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Glucocorticoid exposure in utero: New model for adult hypertension
Abstract
Hypertension is strongly predicted by the combination of low birthweight and a large placenta. This association could be due to increased fetal exposure to maternal glucocorticoids. Fetal protection is normally effected by placental 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which converts physiological glucocorticoids to inactive products. We found that rat placental 11 beta-OHSD activity correlated positively with term fetal weight and negatively with placental weight. Offspring of rats treated during pregnancy with dexamethasone (which is not metabolised by 11 beta-OHSD) had lower birthweights and higher blood pressure when adult than did offspring of control rats. Increased fetal glucocorticoid exposure secondary to attenuated placental 11 beta-OHSD activity may link low birthweight and high placental weight with hypertension.
... The developmental origins of health and disease (DoHaD) hypothesis proposes that events in early life may influence long-term health [5], and one key proposed mechanism is exposure to excess corticosteroids during critical periods of development resulting in persisting changes in hypothalamic-pituitary-adrenal axis function [6,7]. In animal studies across a range of species, antenatal exposure to corticosteroids has resulted in altered cardiovascular function including elevated blood pressure (BP) and sympathetic nerve activity, changes in hepatic metabolism, glucose homeostasis, and insulin resistance [7][8][9][10][11][12][13][14]. Human observational data have variably reported either higher or unchanged BP, although most studies assessed outcomes in adolescence or early adulthood [15][16][17]. ...
... A recent systematic review of cardiovascular function after antenatal corticosteroid exposure, based predominantly on observational data, also concluded that there was no association between antenatal corticosteroid exposure and offspring BP but the evidence was too limited to draw firm conclusions about other aspects of cardiovascular function [17]. Concerns regarding premature cardiovascular disease after antenatal exposure to corticosteroids have followed the evidence of increased cardiovascular risk factors in animal models and human evidence for a potential role of the hypothalamic-pituitary-adrenal axis in cardiovascular disease pathophysiology [8][9][10][11]36]. Previous studies investigating the cardiovascular effects of antenatal corticosteroids, both follow-up of clinical trials and observational studies, have focused on secondary endpoints such as risk factors rather than adverse cardiovascular events which are clinically of greater importance [8,17,37,38]. ...
Background
Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids.
Methods and findings
We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments.
Conclusions
There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.
... One molecular mediator of ELS is prolonged elevated maternal glucocorticoids (GCs) during pregnancy and early life development 3 (Krontira et al. 2020), and thus in utero chronic activation of its cognate receptors, glucocorticoid receptors (GR). There is a wellestablished relationship between dysregulation of maternal GCs/GR signalling and increased GC exposure to the foetal system 4,5,6,7 (Benediktsson et al. 1993 . CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. ...
... One molecular mediator of ELS is prolonged elevated maternal glucocorticoids (GCs) during pregnancy and early life development 3 (Krontira et al. 2020), and thus in utero chronic activation of its cognate receptors, glucocorticoid receptors (GR). There is a wellestablished relationship between dysregulation of maternal GCs/GR signalling and increased GC exposure to the foetal system 4,5,6,7 (Benediktsson et al. 1993 . CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. ...
Early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in children. Increasingly, the importance of microglia in these disorders has been recognised. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre-expoure of human iPS-microglia to GCs during primitive haematopoiesis (the critical stage of iPS-microglial differentiation) and then examined how this exposure affected the microglial phenotype as they differentiated and matured to microglia. The iPS-microglia predominately expressed glucocorticoid receptors over mineralocorticoid receptors, and the GR-α splice variant. Chronic GCs exposure during primitive haematopoiesis was able to recapitulate in vivo ELS effects. Thus pre-exposure to prolonged GCs resulted in increased type I interferon signalling, the presence of Cyclic GMP-AMP synthase-positive (cGAS) micronuclei, and cellular senescence in the matured iPS-microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC-mediated ELS- associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autistic spectrum disorder.
Highlights
Human iPS-derived-microglia predominantly express glucocorticoid receptor NR3C1 compared with mineralocorticoid receptor NR3C2, and a predominant splice variant of the NR3C1 of GR-α.
GC expression shows a differentiation-linked increment from iPSC to iPS-microglia.
An early-life stress model was established by exposing iPSC to glucocorticoids during primitive haematopoiesis.
RNA-seq analysis revealed that this early glucocorticoid exposure led to enhanced type I interferon inducible gene expression in the subsequent iPS-microglia.
Furthermore, micronuclei formation and cellular senescence markers were upregulated in the iPSC-microglia, indicating genomic instability due to early chronic GC exposure.
These findings have ramifications for the microglial responses in ELS linked neurodevelopmental disorders such as schizophrenia, attention-deficit hyperactivity disorder and autistic spectrum disorder.
Graphical abstract
... We generated a rat model of LBW as previously described [22] and summarized in ( Figure 1A) to study early molecular alterations of the kidney. As shown in (Table 1), we compared rats in the two different body weight groups: NBW (n = 7) vs. LBW (n = 7). ...
... Eight pregnant rats were fed standard chow ad libitum. By intraperitoneally injecting dexamethasone (DEXA) (0.2 mg/kg) into pregnant rats (n = 5) consecutively at 15 and 16 days of gestation, LBW rats were born at high rates, as shown in previous reports [22]. For controls, we injected the same volume of saline (n = 3). ...
The hyperfiltration theory has been used to explain the mechanism of low birth weight (LBW)-related nephropathy. However, the molecular changes in the kidney proteome have not been defined in this disease, and early biomarkers are lacking. We investigated the molecular pathogenesis of LBW rats obtained by intraperitoneal injection of dexamethasone into pregnant animals. Normal-birth-weight (NBW) rats were used as controls. When the rats were four weeks old, the left kidneys were removed and used for comprehensive label-free proteomic studies. Following uninephrectomy, all rats were fed a high-salt diet until 9 weeks of age. Differences in the molecular composition of the kidney cortex were observed at the early step of LBW nephropathy pathogenesis. Untargeted quantitative proteomics showed that proteins involved in energy metabolism, such as oxidative phosphorylation (OXPHOS), the TCA cycle, and glycolysis, were specifically downregulated in the kidneys of LBW rats at four weeks. No pathological changes were detected at this early stage. Pathway analysis identified NEFL2 (NRF2) and RICTOR as potential upstream regulators. The search for biomarkers identified components of the mitochondrial respiratory chain, namely, ubiquinol-cytochrome c reductase complex subunits (UQCR7/11) and ATP5I/L, two components of mitochondrial F1FO-ATP synthase. These findings were further validated by immunohistology. At later stages of the disease process, the right kidneys revealed an increased frequency of focal segmental glomerulosclerosis lesions, interstitial fibrosis and tubular atrophy. Our findings revealed proteome changes in LBW rat kidneys and revealed a strong downregulation of specific mitochondrial respiratory chain proteins, such as UQCR7.
... There are accumulating evidence about solid role played by fetal overexposure to both endogenous or synthetic GCs and the risk of developing metabolic and cardiovascular disease in adulthood (141,142). This remote response to an intrauterine insult has been termed (fetal programming of adult disease). ...
... This hypothesis has many supporting evidence from low protein diet model and other human studies. In rodent, treatment of pregnant dams with placental 11 β-HSD 2 inhibitor, carbenoxolone, resulted in low birth weight and hypertension at adulthood (141). Hypertension in low protein model also was glucocorticoid dependent as maternal adrenalectomy significantly reduced the blood pressure to control levels and corticosterone replacement restored the hypertensive state seen these exposed offspring (151). ...
... Los receptores intracelulares de glucocorticoides se expresan en la mayoría de los tejidos fetales ya desde la mitad de la gestación o antes. En animales de experimentación se ha demostrado que la exposición prenatal a glucocorticoides produce elevación de la presión arterial de sus descendientes en la edad adulta, así como hiperglicemia (39,40). ...
Los genes tienen gran influencia en el crecimiento de un feto. Sin embargo, diversos estudios en seres humanos y animales parecen indicar que su crecimiento se ve limitado por factores ambientales; especialmente, por los nutrientes y el oxígeno que el feto recibe. Desde el punto de vista de la evolución, hay muchas posibles ventajas en esa tendencia del cuerpo a permanecer plástico durante su desarrollo en vez de regirse estrictamente por las instrucciones genéticas adquiridas en la concepción.Los estudios epidemiológicos, sobre todo los del grupo de Barker en Southampton, muestran que aquellos individuos con un bajo peso al nacimiento tienen un riesgo aumentado de padecer enfermedad cardiovascular y otras alteraciones asociadas (accidente cerebrovascular, diabetes tipo 2, hipertensión arterial y síndrome metabólico) en la edad adulta. Estos hallazgos dieron lugar a la hipótesis del origen fetal de la enfermedad o de la programación fetal, que establece que la enfermedad cardiovascular y la diabetes tipo 2 se originan por la adaptación del feto a la malnutrición intrauterina.
... Of special importance was the finding that maternal cholestasis in pregnancy programs metabolic disease in the offspring (males had increased BMI and females increased waist and hip girth) [62]. This was very much in keeping with our studies in pregnant rats given dexamethasone in pregnancy [64]. Given the current global obesity pandemic it would be important to determine what role such neonatal programming is playing in the genesis of the disease. ...
Human and sheep parturition are more akin than currently recognised. In both glucocorticoids are key. The difference being mechanisms controlling glucocorticoid levels. Sheep have low cortisol during pregnancy which rise at term: humans control local glucocorticoid levels via the fetal adrenal and DHEA-sulphate. This increases 11β-HSD2 expression protecting the fetus from maternal cortisol by converting this to cortisone. During pregnancy DHEA inhibits placental and fetal membrane 11β-HSD1 expression. This plus hexose-6-phosphate dehydrogenase inhibition decreases 11β-HSD1 oxido-reductase/increases dehydrogenase action converting cortisol to cortisone via transcription factor C/EBPβ. This has a key role in progesterone synthesis blocking COX-2 transcription and prostaglandin synthesis. DHEA-induced protection reverses at parturition onset via pro-inflammatory cytokines increasing C/EBPα. This lowers progesterone and enhances local glucocorticoid production stimulating prostaglandins, oxytocin receptor production and cervical ripening. Lowered progesterone and increased TNFα/IL-1β markedly increase myometrial purinergic receptors promoting calcium entry, contraction and hence parturition.
... Studies have included uterine artery ligation [38], and the occlusion showed the limited occurrence of FGR with a high level of fetal mortality/loss [39]. The same results have been achieved by administering dexamethasone and L-NAME [40,41]. Furthermore, diet-induced FGR (nutritional or protein restriction) has not been shown to exhibit as elevated results as the transgenic model [42]. ...
Citation: Orzeł, A.; Unrug-Bielawska, K.; Filipecka-Tyczka, D.; Berbeka, K.; Zeber-Lubecka, N.; Zielińska, M.; Kajdy, A. Molecular Pathways of Altered Brain Development in Fetuses Exposed to Hypoxia. Int. J. Mol. Sci. 2023, 24, 10401. https:// Abstract: Perinatal hypoxia is a major cause of neurodevelopmental impairment and subsequent motor and cognitive dysfunctions; it is associated with fetal growth restriction and uteroplacental dysfunction during pregnancy. This review aims to present the current knowledge on brain development resulting from perinatal asphyxia, including the causes, symptoms, and means of predicting the degree of brain damage. Furthermore, this review discusses the specificity of brain development in the growth-restricted fetus and how it is replicated and studied in animal models. Finally, this review aims at identifying the least understood and missing molecular pathways of abnormal brain development, especially with respect to potential treatment intervention.
... This paradigm was elaborated primarily in a series of epidemiologic studies 20-30 yr ago and soon after that, in the investigations using experimental models of laboratory animals [28]. In particular, experimental models have clearly shown that administration of exogenous GC to laboratory animals (principally, rats and sheep) during gestation resulted, as referred to their offspring, in hypertension that was amplified along postnatal ontogeny scale [29,30]. Obviously, the necessity emerged soon to explain this pathogenic capability of GC and paradoxically, the principal organs important for such explanation were the kidneys and not those of CV system [31] (see In fact, the use of exogenous GC at the end of gestation and the beginning of postnatal life caused a diminution of the number of nephrons, principal morpho-functional units of kidneys. ...
