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Antenatal dexamethasone and decreased birth weight
Abstract
To test the hypothesis that antenatal dexamethasone treatment to promote fetal lung maturation results in decreased birth weight corrected for gestational age.
The birth weights of all dexamethasone-treated, singleton, live-born infants delivered at our hospital were compared with our overall obstetric population; a group of untreated infants frequency matched approximately 3:1 according to maternal race, infant sex, and gestational age at delivery; and an historical cohort of infants with an indication for dexamethasone but delivered in the 12 months before the introduction of corticosteroid therapy at our hospital.
Dexamethasone-treated infants (n = 961), when compared with either the overall population (n = 122,629) or matched controls (n = 2808), had significantly lower birth weights after adjustment for week of gestation (P <.001). Compared with the historical cohort of infants, the average birth weight of dexamethasone-treated infants was smaller by 12 g at 24-26 weeks, 63 g at 27-29 weeks, 161 g at 30-32 weeks, and 80 g at 33-34 weeks' gestation.
Antenatal dexamethasone administered to promote fetal maturation is associated with diminished birth weight.
... For instance, higher maternal cortisol during pregnancy has been consistently associated with obstetric complications (OCs) and premorbid difficulties found in the histories of schizophrenia patients. Specifically, higher maternal cortisol (particularly in the 2nd trimester) has been associated with decreased gestational age and decreased birth weight/fetal growth restriction, OCs that have been associated with schizophrenia (Abel et al., 2010;Bloom et al., 2001;Cannon et al., 2002;Eide et al., 2013;Ellman et al., 2008;French et al., 1999;Ichiki et al., 2000;Lane and Albee, 1966;Murphy et al., 2006;Reinisch et al., 1978;Trainer, 2002). In addition, we have previously found that both fetal hypoxia and exposure to maternal influenza during pregnancy are associated with decreased fetal growth, but only for infants that later go on to develop schizophrenia and not controls, indicating that vulnerability associated with schizophrenia may interact with these prenatal events to impair fetal growth . ...
... In addition, this study investigated whether timing of exposure to cortisol and fetal sex contributed to the findings. Although there has been some variability in previous results, most studies have linked 2nd trimester maternal stress with offspring schizophrenia and outcomes associated with schizophrenia (Bloom et al., 2001;Cannon et al., 2002;Ellman et al., 2008;French et al., 1999;Ichicki et al., 2000;Lane and Albee, 1966;Murphy et al., 2006;Reinisch et al., 1978;Trainer, 2002). Finally, the present study aimed to investigate whether higher maternal cortisol during pregnancy was associated with decreased fetal growth and whether this association was influenced by fetal sex and case status, as has previously been suggested (Chan et al., 2018;Ellman et al., 2008;Fineberg et al., 2016;Khashan et al., 2008;Mueller and Bale, 2008;Sandman et al., 2013;Van Os and Selten, 1998). ...
... Finally, the present study aimed to investigate whether higher maternal cortisol during pregnancy was associated with decreased fetal growth and whether this association was influenced by fetal sex and case status, as has previously been suggested (Chan et al., 2018;Ellman et al., 2008;Fineberg et al., 2016;Khashan et al., 2008;Mueller and Bale, 2008;Sandman et al., 2013;Van Os and Selten, 1998). This latter aim was explored given the strong possibility that higher maternal cortisol during pregnancy is associated with an intermediate phenotype associated with both schizophrenia and prenatal cortisol, instead of the full diagnostic criteria for the disorder (Abel et al., 2010;Bloom et al., 2001;Cannon et al., 2002;Eide et al., 2013;Ellman et al., 2008;French et al., 1999;Ichicki et al., 2000;Lane and Albee, 1966;Murphy et al., 2006;Reinisch et al., 1978;Trainer, 2002). We hypothesized that higher levels of 2nd trimester maternal cortisol would be associated with increased odds of schizophrenia and decreased fetal growth among cases. ...
Introduction:
Maternal stress during pregnancy has been repeatedly linked to increased risk for schizophrenia; however, no study has examined maternal cortisol during pregnancy and risk for the disorder. Study aims were to determine whether prenatal cortisol was associated with risk for schizophrenia and risk for an intermediate phenotype-decreased fetal growth-previously linked to prenatal cortisol and schizophrenia. Timing of exposure and fetal sex also were examined given previous findings.
Methods:
Participants were 64 cases diagnosed with schizophrenia spectrum disorders (SSD) and 117 controls from a prospective birth cohort study. Maternal cortisol was determined from stored sera from each trimester and psychiatric diagnoses were assessed from offspring using semi-structured interviews and medical records review.
Results:
Maternal cortisol during pregnancy was not associated with risk for offspring schizophrenia. There was a significant interaction between 3rd trimester cortisol and case status on fetal growth. Specifically, cases exposed to higher 3rd trimester maternal cortisol had significantly decreased fetal growth compared to controls. In addition, these findings were restricted to male offspring.
Conclusions:
Our results indicate that higher prenatal cortisol is associated with an intermediate phenotype linked to schizophrenia, fetal growth, but only among male offspring who developed schizophrenia. Findings were consistent with evidence that schizophrenia genes may disrupt placental functioning specifically for male fetuses, as well as findings that males are more vulnerable to maternal cortisol during pregnancy. Finally, results suggest that examining fetal sex and intermediate phenotypes may be important in understanding the mechanisms involved in prenatal contributors to schizophrenia.
... Concerns have been raised regarding the potential adverse effects of repetitive antenatal glucocorticoids in humans . Non-randomised cohort studies in humans have reported reductions in birth weight (Reinisch et al., 1978;Banks et al., 1999;French et al., 1999;Bloom et al., 2001;Thorp et al., 2002) and head circumference (French et al., 1999;Abbasi et al., 2000;Thorp et al., 2002) in pre-term infants exposed to multiple doses of prenatal glucocorticoids. In contrast, the 2003 ...
... Antenatal glucocorticoid therapy in humans has been associated with reduced birth weight in a number of non-randomised studies (Reinisch et al., 1978;Banks et al., 1999;French et al., 1999;Bloom et al., 2001;Thorp et al., 2002). The long-term effects of prenatal glucocorticoid exposure on adult-onset diseases, such as hypertension, are uncertain. ...
... The beneficial effects of antenatal glucocorticoids were thought to diminish after seven days, based on data showing no difference in the incidence of RDS in glucocorticoid-and placebo-exposed infants delivered more than a week after treatment (Liggins & Howie, 1972;Crowley, 1995). Repetitive antenatal glucocorticoid therapy has been associated with reduced birth weight in non-randomised studies (Reinisch et al., 1978;Banks et al., 1999;French et al., 1999;Bloom et al., 2001;Thorp et al., 2002). Recent randomised controlled trials have reported no difference in mean birth weight in infants exposed to placebo or repeated corticosteroids; however, there were more neonates weighing less than the 10 th percentile in the repeat group (Crowther et al., 2006;Wapner et al., 2006). ...
... 1,2 There is strong evidence that they reduce mortality and morbidity among preterm newborns, but there is also concern that they may restrict growth. 1,3,4 Studies have reported that antenatal corticosteroids are associated with reduced head circumference, weight and length at birth, independently of other predictive factors. 3,[5][6][7] Moreover, the apparent link between the extent of growth restriction and the corticosteroid dose suggests a causal relation between them. ...
... 1,3,4 Studies have reported that antenatal corticosteroids are associated with reduced head circumference, weight and length at birth, independently of other predictive factors. 3,[5][6][7] Moreover, the apparent link between the extent of growth restriction and the corticosteroid dose suggests a causal relation between them. 8,9 Most studies examining the possible adverse effects of antenatal steroids have focused on preterm infants, but more than half the women admitted for preterm labor who receive corticosteroids finally give birth after 37 weeks of gestation. ...
Introduction:
Our main objective was to evaluate whether antenatal corticosteroids increase the risk of small head circumference in children born at term. Secondary objectives were to evaluate whether they increase the risk of small birthweight and birth length among those children.
Material and methods:
A historical cohort included 275 270 live term born children between 2000 and 2013 in 175 French maternity units. The rate of head circumference below the fifth percentile among children born at term and exposed to antenatal corticosteroids was compared with that of two unexposed groups: those children born at term whose mothers had an episode of threatened preterm labour without corticosteroids and those whose mothers had neither threatened preterm labour nor corticosteroids. The association between this treatment and head circumference was evaluated by calculating adjusted risk ratios (aRRs) and their 95% confidence intervals (CIs). The main outcome measure was a head circumference below the fifth percentile at birth, adjusted for sex and gestational age according to the AUDIPOG curves. Secondary outcomes were birthweight and birth length below the fifth percentile.
Results:
The rate of head circumference below the fifth percentile was 5.8% (n=3388) among children exposed to antenatal corticosteroids and 4.3 % (n=7077) and 4.6% (n=198462) respectively for the two unexposed groups. After adjustment, the risk of having a head circumference below the fifth percentile did not differ between the exposed group and the two control groups (aRR 1.28 (95% CI: 0.97-1.69) and aRR 0.91 (95% CI: 0.74-1.13)). We did not find an association between antenatal corticosteroids and the rate of birthweight below the fifth percentile. Children exposed to antenatal corticosteroids had a higher risk of a birth length below the fifth percentile when compared to those with neither exposure to threatened preterm labour nor corticosteroids.
Conclusions:
We found no association between antenatal corticosteroids and increased risk of head circumference below the fifth percentile in children born at term.
... Cushing's syndrome (excess cortisol production) is associated with increased weight gain, hypertension, type 2 diabetes, and fatty tissue deposits (143,144), suggesting a pro-adipogenic effect of glucocorticoids in humans as well. Further, prenatal/antenatal dexamethasone (GR agonist) is often utilized to promote development of lungs in infants at risk of being born premature (145,146). Epidemiological studies have reported that dexamethasone treatment is associated with reduced birth weight in infants, even after correcting for weeks of gestation (145,146), and exhibited hypertension and greater subsequent administration of insulin for hyperglycemia (146). ...
... Further, prenatal/antenatal dexamethasone (GR agonist) is often utilized to promote development of lungs in infants at risk of being born premature (145,146). Epidemiological studies have reported that dexamethasone treatment is associated with reduced birth weight in infants, even after correcting for weeks of gestation (145,146), and exhibited hypertension and greater subsequent administration of insulin for hyperglycemia (146). ...
Obesity and metabolic disorders are of great societal concern and generate substantial human health care costs globally. Interventions have resulted in only minimal impacts on disrupting this worsening health trend, increasing attention on putative environmental contributors. Exposure to numerous environmental contaminants have, over decades, been demonstrated to result in increased metabolic dysfunction and/or weight gain in cell and animal models, and in some cases, even in humans. There are numerous mechanisms through which environmental contaminants may contribute to metabolic dysfunction, though certain mechanisms, such as activation of the peroxisome proliferator activated receptor gamma or the retinoid x receptor, have received considerably more attention than less-studied mechanisms such as antagonism of the thyroid receptor, androgen receptor, or mitochondrial toxicity. As such, research on putative metabolic disruptors is growing rapidly, as is our understanding of molecular mechanisms underlying these effects. Concurrent with these advances, new research has evaluated current models of adipogenesis, and new models have been proposed. Only in the last several years have studies really begun to address complex mixtures of contaminants and how these mixtures may disrupt metabolic health in environmentally relevant exposure scenarios. Several studies have begun to assess environmental mixtures from various environments and study the mechanisms underlying their putative metabolic dysfunction; these studies hold real promise in highlighting crucial mechanisms driving observed organismal effects. In addition, high-throughput toxicity databases (ToxCast, etc.) may provide future benefits in prioritizing chemicals for in vivo testing, particularly once the causative molecular mechanisms promoting dysfunction are better understood and expert critiques are used to hone the databases. In this review, we will review the available literature linking metabolic disruption to endocrine-mediated molecular mechanisms, discuss the novel application of environmental mixtures and implications for in vivo metabolic health, and discuss the putative utility of applying high-throughput toxicity databases to answering complex organismal health outcome questions.
