age, steroids were associated with a negative effect on physical growth OR 5.

The authors concluded that the potential benefits of antenatal corticosteroid use outweigh the potential risks. Current national guidelines on steroid administration, which generally support the use of antenatal corticosteroids in women with suspected fetal growth restriction at risk of preterm delivery, agree with this conclusion.

Animal studies have suggested both potential benefits and harms of clinically relevant doses of corticosteroids in models of growth restriction. For example, in sheep where fetal growth restriction was induced by ligation of a single umbilical artery, betamethasone increased surfactant protein expression and morphological changes in lung tissue, despite higher cortisol levels in the growth-restricted fetuses Miller et al. This suggests that exogenous steroids have potential to enhance lung maturity, even when endogenous steroids are high secondary to placental insufficiency and growth restriction.

However, betamethasone administration to sheep with growth restriction induced by single umbilical artery ligation has been seen to increase oxidative brain damage when compared with twin controls without growth restriction Miller et al. Effects of antenatal corticosteroids on feto-maternal blood flow are evident in human growth-restricted fetuses. Fetuses that do not respond to steroids in this way have worsened neonatal respiratory outcomes requirement for assisted ventilation, longer duration of assisted ventilation and oxygen requirement Guerin et al.

However, it remains to be determined if alterations in umbilical artery blood flow, which may be at the cost of cerebral blood flow, may have other detrimental effects to growth-restricted fetuses. In summary, there is no conclusive evidence that antenatal corticosteroids benefit growth restricted fetuses, and there is potential for increased effects on fetal programming, compounded by exogenous steroid use on a background of high endogenous steroids.

Nevertheless, current recommendations, based mainly on observational studies, endorse the clinical use of antenatal corticosteroids in growth-restricted fetuses delivered preterm, and they are frequently given in clinical practice. The risk of respiratory morbidity declines as gestation increases, but there is an excess of neonatal unit admissions of newborn infants with respiratory distress or transient tachypnoea at late preterm 34—36 weeks and early term 37—38 weeks gestations, particular with surgical deliveries.

The rationale for ANS administration when delivery is anticipated or planned prior to 38 weeks gestation is to decrease respiratory morbidity, although there is a lack of good quality trial data to support this practice. Similarly, there was no benefit for neonatal survival or chorioamnionitis at 33 weeks' gestation onward.

Porto et al. This trial will be powered to evaluate ANS effects on common complications including pre-eclampsia and diabetes. ANS have been administered at even later gestational ages, prior to Caesarean delivery, to avoid a two-fold increased risk of neonatal unit admission for respiratory problems after planned Caesarean delivery when compared with vaginal delivery Kolas et al.

Stutchfield et al. Betamethasone decreased admissions to the special care nursery for respiratory distress RR 0. There were no significant reductions in individual respiratory morbidities. The findings are suggestive of benefit, but the study was open label and not placebo controlled, and therefore vulnerable to bias. The absolute risk of respiratory morbidity at term is low in term neonates, even after elective Caesarean delivery, therefore the number needed to treat to prevent one case of RDS would be high.

The number needed to treat has been estimated at for gestations after 34 weeks, versus around 5 for infants at 30 weeks Kamath-Rayne et al. Prematurity is a global problem, with middle and low development countries reporting some of the highest rates of preterm birth that result in very high infant mortality March of Dimes, Whether antenatal corticosteroid efficacy and safety data from high-resource settings can be applied to the developing world is a question of great importance, especially in light of recent findings associating antenatal corticosteroid administration with an increased risk of death in large fetuses exposed to ANS Althabe et al.

Of the 21 studies considered in the meta-analysis of Roberts and Daziel, none were from countries represented in the lowest grade low human development of the United Nations Development Program Human Development Index HDI. Of the 21 studies, 17 were from countries in the highest very high human development category of human development and only one study was from a country South Africa ranked outside the top developed countries Program, Although both the United States and Brazil from which 11 studies included in the review were drawn report high rates of preterm birth, there is a lack of efficacy data from low development countries, notably in Southern Asia and Sub-Saharan Africa, which feature strongly in preterm birth and mortality statistics March of Dimes, McLure and colleagues have called for studies to evaluate ANS use in low-resource settings, noting that p.