Previously the opinion has been formed about significant relationship between stress and various diseases including cardiovascular disorders. However, the advances in biomedical science during the last decades provoke the necessity of updating this opinion. Therefore, this work aimed at presentation of bibliographic data that confirm the important role of stress in the etiopathogeny of arterial hypertension and other cardiovascular diseases.
... Cortisol of maternal origin represents the primary source of cortisol in early gestation of the feotus (Harris & Seckl, 2011). Dysregulated maternal GCs/GR signaling increases fetal GC exposure (Benediktsson et al., 1993;Chen et al., 2021;Quinn et al., 2019;Swanson & David, 2015). ...
One form of early life stress, prenatal exposure to glucocorticoids (GCs), confers a higher risk of psychiatric and neurodevelopmental disorders in later life. Increasingly, the importance of microglia in these disorders is recognized. Studies on GCs exposure during microglial development have been limited, and there are few, if any, human studies. We established an in vitro model of ELS by continuous pre-exposure of human iPS-microglia to GCs during primitive hematopoiesis (the critical stage of iPS-microglial differentiation) and then examined how this exposure affected the microglial phenotype as they differentiated and matured to microglia, using RNA-seq analyses and functional assays. The iPS-microglia predominantly expressed glucocorticoid receptors over mineralocorticoid receptors, and in particular, the GR-α splice variant. Chronic GCs exposure during primitive hematopoiesis was able to recapitulate in vivo ELS effects. Thus, pre-exposure to prolonged GCs resulted in increased type I interferon signaling, the presence of Cyclic GMP-AMP synthase-positive (cGAS) micronuclei, cellular senescence and reduced proliferation in the matured iPS-microglia. The findings from this in vitro ELS model have ramifications for the responses of microglia in the pathogenesis of GC- mediated ELS-associated disorders such as schizophrenia, attention-deficit hyperactivity disorder and autism spectrum disorder.
... Corticosteroids administered in the antenatal period have been an important area of investigation. Rat offspring that were exposed to dexamethasone throughout pregnancy developed growth restriction, reduced glomeruli number, and hypertension at 60 postnatal days [96]. Bilateral renal denervation normalized blood pressure at 8 weeks of age in exposed rats in part by normalized tubular sodium transporter expression [97]. ...
Purpose of Review
Synthesize the clinical, epidemiological, and preclinical evidence for antenatal programming of hypertension and critically appraise paradigms and paradoxes to improve translation.
Recent Findings
Clinical and epidemiological studies persistently demonstrate that antenatal factors contribute to programmed hypertension under the developmental origins of health and disease framework, including lower birth weight, preterm birth, and fetal growth restriction. Preclinical mechanisms include preeclampsia, maternal diabetes, maternal undernutrition, and antenatal corticosteroid exposure. However, clinical and epidemiological studies to date have largely failed to adequately identify, discuss, and mitigate many sources and types of bias in part due to heterogeneous study designs and incomplete adherence to scientific rigor. These limitations have led to incomplete and biased paradigms as well as persistent paradoxes that have significantly limited translation into clinical and population health interventions.
Summary
Improved understanding of these paradigms and paradoxes will allow us to substantially move the field forward.
... In other studies, examining the long-term effects of patients with AKI, the frequency of hypertension varied between 3 and 20% [12,13,35,43]. Animal and human studies suggest that infants with prematurity or low birth weight (< 2,500 g) have a greater risk of developing hypertension, dyslipidemia, cardiovascular diseases and diabetes mellitus in adulthood [44,45]. In our study, however, the presence of prematurity (14.3% vs. 11.8%, ...
Abstract Background Data on the long-term effects of neonatal acute kidney injury (AKI) are limited. Methods We invited 302 children who had neonatal AKI and survived to hospital discharge; out of 95 patients who agreed to participate in the study, 23 cases were excluded due to primary kidney, cardiac, or metabolic diseases. KDIGO definition was used to define AKI. When a newborn had no previous serum creatinine, AKI was defined as serum creatinine above the mean plus two standard deviations (SD) (or above 97.5th percentile) according to gestational age, weight, and postnatal age. Clinical and laboratory features in the neonatal AKI period were recorded for 72 cases; at long-term evaluation (2–12 years), kidney function tests with glomerular filtration rate (eGFR) by the Schwartz formula, microalbuminuria, office and 24-h ambulatory blood pressure monitoring (ABPM), and kidney ultrasonography were performed. Results Forty-two patients (58%) had stage I AKI during the neonatal period. Mean age at long-term evaluation was 6.8 ± 2.9 years (range: 2.3–12.0); mean eGFR was 152.3 ± 26.5 ml/min/1.73 m2. Office hypertension (systolic and/or diastolic BP ≥ 95th percentile), microalbuminuria (> 30 mg/g creatinine), and hyperfiltration (> 187 ml/min/1.73 m2) were present in 13.0%, 12.7%, and 9.7% of patients, respectively. ABPM was performed on 27 patients, 18.5% had hypertension, and 40.7% were non-dippers; 48.1% had abnormal findings. Female sex was associated with microalbuminuria; low birth weight (
... Blood pressure, first measured at 5 weeks and finally at 14 weeks at the end of the study, did not differ between IF and control offspring of either sex. This is in marked contrast to other models of developmental programming, including calorific restriction [41], high fat [42] and LP diets [14] as well as fetal exposure to glucocorticoids [43], in which hypertension is a common feature. It is possible that IF rats may go on to develop high blood pressure later in life: Kahn et al. [42] reported that the female offspring of dams fed a high fat diet were not hypertensive until 180 days old, and that males still had not developed high blood pressure at 360 days of age. ...
Pregnant Muslim women are exempt from fasting during Ramadan; however a majority are reported to fast. The impact of this form of maternal intermittent fasting (IF) on fetal development and offspring health is not well defined. Using a rat model, we have shown previously that maternal IF results in fetal growth restriction accompanied by changes in placental nutrient transport function. The aim of this study was to assess cardiovascular, metabolic and renal function in adult offspring of IF-exposed dams. Food was withheld from Wistar rats from 17:00 to 09:00 daily throughout pregnancy; controls had ad libitum access to food. Birth weight was unaffected; however male IF pups grew more slowly up to 10 weeks of age ( P < 0.01) whereas IF females matched their control counterparts. Systolic blood pressure (SBP), glucose tolerance and basal renal function at 14 weeks were not affected by IF exposure. When offered saline solutions (0.9–2.1%) to drink, females showed a greater salt preference than males ( P < 0.01); however there were no differences between dietary groups. A separate group of pups was weaned onto a 4% NaCl diet. SBP increased in IF pups sooner, at 7 weeks ( P < 0.01), than controls which became hypertensive from 10 weeks. Renal function did not appear to differ; however markers of renal injury were elevated in IF males ( P < 0.05). Maternal IF does not affect resting cardiovascular, metabolic and renal function; but when challenged by dietary salt load male IF offspring are more prone to renal injury.
... In contrast, hypoxia does not affect the expression of 11β-HSD type 1, which converts inactive cortisone to active cortisol [158]. Many articles have analysed the effect of antenatal glucocorticoid exposure on the development of the foetal cardiovascular system [159]. Antenatal glucocorticoids have direct and mediated (Ang II, catecholamines) pressor and morphological effects, such as cardiomyocytes maturation as well as growth and differentiation of the smooth muscle and endothelial cells in vessels [160]. ...
Prenatal hypoxia during the prenatal period can interfere with the developmental trajectory and lead to developing hypertension in adulthood. Prenatal hypoxia is often associated with intrauterine growth restriction that interferes with metabolism and can lead to multilevel changes. Therefore, we analysed the effects of prenatal hypoxia predominantly not associated with intrauterine growth restriction using publications up to September 2021. We focused on: (1) The response of cardiovascular regulatory mechanisms, such as the chemoreflex, adenosine, nitric oxide, and angiotensin II on prenatal hypoxia. (2) The role of the placenta in causing and attenuating the effects of hypoxia. (3) Environmental conditions and the mother’s health contribution to the development of prenatal hypoxia. (4) The sex-dependent effects of prenatal hypoxia on cardiovascular regulatory mechanisms and the connection between hypoxia-inducible factors and circadian variability. We identified that the possible relationship between the effects of prenatal hypoxia on the cardiovascular regulatory mechanism may vary depending on circadian variability and phase of the days. In summary, even short-term prenatal hypoxia significantly affects cardiovascular regulatory mechanisms and programs hypertension in adulthood, while prenatal programming effects are not only dependent on the critical period, and sensitivity can change within circadian oscillations.
... These changes are similar to those seen in the human placenta from women with pregnancies complicated by IUGR. Third, various animals with maternal exposure to DEX have been widely used to study the link between low birth weight and later development of cardiovascular or metabolic diseases and neurodevelopmental deficits (47)(48)(49)(50). One limitation of this study is that we only investigated the effect of LIPUS on DEX-induced IUGR in rats. ...
Intrauterine growth restriction (IUGR) is a leading cause of perinatal mortality and morbidity, and IUGR survivors are at increased risk of neurodevelopmental deficits. No effective interventions are currently available to improve the structure and function of the IUGR brain before birth. This study investigated the protective effects of low-intensity pulsed ultrasound (LIPUS) on postnatal neurodevelopmental outcomes and brain injury using a rat model of IUGR induced by maternal exposure to dexamethasone (DEX). Pregnant rats were treated with DEX (200 μg/kg, s.c.) and LIPUS daily from gestational day (GD) 14 to 19. Behavioral assessments were performed on the IUGR offspring to examine neurological function. Neuropathology, levels of neurotrophic factors, and CaMKII-Akt-related molecules were assessed in the IUGR brain, and expression of glucose and amino acid transporters and neurotrophic factors were examined in the placenta. Maternal LIPUS treatment increased fetal weight, fetal liver weight, and placental weight following IUGR. LIPUS treatment also increased neuronal number and myelin protein expression in the IUGR brain, and attenuated neurodevelopmental deficits at postnatal day (PND) 18. However, the number of oligodendrocytes or microglia was not affected. These changes were associated with the upregulation of brain-derived neurotrophic factor (BDNF) and placental growth factor (PlGF) protein expression, and enhancement of neuronal CaMKII and Akt activation in the IUGR brain at PND 1. Additionally, LIPUS treatment promoted glucose transporter (GLUT) 1 production and BDNF expression in the placenta, but had no effects on GLUT3 or amino acid transporter expression. Our findings suggest that antenatal LIPUS treatment may reduce IUGR-induced brain injury via enhancing cerebral BDNF/CaMKII/Akt signaling. These data provide new evidence that LIPUS stimulation could be considered for antenatal neuroprotective therapy in IUGR.
... However, most women with symptoms of preterm labour will not deliver preterm. Predicting with higher accuracy which women will go on to deliver, could avoid exposure of both fetus and mother to unnecessary treatment(s) with potentially negative effects [3,4]. Estimating if one will deliver preterm can be based on the presence of risk factors, the symptoms at presentation, and predictive methods. ...
An accurate prognostic method for preterm birth (PTB) could avoid unnecessary treatment(s) with potentially negative effects. The objective was to explore the prognostic accuracy of commercially available bedside cervicovaginal biomarker tests in combination with cervical length (CL) compared to CL measurement alone and/or a biomarker test alone, for PTB within 7 days after testing symptomatic women at 22–34 weeks. The MEDLINE, Cochrane, Embase and Web of Science databases were searched from inception to August 28th, 2019. Seven hundred and eight articles were identified and screened using Rayyan. Studies reporting on the predictive accuracy of combined tests compared to CL or biomarker alone for the prediction of PTB within 7 days of testing in symptomatic women with intact membranes were included. A piloted data extraction form was used. Direct comparisons of the prognostic accuracy of the combination test with CL measurement or a biomarker alone were done, as well as comparisons of prognostic accuracy of the included combination tests (indirect comparisons). Twelve articles were included (seven on fetal fibronectin, four on phosphorylated insulin-like growth factor binding protein-1, one comparing both). A variety of CL cut-offs was reported. The results could not demonstrate superiority of a combination method compared to single methods. Due to data scarcity and quality, the superiority of either predictive test for PTB, either combination or single, cannot be demonstrated with this systematic review. We recommend further research to compare available biomarkers.
... with pre-eclampsia 18 or intrauterine growth retardation 19 where there is reduced placental 11β-HSD2 expression. Furthermore, 11β-HSD2 is ineffective in metabolizing synthetic GCs, therefore DEX is able to pass through the transplacental passage and into the in-utero environment 20 . Clinically, synthetic GCs have proven to accelerate fetal lung maturation and is therefore given to pregnant women at risk of preterm birth 21 . ...