... (1,3) Os efeitos colaterais da terapia transplacentária devem ser monitorizados, destacando-se que o uso de corticoides pela mãe está associado a efeitos colaterais maternos (hipertensão arterial e diabetes, entre outros) e fetais (oligodrâmnio e restrição de crescimento, entre outros). (13,14,15) No caso em questão a paciente utilizou corticoide por pouco tempo e não chegou a ter repercussão como hipertensão ou diabetes. A medicação que lhe causou mais efeito colateral foi o salbutamol, sendo a medicação suspensa após piora dos sintomas. ...
O bloqueio atrioventricular total (BAVT) congênito é a principal bradiarritmia no Brasil, estando presente, em média, a cada 1:20 mil nascidos vivos, podendo estar relacionado a processos imunológicos e não imunológicos. No BAVT ocorre dissociação completa entre os átrios e os ventrículos pela ausência de condução átrio-ventricular e a frequência ventricular é tipicamente de 50 a 80 bpm, podendo ter como complicações mais graves a insuficiência cardíaca e a hidropsia fetal. O diagnóstico deve ser preferencialmente intrauterino através de ultrassonografia e ecocardiografia fetal e o tratamento depende da etiologia, da presença de descompensação hemodinâmica fetal e do valor da frequência ventricular. Neste trabalho, foram avaliadas a fisiopatologia do BAVT, suas complicações, seu manejo, tratamento e acompanhamento fetal durante a gestação.
... B) Long-term neonatal effects are principally related to repeated ACST courses: • decreased birth weight Bloom et al. observed the link between low neonatal birth weight and repeated maternal ACST course in the third trimester of gestation. (34). This birth weight reduction presumably reflected the catabolic actions of exogenous steroids (33). ...
Antenatal corticosteroid therapy (ACST) is very important in reducing the sequelae of prematurity, respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC). This therapy has short-term and long-term neonatal consequences that range from reduced neonatal body weight, brain growth, hypertension, hypoglycemia and obesity to delayed neurological development. In addition to undeniable importance this type of therapy has on fetal maturation, it may also impact programming of fetuses future development and health during childhood and adulthood. ACST must be personalized, as a single course, and determined by indications and assessment of the expected time of delivery, so that the exposure time of the fetus to the effects of endogenous and exogenous steroids is shortened.
... Previous studies have found that although treatment with dexamethasone during pregnancy can effectively reduce perinatal mortality, dexamethasone is the exact cause of developmental toxicity in the offspring [6,7]. Clinical studies have found that even the dose of dexamethasone recommended by the US Department of Health during pregnancy can lead to an increase in the incidence of low birth weight in newborns [8,9]. The developmental toxicity of bone caused by dexamethasone has been a wide concern for researchers. ...
Maternal exposure to dexamethasone can cause developmental toxicity of long bones in offspring. However, the effect of dexamethasone on the trans-differentiation of growth plate chondrocytes into osteoblasts and its role in bone dysplasia of fetuses caused by prenatal dexamethasone exposure (PDE) remains unclear. In this study, pregnant mice were treated with different doses, stages, and courses of dexamethasone according to clinical practice to reveal the phenomenon. Further, growth plate chondrocytes were treated with dexamethasone in vitro to clarify the phenomenon and mechanism. The results showed that PDE caused dysplasia of fetal long bones in female and male mice, accompanied by the delayed formation of the primary ossification center and the widening hypertrophic zone of growth plate cartilage. Meanwhile, PDE increased the number of hypertrophic chondrocytes at growth plate cartilage and decreased the number of osteoblasts at the primary ossification center. Moreover, PDE significantly decreased the expression of osteogenic transcription factor Runx2 but increased the expression of hypertrophic chondrocytes marker Col10. These above phenomena were more significant in the high dose, early stage, and double courses of dexamethasone exposure groups, and the male fetal mice showed more obvious than the female fetal mice. In vitro , dexamethasone significantly inhibited the trans-differentiation of growth plate chondrocytes into osteoblasts, accompanied by a decrease in Runx2 expression and an increase in Col10 expression. In conclusion, this study revealed the phenomenon and mechanism of fetal bone dysplasia caused by PDE from the new perspective of trans-differentiation disorder of growth plate chondrocytes to osteoblasts.
... Animal studies have found that betamethasone had a greater effect on brain development in rats [25,26] and abnormalities of the insulin resistance system over the age of 30, which in turn increased the risk of diabetes [27]. An increasing number of animal and human studies have found that multiple courses of steroids may slow the development of infants [28][29][30][31] and cerebral palsy in children 2 years of age delivered from mothers receiving 1 or more courses of betamethasone [32]. However, the condition was not found in children delivered from mothers administered a half course of betamethasone [33], which was also as effective in stimulating lung development as a full course [34,35]. ...
Objective
To compare the effects of an incomplete course and more than 1 course of dexamethasone, relative to a control of a single complete course, on foetal respiratory problems and other adverse outcomes of preterm birth.
Methods
This was a retrospective chart review of 1800 women with preterm delivery. Data were collected on newborns whose mothers administered 1 full course of dexamethasone (916/1800; 50.9%), a partial course (716/1800; 39.8%) and more than 1 course (168/1800; 9.3%). Demographic data and adverse maternal and neonatal outcomes were recorded.
Results
Preterm singleton newborns whose mothers received several steroid hormone courses were significantly more likely to have adverse outcomes than newborns of mothers given 1 course. The negative outcomes were the need for positive pressure ventilation ([aOR] 1.831; 95% CI, (1.185,2.829); P = 0.019), ventilator support ([aOR] 1.843; 95% CI, (1.187,2.861); P = 0.011), and phototherapy ([aOR] 1.997; 95% CI, (1.378,2.895); P < 0.001), transient tachypnoea of the newborn ([aOR] 1.801; 95% CI, (1.261,2.571); P = 0.002), intraventricular haemorrhage ([aOR] 2.215; 95% CI, (1.159, 4.233); P = 0.027), sepsis ([aOR] 1.737; 95% CI, (1.086, 2.777); P = 0.007), and admission to neonatal intensive care ([aOR] 1.822; 95% CI, (1.275,2.604); P = 0.001). In the group of very preterm infants, newborns of mothers administered an incomplete course had developed respiratory distress syndrome (RDS) ([aOR] 3.177; 95% CI, (1.485, 6.795); P = 0.006) and used ventilatory support ([aOR] 3.565; 95% CI, (1.912, 6.650); P < 0.001) more than those of mothers receiving a single course.
Conclusions
Preterm singleton newborns whose mothers were given multiple courses of dexamethasone had an increased incidence of RDS and other adverse outcomes than those of mothers receiving a full course. However, very preterm newborns whose mothers were administered 1 full dexamethasone course had a significantly lower incidence of RDS than those whose mothers were given partial courses.
... 28 However there are a number of studies that have proven that a single course of antenatal corticosteroids is not related to an increased risk of maternal or fetal infection and has no adverse neurological effects. [29][30][31][32] Besides the mode of delivery, gestational age at the time of delivery also affects the risk of Neonatal respiratory problems as well as compromises mother-infant bonding due to staying in the neonatal nursery. In 2013, The American College of Obstetricians and Gynecologists (ACOG) suggested that early-term should be defined as delivery occurring between 37 to 39 weeks gestation. ...
Performing elective caesarean section prior to 39 completed weeks, it can lead to breathing problems in neonates as compare to those, who are born through caesarean section without antenatal Corticosteroid. WHO recommends the administration of intramuscular corticosteroids either dexamethasone or betamethason (total 24mg in divided doses) in the antenatal period, when there is a risk of preterm birth. The advantages and disadvantages of a similar regimen given after 37 weeks of pregnancy prior to elective caesarean section (LSCS) to prevent respiratory morbidity in a newborn is yet a topic of discussion.
In Pakistan still, many clinicians are doing caesarean section at 37 or 38 weeks without antenatal Corticosteroids. The rationale is to emphasize the use of steroids before caesarean at 39 weeks.
... This is also supported by the fact that the synthetic glucocorticoid dexamethasone is administered to pregnant women who are at risk of preterm birth [2]. In addition to immediately observable side effects of a pathologically increased corticosterone concentration, such as reduced fetal birth weight [3] and developmental toxicity [4], possible epigenetic regulation patterns are of substantial interest, to investigate associated mechanisms of possible longterm consequences. To approach the research question of possible glucocorticoidinduced epigenetic changes in early embryonic development, we will perform in ovo injections of corticosterone into the yolk sac of the developing chicken embryo. ...
Prenatal stress can have a significant impact on embryonic development processes and postnatal behavioral changes.
In this research project, we plan to perform standardized in-ovo glucocorticoid injections in chicken embryos – a well-established model organism for developmental research.
With the controlled glucocorticoid application, we hope to induce steroid-mediated influences on the epigenome during brain maturation. Results may lead to an improved understanding of the influences of prenatal stress on an epigenetic level.
Prolonged exposure to stress is known to affect the body in various ways, including the activation of the hypothalamic-pituitary-adrenal axis and the subsequent secretion of glucocorticoids from the zona fasciculata layer of the adrenal cortex. The primary glucocorticoid in avian species is corticosterone, the equivalent of the human glucocorticoid cortisol.
Since it has already been shown that the maternal glucocorticoid concentration correlates with the fetal circulatory system, an increased embryonic glucocorticoid concentration is not an unlikely event. This is also supported by the fact that the synthetic glucocorticoid dexamethasone is administered to pregnant women who are at risk of preterm birth. In addition to immediately observable side effects of a pathologically increased corticosterone concentration, such as reduced fetal birth weight and developmental toxicity, possible epigenetic regulation patterns are of substantial interest, to investigate associated mechanisms of possible long-term consequences in detail. To approach the research question of possible glucocorticoid-induced epigenetic changes in early embryonic development, we will perform in ovo injections of corticosterone into the yolk sac of the developing chicken embryo. We will then be able to study potential GC effects on DNA methylation and RNA expression in freshly isolated brain tissue.
... Elucidation of such predisposing factors is also of great importance in development of nicotine addiction [6] since nicotine dependence is a serious public health concern and its intake causes enormous healthcare expenses [7]. Clinical data and results of animal studies show both the effect of maternal stress, accompanied by release of endogenous glucocorticoid hormones, and the effect of placental pathologies, on the further physical [8][9][10][11] and cognitive development of offspring. Prenatal hypoxia, being one of the most common types of prenatal stressors [12,13], can develop under various conditions, including pregnancy with anemia, placental insufficiency, umbilical cord compression, and preeclampsia, as well as maternal cardiovascular diseases [14][15][16]. ...