Infants exposed to ANS were also less likely to be still born or die in hospital prior to discharge compared with those who were not exposed. However, they also found that if an infant was born alive, it was more likely to survive to discharge if it had not been exposed to antenatal corticosteroids, and the infant's mother was less likely to develop either post-partum haemorrhage or pyrexia if not treated with ANS therapy Pattanittum et al.

The authors reported that p. The reasons for these concerning outcomes are unclear; a lack of efficacy in the absence of tertiary neonatal intensive care, difficulties in accurately predicting women at risk of preterm birth and errors in determining gestational age may each have contributed to these findings. Socio-economic factors including sub-optimal maternal nutrition, variable access to clean water and quality housing, and variable hospital infection control practices may also contribute to both the lack of efficacy and increase in suspected maternal infection.

Similarly, the use of these agents in high-resource settings with improved antibiotic coverage and aseptic practice may camouflage an increased susceptibility to infection. What is clear, however, is that new research into the use of ANS that considers pregnancy-specific factors and medical resources are needed. In addition to efficacy and safety per se, healthcare providers need to have adequate information to appropriately administer ANS therapy, an additional challenge in low- and middle-resource settings.

Potential concerns regarding appropriate use of ANS therapy are highlighted by a study of midwives and physicians in Latin America, which reported substantial differences in ANS administration practice, including in the use of repeated courses of steroids Aleman et al.

Similarly, the authors of a recent Chinese study concluded that ANS were often under-prescribed to women at risk of preterm birth and inappropriately prescribed to women after 35—36 weeks of pregnancy Wang et al. ANS are of benefit if delivery occurs between 24 h and 7 days after treatment administration Roberts and Dalziel, Delivery outside of this timeframe is associated with increased risk of adverse outcomes McLaughlin et al.

However, the optimal timing for administration of antenatal corticosteroids is hampered by the imprecise identification of women at risk of preterm delivery and the likely remaining latency. The majority of preterm births are spontaneous i. Conditions such as pre-eclampsia and intrauterine growth restriction that may necessitate medically indicated preterm delivery are variable in presentation and progression. Evidence supports prolonging a preterm gestation until the benefits of delivery clearly outweigh the risks, thus delivery may be delayed for some time after initial diagnosis Stock et al.

The recommendations are to give ANS at the first signs of impending delivery or potential indication for medically indicated PTB. Given the clear advantages of ANS to babies born preterm, it is understandable that a treat-all approach is often taken, but this is at the expense of optimally-timed ANS administration. The magnitude of the problem of timing ANS administration is demonstrated in a recent population study from Canada, which reported that as uptake of appropriate ANS increased over time, so did inappropriate administration Razaz et al.

Despite well-developed maternity care systems and guidelines for administration for steroids, more than half of women who received steroids in delivered at 35 weeks of gestation or greater Razaz et al. Difficulty in predicting preterm delivery results in unnecessary steroid exposure to babies who eventually deliver at term. It also leads to uncertainty regarding the best course of management if delivery does not occurs within 7 days, but high risk of preterm delivery persists.

The administration of multiple courses of antenatal corticosteroids remains a matter of contention. On the one hand, a number of clinical and experimental studies have reported fetal growth restriction and alterations in organ notably brain development and childhood behaviour in association with repeated ANS administration French et al. Two observations support the argument for administering repeated doses of ANS: i the beneficial effects of ANS therapy on preterm respiratory function appear to be lost approximately 7 days after completion of the initial treatment; and ii delivery more than 7 days after a single course of treatment is associated with an increased risk of perinatal death and maternal infection McLaughlin et al.