Prenatal glucocorticoid exposure is associated with the development of hypertension in adults. We have previously demonstrated that antenatal dexamethosone (DEX) administration in Wistar-Kyoto dams results in offspring with increased blood pressure coupled with elevated plasma epinephrine levels. In order to elucidate the molecular mechanisms responsible for prenatal DEX-mediated programming of hypertension, a whole-transcriptome analysis was performed on DEX programmed WKY male adrenal glands using the Rat Gene 2.0 microarray. Differential gene expression (DEG) analysis of DEX-exposed offspring compared with saline-treated controls revealed 142 significant DEGs (109 upregulated and 33 downregulated genes). DEG pathway enrichment analysis demonstrated that genes involved in circadian rhythm signaling were most robustly dysregulated. RT-qPCR analysis confirmed the increased expression of circadian genes Bmal1 and Npas2, while Per2, Per3, Cry2 and Bhlhe41 were significantly downregulated. In contrast, gene expression profiling of Spontaneously Hypertensive (SHR) rats, a genetic model of hypertension, demonstrated decreased expression of Bmal1 and Npas2, while Per1, Per2, Per3, Cry1, Cry2, Bhlhe41 and Csnk1D were all upregulated compared to naïve WKY controls. Taken together, this study establishes that glucocorticoid programmed adrenals have impaired circadian signaling and that changes in adrenal circadian rhythm may be an underlying molecular mechanism responsible for the development of hypertension.
... 7,8 However, stress or GC exposure has harmful effects on reproduction, such as fetal growth restriction, infertility, miscarriage, stillbirth, preterm birth, low birth weight, and postnatal hypertension. [9][10][11][12][13][14][15][16] Post-traumatic stress disorder (PTSD), a serious psychological condition that occurs following exposure to a traumatic event, has a negative impact on female reproduction. 17,18 A traumatic event can stimulate the release of GCs from adrenal cortex into the bloodstream by initiating hypothalamic-pituitary-adrenal axis. ...
Glucocorticoids (GCs), stress‐induced steroid hormones, are released by adrenal cortex and essential for stress adaptation. Recently, there has been renewed interest in the relationship between GCs and pregnancy following the discovery that glucocorticoid receptor is necessary for implantation. It has been widely recognized that stress is detrimental to pregnancy. However, effects of stress‐induced GC exposure on uterine receptivity and decidualization are still poorly understood. This study aims to explore the effects of GCs exposure on uterine receptivity, decidualization, and their underlying mechanisms in mice. Single prolonged stress (SPS) and corticosterone (Cort) injection models were used to analyze effects of GC exposure on early pregnancy, respectively. SPS or Cort injection inhibits embryo implantation by interfering Lif signaling and stimulating the uterine deposition of collagen types I, III, and IV on day 4 of pregnancy. Uterine decidualization is also attenuated by SPS or Cort injection through suppressing Cox‐2 expression. Cort‐induced collagen disorder also suppresses decidualization through regulating mesenchymal‐epithelial transition. Our data should shed lights for a better understanding for the effects of GCs on embryo implantation for clinical research.
... Les troubles du développement sont attribuables aux modifications durables du fonctionnement de l´axe hypothalamo-hypophyso-cortico-surrénalienne, du dispositif perceptuel congénital et du système des morphines endogènes [1,3,38,39], l´hyperactivité adrénergique et l´hypercortisolémie associées à la détresse psychologique maternelle avec anxiété prédominante [39,40,41]. La structure et de la fonctionnalité de l´hippocampe, de noyau amygdalien et du cortex préfrontal sont affectées par l´effet des minéral corticoïdes et des glucocorticoïdes [1,33,42]. ...
Introduction:
the impact of prenatal maternal affectivity on infant development is poorly documented in Africa. The purpose of our study is to determine the relationship between mother feelings about pregnancy and childbirth, infant´s behavior and development.
Methods:
one hundred and twenty mothers aged 28,4 years (± 12,18 years) with their babies aged 38,70 months (± 19,19) were enrolled in a cross-sectional study based on an interview and questionnaire on maternal affectivity, mother-child relationship, infant´s behavior and psychosocial development. Maternal depression was assessed by Edinburgh (EPDS), Goldberg Depression and anxiety scales and DSM-IV (MINI) criteria. Chi-square and Mann-Whitney were used to describe the relationship between maternal affectivity and infant's behavior and health.
Results:
unintended pregnancy and fear of childbirth were associated with high anxiety and depression scores. Negative feelings about pregnancy were associated with the lack of social support by the child´s father (0.0110), stress when women were pregnant with a frustrated child (p=0.046), difficult consolability (p<0.001), poor baby's health (p=0.010), infant non-affiliative behavior (p=0.034) and depression identified by using EPDS (p=0.028). Fear of childbirth was associated with delayed or absent responses to infant´s signals (p=0.002) and stress if they were carrying a frustrated baby (p=0.020).
Conclusion:
negative feelings during pregnancy are predictive of maternal depression, mother-child relationship disorders, infant´s health and development.
... Raised glucocorticoid exposure can alter fetal growth, affect cellular differentiation and development, and alter the timing of organ maturation. Indeed exogenous administration of glucocorticoids during pregnancy retards fetal growth resulting in low birth weight in humans and other mammals, and also elevates the blood pressure of offspring in rat and sheep models (Reinisch et at., 1978;Benediktsson et al., 1993;Dodic et ai., 1998). ...
p>In the first study ewes received either 100% (C) or 50% (R) of total nutrient requirements for the first 31 days of gestation (dGA), and 100% requirements thereafter. In the second study ewes received either 100% (C) of total nutrient requirements throughout gestation, 40% (E) from 1-31 dGA or 50% (L) from 104 dGA onwards, at all other times ewes were fed 100% requirements. In late gestation, fetuses were surgically instrumented and basal CV and renal parameters, and responses to a number of stimuli were measured.
The first study found that a 50% maternal nutrient restriction did not alter fetal body or organ weights, kidney biometry, basal CV function or baroreflex during late gestation. 50% maternal nutrient restriction had no effect on fetal renin angiotensin system (RAS) in terms of CV or renal response to frusemide. However, the responsiveness to Angiotensin II (Ang II) was blunted in the maternal restricted fetuses. The second study found that neither a more severe peri-implantation nor a late gestation maternal nutrient restriction altered any of the fetal parameters measured in the first study. Maternal nutrient restriction did not alter fetal nephron number in late gestation. There was no difference between the groups in the overall CV response to hypoxia.
These findings suggest that poor in utero nutrition does not alter renal development and function, basal CV control, baroreflex or chemoreflex in fetal life. Peri-implantation restriction blunted the fetal mean arterial pressure response to Ang II, dependent on intensity of challenge, which may indicate altered Ang II receptors populations in the peripheral vasculature. In conclusion reduced maternal nutrition during peri-implantation and late gestation, periods previously implicated as critical periods of development, appear to have no effect on fetal renal development.</p
... Studies in pregnant rodents showed that administration of supraphysiologic levels of glucocorticoids led to lower birthweight and hyperglycemia in the offspring suggesting an impaired uptake of nutrients and insulin resistance of fat and muscle cells (Harris and Seckl, 2011). Subsequently, it was shown, that these rodents later very consistently developed insulin resistance, increased anxiety and depression-like behavior, and also exhibited increased basal and stress-induced glucocorticoid levels in adulthood (Benediktsson et al., 1993). Nyirenda et al. (1998) pointed out, that rodents exposed to this in utero stress model show altered GR expression in the central nervous system. ...
It is debated as to whether major depressive disorder (MDD) and the burnout syndrome represent different aspects of the same syndrome or whether they reflect separate entities. A dysregulation of the hypothalamus-pituitary-adrenal-axis has been related to both conditions separately. Dissecting the pathophysiology of the conditions and describing differences and similarities with regard to stress physiological systems might further clarify whether underlying etiological models of these syndromes differ. A systematic literature search including MDD and the burnout syndrome and peripheral cortisol measures was performed and resulted in 190 studies for inclusion in the qualitative synthesis. For MDD, findings suggest a general state of hypercortisolism and glucocorticoid resistance reflected by increased basal cortisol levels, reduced reactivity to psychosocial stress and a reduced cortisol suppression in pharmacological challenge tests. For the burnout syndrome, two central factors limit further conclusions: i) there is not a suf cient amount of studies examining the burnout syndrome and different cortisol secretion patterns to provide an evidence base, ii) the burnout syndrome is assessed heterogeneously reflecting imprecision of the measured constructs. Large prospective cohort studies examining both conditions in parallel rigorously controlling for confounders are required to further elucidate the differences and similarities of the HPA axis in MDD and the burnout syndrome.
... The salient effects on fetal basal cardiovascular function of antenatal glucocorticoid therapy used at human clinically relevant doses in preterm fetal sheep are: (i) an increase in baseline peripheral vascular resistance; (ii) an increase in basal arterial blood pressure; and (iii) persistent resetting of the fetal cardiac baroreflex towards a greater set point. Similar effects of synthetic steroids in promoting an increase in basal arterial blood pressure have been noted in fetal baboons [145] and in human infants following maternal antenatal glucocorticoid therapy [146], prompting scientists to warn against possible glucocorticoid-induced developmental programming of an increased risk of hypertension and cardiovascular dysfunction in later life [147][148][149][150]. For instance, synthetic glucocorticoid exposure in rat pups and in preterm human infants has been linked with cardiac dysfunction and increased aortic arch stiffness in adulthood [147,150,151]. ...
The last decade has seen rapid advances in the understanding of the central role of glucocorticoids in preparing the fetus for life after birth. However, relative to other organ systems, maturation by glucocorticoids of the fetal cardiovascular system has been ignored. Here, we review the effects of glucocorticoids on fetal basal cardiovascular function and on the fetal cardiovascular defense responses to acute stress. This is important because glucocorticoid-driven maturational changes in fetal cardiovascular function under basal and stressful conditions are central to the successful transition from intra- to extrauterine life. The cost-benefit balance for the cardiovascular health of the preterm baby of antenatal glucocorticoid therapy administered to pregnant women threatened with preterm birth is also discussed.
... We also found that elevated DNA methylation of HSD11B2 was associated with reduced fetal growth. Placenta-specific HSD11B2 is a vital gene that regulates glucocorticoid metabolism (Benediktsson et al., 1993;Reinisch et al., 1978). In keeping with our results, a cross sectional study by Marsit et al. reported that DNA methylation of HSD11B2 could negatively affect neonatal birth weight and placental HSD11B2 expression (Marsit et al., 2012). ...
Background:
Polybrominated diphenyl ethers (PBDEs) are environmental chemicals with harmful effects on pregnancy, but their effects on adverse developmental outcomes are not fully understood. The placental DNA methylation is strongly influenced by prenatal environmental factors and has been linked to fetal growth.
Objective:
To evaluate the association between in utero PBDEs exposure, placental DNA methylation changes (growth regulatory genes), and pathophysiology of fetal growth (birth outcomes, fetal growth retardation) in a population-based pregnancy cohort study.
Methods:
This was a nested case-control study within the prospective Wenzhou Birth Cohort including 130 fetal growth retardation (FGR) cases and 130 healthy controls and their mothers recruited from June 2016 to June 2017. FGR was diagnosed based on the comprehensive evaluation of ultrasound results at 24, 28, and 32 weeks of gestation. Neonatal birth measurements were obtained from medical records. Gestational exposure to 19 PBDEs, including 13 lower BDE congeners (BDE-17-190) and 6 higher brominated BDE congeners (BDE-196-209), were determined by gas chromatography tandem mass spectrometry in the umbilical cord blood. Placental DNA methylation changes of one repetitive element (LINE1) and two candidate genes (HSD11B2, IGF2) were characterized by quantitative polymerase chain reaction-pyrosequencing. Multiple linear regression and logistic regression models were used to examine the associations among PBDEs exposure, fetal growth indicators, and DMR (differential methylation region) methylation fractions. Sobel tests were conducted to assess DNA methylation as a mediator in multivariate models.