The role of damaging factors in the prenatal period as a basis for drug addiction in offspring is of great interest. In this study, we aim at deciphering the effects and possible mechanisms of prenatal severe hypoxia (PSH) on predisposition to nicotine addiction in adult rats. In PSH rats, we found an increasing tendency to nicotine consumption in the two-bottle choice test. After 2 weeks of chronic treatment with nicotine via osmotic minipump (9 mg/kg per day), we assessed the symptoms of withdrawal in the conditioned place aversion test after mecamylamine (an antagonist of nicotinic acetylcholine receptors, nAChR) treatment. We showed that the mecamylamine-precipitated withdrawal aversion was stronger in the PSH group than in the control group. This suggests that PSH acts as a predisposing factor for developing nicotine addiction in adulthood. PSH rats also demonstrated an increased level of phosphorylated DARPP-32 protein (known as the relay for dopamine and glutamate signaling) at 34 threonine (pThr34DARPP-32) in relation to its total amount in the nucleus accumbens of the striatum (NAc). Meanwhile, no changes in both the content of dopamine in the mesolimbic pathway and the first type of dopamine receptors (DAR1) in NAc were found. The increased rate of DARPP-32 phosphorylation in adult PSH rats might result from excessive glutamatergic stimulation of the dopaminergic (DA) neurons of the ventral tegmental area (VTA) caused by activation of presynaptic nAChR by nicotine. This hypothesis is supported by the observed increase in VGluT2-positive terminals to Nurr1-positive neuronal bodies in VTA in PSH animals. Thus, the altered glutamate signaling phenotype might play a significant role in the development of PSH-related nicotine addiction.
... Increased levels of GCs induce accelerated tissue differentiation and maturation at the expense of tissue growth (23). While this effect is utilized to induce lung maturation in fetuses at risk of premature birth (24), it occurs in all organ systems and is reflected in a reduced birth weight following antenatal GC treatment (25). Out of all organ systems, the developing brain is particularly vulnerable to elevated GC concentrations due to its complex sequence of precisely coordinated steps of maturation and its intrinsic plasticity (26), a basic property of the brain enabling learning and adaptation. ...
Introduction
Multiple Sclerosis (MS) is the most common neuroimmunological disease in women of childbearing age. Current MS therapy consists of immunomodulatory relapse prevention with disease-modifying therapies (DMTs) and acute relapse therapy with the synthetic glucocorticoid (GC) methylprednisolone (MP). As most DMTs are not approved for use during pregnancy, treatment is usually discontinued, increasing the risk for relapses. While MP therapy during pregnancy is considered relatively save for the fetus, it may be detrimental for later cognitive and neuropsychiatric function. The underlying mechanism is thought to be an epigenetically mediated desensitization of GC receptors, the subsequent increase in stress sensitivity, and a GC-mediated impairment of brain development. The aim of this study is to investigate the associations of fetal MP exposure in the context of MS relapse therapy with later cognitive function, brain development, stress sensitivity, and behavior.
Methods and Analysis
Eighty children aged 8–18 years of mothers with MS will be recruited. Forty children, exposed to GC in utero will be compared to 40 children without fetal GC exposure. The intelligence quotient will serve as primary outcome. Secondary outcomes will include attention, motor development, emotional excitability, Attention-Deficit Hyperactivity Disorder-related symptoms, and behavioral difficulties. The Trier Social Stress Test will test stress sensitivity, EEG and MRI will assess functional and structural brain development. To determine underlying mechanisms, DNA methylation of the GC receptor gene and the H19/IGF2 locus and changes in the microbiome and the metabolome will be investigated. Primary and secondary outcomes will be analyzed using linear regression models. Time-variant outcomes of the stress test will be analyzed in two mixed linear models exploring overall activity and change from baseline.
Ethics and Dissemination
This study was approved by the participating institutions' ethics committees and results will be presented in accordance with the STROBE 2007 Statement.
Trial Registration
https://clinicaltrials.gov/ct2/show/NCT04832269?id=ZKSJ0130
... Prenatal stress may alter the newborn through glucocorticoid effects or autonomic CRH effects [401]. For instance, glucocorticoid exposure during pregnancy results in lower birth weight [402,403] and predisposition to obesity in later life. Similarly, offspring born of prenatal stress demonstrate altered glucose and insulin homeostasis upon reaching adulthood [404] and are more vulnerable to a high fat diet in later life [405]. ...
Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY3-36) is essential for controlling energy homeostasis and feeding behavior. It describes the distinct types of adipocytes and how fat cell development is controlled by hormones and growth factors acting via a variety of receptors, including peroxisome proliferator-activated receptor-gamma, retinoid X, insulin, estrogen, androgen, glucocorticoid, thyroid hormone, liver X, constitutive androstane, pregnane X, farnesoid, and aryl hydrocarbon receptors. Finally, it demonstrates that obesity likely has origins in utero. Understanding these biochemical drivers of adiposity and metabolic dysfunction throughout the life cycle lends plausibility and credence to the “obesogen hypothesis” (i.e., the importance of environmental chemicals that disrupt these receptors to promote adiposity or alter metabolism), elucidated more fully in the two companion reviews.
... Furthermore, the potential toxic effects of dexamethasone on offspring bone development during pregnancy have attracted extensive attention. Clinical studies have shown that the birth weight and body length of infants receiving dexamethasone treatment are lower than those of infants of the same gestational age; moreover, dexamethasone is an essential factor leading to a decrease in bone mineral content and bone mineral density after birth 10,11 . Animal studies also found that exposure to dexamethasone during the last 24 days of the fetal period in piglets can significantly decrease bone density and mass 12 . ...
As a synthetic glucocorticoid, dexamethasone is widely used to treat potential premature delivery and related diseases. Our previous studies have shown that prenatal dexamethasone exposure (PDE) can cause bone dysplasia and susceptibility to osteoporosis in female rat offspring. However, whether the effect of PDE on bone development can be extended to the third generation (F3 generation) and its multigenerational mechanism of inheritance have not been reported. In this study, we found that PDE delayed fetal bone development and reduced adult bone mass in female rat offspring of the F1 generation, and this effect of low bone mass caused by PDE even continued to the F2 and F3 generations. Furthermore, we found that PDE increases the expression of miR-98-3p but decreases JAG1/Notch1 signaling in the bone tissue of female fetal rats. Moreover, the expression changes of miR-98-3p/JAG1/Notch1 caused by PDE continued from the F1 to F3 adult offspring. Furthermore, the expression levels of miR-98-3p in oocytes of the F1 and F2 generations were increased. We also confirmed that dexamethasone upregulates the expression of miR-98-3p in vitro and shows targeted inhibition of JAG1/Notch1 signaling, leading to poor osteogenic differentiation of bone marrow mesenchymal stem cells. In conclusion, maternal dexamethasone exposure caused low bone mass in female rat offspring with a multigenerational inheritance effect, the mechanism of which is related to the inhibition of JAG1/Notch1 signaling caused by the continuous upregulation of miR-98-3p expression in bone tissues transmitted by F2 and F3 oocytes.
... Increased levels of GCs induce accelerated tissue differentiation and maturation at the expense of tissue growth [22]. While this effect is utilised to induce lung maturation in foetuses at risk of premature birth [23], it occurs in all organ systems and is reflected in a reduced birth weight following antenatal GC treatment [24]. Out of all organ systems, the developing brain is particularly vulnerable to elevated GC concentrations due to its complex sequence of precisely coordinated steps of maturation and its intrinsic plasticity ...
Introduction: Multiple Sclerosis (MS) is the most common neuroimmunological disease in women of childbearing age. Current MS therapy consists of immunomodulatory relapse prevention with disease-modifying therapies (DMTs) and acute relapse therapy with the synthetic glucocorticoid (GC) methylprednisolone (MP). As most DMTs are not approved for use during pregnancy, treatment is usually discontinued, increasing the risk for relapses. While MP therapy during pregnancy is considered relatively save for the foetus, it may be detrimental for later cognitive and neuropsychiatric function. The underlying mechanism is thought to be an epigenetically mediated desensitisation of GC receptors, the subsequent increase in stress sensitivity, and a GC-mediated impairment of brain development. The aim of this study is to investigate the associations of foetal MP exposure in the context of MS relapse therapy with later cognitive function, brain development, stress sensitivity, and behaviour.
Methods and analysis: 80 children aged 8 to 18 years of mothers with MS will be recruited. 40 children, exposed to GC in utero will be compared to 40 children without foetal GC exposure. The intelligence quotient will serve as primary outcome. Secondary outcomes will include attention, motor development, emotional excitability, Attention-Deficit Hyperactivity Disorder-related symptoms, and behavioural difficulties. The Trier Social Stress Test will test stress sensitivity, EEG and MRI will assess functional and structural brain development. To determine underlying mechanisms, DNA methylation of the GC receptor gene and the H19/IGF2 locus and changes in the microbiome and the metabolome will be investigated. Primary and secondary outcomes will be analysed using linear regression models. Time-variant outcomes of the stress test will be analysed in two mixed linear models exploring overall activity and change from baseline.
Ethics and dissemination: This study was approved by the participating institutions' ethics committees and results will be presented in accordance with the STROBE 2007 Statement.
Trial registration: https://clinicaltrials.gov/ct2/show/NCT04832269?id=ZKSJ0130
... A short course of poorly metabolized betamethasone can be used to prevent fetal respiratory distress in selected cases. Only excessive glucocorticoid administration can influence fetal growth [82][83][84] and results in dysfunction of the fetal hypothalamic-pituitary-adrenal axis [85]. This phenomenon, termed early life programming, may be associated in the long-term with impaired brain growth and increased susceptibility to cardiovascular disease. ...
Pregnancy is not contraindicated in kidney transplant women but entails risks of maternal and fetal complications. Three main conditions can influence the outcome of pregnancy in transplant women: preconception counseling, maternal medical management, and correct use of drugs to prevent fetal toxicity. Preconception counseling is needed to prevent the risks of an unplanned untimely pregnancy. Pregnancy should be planned ≥2 years after transplantation. The candidate for pregnancy should have normal blood pressure, stable serum creatinine <1.5 mg/dL, and proteinuria <500 mg/24 h. Maternal medical management is critical for early detection and treatment of complications such as hypertension, preeclampsia, thrombotic microangiopathy, graft dysfunction, gestational diabetes, and infection. These adverse outcomes are strongly related to the degree of kidney dysfunction. A major issue is represented by the potential fetotoxicity of drugs. Moderate doses of glucocorticoids, azathioprine, and mTOR inhibitors are relatively safe. Calcineurin inhibitors (CNIs) are not associated with teratogenicity but may increase the risk of low birth weight. Rituximab and eculizumab should be used in pregnancy only if the benefits outweigh the risk for the fetus. Renin–angiotensin system inhibitors, mycophenolate, bortezomib, and cyclophosphamide can lead to fetal toxicity and should not be prescribed to pregnant women.
... Un grado A de evidencia respalda el uso de cursos únicos y no múltiples de glicocorticoides anteparto, entre las 24 y 34 semanas (48) . Los estudios refieren ciertos efectos negativos de la dexametasona (49) (Recomendación C, nivel de evidencia 4). Por otra parte, se observó un mayor efecto protector de la betametasona sobre la leucomalacia periventricular en los recién nacidos de peso muy bajo (50) (Nivel de evidencia Ib). ...
Se hace un esbozo del manejo del parto pretérmino, basado en las evidencias, haciendo énfasis en la importancia de un buen diagnóstico clínico, ecográfico y de laboratorio. A pesar que la terapia tocolítica para disminuir la actividad contráctil y las modificaciones del cuello uterino no parece disminuir la tasa de parto pretérmino, permitiría prolongar la gestación de manera de administrar glicocorticoides y transportar in útero al feto a una unidad de atención especializada. Si se va a emplear un agente tocolítico, los agonistas beta ya no son de elección, sino el atosiban o el nifedipino, con menos efectos maternos adversos. Una sola dosis de glicocorticoides entre las 24 y 34 semanas de gestación reduce el riesgo de muerte, síndrome de distrés respiratorio y hemorragia intraventricular en el bebe pretérmino. El parto pretérmino es un problema social de mayor importancia y, como tal, se debe poner más énfasis en su prevención primaria y el tratamiento de la inmadurez.