A number of large, well-controlled studies have now been repeated to determine the efficacy and safety of repeated ANS administration. Several excellent structured reviews, including that by Crowther and colleagues for the Cochrane Collaboration, provide an in-depth composite picture of the outcomes. The repeated administration of corticosteroids is associated with a small but significant decrease in RDS and a reduction in serious adverse infant outcomes Crowther et al.

One of the central issues relating to the repeated administration of ANS is that the dose for repeated courses of antenatal steroids has not been empirically optimized. Some trials have simply repeated the initial treatment used by Liggins and Howie in Liggins and Howie, whereas others have used modified treatment schedules. This hospital-based study investigated the use of a single, weekly dose of The study reported reduced respiratory distress, and reduced severe lung injury with repeated doses of corticosteroids.

Interestingly, the significant reductions in weight, length and head circumference at birth in babies exposed to repeated corticosteroid treatment were not maintained at discharge Crowther et al. Of note is the authors' observation that there was no difference in perinatal mortality between the repeated steroid and placebo groups, and that the causes of death were p.

This finding is a significant departure from the original trial conducted by Liggins and Howie, which demonstrated a significant reduction in perinatal mortality between a single ANS course infants and those receiving placebo control 3. Assuming that repeated ANS administration does indeed convey a benefit to the preterm infant, the reasons for the similarity in risk of death between groups are unclear. Advances in neonatal care over the past four decades especially with regards ventilation and surfactant therapy contribute to increased survival and blunt any benefit from repeated corticosteroid therapy.

Whether or not this finding of equivalence would be replicated in a patient population drawn from mid and low-resource settings is of interest, given the high preterm birth and mortality burden in the developing world. In a 2-year follow-up to the ACTORDS study, the authors concluded that aside from an increase in treatment for attention problems, there were no statistically significant differences in body size, blood pressure or health service utilization between children exposed to repeated ANS and those exposed to placebo Crowther et al.

There is a strong body of epidemiological data demonstrating an association between low birthweight, accelerated neonatal growth and chronic diseases including type-2 diabetes, obesity, cardiovascular disease, hypertension and depression van Deutekom et al. Whilst noting the need for further, long-term follow-up, the authors concluded that the equivalence of 2-year survival free of major neurosensory disability supports consideration of administering a weekly treatment with a single dose of betamethasone in women who remain at risk of very preterm delivery 7 or more days after their initial corticosteroid treatment.

Additional reassurance is provided by data from a 6—8 year follow-up, suggesting no association between repeat antenatal corticosteroid exposure and cardio-metabolic disease risk in early school age McKinlay et al. However, an alternative view is that these rigorous clinical studies in fact support the adoption of a more conservative position. In light of ongoing concerns regarding administration of multiple courses of ANS discussed below, a demonstrated equivalence in perinatal morbidity and overall childhood wellbeing argues in favour of not administering repeated doses of ANS to women at continued risk of preterm delivery.

The multiple courses of antenatal corticosteroids for preterm birth study MACS evaluated the effect of repeated courses of ANS given at two weekly intervals in high-risk women who had failed to deliver 14—21 days after initial treatment Murphy et al. The study involved women drawn, importantly, from a number of countries with differing levels of economic development and large differences in perinatal mortality rates.

There was no difference in a composite primary outcome perinatal mortality and morbidities associated with prematurity including severe respiratory distress syndrome, neurological injury, haemorrhage and necrotising enterocolitis between the corticosteroid and placebo groups.

However, there were small but significant reductions in weight, length and head circumference at birth in infants exposed to repeated courses of antenatal corticosteroids. A pre-discharge study assessing the effect of repeated ANS exposure on auditory brainstem response in preterm infants found no difference in brain maturity or auditory function but did identify significant reductions in birthweight, length, and head circumference in association with repeated antenatal corticosteroid exposure Church et al.