Results:
After excluding women who withdrew from the study or were lost to follow-up or failed to provide placenta or umbilical cord blood, 249 mother-newborn pairs (124 FGR cases, 125 controls) were included in the final analysis. Elevated BDE-206 (OR: 1.569, 95% CIs: 1.053-2.338), BDE-17-190 (OR: 2.860, 95% CIs: 1.233-6.634), BDE-196-209 (OR: 1.688, 95% CIs: 1.024-2.783) and ∑19PBDEs (OR: 2.387, 95% CIs: 1.220-4.668) concentrations were associated with increased risk of FGR in newborns. FGR birth was also associated with increased DNA methylation of HSD11B2 (OR: 1.145, 95% CIs: 1.032-1.270) and decreased DNA methylation of IGF2 (OR: 0.892, 95% CIs: 0.845-0.941). In addition, BDE-17-190 showed significant associations with DNA methylation of HSD11B2 and IGF2 (β: 1.127, 95% CIs: 0.069-2.186; β: -3.452, 95% CIs: -5.512-1.392), indicating placental DNA methylation changes of HSD11B2 and IGF2 were related to both lower BDE congeners exposure and fetal growth. Further mediation analyses showed that IGF2 methylation mediated about 40% of the effects of BDE-17-190 in umbilical cord blood on neonatal FGR.
Conclusion:
We report an inverse association between in utero exposures to PBDEs and fetal growth and provide evidence supporting epigenetic gene plasticity in these associations. Changes in placental DNA methylation might be part of the underlying biological pathway between prenatal PBDEs exposure and adverse fetal growth.
According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, exposure to certain environmental influences during early life may be a key determinant of fetal development and short- and long-term offspring health. Indeed, adverse conditions encountered during the fetal, perinatal, and early childhood stages can alter normal development and growth, as well as put the offspring at elevated risk of developing long-term health conditions in adulthood, including chronic kidney disease (CKD) and cardiovascular diseases. Of relevance in understanding the mechanistic basis of these long-term health conditions, are previous findings showing low glomerular number in human intrauterine growth restriction and low birth weight - indicators of a sub-optimal intrauterine environment. In different animal models, the main sub-optimal intrauterine conditions studied relate to maternal dietary manipulations, poor micronutrient intake, prenatal ethanol exposure, maternal diabetes, glucocorticoid and chemical exposure, hypoxia, and placental insufficiency. These studies have demonstrated changes in kidney structure, glomerular endowment, and expression of key genes and signalling pathways controlling endocrine, excretion and filtration function of the offspring. This review aims to summarize those studies to uncover the effects and mechanisms by which adverse gestational environments impact offspring renal and vascular health in adulthood. This is important for identifying agents and interventions that can prevent and mitigate the long-term consequences of an adverse intrauterine environment on the subsequent generation.
Background:
The bed nucleus of the stria terminalis (BNST) is a structure with a peculiar neurochemical composition involved in modulating anxietylike behavior and fear.
Aim:
The present study investigated the effects on the BNST neurochemical composition and neuronal structure in critical moments of the postnatal period in gestational protein-restricted male rats' offspring.
Methods:
Dams were maintained during the pregnancy on isocaloric rodent laboratory chow with standard protein content [NP, 17%] or low protein content [LP, 6%]. BNST from male NP and age-matched LP offspring was studied using the isotropic fractionator method, Neuronal 3D reconstruction, dendritic-tree analysis, blotting analysis, and high-performance liquid chromatography.
Results:
Serum corticosterone levels were higher in male LP offspring than NP rats in 14-day-old offspring, without any difference in 7-day-old progeny. The BNST total cell number and anterodorsal BNST division volume in LP progeny were significantly reduced on the 14th postnatal day compared with NP offspring. The BNST HPLC analysis from 7 days-old LP revealed increased norepinephrine levels compared to NP progeny. The BNST blot analysis from 7-day-old LP revealed reduced levels of GR and BDNF associated with enhanced CRF1 expression compared to NP offspring. 14-day-old LP offspring showed reduced expression of MR and 5HT1A associated with decreased DOPAC and DOPA turnover levels relative to NP rats. In Conclusion, the BNST cellular and neurochemical changes may represent adaptation during development in response to elevated fetal exposure to maternal corticosteroid levels. In this way, gestational malnutrition alters the BNST content and structure and contributes to already-known behavioral changes.
Successful reproduction is a cornerstone in food animal industry in order to sustain food production for human. Therefore, various methods focusing on genetics and postnatal environment have been identified and applied to improve fertility in livestock. Yet there is evidence indicating that environmental factors during prenatal and/or neonatal life can also impact the function of reproductive system and fertility in the animals during adulthood, which is called the developmental programming of reproduction. The current review summarizes data associated with the developmental origins of reproduction in the female animals. In this regard, this review focuses on the effect of plane of nutrition, maternal body condition, hypoxia, litter size, maternal age and parity, level of milk production and milk components, lactocrine signaling, stress, thermal stress, exposure to androgens, endocrine disrupting chemicals, mycotoxins and pollutants, affliction with infection and inflammation, and maternal gut microbiota during prenatal and neonatal periods on the neuroendocrine system, puberty, health of reproductive organs and fertility in the female offspring. It is noteworthy that these prenatal and neonatal factors do not always exert their effects on the reproductive performance of the female by compromising the development of organs directly related to reproductive function such as hypothalamus, pituitary, ovary, oviduct and uterus. Since they can impair the development of non-reproductive organs and systems modulating reproductive function as well (e.g., metabolic system and level of milk yield in dairy animals). Furthermore, when these factors affect the epigenetics of the offspring, their adverse effects will not be limited to one generation and can transfer transgenerationally. Hence, pinpointing the factors influencing developmental programming of reproduction and considering them in management of livestock operations could be a potential strategy to help improve fertility in food animals.
Embryo implantation failure and spontaneous abortions represent the main causes of infertility in developed countries. Unfortunately, incomplete knowledge of the multiple factors involved in implantation and fetal development keeps the success rate of medically assisted procreation techniques relatively low. According to recent literature, cellular and molecular mechanisms of 'immunogenic tolerance' towards the embryo are crucial to establish an 'anti-inflammatory' state permissive of a healthy pregnancy. In this review we dissect the role played by the immune system in the endometrial-embryo crosstalk, with a particular emphasis towards the fork-head-box-p3 (Foxp3+) CD4+CD25+ regulatory T (Treg) cells and discuss the most recent therapeutic advances in the context of early immune-mediated pregnancy loss.
Stressors, broadly defined as any real or perceived challenges to homeostasis, trigger adaptive responses, leading to a cascade of physiologic changes. Once activated, the sympathetic nervous system prepares the body to take action by speeding up the heart, dilating airways, increasing blood flow to skeletal muscles, and slowing gastrointestinal and urinary functions. Acutely, these responses can be lifesaving, but they become harmful when chronically activated. Chronic stress can result in a range of symptoms such as anxiety, muscle aches and pains, GI distress, and headaches, and is linked to the development of diseases including heart disease, diabetes, and depression. When it comes to functional head and neck illnesses, it is important to consider the role stress may play in both pathogenesis and symptom exacerbation. By offering support and stress management strategies, providers can significantly reduce both symptom severity and mental stress for their patients.
The concept of the early life developmental origins of health and disease (DOHaD) in adults has stimulated a new approach to understanding disease trajectories, with major public health implications. Indeed, the principle of the 'lifecourse of disease' now influences health policies internationally. Environmental influences during pregnancy and early life that affect lifelong health are well documented, but there is a new focus on the preconception period and the significance of paternal health on the fetus. This fully revised second edition highlights scientific and clinical advances in the field, exploring new understanding of mechanisms such as epigenetics and the increasingly recognised role of external influences, including pollution. The book is structured logically, covering environment, clinical outcomes, mechanisms of DOHaD, interventions throughout the lifespan and finally implications for public health and policy. Clinicians and scientists alike will improve their understanding of the developmental origins of health and disease with this essential text.
Despite how common hypertension is in children, adolescents, and adults, the antecedent mechanisms underlying its origins remain incompletely understood. Increasingly strong evidence from clinical, epidemiological, and preclinical studies support the concept of early-life programming of hypertension within the framework of the developmental origins of health and disease theory. In essence, harmful antenatal exposures cause the fetus (and the intrauterine environment) to alter its physiological, structural, and metabolic development to adapt to this deleterious environment to improve short-term survival. However, if of sufficient severity, number, timing, or duration, such exposure-induced developmental plasticity can program persistent, maladaptive cardiovascular phenotypes that appear later on over the life course and ultimately increase the risk of developing hypertension. Well-described antenatal exposures can come from a variety of sources – maternal, paternal, fetal, and environmental – and can occur throughout pregnancy, from gametogenesis through birth. These exposures include abnormal maternal-fetal vascular supply and nutrient delivery (both restricted and excess), maternal stress causing increased exposure to endogenous glucocorticoids, inflammation, and exogenous exposures. Programming mechanisms can occur directly or indirectly via placental insufficiency and/or growth restriction; they likely do not simply occur due to low birth weight in isolation. Programming alters organ structure and function, tissue cell type, number, and distribution, blood supply, and hormonal system enzyme, substrate, and receptor expression and function in a variety of cardiovascular tissues including the kidneys, brain, vasculature, and heart. Additional factors further contribute to the programming of hypertension, including epigenetic changes as well as preconception and postnatal exposures. This chapter reviews the preclinical evidence for antenatal factors that result in programmed hypertension, including the complex interactions among these mechanisms, and highlights gaps in the field that limit translation to patient care. Understanding these programming factors has important implications for primordial prevention and treatment strategies.
Dexamethasone is the first and an important therapy that significantly reduces the risk of death in patients with severe COVID-19 disease. Nevertheless, a lot of studies have revealed that it has adverse impacts on multiple systems of the body especially the reproductive system, and dexamethasone exposure during the human foetal period may be associated with various diseases. In this paper, we reviewed the literature regarding the adverse effects of COVID-19 and dexamethasone administration on the reproductive system as well as related disease pathogenesis, in an attempt to clarify the potential harms of dexamethasone treatment in COVID-19 patients. Overall, we strongly support the application of dexamethasone as a pharmaceutical therapy in critical COVID-19 patients before a better therapy is developed, but the adverse side effects that may arise cannot be ignored. Our review will help medical professionals in the prognosis and follow-up of patients treated with dexamethasone. In addition, given that a considerable amount of uncertainty, confusion and even controversy that still remains, further studies and more clinical trials are urgently needed to improve the understanding of the parameters and the effects of dexamethasone on reproductive function of patients with severe acute respiratory syndrome coronavirus 2 infection.
Background
Gestational protein intake restriction-induced long-lasting harmful outcomes in the offspring's organs and systems. However, few studies have focused on this event's impact on the brain's structures and neurochemical compounds.
Aim
The present study investigated the effects on the amygdala neurochemical composition and neuronal structure in gestational protein-restricted male rats' offspring.
Methods
Dams were maintained on isocaloric standard rodent laboratory chow with regular protein [NP, 17%] or low protein content [LP, 6%]. Total cells were quantified using the Isotropic fractionator method, Neuronal 3D reconstruction, and dendritic tree analysis using the Golgi–Cox technique. Western blot and high-performance liquid chromatography performed neurochemical studies.
Results
The gestational low-protein feeding offspring showed a significant decrease in birth weight up to day 14, associated with unaltered brain weight in youth or adult progenies. The amygdala cell numbers were unchanged, and the dendrites length and dendritic ramifications 3D analysis in LP compared to age-matched NP progeny. However, the current study shows reduced amygdala content of norepinephrine, epinephrine, and dopamine in LP progeny. These offspring observed a significant reduction in the amygdala glucocorticoid (GR) and mineralocorticoid (MR) receptor protein levels. Also corticotrophin-releasing factor (CRF) amygdala protein content was reduced in 7 and 14-day-old LP rats.
Conclusion
The observed amygdala neurochemical changes may represent adaptation during embryonic development in response to elevated fetal exposure to maternal corticosteroid levels. In this way, gestational malnutrition stress can alter the amygdala's neurochemical content and may contribute to known behavioral changes induced by gestational protein restriction.