... CTRL (white) compared with DEX (red) female offspring studies in humans show exposure to stress mediators (GC) during pregnancy correlates with reduced birthweight and adverse outcomes in the offspring, especially if GC are administered during late gestation, when growth is accelerating and presumably most susceptible to the catabolic effects of steroids. 21 The reduction in birthweight is also strongly suspected to contribute to the development of obesity later in life. 22 Our study is also in line with some experimental studies reporting a decrease in body weight at birth in females and males prenatally exposed to stress, 23,24 though the animal model, route, GC dose and the duration of administration were different. ...
Background
Prenatal stress is associated with increased susceptibility to psychiatric and metabolic disorders later in life. Prenatal exposure to stress mediators may have sex-dependent effects on offspring brain and metabolic function, promoting a sex-specific vulnerability to psychopathology and metabolic alterations at adulthood. In this work, the impact of prenatal stress on glucose homeostasis and peripheral metabolism of male and female offspring was investigated in a chronic anxiety animal model.
Methods
Pregnant Wistar rats were injected with saline or glucocorticoid (dexamethasone: 1 mg/kg, subcutaneous) at gestational days 18 and 19. Male and female offspring weight was monitored, and anxious-like behavior and peripheral insulin sensitive tissues were analyzed at adulthood.
Results
At birth, females and males prenatally exposed to stress presented decreased body weight which remained low in females. At adulthood a morphological disorganization of the Langerhans islets was observed in both sexes prenatally exposed to stress, yet not changes in insulin levels were detected. Also, prenatal stress increased glucose transporter 4 (GLUT-4) levels in female and male adipose tissue, and decreased insulin receptor levels in the liver and skeleton muscle but only in females.
Conclusions
Exposure to stress mediators in critical periods of development negatively affects behavior and metabolism. Prenatal stress programs offspring peripheral metabolism in a sex-specific manner, emphasizing that the response to stress in critical periods of development may be sex-specific having each sex different vulnerabilities to psychiatric and metabolic disorders. Considering sex-specificities may provide critical clues for the design of preventive strategies and for early therapeutic intervention.
... In order to promote the growth of the fetus's lungs for those women who are at the risk of delivering prematurely. It happens due to low birth weight [19]. It is also used during the pregnancy as off-label in the treatment of congenital adrenal hyperplasia (CAH) in female pregnancy. ...
Dexamethasone sodium phosphate and prednisolone acetate are corticosteroids, both the drugs are available in a veterinary injectable suspension dosage form as DMSP 3.291 mg per ml and PA 7.923 mg per ml. The chromatographic separation was carried out on a reversed-phase C18 column (250mm X 4.6 mm, 5µm) in isocratic mode using acetonitrile: phosphate buffer 0.1% (50:50), at pH 3.0 adjusted with diluted orthophosphoric acid as the mobile phase at a flow rate of 1.0 ml/min. Retention times of DMSP and PA were 2.25 min and 4.50 min respectively. Quantification was carried out with UV detector at 254 nm. The linearity of DMSP and PA was in the range of 10.528µg/ml-23.1616µg/ml and 13.392µg/ml-24.106µg/ml respectively. A simple high-performance chromatography method was developed for the simultaneous determination of dexamethasone sodium phosphate and prednisolone acetate. The developed method is economical in terms of the time taken and the number of solvents consumed for each analysis. The method was validated as per ICH and successfully applied to the simultaneous determination of dexamethasone sodium phosphate and prednisolone acetate in bulk and pharmaceutical dosage forms.
... A research launched by World Health Organization (WHO) demonstrated that the average rate of antenatal corticosteroid use was 54% in 359 facilities in 29 countries [10]. However, clinical research has found that antenatal dexamethasone not only reduce fetal birth weight [11], but also altered the expression and function of some placental transporters, such as breast cancer resistant protein and P-glycoprotein [12,13]. Meanwhile, some xenobiotics (such as cadmium) during pregnancy has been reported to impair placental cholesterol transport [14]. ...
Due to the insufficient fetal cholesterol synthesis, maternal cholesterol transport through the placenta becomes an important source of fetal cholesterol pool, which is essential for fetal growth and development. This study aimed to investigate the effects of dexamethasone on fetal cholesterol levels, and explore its placental mechanism. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.8 mg/kg·d) from gestational day 9 to 20. Results showed that dexamethasone increased maternal serum total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) levels, as well as placental cholesterol synthesis and TC concentration, while reduced fetal birth weight, and serum TC, HDL-C and LDL-C levels. Meanwhile, the expression of placental cholesterol transporters, including low-density lipoprotein receptor (LDLR), scavenger receptor class B type I (SR-B1) and ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) were decreased by dexamethasone. Furthermore, the expression of glucocorticoid receptor (GR) and histone deacetylase 3 (HDAC3) were increased, while the H3K9ac and expression levels of liver X receptor α (LXRα) promoter were reduced. In human trophoblast cell line (BeWo), dexamethasone concentration-dependently decreased the expression levels of LDLR, SR-B1, ABCA1, ABCG1 as well as LXRα. Dexamethasone (2500 nM) induced GR translocation into nucleus and recruited HDAC3. Furthermore, LXRα agonist and GR inhibitor reversed respectively dexamethasone-induced the expression inhibitions of cholesterol transporter and LXRα, and HDAC3 siRNA reversed the H3K9ac level of LXRα promoter and its expression. Together, dexamethasone impaired placental cholesterol transport and eventually decreased fetal cholesterol levels, which is related to the down-regulation of LXRα mediated by GR/HDAC3/H3K9ac signaling.
... Además no hay datos que respalden el uso de corticosteroides antes de la viabilidad, y actualmente no se recomienda la administración de corticosteroides en este contexto. Por otro lado, la administración semanal de corticosteroides se ha asociado con una reducción en el peso al nacer y la circunferencia de la cabeza y no se recomienda (45,46) . ...
The obstetrician and gynecologist must frequently face complicated situations in the practice of obstetrics, one of them is the rupture of the membranes in a preterm pregnancy. While the medical conduct is to preserve both maternal and fetal health, many times the decision may affect fetal health in order to preserve the maternal health. This occurs when the presence of an infection makes it impossible to maintain the normal course of pregnancy and complete gestational age. In many cases the complications that cause prematurity of the newborn will put mother’s life at risk and we must therefore be prepared to minimize the consequences of our decision. In this article we review evidence-based management that the obstetriciangynecologist should consider when this situation occurs.
... Inactive ingredients include: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch [4]. Dexamethasone people believed that it played a role in causing malignances, it may given at risk at delivering of premature in order to cause maturation of fetus lungs [5,6]. No detectable amounts of unchanged drug were present in the urine of patients on chronic 12 to 20 mg daily doses. ...
... Inactive ingredients include: lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch [4]. Dexamethasone people believed that it played a role in causing malignances, it may given at risk at delivering of premature in order to cause maturation of fetus lungs [5,6]. No detectable amounts of unchanged drug were present in the urine of patients on chronic 12 to 20 mg daily doses. ...
... Among these, EDCs that modulate glucocorticoid receptor (GR) signaling remain understudied, and little is known about the long-term consequences of early-life exposure to GRmodulating EDCs despite the critical role that maternal and fetal glucocorticoids play in the development of key metabolic tissues, including pancreatic β-cells [9], adipose tissue [10], and liver [11]. In humans, prenatal treatment with pharmacological glucocorticoids administered to accelerate lung maturation has been shown to decrease birth weight [12] and may lower insulin sensitivity during adulthood, potentially with more pronounced effects in women [13]. Multiple animal studies have shown that dexamethasone (DEX) treatment during the last week of gestation promotes later-life metabolic defects, including insulin resistance and the upregulation of the hepatic gluconeogenic machinery [14][15][16]. ...
Endocrine-disrupting chemicals (EDCs) are implicated in the developmental mis-programming of energy metabolism. This study examined the impact of combined gestational and lactational exposure to the fungicide tolylfluanid (TF) on metabolic physiology in adult offspring. C57BL/6 J dams received standard rodent chow or the same diet containing 67 mg/kg TF. Offspring growth and metabolism were assessed up to 22 weeks of age. TF-exposed offspring exhibited reduced weaning weight. Body weight among female offspring remained low throughout the study, while male offspring matched controls by 17 weeks of age. Female offspring exhibited reduced glucose tolerance, markedly enhanced systemic insulin sensitivity, reduced adiposity, and normal gluconeogenic capacity during adulthood. In contrast, male offspring exhibited impaired glucose tolerance with unchanged insulin sensitivity, no differences in adiposity, and increased gluconeogenic capacity. These data indicate that developmental exposure to TF induces sex-specific metabolic disruptions that recapitulate key aspects of other in utero growth restriction models.
... Stress und seine Auswirkungen auf die Geburtsparameter konnte, neben einer gezielten Stressinduktion der Versuchstiere, teilweise durch exogene Zufuhr synthetischer Glucocorticoide respektive Corticoliberine (ACTH) nachgeahmt (Jobe et al., 2003;Sloboda et al., 2000) und durch maternale Adrenalektomie (chirurgische Entfernung der Nebenniere, Ort der endogenen Steroidsynthese) in seiner Wirkung abgeschwächt werden (Weinstock, 2005). Die pränatale Verabreichung synthetischer Glucocorticoide, wie sie zur exogenen Lungenreife bei drohender Frühgeburt eingesetzt werden, konnte in Humanstudien, unter Berücksichtigung der Gestationsdauer, ebenfalls mit verringerten Gewichten bei Geburt in Zusammenhang gebracht werden (Bloom et al., 2001;French et al., 1999) Sun et al., 1997), so dass lediglich circa 10 -20 % des im mütterlichen Kreislauf zirkulierenden Cortisols den fetalen Kreislauf erreichen (Benediktsson et al., 1997). Parallel zum progressiven maternalen Cortisolanstieg im Verlauf der Schwangerschaft steigt die 11ß-HSD-Konzentration in der Plazenta an (McTernan et al., 2001) und schützt den Feten vor den bis zu 3-fach höheren mütterlichen Cortisolkonzentrationen (Edwards et al., 1993). ...