The subsequent 5-year follow-up to the MACS study concluded that there were no significant differences in the risk of neurodevelopmental disability or death Asztalos et al. These conflicting data suggest that, if there are indeed changes in fetal neurodevelopment as a result of repeated antenatal corticosteroid exposure, then any adverse effects may be partially dependent on the gestational age at which the infant was born and also the post-natal age that neurosensory function is assessed.

Additionally, sex-dependent effects of antenatal corticosteroid exposure were observed in juvenile baboons Rodriguez et al. Long-term follow-up studies of children at risk of congenital adrenal hyperplasia and treated with dexamethasone in early pregnancy have suggested variable effects on brain function.

Meyer-Bahlburg performed a questionnaire survey of children exposed prenatally to dexamethasone including 48 with congenital adrenal hyperplasia and unexposed children including with congenital adrenal hyperplasia between 1 month to 12 years of age Meyer-Bahlburg et al. They found no significant effect of dexamethasone treatment on nine different social or developmental scales. These results conflict with those of a prospective follow-up study, of 40 children treated prenatally with dexamethasone and aged 7—17 years, which included neuropsychological testing as well as validated child and parental questionnaires Hirvikoski et al.

These studies suggest possible negative cognitive and behavioural effects resulting from steroids in early pregnancy. Although further long-term studies are needed, the potential long-term effects on brain function should be considered when weighing up the risks and benefits of early pregnancy steroid use.

The intrauterine environment plays a key role in regulating fetal growth and development; data, predominantly from rodent studies, also suggest that it can also program health throughout life. Corticosteroids are key mediators in this process, and excess exposure to antenatal corticosteroids is associated with adverse pregnancy outcomes, including reduced birthweight, and a host of persistent changes in hypothalamic—pituitary—adrenal HPA axis programming that manifest as elevated stress responses, hypertension and changes in glucose metabolism, behaviour and motivation Reynolds, ; Moisiadis and Matthews, Precisely how excess exposure to antenatal corticosteroids might affect pathological changes on the fetus remains unclear; however, several excellent reviews have recently highlighted the potential roles of the fetal HPA axis and the placenta Braun et al.

Impaired HPA axis function is associated with changes in behaviour and neurodevelopment along with an increased risk of chronic cardiovascular and metabolic diseases. Antenatal steroid exposure appears to differentially affect basal cortisol activity in neonates based on fetal sex, post-natal age at which studies are undertaken, and whether the infant was delivered preterm or at term Moisiadis and Matthews, Interestingly, a year follow-up of adults exposed to a single course of antenatal corticosteroids concluded that treatment did not adversely impact cardiovascular function but might cause insulin resistance Dalziel et al.

There are limited human data available on the long-term effects of repeated antenatal corticosteroid exposure on HPA axis function, although studies in sheep suggest that changes in HPA function associated with repeated antenatal corticosteroid exposure persist into adulthood Moisiadis and Matthews, Antenatal corticosteroids may also unbalance maturational effects in certain systems by selective stimulation of GR.

In contrast, synthetic corticosteroids selectively activate GR. In general, mineralocorticoid target tissues co-express 11 Beta-HSD-2, which converts cortisol to inactive cortisone to prevent unwanted stimulation of MR by cortisol Chapman et al. However, some of the functions of endogenous corticosteroids that mediate maturation of the developing fetus are signalled through MR not GR.

There is thus the potential that dexamethasone or betamethasone may perturb maturation in extra pulmonary systems by only stimulating GR Rog-Zielinska et al. Relative to late pregnancy, surprisingly little is known about the effects of GC exposure on the developing fetus in early pregnancy. Using a sheep model of pregnancy, Dodic and colleagues reported that transient 2 day exposure to dexamethasone at Day 27 of pregnancy resulted in hypertension, left ventricular hypertrophy, and reduced cardiac function in adult offspring Dodic et al.