Developmental origins of health and disease (DOHaD) and epigenetics have expanded understanding of how the environment affects the health of women before and during pregnancy—with lifelong health consequences for the fetus. This has translated to a narrow focus on women’s lifestyle during pregnancy, especially for women classified as obese. In this study, we show that psychosocial harms such as distress or shame felt by pregnant women are rarely countenanced in these endeavors. To demonstrate this, we examine published documents about a large set of trials of lifestyle interventions united through an international consortium. Yet there is now a literature in which pregnant women with large bodies report feeling humiliated and a wider literature on the stigma of obesity. We argue that shame is produced and reproduced through the discursive and material knowledge-making scientific practices of DOHaD translation. Interventions that intensify the shame of large body size in pregnancy may be stressful, and neurophysiological stress pathways are well-known within DOHaD to have consequences for fetal development, so these interventions potentially undermine the very processes they set out to protect. A feminist response may protect women from shame and redirect attention to the social and structural determinants of health.
p>The first study compared three tests of central HPAA function in a group of low birthweight men aged 60-69 years from Hertfordshire, UK. There were no differences in the free cortisol response to awakening or ACTH and cortisol responses during a 100μg corticotrophin-releasing hormone (CRH) test, but low birthweight men had significantly smaller pituitary-adrenal responses during a dexamethasone-suppressed CRH test. While these findings do not explain the HPAA abnormalities associated with low birthweight in previous studies, they provide further evidence of dysregulation of the HPAA in men who were small at birth.
In further analysis of the data, blood pressure, glucose tolerance and plasma lipid concentrations were not related to these measures of central HPAA activity, despite significant positive correlations with morning cortisol concentrations. These data suggest that other mechanisms, for example altered glucocorticoid metabolism, are responsible for elevating circulating cortisol concentrations in men with cardiovascular risk factors.
The second study explored cortisol and blood pressure responses to a series of psychological stress tests in a group of young men and women from Adelaide, Australia. Cortisol responses were not related to size at birth in either sex, but in women there was a significant inverse relationship between birthweight and blood pressure reactivity. This study provides the first human evidence that haemodynamic responses to psychological stress may be programmed antenatally, suggesting a potential mechanism linking reduced fetal growth with raised blood pressure and cardiovascular disease in later life.
In summary, this research does not support the idea that the HPAA is upregulated centrally in low birthweight individuals, but adds to the evidence that the activity of the axis may be influenced by factors affecting fetal growth. The work presented in this thesis has added complexity to the role of the HPAA in the fetal origins of adult disease, and confirms that this is likely to remain an exciting area of research in years to come.</p
p>The work in this thesis investigates the idea that diminished elastin synthesis during fetal and early postnatal life leads to modifications in arterial structure resulting in a reduction in the elastic properties of the arteries and a rise in blood pressure.
The work falls into two parts. The first concerns epidemiological studies in humans. The aim was to examine relationships between indicators of poor fetal growth and arterial compliance in three groups: elderly men and women, young adults and children. Detail birth records were available for all.
Arterial compliance was estimated by measuring pulse wave velocity. The technique depends on the principle that the speed at which pulse waves travel through a liquid filled tube is inversely proportional to the square root of the compliance of the tube's wall.
The results of the studies in humans showed that people who were born with indicators of fetal growth restriction in mid to late pregnancy tended to have faster pulse wave velocities in the aorta to femoral, aorta to radical and aorta to foot arterial segments. Although the actual birth measurements that were related to pulse wave velocity were not the same across the studies, the likely timing of the growth restricting factors was consistent. For example, in elderly men and women, for each unit decrease in ponderal index (oz/in<sup>3</sup> x 1000), aorta to femoral pulse wave velocity increased by 16% (p=0.05). In elderly men and women, for each gram increase in placental weight, aorta to radial pulse wave velocity increased by 0.033 m/sec (p=0.02). For each day decrease in gestational age, aorta to foot pulse wave velocity increased by 0.5% (p=0.01) in young adults and by 0.013 m/sec (p=0.04) in children.
The second part of this thesis concerns experiments on animals.</p
p>Cardiovascular disease is a major cause of death throughout the world. Hypertension is a risk factor for cardiovascular disease, which is caused by a combination of genetic, environmental and lifestyle factors. It is hypothesised that maternal nutrition during pregnancy may also contribute to the risk of adult hypertension in her offspring. A rat model has been developed which supports this hypothesis. Rats are fed either a 9% casein (low protein) diet or an 18% casein (control) diet throughout pregnancy. The offspring of the low protein fed rats have elevated blood pressure in later life compared with controls. This thesis examines the role of the renin- angiotensin system in the development of the elevated blood pressure observed in this rat model. Feeding a 9% casein diet during pregnancy led to a decrease in weight gain compared to rats fed a control diet, but did not effect litter size. The offspring were of low to normal birthweight, and had a tendency to gain more weight than control rats in later life. Systolic blood pressure was significantly elevated fi-om 4 weeks of age in the rats exposed to a maternal low protein diet compared, with control rats. Plasma renin activity, angiotensin II and angiotensinogen concentrations were unchanged in the offspring of rats fed a low protein diet compared with rats fed a control diet. Pulmonary angiotensin converting enzyme (ACE) activity tended to be higher in the low protein exposed rats from early life, compared with control rats. This difference was statistically significant by 12 weeks of age. prostaglandin E2 (PGE2) excretion was elevated in the offspring of rats fed a low protein diet. Urinary PGE2 excretion was also measured in a group of children whose birth characteristics were known. PGE2 concentration was inversely correlated with head circumference and ponderal index, which are markers of fetal growth. Intervention with an ACE inhibitor (captopril) reduced the blood pressure in the low protein exposed rats to control levels during the treatment period. Early treatment with captopril or losartan (an angiotensin II receptor antagonist) prevented the onset of hypertension in this model and had no effect upon the blood pressures of the control rats. Treatment with an alternative anti-hypertensive drug (nifedipine), which does not target the renin-angiotensin system, had no effect upon the blood pressures of the low protein exposed rats. Urinary This thesis supports the hypothesis that maternal diet during pregnancy programmes blood pressure in her offspring. The results show that the renin-angiotensin system is altered in this model of matemal-diet-induced hypertension. The results of the intervention studies are suggestive of a role for the renin-angiotensin system in the development of the elevated blood pressure that is observed in the low protein exposed rats. These findings also show that the development of elevated blood pressure in this model is preventable. This may have implications for future public health.</p
Maternal stress in pregnancy is thought to be a contributing factor in adverse pregnancy outcome, including stillbirth and prematurity. Previous studies in our laboratory have shown that chronic elevation in maternal cortisol concentration in ewes (by maternal infusion of 1 mg·kg ⁻¹ ·day ⁻¹ ) during the late gestion increased the incidence of stillbirth and altered fetal heart rate and blood pressure at birth. We designed the current study to test the effect of chronically elevated maternal cortisol on fetal cardiac adaption from in utero life to ex utero life. The combined risk of stillbirth or prematurity was significantly greater in the pregnancies with maternal hypercortisolemia: in this cohort, 40% of the lambs of cortisol-infused ewes died in utero or at birth compared to 25% of lambs of control ewes, and 24% of lambs of cortisol-infused ewes were born preterm, whereas no lamb was born preterm in the control group. Compared to control lambs, the lambs of cortisol-infused ewes born at full term exhibited a significant increase in mean aortic pressure just prior to birth, and a significant decrease in mean aortic pressure that was evident during the first 9 hours after birth. The QT interval was decreased prior to birth and increased immediately after birth in the newborns of cortisol-treated ewes compared to control lambs. These findings suggest that an excess in utero corticosteroid exposure adversely affects fetal cardiac adaptation to extrauterine life and that chronic maternal stress or hypersecretion of corticosteroids may contribute to adverse obstetric outcomes.
Background:
Infants born preterm (before 37 weeks' gestation) are at risk of respiratory distress syndrome (RDS) and need for respiratory support due to lung immaturity. One course of prenatal corticosteroids, administered to women at risk of preterm birth, reduces the risk of respiratory morbidity and improves survival of their infants, but these benefits do not extend beyond seven days. Repeat doses of prenatal corticosteroids have been used for women at ongoing risk of preterm birth more than seven days after their first course of corticosteroids, with improvements in respiratory outcomes, but uncertainty remains about any long-term benefits and harms. This is an update of a review last published in 2015.
Objectives:
To assess the effectiveness and safety, using the best available evidence, of a repeat dose(s) of prenatal corticosteroids, given to women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with the primary aim of reducing fetal and neonatal mortality and morbidity.
Search methods:
For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), and reference lists of retrieved studies.
Selection criteria:
Randomised controlled trials, including cluster-randomised trials, of women who had already received one course of corticosteroids seven or more days previously and were still at risk of preterm birth, randomised to further dose(s) or no repeat doses, with or without placebo. Quasi-randomised trials were excluded. Abstracts were accepted if they met specific criteria. All trials had to meet criteria for trustworthiness, including a search of the Retraction Watch database for retractions or expressions of concern about the trials or their publications.
Data collection and analysis:
We used standard Cochrane Pregnancy and Childbirth methods. Two review authors independently selected trials, extracted data, and assessed trial quality and scientific integrity. We chose primary outcomes based on clinical importance as measures of effectiveness and safety, including serious outcomes, for the women and their fetuses/infants, infants in early childhood (age two to less than five years), the infant in mid- to late childhood (age five to less than 18 years) and the infant as an adult. We assessed risk of bias at the outcome level using the RoB 2 tool and assessed certainty of evidence using GRADE.
Main results:
We included 11 trials (4895 women and 5975 babies). High-certainty evidence from these trials indicated that treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s) of corticosteroids, compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary infant outcome of RDS (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.74 to 0.90; 3540 babies; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 11 to 29) and had little or no effect on chronic lung disease (RR 1.00, 95% CI 0.83 to 1.22; 5661 babies). Moderate-certainty evidence indicated that the composite of serious infant outcomes was probably reduced with repeat dose(s) of corticosteroids (RR 0.88, 95% CI 0.80 to 0.97; 9 trials, 5736 babies; NNTB 39, 95% CI 24 to 158), as was severe lung disease (RR 0.83, 95% CI 0.72 to 0.97; NNTB 45, 95% CI 27 to 256; 4955 babies). Moderate-certainty evidence could not exclude benefit or harm for fetal or neonatal or infant death less than one year of age (RR 0.95, 95% CI 0.73 to 1.24; 5849 babies), severe intraventricular haemorrhage (RR 1.13, 95% CI 0.69 to 1.86; 5066 babies) and necrotising enterocolitis (RR 0.84, 95% CI 0.59 to 1.22; 5736 babies). In women, moderate-certainty evidence found little or no effect on the likelihood of a caesarean birth (RR 1.03, 95% CI 0.98 to 1.09; 4266 mothers). Benefit or harm could not be excluded for maternal death (RR 0.32, 95% 0.01 to 7.81; 437 women) and maternal sepsis (RR 1.13, 95% CI 0.93 to 1.39; 4666 mothers). The evidence was unclear for risk of adverse effects and discontinuation of therapy due to maternal adverse effects. No trials reported breastfeeding status at hospital discharge or risk of admission to the intensive care unit. At early childhood follow-up, moderate- to high-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids for primary outcomes relating to neurodevelopment (neurodevelopmental impairment: RR 0.97, 95% CI 0.85 to 1.10; 3616 children), survival without neurodevelopmental impairment (RR 1.01, 95% CI 0.98 to 1.04; 3845 children) and survival without major neurodevelopmental impairment (RR 1.02, 95% CI 0.98 to 1.05; 1816 children). An increase or decrease in the risk of death since randomisation could not be excluded (RR 1.06, 95% CI 0.81 to 1.40; 5 trials, 4565 babies randomised). At mid-childhood follow-up, moderate-certainty evidence identified little or no effect of exposure to repeat prenatal corticosteroids compared with no repeat corticosteroids on survival free of neurocognitive impairment (RR 1.01, 95% CI 0.95 to 1.08; 963 children) or survival free of major neurocognitive impairment (RR 1.00, 95% CI 0.97 to 1.04; 2682 children). Benefit or harm could not be excluded for death since randomisation (RR 0.93, 95% CI 0.69 to 1.26; 2874 babies randomised) and any neurocognitive impairment (RR 0.96, 95% CI 0.72 to 1.29; 897 children). No trials reported data for follow-up into adolescence or adulthood. Risk of bias across outcomes was generally low although there were some concerns of bias. For childhood follow-up, most outcomes had some concerns of risk of bias due to missing data from loss to follow-up.