Epidemiologische, klinische und experimentelle Daten legen nahe, dass der Ursprung somatischer und psychiatrischer Erkrankungen teilweise im Mutterleib zu finden ist. Ungünstige intrauterine Ein-flüsse, wie Stressbelastung, Mangelernährung und Exposition gegenüber Noxen stellen pränatale Stressfaktoren für das ungeborene Kind dar. Nach Hypothese der fetalen Programmierung können diese langandauernde Effekte auf Organogenese, Geburtsausgang und Stoffwechsellage haben und konsekutiv die physische sowie seelische Gesundheit nachhaltig und anhaltend beeinflussen. Die vorliegende Arbeit untersuchte, innerhalb der prospektiven Längsschnitt-Studie POSEIDON (Pre-, Peri- and POstnatal Stress: Epigenetic Impact on DepressiON), die Auswirkungen maternaler psycho-sozialer Stressbelastung während der Spätschwangerschaft auf den Ausgang der Geburt. Die psy-chosoziale Stressbelastung des untersuchten Studienkollektivs von N = 405 Probandinnen im letzten Trimenon der Schwangerschaft (36,77 ± 1,89 SSW p.m.) wurde über sechs schwangerschaftsspezifi-sche Stressvariablen erhoben und lieferten die Grundlage zur Stressgruppeneinteilung. Der Einfluss pränataler psychosozialer Stressbelastung auf die kindliche Entwicklung im Mutterleib wurde anhand der Geburtsparameter: Gestationsalter, Gewicht, Größe und Kopfumfang als Marker einer ungünsti-gen intrauterinen Umgebung der N = 405 Nachkommen untersucht. Zur Analyse der neuroendokrinen Stressachse respektive Aktivität der Hypothalamus-Hypophysen-Nebennierenrinden-Achsen (HHNA), als vermeidlich vermittelnde Instanz pränataler psychosozialer Stressoren, wurde die Stresshormon-konzentration (Cortisol) aus Speichelproben der Mütter und aus in utero angelegten Fingernagel-Abschnitten der Neugeborenen bestimmt. Eine hohe psychosoziale Stressbelastung in der Spätschwangerschaft konnte in der vorliegenden Arbeit mit einer Dysregulation des maternalen Cortisoltagesprofils und einem negativen Geburtsaus-gang assoziiert werden. In diesem Zusammenhang ging ein hohes Maß an milde einzustufenden psy-chosozialen Stressoren mit einer signifikanten Reduktion des Geburtsgewichtes um 217 g (-6,7 %, p = .003), der Größe um 1,2 cm (-2,3 %; p = .003) und des Kopfumfangs um 0,8 cm (-2,3 %; p < .001), auch nach Kontrolle für Störfaktoren, einher. Eine hohe psychosoziale Stressbelastung konnte zudem mit einer Abflachung des Cortisoltagesprofils im Sinne eines verminderten Abfalls der Cortisolkonzentration über den Tag (↓ Cortisol decline, p = .023) assoziiert werden, welche wiederum in Zusammenhang mit signifikant verkürzten Gestationszeiten (p = .003) stand. Darüber hinaus wurden in der vorliegenden Arbeit die Interaktion beider Steroidkonzentrationen untereinander, deren Auswirkungen auf den Geburtsausgang und der Einfluss psychosozialer Stressbelastung auf die Höhe der kindlichen Stresshormonkonzentrationen untersucht. Insgesamt unterstützen die Studienergebnisse zusammen mit Evidenzen aktueller wissenschaftlicher Literatur einen ungünstigen Einfluss pränataler psychosozialer Stressoren auf das ungeborene Kind. Ein wichtiger zugrundeliegender Pathomechanismus der pränatalen Stressübertragung scheint, zu-mindest teilweise, durch eine stressinduzierte Dysregulation der maternalen HHNA-Aktivität mit kon-sekutiver fetaler Glucocorticoid-Überexposition vermittelt zu sein. Diese können den Feten im Mutter-leib für kürzere Gestationszeiten, geringere Geburtsgewichte und deren assoziierte Erkrankungen prädispositionieren. Langanhaltende Konsequenzen der pränatalen psychosozialen Stressbelastung für die kindliche Ent-wicklung und die somatische sowie seelische Gesundheit der POSEIDON-Kinder sollen im Rahmen von Follow-up-Studien untersucht werden. Die frühzeitige Identifizierung von Nachkommen mit be-sonders hohem Risiko für pränatal programmierte Erkrankungen durch psychosoziale Stressfaktoren könnte neue Dimensionen präventiver Ansätze liefern.
... Furthermore, results from animal and human studies have shown that these side-effects could be dose-related. Indeed, studies in sheep [27], rabbits [28], mice [29] and rhesus monkeys [30] have demonstrated that repeated ACS courses were associated with alterations in fetal growth, findings confirmed in several large retrospective human studies [31][32][33][34] and in randomised trials comparing single and multiple courses [35][36][37][38][39]. Similarly, a trend toward increased rates of cerebral palsy has been reported at 2 years of age in children born after 34 weeks of gestation who received four or more full courses of betamethasone [40], but not half courses [41]. In a subgroup of children finally born at term, repeated antenatal betamethasone was associated with increased rates of neurosensory disabilities at 5 years [42]. ...
Background
Although antenatal betamethasone is recommended worldwide for women at risk of preterm delivery, concerns persist regarding the long-term effects associated with this treatment. Indeed, adverse events, mainly dose-related, have been reported. The current recommended dose of antenatal betamethasone directly derives from sheep experiments performed in the late 60’s and has not been challenged in 45 years. Therefore, randomized trials evaluating novel dose regimens are urgently needed.
Methods
A randomised, double blind, placebo-controlled, non-inferiority trial will be performed in 37 French level 3 maternity units. Women with a singleton pregnancy at risk of preterm delivery before 32 weeks of gestation having already received a first 11.4 mg injection of betamethasone will be randomised to receive either a second injection of 11.4 mg betamethasone (full dose arm) or placebo (half dose arm) administered intramuscularly 24 h after the first injection. The primary binary outcome will be the occurrence of severe respiratory distress syndrome (RDS), defined as the need for exogenous intra-tracheal surfactant in the first 48 h of life. Considering that 20% of the pregnant women receiving the full dose regimen would have a neonate with severe RDS, 1571 patients in each treatment group are required to show that the half dose regimen is not inferior to the full dose, that is the difference in severe RDS rate do not exceed 4% (corresponding to a Relative Risk of 20%), with a 1-sided 2.5% type-1 error and a 80% power. Interim analyses will be done after every 300 neonates who reach the primary outcome on the basis of intention-to-treat, using a group-sequential non-inferiority design.
Discussion
If the 50% reduced antenatal betamethasone dose is shown to be non-inferior to the full dose to prevent severe RDS associated with preterm birth, then it should be used consistently in women at risk of preterm delivery and would be of great importance to their children.
Trial registration
ClinicalTrials.gov identifier: NCT 02897076 (registration date 09/13/2016).
Electronic supplementary material
The online version of this article (10.1186/s12884-019-2206-x) contains supplementary material, which is available to authorized users.
To improve care for extremely premature infants, the development of an extrauterine environment for newborn development is being researched, known as Artificial Placenta and Artificial Womb (APAW) technology. APAW facilitates extended development in a liquid-filled incubator with oxygen and nutrient supply through an oxygenator connected to the umbilical vessels. This setup is intended to provide the optimal environment for further development, allowing further lung maturation by delaying gas exposure to oxygen. This innovative treatment necessitates interventions in obstetric procedures to transfer an infant from the native to an artificial womb, while preventing fetal-to-neonatal transition. In this narrative review we analyze relevant fetal physiology literature, provide an overview of insights from APAW studies, and identify considerations for the obstetric procedure from the native uterus to an APAW system. Lastly, this review provides suggestions to improve sterility, fetal and maternal well-being, and the prevention of neonatal transition.
Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.
Osteoporotic osteoarthritis is primarily associated with low subchondral bone mass. However, the mechanisms and therapeutic targets of osteoporotic osteoarthritis caused by prenatal dexamethasone exposure (PDE) in offspring remain unclear. In this study, pregnant Wistar rats were injected with dexamethasone to obtain bone tissue from fetal and postnatal rat offspring for analysis. Bone marrow mesenchymal stem cells (BMSCs) were isolated in vitro to elucidate the underlying molecular mechanisms. We determined in vivo that PDE reduced subchondral bone mass in adult female rat offspring, which originated from dysplasia of the subchondral bone. PDE led to a continuous increase in miR-6215 expression, accompanied by a decrease in FERM domain-containing protein 6 (FRMD6) expression. In vitro, dexamethasone upregulated miR-6215 expression through the glucocorticoid receptor, thereby inhibiting FRMD6 expression, promoting the translocation of yes-associated protein 1 (YAP1) into the nucleus of BMSCs, and downregulating downstream osteogenic marker genes. Finally, the rAAV-miR-6215 inhibitor rescued the low subchondral bone mass and osteoarthritis susceptibility caused by PDE in rat offspring. In conclusion, increased expression of miR-6215 mediates low subchondral bone mass caused by PDE through FRMD6/YAP1 signaling. Therefore, miR-6215 is a promising therapeutic target for PDE-induced low subchondral bone mass in offspring.
Cardiovascular disease (CVD) is a leading cause of death globally, with the prevalence projected to keep rising. Risk factors for adult CVD emerge at least as early as the prenatal period. Alterations in stress-responsive hormones in the prenatal period are hypothesized to contribute to CVD in adulthood, but little is known about relations between prenatal stress-responsive hormones and early precursors of CVD, such as cardiometabolic risk and health behaviors. The current review presents a theoretical model of the relation between prenatal stress-responsive hormones and adult CVD through cardiometabolic risk markers (e.g., rapid catch-up growth, high BMI/adiposity, high blood pressure, and altered blood glucose, lipids, and metabolic hormones) and health behaviors (e.g., substance use, poor sleep, poor diet and eating behaviors, and low physical activity levels). Emerging evidence in human and non-human animal literatures suggest that altered stress-responsive hormones during gestation predict higher cardiometabolic risk and poorer health behaviors in offspring. This review additionally highlights limitations of the current literature (e.g., lack of racial/ ethnic diversity, lack of examination of sex differences), and discusses future directions for this promising area of research.
Maternal exposure to dexamethasone can cause developmental toxicity of long bones in offspring. However, the effect of dexamethasone on the trans-differentiation of growth plate chondrocytes into osteoblasts and its role in bone dysplasia of fetuses caused by prenatal dexamethasone exposure (PDE) remains unclear. In this study, pregnant mice were treated with different doses, stages, and courses of dexamethasone according to clinical practice to reveal the phenomenon. Further, growth plate chondrocytes were treated with dexamethasone in vitro to clarify the phenomenon and mechanism. The results showed that PDE caused dysplasia of fetal long bones in female and male mice, accompanied by the delayed formation of the primary ossification center and the widening hypertrophic zone of growth plate cartilage. Meanwhile, PDE increased the number of hypertrophic chondrocytes at growth plate cartilage and decreased the number of osteoblasts at the primary ossification center. Moreover, PDE significantly decreased the expression of osteogenic transcription factor Runx2 but increased the expression of hypertrophic chondrocytes marker Col10. These above phenomena were more significant in the high dose, early stage, and double courses of dexamethasone exposure groups, and the male fetal mice showed more obvious than the female fetal mice. In vitro, dexamethasone significantly inhibited the trans-differentiation of growth plate chondrocytes into osteoblasts, accompanied by a decrease in Runx2 expression and an increase in Col10 expression. In conclusion, this study revealed the phenomenon and mechanism of fetal bone dysplasia caused by PDE from the new perspective of trans-differentiation disorder of growth plate chondrocytes to osteoblasts.
Mounting evidence indicates that adverse intrauterine conditions increase offspring’s hypercholesterolemia susceptibility in adulthood. This study aimed to confirm prenatal dexamethasone exposure (PDE)-induced hypercholesterolemia susceptibility in female adult offspring rats, and elucidate its intrauterine programming mechanism. Pregnant Wistar rats were injected with dexamethasone subcutaneously (0, 0.1 and 0.2 mg/kg·d) from gestational day (GD) 9 to 20. Serum and liver of the female offspring were collected at GD21 and postnatal week (PW) 12 and 28. PDE offspring showed elevated serum total cholesterol (TCH) levels and a cholesterol phenotype of high cardiovascular disease risk at PW12 and PW28. The histone acetylation levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) and its expression were consistently increased in the PDE offspring both in utero and after birth. Moreover, PDE promoted glucocorticoid receptor (GR) nuclear translocation and miR-133a-3p expression and inhibited sirtuin-1 (Sirt1) expression in the fetal liver. In vitro, dexamethasone increased intracellular and supernatant TCH levels and miR-133a-3p expression, decreased SIRT1 expression, and promoted HMGCR histone acetylation and expression in bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and HepG2 cell line. GR siRNA, miR-133a-3p inhibitor or SIRT1 overexpression reversed dexamethasone-induced downstream molecular and phenotypic changes. Furthermore, elevated TCH levels in umbilical cord blood and increased HMGCR expression in peripheral blood mononuclear cells (PBMCs) were observed in human female neonates who had received dexamethasone treatment during pregnancy. In conclusion, PDE can cause persistent enhancement of hepatic cholesterol synthesis function before and after birth through GR/miR-133a-3p/Sirt1 pathway, eventually leading to increased hypercholesterolemia susceptibility in female offspring rats.