The same group demonstrated changes in nephrogenesis in adult sheep exposed to corticosteroids in early pregnancy Wintour et al. Antenatal dexamethasone exposure in early pregnancy has been demonstrated to alter HPA axis function and maturation in fetal lambs Braun et al. If we are to understand how we might refine the use of antenatal corticosteroids then we must attempt to clarify how the maternal and fetal responses to such treatment might be modified by preterm birth-associated factors.

Factors including gestational age, maternal diet, the presence of intrauterine infection, and fetal sex have each been implicated as potential modulators of corticosteroid effects Fig. The scope for refining the use of ANS is highlighted by the observation that, under current obstetric protocols, a 60 kg women carrying a 33 week fetus would be given the exact same the same dose of ANS as a kg woman carrying a 24 week fetus in an attempt to improve neonatal outcomes.

Factors that may influence the effectiveness of antenatal corticosteroids in reducing morbidity and mortality associated with prematurity. T here are good data to suggest that GR density in target organs is critical in determining the level of response, or resistance, to corticosteroid stimulation. Accordingly, the ontology of GR receptor expression in the developing fetal lung should also be taken into account in future studies investigating gestation-specific antenatal steroid dosing. Nuclear localization of labelled dexamethasone was also dependent on the cytoplasmic receptor.

The lung is the human fetal tissue with the highest GR concentration and the GR is expressed from as early as 12 weeks gestation through to term. GR expression was also detected in the human fetal liver, kidney, heart, intestine, muscle and skin Ballard and Ballard, , GR mRNA expression was detected in the fetal rat brain from embryonic day Interestingly, Ballard and Ballard concluded that with regards the developing lung p.

This observation is supported by the findings of Labbe et al. More recently, Rajatapati and colleagues surveyed GR expression in human fetal lung samples collected at 16 pseudoglandular phase , Using immunohistochemistry, they identified nuclear GR reactivity in all samples analysed and, interestingly, that the GR mRNA concentration did not significantly differ with gestational age Rajatapiti et al. Maternal nutrition is one factor that may warrant consideration in any future optimization of antenatal corticosteroid dosing regimens, both in low-resource settings with maternal nutrient restriction and in the increasingly obese developed world.

Overweight or obese women are at an increased risk of gestational diabetes, potentially resulting a hyperglycaemic, hyperinsulaemic fetus. In sheep, maternal nutrient restriction did not impact lung growth but did result in small increases relative to animals maintained on normal diets in lung GR mRNA expression at 80 and days gestation in singleton lambs Gnanalingham et al. Interestingly, studies in sheep have suggested that maternal undernutrition is associated with substantial changes in GR methylation and increased hypothalamic GR mRNA and protein expression in both male and female offspring Begum et al.

In baboons, maternal nutrient restriction resulted in sex-dependent changes in GR mRNA, but not protein, expression. How sub-optimal maternal nutrition might impact the fetal maturational effects mediated by corticosteroids remains poorly understood. However, the accumulating body of evidence suggests that maternal diet can influence the corticosteroid signalling machinery. Whether or not infection might alter fetal and maternal responses to antenatal corticosteroid therapy is another important consideration.

Intrauterine infection and inflammation are strongly associated with preterm birth, especially those deliveries occurring at or below 32 weeks of gestation Goldenberg et al. Histologic chorioamnionitis is the hallmark of intrauterine infection most commonly identified in early gestation deliveries Lahra and Jeffery, Intrauterine infection is frequently polymicrobial and access of organisms to the fetal environment has been suggested to occur following a discrete breach in the chorioamniotic membranes Jones et al.

Ureaplasma species are commonly isolated from the gestational tissues in preterm birth Goldenberg et al. In the sheep model of pregnancy, chronic Ureaplasma infection increased surfactant production and had a surfactant-independent additive effect on lung compliance following a single course of antenatal betamethasone Moss et al. Similar additive improvements in fetal ovine lung compliance in the absence of increased surfactant production were identified following the co-administration of maternal betamethasone with intraamniotic lipopolysaccharides from Escherichia coli Newnham et al.