Authors' conclusions:
The short-term benefits for babies included less respiratory distress and fewer serious health problems in the first few weeks after birth with repeat dose(s) of prenatal corticosteroids for women still at risk of preterm birth seven days or more after an initial course. The current available evidence reassuringly shows no significant harm for the women or child in early and mid-childhood, although no benefit. Further research is needed on the long-term benefits and risks for the baby into adulthood.
Dexamethasone has been widely used in clinical practice to promote fetal lung maturity and reduce neonatal respiratory distress syndrome and perinatal mortality. Nevertheless, its administration is a double-edged sword, as a large number of studies have shown that there are obvious disadvantages in pregnant women and fetal development. In this review, we comprehensively retrospect the latest literature on the toxicological effects and mechanisms of dexamethasone on fetal development, in an attempt to provide a valuable basis for further studies and clinical trials in the future. Overall, prenatal dexamethasone exposure could lead to some adverse consequences on fetal organ systems through intrauterine programming based on the results of current animal and human researches. Potential sequelae include osteoarthritis, hypertension, fatty liver, glomerulosclerosis, depression, diabetes and infertility, some of which can pass on to the next generation. It must be noted that the evidence in humans is preliminary and limited by the small sample size. More studies in large-scale populations are needed to confirm if it raises the risk of sequelae in humans. In addition, we strongly support the application of dexamethasone as a pharmaceutical therapy in pregnant women with coronavirus disease 2019 before a better therapy is developed. However, the adverse side effects that may arise also cannot be ignored.
The use of corticosteroids is one of the most important therapies used in prenatal care to improve the outcomes of the newborn by reducing the rates of respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis and contribute to the survival of extreme preterm infants. In addition to steroids, the use of magnesium sulfate protects the newborn from cerebral palsy in cases of extreme preterm births. All of these conditions increase perinatal morbidity/mortality and are related to potentially serious illness in the newborn requiring care in neonatal intensive units. The use of corticosteroids and magnesium sulfate are measured to prevent unfavorable outcomes of premature newborns admitted to a neonatal intensive care unit. The incidence of twin pregnancy is only 3% of all live births, however, it accounts for 15% of extreme preterm births less than 32 weeks. Women with multiple pregnancies are six times more likely to terminate the pregnancy before term compared to single pregnancies. The determination of the use of corticosteroids in multiple pregnancies remains conflicting due to the scarcity of studies related to this group. Therefore, this chapter aims to evaluate the effectiveness of the use of corticosteroids in twin pregnancies in early and late preterm, evaluating its outcome in respiratory morbidity and metabolic aspects of the newborn.
Maternal vascular malperfusion (MVM) largely results from defective remodeling of uteroplacental spiral arteries, which normally are transformed into high-capacitance, low-resistance vessels to supply blood to the placenta. MVM is characterized by a constellation of recognizable placental and decidual pathologic findings related to alterations in uterine and intervillous blood flow. Classic among these findings and a unique lesion of pregnancy is spiral artery acute atherosis. MVM is associated with significant morbidity and mortality for the mother and baby. Women with gestations complicated by MVM have short- and/or long-term risks of developing hypertension and metabolic syndromes and an increased risk of recurrence of MVM in a subsequent pregnancy. Moreover, mounting evidence indicates MVM can result in intrauterine programming of the fetus that later renders it more susceptible to developing disorders such as hypertension, cardiovascular disease, and chronic renal failure during adulthood. This chapter discusses key findings of MVM, their updated definitions, and the common underlying role of poor spiral artery remodeling and defective deep placentation in the pathogenesis of a group of disorders now referred to as the great obstetrical syndromes (pregnancy-induced hypertension (PIH)/preeclampsia, fetal growth restriction, preterm labor, preterm premature rupture of membranes, spontaneous abortion, and placental abruption). An update on our understanding of the uterine circulation during pregnancy is detailed since defective remodeling of the spiral arteries is likely not the only component of abnormalities of blood supply to the intervillous space in the obstetrical syndromes. Placentas delivered of women with primary chronic inflammatory conditions, such as systemic lupus erythematosus, and other chronic inflammatory comorbidities such as obesity and diabetes mellitus (Chap. 20) can also exhibit spiral artery acute atherosis. This chapter thus also includes a discussion of the recent hypothesis that atherosis represents a lesional endpoint of several pathologic etiologies whose pathways converge to produce excessive decidual inflammation.
A balanced diet with adequate nutrient intake is vital for normal fetal kidney development to occur. In contrast, maternal malnourishment during pregnancy impairs fetal kidney development due to a deficiency in nutrients that the mother and growing fetus have access to. Nutritional deficiency not only reduces the structural building blocks needed for nephron generation but also impacts various signaling pathways, growth factors, epigenetic modifications, gene expression, and oxidative stress that collectively blunts nephrogenesis. These effects of nutritional deficiency consequently reduce the stem cell pool that is available for nephron building by altering their self-renewal, survival, and patterned differentiation. As a result, the fetus is born following maternal malnourishment with significantly fewer nephrons, underdeveloped kidneys, potential kidney dysfunction, and a lifelong increased susceptibility to kidney and cardiovascular disease. Discussed in this chapter are the specific affects that vitamins, minerals, amino acids, lipids, and fatty acids have on stem cells, nephrogenesis, and kidney development.
Stress-induced deviations in central nervous system development has long-term effects on adult mental health. Previous research in humans demonstrates that prenatal or adolescent stress increases the risk for psychiatric disorders. Animal models investigating the effects of stress during prenatal or adolescent development produces behavioral outcomes analogous to those observed in humans. However, whether adolescent stress exposure potentiates the effects of prenatal stress is currently unknown. Thus, the current study tested whether adolescent stress increases the impact of prenatal stress on contextual and cued fear memory in adulthood. Male and female Sprague Dawley rats were exposed to a chronic variable stress schedule during the last week of gestation, during adolescence, or during both developmental periods before undergoing fear conditioning training in adulthood. Our hypothesis predicted that the combined effects of prenatal and adolescent stress on contextual and cued fear memory would be greater than the effects of stress during either time period alone. In contrast to our hypothesis, however, we found independent effects of prenatal and adolescent stress on contextual and cued fear memory in both sexes, with no additional combined impact of stress exposure during both developmental phases. In males, developmental stress increased freezing behavior during contextual and cued testing regardless of whether stress exposure was prenatal, adolescent, or combined prenatal and adolescent stress exposure. In contrast, the effects of developmental stress in females were both test- and ovarian hormone status-dependent. During cued testing, nonstressed female freezing behavior depended on estrous cycle phase, whereas freezing behavior in stressed females did not, suggesting that developmental stress interferes with hormone-dependent cued fear memory. No effects of developmental stress or estrous cycle phase were observed for contextual fear memory in females. The results of the current study suggest that the effects of prenatal and adolescent stress on contextual and cued fear memory are not cumulative, but the effects of developmental stress on associative memory differ between males and females.
Background:
Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. Despite early evidence indicating a beneficial effect of antenatal corticosteroids on fetal lung maturation and widespread recommendations to use this treatment in women at risk of preterm delivery, some uncertainty remains about their effectiveness particularly with regard to their use in lower-resource settings, different gestational ages and high-risk obstetric groups such as women with hypertension or multiple pregnancies. This updated review (which supersedes an earlier review Crowley 1996) was first published in 2006 and subsequently updated in 2017.
Objectives:
To assess the effects of administering a course of corticosteroids to women prior to anticipated preterm birth (before 37 weeks of pregnancy) on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life.
Search methods:
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (3 September 2020), ClinicalTrials.gov, the databases that contribute to the WHO International Clinical Trials Registry Platform (ICTRP) (3 September 2020), and reference lists of the retrieved studies.
Selection criteria:
We considered all randomised controlled comparisons of antenatal corticosteroid administration with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following rupture of membranes or spontaneous labour), regardless of other co-morbidity, for inclusion in this review.
Data collection and analysis:
We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion, assessed risk of bias, evaluated trustworthiness based on predefined criteria developed by Cochrane Pregnancy and Childbirth, extracted data and checked them for accuracy, and assessed the certainty of the evidence using the GRADE approach. Primary outcomes included perinatal death, neonatal death, RDS, intraventricular haemorrhage (IVH), birthweight, developmental delay in childhood and maternal death.
Main results:
We included 27 studies (11,272 randomised women and 11,925 neonates) from 20 countries. Ten trials (4422 randomised women) took place in lower- or middle-resource settings. We removed six trials from the analysis that were included in the previous version of the review; this review only includes trials that meet our pre-defined trustworthiness criteria. In 19 trials the women received a single course of steroids. In the remaining eight trials repeated courses may have been prescribed. Fifteen trials were judged to be at low risk of bias, two had a high risk of bias in two or more domains and we ten trials had a high risk of bias due to lack of blinding (placebo was not used in the control arm. Overall, the certainty of evidence was moderate to high, but it was downgraded for IVH due to indirectness; for developmental delay due to risk of bias and for maternal adverse outcomes (death, chorioamnionitis and endometritis) due to imprecision. Neonatal/child outcomes Antenatal corticosteroids reduce the risk of: - perinatal death (risk ratio (RR) 0.85, 95% confidence interval (CI) 0.77 to 0.93; 9833 infants; 14 studies; high-certainty evidence; 2.3% fewer, 95% CI 1.1% to 3.6% fewer), - neonatal death (RR 0.78, 95% CI 0.70 to 0.87; 10,609 infants; 22 studies; high-certainty evidence; 2.6% fewer, 95% CI 1.5% to 3.6% fewer), - respiratory distress syndrome (RR 0.71, 95% CI 0.65 to 0.78; 11,183 infants; studies = 26; high-certainty evidence; 4.3% fewer, 95% CI 3.2% to 5.2% fewer). Antenatal corticosteroids probably reduce the risk of IVH (RR 0.58, 95% CI 0.45 to 0.75; 8475 infants; 12 studies; moderate-certainty evidence; 1.4% fewer, 95% CI 0.8% to1.8% fewer), and probably have little to no effect on birthweight (mean difference (MD) -14.02 g, 95% CI -33.79 to 5.76; 9551 infants; 19 studies; high-certainty evidence). Antenatal corticosteroids probably lead to a reduction in developmental delay in childhood (RR 0.51, 95% CI 0.27 to 0.97; 600 children; 3 studies; moderate-certainty evidence; 3.8% fewer, 95% CI 0.2% to 5.7% fewer). Maternal outcomes Antenatal corticosteroids probably result in little to no difference in maternal death (RR 1.19, 95% CI 0.36 to 3.89; 6244 women; 6 studies; moderate-certainty evidence; 0.0% fewer, 95% CI 0.1% fewer to 0.5% more), chorioamnionitis (RR 0.86, 95% CI 0.69 to 1.08; 8374 women; 15 studies; moderate-certainty evidence; 0.5% fewer, 95% CI 1.1% fewer to 0.3% more), and endometritis (RR 1.14, 95% CI 0.82 to 1.58; 6764 women; 10 studies; moderate-certainty; 0.3% more, 95% CI 0.3% fewer to 1.1% more) The wide 95% CIs in all of these outcomes include possible benefit and possible harm.
Authors' conclusions:
Evidence from this updated review supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. Treatment with antenatal corticosteroids reduces the risk of perinatal death, neonatal death and RDS and probably reduces the risk of IVH. This evidence is robust, regardless of resource setting (high, middle or low). Further research should focus on variations in the treatment regimen, effectiveness of the intervention in specific understudied subgroups such as multiple pregnancies and other high-risk obstetric groups, and the risks and benefits in the very early or very late preterm periods. Additionally, outcomes from existing trials with follow-up into childhood and adulthood are needed in order to investigate any longer-term effects of antenatal corticosteroids. We encourage authors of previous studies to provide further information which may answer any remaining questions about the use of antenatal corticosteroids without the need for further randomised controlled trials. Individual patient data meta-analyses from published trials are likely to provide answers for most of the remaining clinical uncertainties.
Normal placental development and function is of key importance to fetal growth. Conversely aberrations of placental structure and function are evident in pregnancy complications including fetal growth restriction (FGR) and preeclampsia. Although trophoblast turnover and function is altered in these conditions, their underlying aetiologies and pathophysiology remains unclear, which hampers development of therapeutic interventions.