The most typical condition of the liver in pregnancy is intrahepatic cholestasis of pregnancy (ICP). There is the occurrence of itching/pruritus together with a decline in liver function tests (LFTs) and frequently higher blood levels of total bile acids, which are used to make the diagnosis. ICP often shows symptoms during the third term of pregnancy and sometimes in the second term. After delivery, the disease's symptoms disappear on their own. It is still unclear what causes this disorder. It constitutes a hazard for the infant and is exceedingly stressful for the mother. Although relatively harmless for the expectant mother, ICP poses a significant risk to the unborn child. Preterm birth, meconium excreted in the amniotic fluid, respiratory distress syndrome, foetal distress and abrupt intrauterine foetal death are all risks seen in this disorder. It is still challenging to identify foetuses who are at risk for ICP issues. There needs to be a clear consensus on the best obstetrical care for ICPs. This review is done to brief the research on the foetal consequences of ICP and to discuss treatment strategies for its avoidance. Serum alanine transaminase, aspartate transaminase, total bilirubin, alkaline phosphatase, albumin, direct bilirubin, total protein, and total bile acids were among the biochemical predictors. Blood tests that confirm obstetric cholestasis should alter the course of treatment. Ursodeoxycholic acid may be prescribed to affected individuals to cure itching and prevent the build-up of biliary components of maternal origin in the baby, which may increase the danger of foetal discomfort and stillbirth.
Mitochondria play a key role in placental growth and development, and mitochondrial dysfunction is associated with inflammatory pregnancy pathologies. However, the mechanisms whereby placental mitochondria sense inflammatory signals are unknown. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) is a bi-organellar protein responsible for optimal mitochondrial function, including optimal induction of cellular stress-responsive signaling pathways. Here, in a lipopolysaccharide-induced model of systemic placental inflammation, we show that MNRR1 levels are reduced both in mouse placental tissues in vivo and in human trophoblastic cell lines in vitro. MNRR1 reduction is associated with mitochondrial dysfunction, enhanced oxidative stress, and activation of pro-inflammatory signaling. Mechanistically, we uncover a non- conventional pathway independent of Toll-like receptor 4 that results in ATM kinase-dependent threonine phosphorylation that stabilizes mitochondrial protease YME1L1, which targets MNRR1. Enhancing MNRR1 levels abrogates the bioenergetic defect and induces an anti-inflammatory phenotype. We therefore propose MNRR1 as an anti-inflammatory therapeutic in placental inflammation.
Beyond all physiological states, pregnancy is the one that leads to most dramatic changes in the human body. Changes in the female body initiate with the beginning moment of pregnancy. Various factors as the hormonal effects, fetal growth in the uterus, and physical adaptation of the mother’s body are the causes of these changes.KeywordsGlucocorticoidsInflammationOtolaryngologyPregnancyPostpartum period
Objective
The aim of this study is to compare the respiratory neonatal outcomes utilizing antenatal dexamethasone sodium phosphate (DSP) versus a mixture of betamethasone dipropionate and betamethasone sodium phosphate (B-DP/SP) for preterm births.
Patients and Methods
All neonatal intensive care unit (NICU) admissions for prematurity were retrospectively identified at our center in the period between September 2016 and September 2018. Pregnant women expected to give preterm birth and received steroid injections whether it is DSP or B-DP/SP were included in the study. Maternal and obstetrical data along with the corresponding respiratory neonatal outcomes were extracted and analyzed. The population was categorized according to the gestational age into extremely preterm (less than 28 weeks), very preterm (28 up to 32 weeks) and moderate or late preterm (32 up to 37 weeks) in which the repository outcomes were compared in each sub-group.
Results
A total of 650 premature neonates were included in the analysis. B-DP/SP illustrated a significant reduction in the occurrence of respiratory distress syndrome (RDS) among moderate or late preterm neonates (P = 0.003) compared to DSP. In contrast, a non-significant difference was observed between B-DP/SP and DSP regarding apnea of prematurity and transient tachypnea of the newborn. The number of neonates developed chronic lung disease has been remarkably reduced when using DSP in extremely (P = 0.038) and very (P = 0.046) preterm neonates when compared to B-DP/SP.
Conclusion
The dual acting B-DP/SP formulation could possess a significant potential in reducing RDS in moderate or late preterm neonates, while DSP groups exhibit a favorable result in the development of chronic lung disease in extreme and very preterm cohorts. Such findings emphasize the need of further clinical trials, pharmacokinetics, pharmacodynamics and cost effectiveness studies to evaluate the durability of these findings.
Background
The use of prenatal dexamethasone remains controversial. Our recent studies found that prenatal dexamethasone exposure can induce maternal intrahepatic cholestasis and have a lasting adverse influence on bile acid (BA) metabolism in the offspring. The purpose of this study was to investigate the effects of dexamethasone on fetal-placental-maternal BA circulation during the intrauterine period, as well as its placental mechanism.
Methods
Clinical data and human placentas were collected and analyzed. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.2 mg/kg per day) from gestational day 9 to 20. The metabolomic spectra of BAs in maternal and fetal rat serum were determined by LC-MS. Human and rat placentas were collected for histological and gene expression analysis. BeWo human placental cell line was treated with dexamethasone (20–500 nM).
Results
Human male neonates born after prenatal dexamethasone treatment showed an increased serum BA level while no significant change was observed in females. Moreover, the expression of organic anion transporter polypeptide-related protein 2B1 (OATP2B1) and breast cancer resistance protein (BCRP) in the male neonates’ placenta was decreased, while multidrug resistance-associated protein 4 (MRP4) was upregulated. In experimental rats, dexamethasone increased male but decreased female fetal serum total bile acid (TBA) level. LC-MS revealed that primary BAs were the major component that increased in both male and female fetal serum, and all kinds of BAs were significantly increased in maternal serum. The expression of Oatp2b1 and Bcrp were reduced, while Mrp4 expression was increased in the dexamethasone-treated rat placentas. Moreover, dexamethasone increased glucocorticoid receptor (GR) expression and decreased farnesoid X receptor (FXR) expression in the rat placenta. In BeWo cells, dexamethasone induced GR translocation into the nucleus; decreased FXR, OATP2B1, and BCRP expression; and increased MRP4 expression. Furthermore, GR was verified to mediate the downregulation of OATP2B1, while FXR mediated dexamethasone-altered expression of BCRP and MRP4.
Conclusions
By affecting placental BA transporters, dexamethasone induces an imbalanced fetal-placental-maternal BA circulation, as showed by the increase of primary BA levels in the fetal serum. This study provides an important experimental and theoretical basis for elucidating the mechanism of dexamethasone-induced alteration of maternal and fetal BA metabolism and for exploring early prevention and treatment strategies.
Antenatal corticosteroid therapy (ACT) has been shown to reduce morbidity and mortality rates in preterm delivery, but the fetus is more likely to face the risk of low bone mineralization and low fetal linear growth. However, the mechanism of ACT inducing low bone mineralization remains largely unknown. Pre-osteoclasts, which play an important role in angiogenesis and osteogenesis, are specifically regulating type H vessels (CD31hiEmcnhi) and vessel formation by secreting platelet-derived growth factor-BB (PDGF-BB). We find that the number of pre-osteoclasts and POC-secreted PDGF-BB is dramatically decreased in ACT mice, contributing to the reduction in type H vessels and bone mineralization during the mouse offspring. Quantitative analyses of micro-computed tomography show that the ACT mice have a significant reduction in the mass of trabecular bone relative to the control group. Mononuclear pre-osteoclasts in trabecular bone decreased in ACT mice, which leads to the amount of PDGF-BB reduced and attenuates type H vessel formation. After sorting the Rank+ osteoclast precursors using flow cytometry, we show that the enhancer of zeste homolog 2 (Ezh2) expression is decreased in Rank+ osteoclast precursors in ACT mice. Consistent with the flow data, by using small molecule Ezh2 inhibitor GSK126, we prove that Ezh2 is required for osteoclast differentiation. Downregulating the expression of Ezh2 in osteoclast precursors would reduce PDGF-BB production. Conditioned medium from osteoclast precursor cultures treated with GSK126 inhibited endothelial tube formation, whereas conditioned medium from vehicle group stimulated endothelial tube formation. These results indicate Ezh2 expression of osteoclast precursors is suppressed after ACT, which reduced the pre-osteoclast number and PDGF-BB secretion, thus inhibiting type H vessel formation and ACT-associated low bone mineralization.
Hintergrund und Ziele: Das kindliche Geburtsgewicht stellt nicht nur einen Parameter dar, der für die Geburt und Schwangerschaftsbetreuung von Bedeutung ist, sondern steht auch mit der zukünftigen gesundheitlichen Entwicklung des Kindes in Zusammenhang. In diesem Kontext befassten sich zahlreiche Studien mit dem Einfluss des Glukokortikoidstoffwechsels auf die fetale Entwicklung. Die vorliegende Arbeit untersucht neun Einzelnukleotid-Polymorphismen (englisch: single nucleotide polymorphism, kurz SNP) in Genen, die im Kortisolstoffwechsel entscheidende Rollen spielen. Ein möglicher Einfluss dieser Genvarianten bei Schwangeren auf das kindliche Geburtsgewicht steht dabei im Fokus. Die betrachteten SNPs betreffen das Gen für den Glukokortikoidrezeptor NR3C1 (Nuclear receptor subfamily 3, group C, member 1) (rs41423247, rs6195, rs10482605), das Gen für FKBP5, ein Chaperonmolekül des Glukokortikoidrezeptors (rs1360780, rs9296158, rs3800373, rs9470080) und den Kortikotropin-Releasing-Hormon- Rezeptor 1 (CHRH1) (rs110402 und rs7209436). Ergebnisse dieser Arbeit wurden zur Veröffentlichung in „Archives of Gynecology and Obstetrics“ eingereicht. Methoden: In die FRAMES-Studie (Franconian Maternal Health Evaluation Study) wurden insgesamt 1100 volljährige schwangere Frauen eingeschlossen. Im Studienverlauf erfolgte eine ausführliche Anamneseerhebung sowie die Erfassung der Edinburgh Postnatal Depression Scale (EPDS) zu verschiedenen Zeitpunkten. Von insgesamt 375 Frauen lagen neben den vollständigen Patientendaten, Informationen zur Geburt und EPDS-Bögen auch die Genotypisierung der untersuchten SNPs vor. Anschließend folgte mittels Expectation-Maximization-Algorithmus eine Haplotypenrekonstruktion. Mithilfe eines linearen Modells wurden die Haplotypen hinsichtlich eines Einflusses auf das kindliche Geburtsgewicht getestet. Verwendet wurde dabei die Statistik Software R, Version 3.2.2, (r-project.org). Ergebnisse und Beobachtungen: Unter Berücksichtigung der Einflussfaktoren kindliches Geschlecht, Schwangerschaftsalter bei Entbindung, mütterlicher Body-Mass-Index (BMI) vor der Schwangerschaft, Alter der Mutter, Parität sowie Rauchen während der Schwangerschaft zeigte sich kein statistisch signifikanter Zusammenhang der getesteten SNPs auf das kindliche Gewicht bei Entbindung. Schlussfolgerungen: Die Studienlage zum Zusammenhang von SNPs in Kortisolgenen und Geburtsgewicht ist bislang begrenzt. Ihre Ergebnisse decken sich jedoch mit den Ergebnissen dieser Arbeit und zeigen bis auf wenige Ausnahmen keinen signifikanten Einfluss von SNPs in diesen Genen auf das Geburtsgewicht. Weitere Studien und größere Fallzahlen vor allem für seltene Haplotypen sind wünschenswert, um die multifaktoriellen Einflüsse auf die fetale Entwicklung und die daraus folgende Prägung für das spätere Leben besser zu verstehen.