Differential effects of infection and ANS on pulmonary growth factors may play a role in these observed differences. Fetal sex is known to influence the risk of adverse outcomes in response antenatal corticosteroid therapy. The underlying mechanisms remain poorly understood, although sex-specific differences in the placenta have been hypothesized as being important in determining fetal responses to antenatal insults and prematurity Clifton, Female premature infants respond more effectively to antenatal betamethasone exposure than their male counterparts, with lower rates of respiratory distress syndrome Papageorgiou et al.

This observation from clinical studies has been replicated in a sheep model of prematurity; a retrospective analysis of fetuses that received 0. The observed difference in corticosteroid responsiveness between male and female fetuses does not appear to derive from differences in lung structural development or surfactant production between the sexes Ishak et al. Studies of the fetal programming of hypertension in sheep have shown that betamethasone exposure has a sex-dependent effect on endothelin-1 responsiveness Lee et al.

Zuloaga et al. In baboons, repeated antenatal betamethasone exposure reduces motivation in both male and female offspring; interestingly, reductions in reversal task performance were more pronounced in female offspring compared with males Rodriguez et al. The use of antenatal steroids has prevented the loss of thousands of pregnancies, and prevented significant morbidity in many more.

However, it is also clear that ANS are not innocuous, and may have significant and long lasting effects on health. Maternal and fetal factors, as well as the healthcare setting, can influence the risk benefit ratio for ANS. There is surprisingly little data available to inform drug dosing and timing for early pregnancy complications such as recurrent miscarriage and congenital adrenal hyperplasia.

Even in obstetric medicine, which possesses the strongest empirical evidence base for ANS administration, there are still only two ANS dosing regimens, neither of which have been significantly refined to determine the optimal dose or treatment interval since their clinical introduction. In the era of personalized medicine, we must move away from a one-size fits all approach. There is a need to trial new formulations to maximize benefits and minimize unwanted side effects, provide better delivery systems and dosage, and tailor treatment to individual circumstances, ensuring delivery of the right ANS, to the right pregnancy and at the right time.

In this way, we can realize the full potential of this life saving, and morbidity sparing treatment. The authors declare no conflict of interest. The authors have no financial interest in the contents of this manuscript. Organizations funding the authors not have input to the drafting of this manuscript. Pathway and kinetics of prednisolone metabolism in the human placenta.

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I take prednisone or prednisolone. Can it make it harder for me to get pregnant? I just found out I am pregnant. Should I stop taking prednisone or prednisolone? Talk with your healthcare provider before making any changes to how you take this medication. The benefits of taking prednisone or prednisolone and treating your condition should be weighed against any possible risk to the pregnancy.

Does taking prednisone or prednisolone increase the chance of miscarriage? Miscarriage can occur in any pregnancy. Using prednisone or prednisolone is not expected to increase the chance of miscarriage. Does taking prednisone or prednisolone increase the chance of birth defects? This is called the background risk. Using prednisone or prednisolone is not expected to significantly increase this background birth defect chance.

Older studies suggested a small increased chance for having a baby with a cleft lip, with or without a cleft palate, following the use of prednisone or prednisolone during the first trimester. However, newer studies and further review of the older studies do not support this finding. If there is an increased chance, it appears to be very small and most pregnancies would not be affected. Could taking prednisone or prednisolone cause other pregnancy complications? However, since corticosteroids are used to treat medical conditions that can increase the chance of preterm delivery and low birth weight, these effects may be related to the illnesses being treated and not the medications alone.

Other studies have shown that using prednisone or prednisolone might improve some pregnancy outcomes. The benefits of taking prednisone or prednisolone and treating your condition should be weighed against any possible risks to the pregnancy. Does taking prednisone or prednisolone in pregnancy cause long-term problems in behavior or learning for the baby? Based on the data available, it is not known if prednisone or prednisolone can cause behavior or learning issues.

The amounts of prednisone and prednisolone that enter breast milk are very small.

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