Here we review evidence that supports a role for Estrogen Related Receptor-gamma (ERRγ) in the development of placental dysfunction in FGR and preeclampsia. This relationship deserves particular consideration because ERRγ is highly expressed in normal placenta, is reduced in FGR and preeclampsia and its expression is altered by hypoxia, which is thought to result from deficient placentation seen in FGR and preeclampsia. Several studies have also found microRNA or other potential upstream regulators of ERRγ negatively influence trophoblast function which could contribute to placental dysfunction seen in FGR and preeclampsia. Interestingly, microRNAs regulate ERRγ expression in human trophoblast. Thus, if ERRγ is pivotally associated with the abnormal trophoblast turnover and function it may be targeted by microRNAs or other possible upstream regulators in the placenta.
This review explores altered expression of ERRγ and upstream regulation of ERRγ-mediated pathways resulting in the trophoblast turnover, placental vascularisation, and placental metabolism underlying placental dysfunctions. This demonstrates that the ERRγ pathway merits further investigation as a potential therapeutic target in FGR and preeclampsia.
Perfluorooctane sulfonate (PFOS) is a metabolic-disrupting chemical. There is a strong association between maternal and cord blood PFOS concentrations, affecting metabolism in early life. However, the underlying effects have not been fully elucidated. In this study, using the maternal-fetal model, we investigated the impact of gestational PFOS exposure on the placental structure and nutrient transport. Pregnant mice were oral gavaged with PFOS (1 or 3 μg PFOS/g body weight) from gestational day (GD) 4.5 until GD 17.5. Our data showed a significant reduction in fetal body weight at high dose exposure. There were no noticeable changes in placental weights and the relative areas of junctional and labyrinth zones among the control and exposed groups. However, a placental nutrient transport assay showed a significant reduction in maternal-fetal transport of the glucose and amino acid analogues. Western blot analysis showed a significant decrease in the expression levels of placental SNAT4 upon PFOS exposure. Moreover, in the high-dose exposed group, placenta and fetal livers were found to have significantly higher corticosterone levels, a negative regulator of fetal growth. The perturbation in the placental transport function and corticosterone levels accounted for the PFOS-induced reduction of fetal body weights.
Alterations in the circadian cycle are known to cause physiological disorders in the hypothalamic–pituitary–adrenal and the hypothalamic–pituitary–gonadal axes in adult individuals. Therefore, the present study aimed to evaluate whether exposure of pregnant rats to constant light can alter the reproductive system development of male offspring. The dams were divided into two groups: a light–dark group (LD), in which pregnant rats were exposed to an LD photoperiod (12 h/12 h) and a light–light (LL) group, in which pregnant rats were exposed to a photoperiod of constant light during the gestation period. After birth, offspring from both groups remained in the normal LD photoperiod (12 h/12 h) until adulthood. One male of each litter was selected and, at adulthood (postnatal day (PND) 90), the trunk blood was collected to measure plasma testosterone levels, testes and epididymis for sperm count, oxidative stress and histopathological analyses, and the spermatozoa from the vas deferens to perform the morphological and motility analyses. Results showed that a photoperiod of constant light caused a decrease in testosterone levels, epididymal weight and sperm count in the epididymis, seminiferous tubule diameter, Sertoli cell number, and normal spermatozoa number. Histopathological damage was also observed in the testes, and stereological alterations, in the LL group. In conclusion, exposure to constant light during the gestational period impairs the reproductive system of male offspring in adulthood.
Fetal programming describes the relationship between the influence of exogenous and endogenous factors in sensitive phases of fetal development and cell growth and organ development, ultimately resulting in a persistent postnatal change in organ and tissue function. Errors in this process can be associated with the appearance of diseases in later life. Suboptimal intrauterine conditions such as maternal malnutrition, hypoxia, psychological stress, or glucocorticoid (GC) exposure during pregnancy can have lasting effects on fetal development and are often associated with a reduction in birth weight. The possible spectrum of late effects is wide ranging. Antenatal GC treatment appears to be associated with gender-specific fetal growth restriction as well as structural and functional changes in the placenta that can potentially affect health later in life. While female fetuses seem to have a rather continuous sensitivity to GC, possibly in the sense of a preferential survival strategy to ensure reproductive ability with preservation of species, in male fetuses, the placenta seems to develop, at least temporarily, a resistance to GC after GC exposure. The gender-specific sensitivity to GC is probably caused by a different GR (glucocorticoid receptors) distribution pattern, expression, and/or interaction and influenced by treatment with GC. An improved understanding of the placenta-mediated signaling pathways that contribute to fetal programming will be critical in efforts to develop interventional strategies for high-risk groups.
A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
The pharmacologic parameters and toxicity of netilmicin (6 mg/kg/day) given once daily (qd) or thrice daily (tid) for the treatment of urinary tract infections were studied in a randomized prospective study of 60 cancer patients. The overall efficacy was 96%. Nephrotoxicity, assessed by the measure of urinary excretion of phospholipids, was lower for the patients receiving the qd regimen than for those receiving the tid regimen. Elevation of serum creatinine (20% over baseline) occurred in one patient receiving the qd regimen and in three receiving the tid regimen. Cochleotoxicity, assessed by pure-tone audiometry (250 to 18,000 Hz) occurred in one patient receiving the qd regimen and none receiving the tid regimen. Concentrations in sera were measured on days 1 and 5. No significant accumulation was observed in either group. Median serum bactericidal titers, expressed as reciprocal values (percentage of the sera with a titer greater than or equal to 8), were measured against 25 test organisms in samples collected 6 h after the administration of netilmicin and were, for the qd group, 16 (82%) against members of the family Enterobacteriaceae and less than 2 (8%) against Pseudomonas aeruginosa, and for the tid group, 4 (57%) against members of the Enterobacteriaceae and less than 2 (0%) against P. aeruginosa. The rate of killing in serum was rapid (2 to 3 log in 2 h against P. aeruginosa; 3 to 5 log in 2 h against members of the Enterobacteriaceae) and correlated with the sampling time and hence the concentration in serum of netilmicin. The duration of the postantibiotic effect in serum depended also on the strain and the sampling time of the serum.
The developmental growth of the rat placenta was investigated between days 14 and 21 of gestation in normal control, gestational-diabetic, established-diabetic, and insulin-maintained-diabetic mothers. While established-diabetic mothers were hyperglycemic for 2 wk before and throughout the pregnancy, gestational-diabetic mothers were only hyperglycemic for the second half of pregnancy. Daily insulin replacements successfully restored normoglycemia. The wet weight and protein content of control placentas increased linearly between days 14 and 21. Although placentas from diabetic animals were initially smaller, placentomegaly was found at full term. Placental glycogen concentrations were also markedly increased in all diabetic animals. These changes were largely prevented by insulin replacement. The changes in placental size during normal development and in association with the diabetic state were explained by measuring placental rates of protein turnover (in vivo). In normal placentas, protein synthetic and degradative rates progressively declined over the last week of gestation. Because synthesis rates were unchanged in placentas of diabetic mothers, it appears that the differences in placental size primarily arise from alterations in protein degradation.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
A table of exact 95 percent confidence limits for differences and ratios of two proportions and their odds ratio, including one-tailed P values for the Fisher-Irwin exact test, is given for a wide variety of 2 × 2 tables with sample sizes of 20(20)100. The calculations are based on Fisher's [3] conditional theory, and the computer algorithm of Thomas [10 or 11] is used to produce the tables. It is shown how the tables may be used for sample size determination without fixing the power for a given alternative hypothesis.
Once-daily dosing of aminoglycosides has been suggested to improve their efficacy and reduce their toxicity. To test the clinical validity of this suggestion, we conducted a prospective, randomized trial comparing a conventional multiple-daily-dosing regimen of netilmicin with once-daily administration of the same total daily dose of this aminoglycoside.
We enrolled 141 predominantly elderly patients with severe bacterial infections. All patients received once-daily doses of 2 g ceftriaxone, in addition to netilmicin.
Patients randomized to either of the two dosing strategies were comparable regarding age, APACHE II score, concomitant diseases, infection site, and rate of culture-proven bacteremia. Netilmicin treatment did not differ significantly in mean daily dose per kg body weight and days of therapy between the two treatment arms. Compared to patients receiving conventional doses, patients treated with a once-daily dose had higher serum peak netilmicin levels and lower trough levels. Outcome of infection and mortality were not influenced by dosing strategy. Although the overall incidence of nephrotoxicity was similar in both groups (16%), the occurrence of nephrotoxicity in patients treated with once-daily doses of netilmicin was significantly shifted to those given prolonged treatment, i.e., beyond 9 days. Auditory toxicity was documented in one patient treated with conventional doses and two patients treated with once-daily doses.
Once-daily dosing of an aminoglycoside plus a long-acting cephalosporin in these patients constituted cost-effective and safe treatment for severe bacterial infections. Netilmicin-induced toxicity may be reduced by using once-daily dosing regimens and limiting the duration of treatment.
The pathogenesis of aminoglycoside nephrotoxicity is intimately related to the extent of drug accumulated in the renal cortex. In the framework of searching for preventive measures of aminoglycoside-induced nephrotoxicity, we investigated the influence of dosage regimen on the renal cortical accumulation of gentamicin and netilmicin in humans. Patients with a tumor partly involving one kidney, with normal renal function, and scheduled for nephrectomy received one dose of either gentamicin (4.5 mg/kg) or netilmicin (5 mg/kg) as a single short-term infusion or as 24-hour continuous infusion. Treatment started 24 hours before surgery. Serum aminoglycoside pharmacokinetics were examined during treatment and renal cortical tissue was sampled at the moment of operation for drug determination. The short-term infusion schedule yielded cortical concentrations of 103.2 36.3 and 137.4 34.6 g/gm for gentamicin and netilmicin, respectively. Tissue levels after continuous infusion were 158.1 52.9 and 178.5 21.8 g/gm for gentamicin and netilmicin, respectively. For each aminoglycoside, a single short-term infusion resulted in significantly lower renal drug levels than did a continuous infusion of the same dose. From the nephrotoxicity point of view, these data support the administration of gentamicin and netilmicin as once-daily injections. This also supports the appropriateness of further studies to determine clinical efficacy of once-a-day dosing for aminoglycosides.
11β-Hydroxysteroid dehydrogenase activity (E.C. 1.1.1.146) was studied in homogenates of placenta, fetal membranes and decidua obtained at term, using cortisol and cortisone as substrates. For activity in the direction cortisol to cortisone, the distribution of enzyme was choriodecidua > placenta. While choriodecidua catalysed the conversion in both directions, cortisone reduction was negligible in placenta. Amnion contained no measurable enzyme, using either substrate. The activity in the choriodecidua was thought to be of decidual rather than chorionic origin. In both decidua and placenta, the enzyme was localised by subcellular fractionation in the microsomal fraction, and microsomal fractions were used to study the dependence of activity on pH, substrate and enzyme concentration and the inhibitory effect of other steroids. Data on the KM values for cortisol and the inhibition of the enzyme by some steroids, notably androgens, suggest that the enzymes in decidua and placenta may be different. The findings are discussed in relation to the possible role of the enzyme in the control of fetal corticosteroid concentrations.
Peak serum levels of gentamicin were varied in rats by administering a standard nephrotoxic dosage of 40 mg/kg per day in
one (QD), two, or three (TID) daily doses. The QD animals had the highest peak serum levels but showed no appreciable increase
of serum creatinine concentrations over a lO-day treatment period. The TID rats had the lowest peak serum levels, but, after
10 days of drug administration, the serum creatinine concentration (2.8 ± 0.2 mg/IOO ml, mean ± SE) was significantly higher
than in control rats (0.6 ± 0.01 mg/IOO ml) (P < 0.001). After two days of gentamicin treatment, the renal concentration of gentamicin was 269 ± 77 μg/g in the QD rats
and 820 ± 29 μg/g in the TID rats (P < 0.001). In this rat model, the frequency of doses was a more important factor in the development of nephrotoxicity than
the peak serum concentration of gentamicin. The results suggest that dose frequency should be considered when data from different
laboratories are compared.
Prednisone treatment for infertility and subsequent pregnancy maintenance in humans resulted in a significant decrease in
the birth weight of full-term infants and a marked increase in the percentage of newborn infants weighing 2500 grams or less,
that is, "light for dates" in comparison to control offspring. A parallel experiment with mice indicated that the reduction
of birth weight was caused by exposure to corticosteroids rather than to maternal disease or malfunction.