Infant birth weight influences numerous health outcomes throughout the life course including childhood obesity and metabolic morbidities. Maternal experience of stress, both before and during pregnancy, has been hypothesized to influence fetal growth and birth outcomes. However, these associations currently are not fully understood, due to conflicting results in the published literature. Salivary cortisol is often used as a biological biomarker to assess the diurnal pattern of the hypothalamic-pituitary-adrenal axis (HPA-axis) functioning. Cortisol metrics include both the total cortisol concentration secreted during waking hours, reflected by the area under the curve (AUC), and cortisol dynamics, which include the diurnal cortisol slope (DCS) and the cortisol awakening response (CAR). This study examined the association of these cortisol metrics measured during the third trimester of pregnancy and infant birth weight among 240 mother-infant dyads participating in the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) pregnancy cohort study, which is predominately comprised of Hispanic low-income women. There were no significant associations with the maternal biological stress response and infant birth weight in this study. More research is needed in larger studies to better understand how the biological stress response influences birth weight in populations facing health disparities.
This study was conducted to investigate the effect of zinc in dose 15mg/kg.bw daily taken by the mouth and dexamethasone 4mgIkg.Bw by injection for 30days on some hematological biochemical tests and some histological changes of liver spleen in male rabbits. Thirty rabbits were used that divided into 3 randomized groups (each group contain 10 male rabbits ). Control group was taken normal food and water, Zinc group that gave zinc at dose of 15mg/kg.BW/daily/oral on 1, 2, 3, 4 weeks. Dexamethasone with zinc group : Employ dexamethasone 4mg/Kg.Bw . I.M dialy for 1 and 2 weeks for experiment and at 3, 4th weeks they gave zn 15mg/lKg.Bw day/orally. Blood samples were taken from the heart directly in 2 and 4weeks to examine packed cell volume (pcv), white blood cells (WBCs), Red blood cells (RBCs) with differential Leuckcyte count.separation blood collection to plasma and examine glucose mg/dl , cholesterol mg/dl. In histological tests, rabbits were killed and separate their organs tissue from the body to examine liver and spleen. The results revealed a decrease in level of RBCs, pcv after treatment with zinc 15, mg/Kg.Bw orally (zinc group) and increase in WBCs with differential leuckocyte count specially neutrophil cell, while biochemical tests show increase in glucose and cholesterol levels after treatment with dexamethasone 4mglkgBw. I/M seen increase in counts of RBCs , PCV, WBCs and differential lenkocyte count and decrease in glucose with cholesterol parameters, histological changes show change in liver after treatment by dexamethasone 4mglKg.Bw ,spleen tissue seen necrosis and pigmentation with hemorrhage after take dexamethasone 4mglkg in (dexamethasone + zinc group). Results also showed that zinc enhanced the immune system in at normal dose for limited time because of its effect on other mineral such as copper and causes anemia , while the dexamethasone is a drug used for antianflammatory but for a short time.
Objective: To introduce the effect of a single course of betamethasone for pregnant women at risk of preterm delivery (PTD).
Materials and methods: In this study, a single course of 12 mg Bethamethasone was administered twice in 24 h (between 24–34 gestational weeks) for antenatal corticosteroid prophylaxis. Four hundred ninety-three neonates fulfilled the inclusion criteria and they were categorized (259 singletons, 192 twins and 42 triplets who met the inclusion criteria) into two groups according to the utilization of antenatal corticosteroid as control (n = 202) and study (n = 291) groups. We used respiratory distress syndrome (RDS), congenital pneumonia, intraventricular hemorrhage (IVH), neonatal sepsis, and bronchopulmonary dysplasia (BPD) as primary outcomes for the evaluation of neonatal morbidity.
Results: Study and control groups were similar in terms of clinical characteristics. RDS, congenital pneumonia, neonatal sepsis, and BPD rates were significantly higher in the study group (betamethasone) (p = .05, p = .007, 0.003, and 0.004, respectively) between 24–34 gestational weeks (when the neonates of multiple pregnancies were excluded from the analysis, we have demonstrated that congenital pneumonia (p = .033) and neonatal sepsis (p = .030) were still significantly higher in the betamethasone group). The neonates of 24–28 gestational weeks were compared separately and we demonstrated that RDS (p = .012), congenital pneumonia (p = .022), IVH (p = .044), neonatal sepsis (p = .023), and BPD (0.001) were also more frequent in the study group. When the 28–32 gestational week data were compared, IVH (p = .020) and neonatal sepsis (p = .017) were more frequent in the single course betamethasone users. However, we could not demonstrate a significant difference between the control and study groups between 32–34 gestational weeks in terms of the primary neonatal outcomes used in this study.
Conclusion: Single course antenatal betamethasone administration may be ineffective on the respiratory complications of preterm and very preterm infants while it may be unfavorable for extremely preterm infants.
What is new about the paper, what could add to the current knowledge: Pregnant women at risk for preterm labor must be under intensive antenatal care programs, and if possible, necessary precautions must be undertaken to prevent fetal hypoxia together with etiology specific treatments. This approach might contribute to better perinatal outcomes than just administering antenatal corticosteroid therapy.
Prenatal dexamethasone exposure (PDE) induces developmental toxicities of multi-organs and susceptibility to multi-diseases in offspring. However, the effects of PDE on osteoarthritis susceptibility in adult offspring and its mechanism have not been reported. In the present study, we treated pregnant Wistar rats with dexamethasone (0.2 mg/kg) daily on gestational days (GD) 9-20. Some pregnant rats were sacrificed on GD20, and the rest were delivered to obtain the postnatal offspring. The adult female offspring rats were performed with ovariectomy or sham operation during postnatal weeks 22-28. We found that PDE led to osteoarthritis phenotypes in articular cartilage and an increase in modified Mankin's score, but reduced the cartilage thickness in female adult offspring rats, which were more evident after ovariectomy. Moreover, PDE reduced the bone mass of subchondral bone in female adult offspring, which was aggravated by ovariectomy. The correlation analysis results indicated that the osteoarthritic phenotype and cartilage thickness were closely associated with the decreased bone mass of subchondral bone induced by PDE. Further, PDE retarded the development of primary and secondary ossification centers, then led to subchondral bone dysplasia, which could be partly mediated by the inhibited osteogenic function before and after birth. Collectively, the subchondral bone dysplasia partly participated in osteoarthritis susceptibility induced by PDE in female offspring rats.
Pregnancy after liver transplantation (LT) is increasingly common and is a frequent scenario that transplant physicians, obstetricians and midwives encounter. This review summarizes the key issues surrounding pre‐conception, pregnancy‐related outcomes, immunosuppression and breastfeeding in female LT recipients. Pre‐pregnancy counselling in these patients should include recommendations to delay conception for at least one to two years after LT, and discussions about effective methods of contraception. Female LT recipients are generally recommended to continue immunosuppression during pregnancy to prevent allograft rejection, however, individual regimens may need to be altered. Although pregnancy outcomes are overall favourable, there is an increased risk of maternal and fetal complications. Pregnancy in this cohort remains ‘high risk’ and should be managed vigilantly in a multi‐disciplinary setting. We aim to review the available evidence from national registries, population‐based studies and case series and provide recommendations for attending clinicians.
Biochemical changes in utero may alter normal fetal development, resulting in disease later in life, a phenomenon known as fetal programming. Recent epidemiological studies link fetal programming to negative health outcomes, such as low birth weight and hypertension in adulthood. Here, we used a WKY rat model and studied the molecular changes triggered by prenatal glucocorticoid (GC) exposure on the development of hypertension, and on the regulation of phenylethanolamine N-methyl transferase (PNMT), the enzyme responsible for biosynthesis of epinephrine, and a candidate gene linked to hypertension. Clinically, high doses of the synthetic GC dexamethasone (DEX) are used to treat infant respiratory distress syndrome. Elevated maternal GCs have been correlated with fetal programming of hypertension. The aim of this study was to determine if lower doses of DEX would not lead to detrimental fetal programming effects such as hypertension. Our data suggests that prenatal stress programs for increased expression of PNMT and altered regulation of PNMT in males and females. Importantly, we identified that DEX mediated programming was more apparent in the male rats, and the lower dose 10μg/kg/day of DEX did not lead to changes in blood pressure (BP) in female rats suggesting that this dose is below the threshold for programming of hypertension. Furthermore, sex-specific differences were observed in regards to programming mechanisms that may account for hypertension in males.
The environment in which a fetus develops is not only important for its growth and maturation but also for its long-term postnatal health and neurodevelopment. Several hormones including glucocorticosteroids, estrogens and progesterone, insulin growth factor and thyroid hormones, carefully regulate the growth of the fetus and its metabolism during pregnancy by controlling the supply of nutrients crossing the placenta. In addition to fetal synthesis, hormones regulating fetal growth are also expressed and regulated in the placenta, and they play a key role in the vulnerability of the developing brain and its maturation. This review summarizes the current understanding and evidence regarding the involvement of hormonal dysregulation associated with intra-uterine growth restriction and its consequences on brain development.
Objectives: We sought to examine outcome for premature neonates after multiple courses of antenatal corticosteroids compared with a single course. Study Design: We performed a post hoc nonrandomized analysis on 710 neonates of 25-32 weeks’ gestation who were born to mothers enrolled in the North American Thyrotropin-Releasing Hormone Trial and who received 1, 2, or ≥3 courses of antenatal corticosteroids. Results: There was no detectable clinical difference in incidence of respiratory distress syndrome, chronic lung disease, and intraventricular hemorrhage related to courses of antenatal corticosteroids, and outcome was similar for infants delivered at 7-13 days compared with those delivered at 1-6 days after receiving antenatal corticosteroids. Compared with those who received a single course, neonates who received ≥2 courses had lower birth weights (–39 g, P = .02), and those receiving ≥3 courses had increased risk of death (adjusted odds ratio, 2.8; 95% confidence interval, 1.3-5.9; P = .01) and lower levels of plasma cortisol at age 2 hours. Conclusion: In this retrospective analysis multiple courses of antenatal corticosteroids did not improve outcome and were associated with increased mortality, decreased fetal growth, and prolonged adrenal suppression. (Am J Obstet Gynecol 1999;181:709-17.)
Dose-response effects of corticosteroids were investigated in the preterm rabbit. Pregnant rabbits were given two doses of 0.01, 0.03, or 0.1 mg of betamethasone per kilogram every 24 hours, beginning on day 25 of gestation. Saline solution was used in a comparison treatment group. Half of the newborn rabbits received supplemental surfactant therapy after delivery via cesarean section on day 27, and all were ventilated on a ventilator-plethysmograph system for 30 minutes. The 0.01 and 0.03 mg/kg regimens had no effect on birth weight or lung function. The 0.1 mg/kg regimen resulted in fetal growth retardation and improved ventilatory measurements, gas exchange, and decreased protein accumulation in the lung, without increasing surfactant pool size. The induction of lung maturation by corticosteroids has multiple targets in the developing lung and does not exhibit a linear dose response.
Potential side effects of antenatal administration of corticosteroids to prevent neonatal respiratory distress syndrome were studied in 10- to 12-year-old children whose mothers had participated in a randomized, double-blind, placebo-controlled trial of betamethasone. The children had a general physical examination; parents were interviewed about the medical history of their child with special attention to infectious diseases; growth data were collected; and a developmental neurological examination, an ophthalmological examination, and a lung function test were conducted. In the corticosteroid group significantly more hospital admissions because of infectious diseases during the first years of life were reported. On the other variables no differences between the corticoid and the placebo groups were found.
Immature rats were treated with a single dose of dexamethasone (1 mg/kg or 20 mg/kg body weight). At both dose levels the subsequent growth of whole body, brain, and thymus was markedly impaired. Cortisol had smaller but similar effects. These results are discussed in the context of possible glucocorticoid therapy in newborn infants.
In previous studies, we noted that treatment of pregnant rhesus monkeys with betamethasone resulted in a marked increase in fetal lung distensibility. The purpose of the present study was to determine whether these changes persisted during subsequent in utero development. Pregnant rhesus monkeys were treated with 2 mg of betamethasone intramuscularly from day 120 to day 133 and underwent delivery by cesarean section one month later. The treated fetuses were found to have smaller lungs (-31%; p less than 0.005), and lower alveolar stability (-14%; p less than 0.025) than the control fetuses. Additional findings included smaller weights for the brain (p less than 0.01), liver, pancreas, and heart (p less than 0.05). Smaller adrenal (p less than 0.025) and larger pituitary weights (p less than 0.05) and lower plasma corticoid concentrations (p less than 0.001) indicated long-standing adrenal insufficiency in the treated fetuses. These persistent sequelae caution the indiscriminate and prolonged use of these potent glucocorticoids during pregnancy.
In order to elucidate the effects of corticosteroids on fetal hearts during midtrimester, pregnant rats were injected with a daily dose of betamethasone (1 mg/kg) from the 12th day through the 17th day of pregnancy. The fetal cardiovascular and pulmonary systems were studied on the 21st day of pregnancy (term). The treated fetuses showed the following signs of hydrops fetalis: retarded growth, pale, edematous skin, and decreased movement. The thymus and lung displayed prominent hypoplasia. The morphometry of the treated fetuses revealed: decreased right ventricle mass by 37% and decreased left ventricle mass by 29%. We concluded betamethasone had a significant effect on the developing fetal cardiovascular system, inducing hydrops fetalis. Additionally, beta-methasone caused hypoplasia of the thymus and lung.
The objective of the series was to study the effect of prenatal dexamethasone therapy on the growth and neurological development of preterm children until the age of 2 years. Eighty-two children with a mean gestational age of 30 (24-33) weeks and a mean weight of 1291 (530-2360) g at birth, treated antenatally with either dexamethasone (n = 50) or placebo (n = 32), were examined at the adjusted age of 24 months by a paediatric neurologist, a neuropsychologist and a speech therapist. Neurological development was defined as normal if all scores of neuropaediatric, neuropsychological and verbal tests were within the normal range. Normal neurological development was found in 52% of the dexamethasone-treated and in 34% of the placebo-treated children. The incidence of cerebral palsy was 10% in the dexamethasone group and 22% in the placebo group. Minor developmental delay was found in 42% of dexamethasone-treated and in 53% of placebo-treated children. Our follow-up results indicate that the beneficial effect of prenatal glucocorticoid treatment on cerebral complications (intraventricular haemorrhage or periventricular leucomalacia) demonstrated during the neonatal period may be followed by a lower incidence of cerebral palsy in surviving premature children.
We evaluated the effects of multiple fetal exposures to glucocorticoids on postnatal lung function and growth. Ewes were randomized to receive 1 to 4 doses of 0.5 mg/kg betamethasone or saline placebo at 7 d intervals from 104 d to 118 d and at 124 d gestation. All lambs were delivered preterm at 125 d gestation, and postnatal lung function was evaluated. There were sequential improvements in compliance, ventilation efficiency, and lung volumes for two, three, and four doses of betamethasone. The maximal effect was a 150% increase in compliance and a 4-fold increase in lung volume after fetal exposure to four doses of betamethasone. However, birth weights decreased (15% after one dose, 19% after two doses, and 27% after three and four doses). There were no changes in lung to body weight ratios, lung dry to wet weight ratios, lung protein to body weight ratios, or lung hyaluronan content. Prenatal glucocorticoid exposure also altered postnatal cortisol, thyroid, and catecholamine plasma levels. Repetitive 7-d interval exposures of fetal lambs to glucocorticoids progressively enhanced postnatal lung function and resulted in growth and endocrine abnormalities.
Previous studies have demonstrated a correlation between first-trimester size and birth weight. It is not known, however, whether low birth weight is related to first-trimester growth. We sought to determine whether the risk of low birth weight and birth weight that was low for gestational age is related to the size of the embryo or the fetus in the first trimester.
From a data base of ultrasound records of more than 30,000 pregnancies, we identified women who had no important medical problems, a normal menstrual history, and a first-trimester ultrasound scan in which the crown-rump length of the embryo or fetus had been measured. We examined the relation between the outcome of 4229 pregnancies and the difference between the measured and the expected crown-rump length in the first trimester, expressed as equivalent days of growth.
A first-trimester crown-rump length that was two to six days smaller than expected was associated with an increased risk (as compared with a normal or slightly larger than expected crown-rump length) of a birth weight below 2500 g (relative risk, 1.8; 95 percent confidence interval, 1.3 to 2.4), a birth weight below 2500 g at term (relative risk, 2.3; 95 percent confidence interval, 1.4 to 3.8), a birth weight below the fifth percentile for gestational age (relative risk, 3.0; 95 percent confidence interval, 2.0 to 4.4), and delivery between 24 and 32 weeks of gestation (relative risk, 2.1; 95 percent confidence interval, 1.1 to 4.0), but not with delivery between 33 and 36 weeks (relative risk, 1.0; 95 percent confidence interval, 0.7 to 1.5).
Suboptimal first-trimester growth may be associated with low birth weight, low birth-weight percentile, and premature delivery.
The objective was to study the effects of repeated antenatal corticosteroids on birth size, growth, and development in preterm infants.
This observational study followed up for 3 years a prospective geographic cohort in the state of Western Australia of 477 singleton infants born at <33 weeks' gestation.
Birth weight ratio decreased with increasing number of corticosteroid courses (P =.001), and multivariate analyses confirmed a reduction in birth weight of as much as 9% (P =.014) and a reduction in head circumference of as much as 4% (P =.0024). There were no additional benefits in mortality or respiratory outcomes, and there was a trend toward more severe chronic lung disease. At age 3 years growth and severe disability outcomes did not appear to be related to increasing number of corticosteroid courses.
In this cohort study repeated corticosteroid courses were associated with adverse effects on size at birth without apparent benefits. These changes have the potential to affect later development.
At any given gestational age, infants with low birth weight have relatively high morbidity and mortality. It is not known, however, whether there is a threshold weight below which morbidity and mortality are significantly greater, or whether that threshold varies with gestational age.
We analyzed the neonatal outcomes of death, five-minute Apgar score, umbilical-artery blood pH, and morbidity due to prematurity for all singleton infants delivered at Parkland Hospital, Dallas, between January 1, 1988, and August 31, 1996. A distribution of birth weights according to week of gestation at birth was created. Infants in the 26th through 75th percentiles for weight served as the reference group. Data on preterm infants (those born at 24 to 36 weeks of gestation) were analyzed separately from data on infants delivered at term (37 or more weeks of gestation).
A total of 122,754 women and adolescents delivered singleton live infants without malformations between 24 and 43 weeks of gestation. Among the 12,317 preterm infants who were analyzed, there was no specific birth-weight percentile at which morbidity and mortality increased. Among 82,361 infants who were born at term and whose birth weights were at or below the 75th percentile, however, the rate of neonatal death increased from 0.03 percent in the reference group (26th through 75th percentile for weight) to 0.3 percent for those with birth weights at or below the 3rd percentile (P<0.001). The incidence of five-minute Apgar scores of 3 or less and umbilical-artery blood pH values of 7.0 or less was approximately doubled for infants at or below the 3rd birth-weight percentile (P=0.003 and P<0.001, respectively). The incidence of intubation at birth, seizures during the first day of life, and sepsis was also significantly increased among term infants with birth weights at or below the 3rd percentile. These differences persisted after adjustment for the mother's race and parity and the infant's sex.
Mortality and morbidity are increased among infants born at term whose birth weights are at or below the 3rd percentile for their gestational age.
Previous studies have shown that repeated doses of corticosteroids given to pregnant sheep improve postnatal lung function, but restrict fetal growth. Repeated administration of corticosteroids directly to the fetus also enhances postnatal lung function. The purpose of the present study was to investigate and characterize the relative effects on growth of repeated maternal and fetal treatments by study of body, organ, and placental weights.
Date-bred pregnant sheep were given intramuscular betamethasone or saline to either the mother or fetus on three occasions at weekly intervals commencing at 104 days gestation, followed by cesarean section at 125 days. Twenty-two animals which had received three doses of betamethasone were compared with 21 which had received a single dose at 104 days and with 12 saline-treated controls.
Repeated maternal doses of betamethasone resulted in reductions in birthweight and weights of the placenta and major organs. Direct fetal injection did not affect birthweight, placental weight, placental/ birthweight ratio, or weights of the major organs with the exception of the liver.
Administration of repeated doses of betamethasone directly to the sheep fetus does not produce the growth-restricting effects induced by maternal administration and does not affect the placental/birthweight ratio.
To compare the effects of single and repeated courses of corticosteroids on brain growth in fetal sheep.
Pregnant sheep were given intramuscular betamethasone (0.5 mg/kg) at 104 days' gestation followed at 111, 118, and 124 days by equivalent volumes of sterile normal saline (n = 12) or betamethasone (n = 12). Controls received equivalent volumes of sterile normal saline at all four intervals (n = 12). Lambs were delivered at 125 (preterm) or 145 (term) days. After perfusion, we measured weights (grams) for whole brain, cerebrum, cerebellum, and brain stem, volumes (milliliters) for whole brain and cerebrum, and maximum cerebral anterior-posterior length, width, and depth (centimeters).
In the single-injection group at preterm, there were no significant differences (P = .070) in whole-brain weight between the corticosteroid-treated animals (38.0 +/- 1.81 g) and controls (42.5 +/- 1.65 g). Cerebral length and depth were significantly reduced in the corticosteroid group (P < .05); other measures were not significantly different. At term, whole-brain weight was significantly lower (47.5 +/- 1.70 g; P = .022) compared with controls (53.4 +/- 1.73 g). All other measures were significantly reduced (P < .05) except cerebral and brain-stem weights and cerebral length. In the group that received repeated injections at preterm, whole-brain weight was significantly reduced (35.5 +/- 1.65 g; P = .005) compared with controls (42.5 +/- 1.65 g). All other measures were significantly reduced (P < .05) except cerebellar and brain-stem weights. At term, whole-brain weight was also significantly reduced (42.4 +/- 1.52 g; P = .001) compared with controls (53.4 +/- 1.73 g) as were all other measures (P < .05).
Administration of single and repeated courses of corticosteroids to pregnant sheep retarded fetal brain growth.