Recent studies that emphasize the unpredictability of gentamicin serum concentrations have cast doubt on the accuracy of commonly used dosing nomograms. We therefore developed a digital computer program to evaluate gentamicin pharmacokinetics and have tested its ability to predict correctly gentamicin serum levels under clinical conditions. A significant relation (P less than .001) was found between 130 measured (bioassayed) and computer predicted levels from 40 patients. Serum levels were reliably estimated in patients with unstable renal function and were statistically, but not clinically, affected by changes in hematocrit. The calculation of volume of distribution on the basis of the patient's lean body weight rather than total body weight was an important factor that contributed to the accuracy of the predicted level. A new dosing chart is presented that incorporates the important variables affecting gentamicin pharmacokinetics into an easily used, convenient form.
The pathogenesis of aminoglycoside nephrotoxicity is directly related to the accumulation of drug within the renal cortex. To identify measures that might prevent aminoglycoside nephrotoxicity, we investigated the influence of various dosage regimens on the renal cortical accumulation of amikacin and tobramycin in man. Patients undergoing nephrectomy for a renal tumour with normal renal function and no proteinuria received (i) a single dose of either amikacin (15 mg/kg) or tobramycin (4.5 mg/kg) given iv over 30 min, or (ii) a 24-h continuous infusion of either drug or (iii) amikacin as two injections of 7.5 mg/kg or tobramycin as three injections of 1.5 mg/kg over the 24 h preceding nephrectomy. Serum aminoglycoside pharmacokinetics were examined and renal cortical tissue was sampled for drug determination at operation. A single injection yielded cortical concentrations of 115.4 +/- 21.8 and 68.9 +/- 30.3 mg/kg for amikacin and tobramycin, respectively. Tissue levels after continuous infusion were 171.7 +/- 42.9 and 100.0 +/- 30.0 mg/kg for amikacin and tobramycin, respectively. Two injections of 7.5 mg/kg amikacin resulted in renal cortical concentrations of 196.9 +/- 54.9 and three injections of 1.5 mg/kg tobramycin resulted in renal cortical concentration of 76.5 +/- 18 mg/kg. The AUC for the three dosage regimens was not significantly different for the two aminoglycosides indicating linear serum pharmacokinetics for these drugs. In the case of amikacin, a single injection resulted in significantly lower drug levels than did a continuous infusion or administration of the same dose over three injections.(ABSTRACT TRUNCATED AT 250 WORDS)
Two hundred and twenty patients with serious infections verified or suspected to be of Gram-negative aetiology were treated in an open randomized comparative multicentre trial with amikacin 15 mg/kg/day given either as a single dose or in two divided doses at 12-h intervals. Amikacin was administered as a short-term iv infusion. When additional therapy was considered necessary piperacillin or ampicillin was recommended. The trial continues and an interim report on data from the 12 participating Scandinavian hospitals is presented. One hundred and forty-four patients have been evaluated for efficacy and 213 patients for safety. There were no significant differences between the two dosage regimens regarding efficacy and safety. A satisfactory clinical response was recorded in 129 (90%) of the evaluable patients. One serious adverse reaction was seen in a patient in the once-daily group. This was ototoxicity which was superimposed on a long standing hearing defect possibly caused by previous streptomycin therapy.
One hundred and ninety-seven patients with intraabdominal infections were enrolled in a prospective randomized multicenter study of netilmicin administered once daily (n = 98) versus thrice daily (n = 99) in combination with tinidazole administered once daily. Randomization was achieved for the infection site, clinical severity score, daily and total netilmicin dose, and duration of treatment. The mean maximum peak and trough levels of netilmicin in serum were 21.1 and 1.3 mg/l respectively for once daily treated patients, and 10.0 and 2.3 mg/l for thrice daily treated patients (p less than 0.05 for both parameters). The clinical response did not differ between patients treated once daily and those treated thrice daily. Overall rates for clinical cure, improvement and failure of therapy were 77%, 17% and 6% respectively. No significant differences were found between once daily and thrice daily regimens in the occurrence of auditory, vestibular and renal toxicity, overall rates being 5%, 1% and 10% respectively. Impairment of renal function was significantly related to higher maximum netilmicin serum trough levels during therapy, a higher clinical severity score and advanced age. It is concluded that netilmicin given once daily is as effective and safe as the multiple dose regimen. However, monitoring of aminoglycoside serum through levels is still advisable, especially in the old and severely ill patient.
1. We have investigated 22 patients receiving gentamicin, mean (s.d.) age 78 (6) years for auditory toxicity, using a standard audiometric technique in a sound-treated room (Study 1). 2. Use of a portable audiometer might allow a larger and more representative proportion of patients treated with aminoglycosides to be screened for ototoxicity. A method for detecting high frequency loss suitable for use in the ward was evaluated in 12 volunteers aged 27 (4) years (Study 2). 3. The error inherent in taking hearing at the start of treatment as a reference point was measured in 16 patients, aged 81 (8) years, prescribed non-ototoxic antibacterials (Study 3). 4. A significant (P = 0.05) reduction in hearing threshold was detected in Study 1, although psychometric tests revealed unchanged or improved ability to co-operate. This occurred only at 4000 Hz, the highest frequency used. The magnitude of this loss, mean 2.5 dB, was similar to that of the improvement in threshold detected (P = 0.0004) early in the course of treatment in Study 3. Thus, underestimation of ototoxicity is likely. 5. If a change of threshold of 10 dB or more is taken arbitrarily to represent a real change in hearing, then there was a significant excess of patients in Study 1 with losses at 4000 Hz only (P = 0.032). The six with such losses at this frequency were older than the rest. However, there was a significant (P less than 0.02) positive correlation between log mean predose serum gentamicin concentration and age. Thus, it remains to be determined whether presbyacusis sensitizes those hair cells which it does not destroy to toxic damage. 6. The cumulative dose of gentamicin (for a course of the duration given) was calculated according to published prescribing aids. There was no systematic reduction in the ratio of the dose recommended by a given aid to the dose prescribed in the six with hearing losses as defined above. 7. In Study 2, thresholds obtained at 6000 Hz in the open ward were, on average, 0.9 dB higher than in the sound treated room, but the effect of venue did not reach statistical significance. In the morning thresholds were marginally, but significantly (P = 0.04), lower than in the afternoon. Precision, as measured by the standard deviation of replicate determination, was independent of test conditions. Using multiple (ten) threshold determinations appeared to improve resolution.(ABSTRACT TRUNCATED AT 400 WORDS)
To study the effect of intrauterine growth and maternal physique on blood pressure in adult life.
A follow up study of infants born 50 years previously whose measurements at birth were recorded in detail.
Preston, Lancashire.
449 Men and women born in hospital in Preston during 1935-43 and still living in Lancashire.
Placental weight, birth weight, and blood pressure at age 46 to 54 years.
In both sexes systolic and diastolic pressures were strongly related to placental weight and birth weight. Mean systolic pressure rose by 15 mm Hg as placental weight increased from less than or equal to 1 lb (0.45 kg) to greater than 1.5 lb and fell by 11 mm Hg as birth weight increased from less than or equal to 5.5 lb to greater than 7.5 lb. These relations were independent so that the highest blood pressures occurred in people who had been small babies with large placentas. Higher body mass index and alcohol consumption were also associated with higher blood pressure, but the relations of placental weight and birth weight to blood pressure and hypertension were independent of these influences.
These findings show for the first time that the intrauterine environment has an important effect on blood pressure and hypertension in adults. The highest blood pressures occurred in men and women who had been small babies with large placentas. Such discordance between placental and fetal size may lead to circulatory adaptation in the fetus, altered arterial structure in the child, and hypertension in the adult. Prevention of hypertension may depend on improving the nutrition and health of mothers.
The developmental growth of the rat fetus was studied between days 14 and 21 of pregnancy in normal control, established-diabetic, gestational-diabetic, and insulin-maintained-diabetic mothers. Measurements of fetal body weights and protein mass revealed a suppression of growth in the diabetic pregnancies, probably arising from reduced hyperplasia. Growth of the liver and skin appeared to be suppressed in proportion to the whole fetus, whereas the lung, brain, and particularly the heart were relatively well protected from growth retardation. Fetal growth during development, and its retardation in association with the hyperglycemic state, was explained by measuring the rates of fetal protein turnover in vivo. Both the protein synthetic and degradative rates gradually declined during normal development. However, in the diabetic pregnancies, fetal protein synthesis was consistently lower than control rates, whereas protein degradation increased sharply toward the end of gestation. These changes in protein synthesis and breakdown probably combine to yield a smaller fetus in the absence of normoglycemia.
Environmental influences that impair growth and development in early life may be risk factors for ischaemic heart disease. To test this hypothesis, 5654 men born during 1911-30 were traced. They were born in six districts of Hertfordshire, England, and their weights in infancy were recorded. 92.4% were breast fed. Men with the lowest weights at birth and at one year had the highest death rates from ischaemic heart disease. The standardised mortality ratios fell from 111 in men who weighed 18 pounds (8.2 kg) or less at one year to 42 in those who weighed 27 pounds (12.3 kg) or more. Measures that promote prenatal and postnatal growth may reduce deaths from ischaemic heart disease. Promotion of postnatal growth may be especially important in boys who weigh below 7.5 pounds (3.4 kg) at birth.
This multicentric, randomized, double-blind trial compared the efficacy and safety of netilmicin, 4.5 mg/kg od and 1.5 mg/kg tid, in patients with intra-abdominal infections. Of 114 patients enrolled, 57 patients (mean age 40.3 years) in the od group and 55 (mean age 36.8 years) in the tid group were evaluated for efficacy; 58 and 56 patients in corresponding groups were evaluated for safety. Among those evaluated for efficacy were 12 od-treated and 11 tid-treated patients with documented septicaemia, and 32 and 30 patients of respective groups with polymicrobial infections. Initially, 86 and 81 netilmicin-susceptible causative microorganisms were isolated in corresponding groups. Of these pathogens, 55% in the od group and 62% in the tid group were Escherichia coli. Daily dosage of netilmicin ranged from 3.70 to 4.71 mg/kg (mean 4.50) for the od group and from 3.06 to 4.76 mg/kg (mean 4.46) for the tid group. Duration of netilmicin therapy ranged from six to 13 days (mean 8.7 days) for od-treated patients and from seven to 16 days (mean 8.8 days) for tid-treated patients. Concomitant metronidazole was administered to 41 patients of the od group and 34 of the tid group; one patient in the tid group received clindamycin. Clinical and bacteriological responses were assessed, and peak and trough serum netilmicin levels were measured periodically, during therapy. Laboratory tests, including determinations of serum creatinine and blood urea nitrogen values, were performed throughout the trial. A clinical cure was achieved in 57/57 od-treated patients and 54/55 tid-treated patients; treatment failed in one tid-treated patient (1/55). In od and tid groups, 86/86 and 80/81 netilmicin-susceptible pathogens initially isolated were considered to be eliminated, respectively; one isolate (Esch. coli) persisted in the tid group. Mean peak serum netilmicin concentration in the od group was approximately two-fold greater than that in the tid group; mean trough serum netilmicin concentrations were similar for the two groups. Adverse reactions were limited to mild pain at the site of netilmicin administration in several patients in each treatment group. Netilmicin od and tid (alone or in combination with metronidazole) were similarly efficacious in the treatment of patients with appendicitis and other intra-abdominal infections caused by netilmicin-susceptible pathogens. Both dosage regimens of netilmicin were safe and well tolerated.
Seventy patients with culture-proven bacteremia with gram-negative rods were randomly treated with either a single (S) dose
daily or multiple (M) doses daily of netilmicin. All bacterial strains were susceptible to the antibiotic. No differences
were found with respect to efficacy. Therapy for bacteremia failed in two M patients, but bacteria persisted in 17 (10 S,
7 M) at the primary infection site. In 12 there was an anatomic or physiologic factor contributing to this persistence. One
S patient showed mild nephrotoxicity, but ototoxicity was not found in any of the 35 patients who underwent serial audiography,
Mild reversible rises of transaminases were found in 5 of 35 S patients and in 3 of 34 M patients. Once-daily administration
of netilmicin seems to be as effective and as safe as conventional multiple daily doses.
Glucocorticoid-induced hypertension in rats has been studied using long-term, low-dose dexamethasone treatment. Dose-related increases in systolic blood pressure were achieved, without loss in body weight, with subcutaneous continuous infusions of 1, 2 and 5 micrograms dexamethasone per day, respectively, for 4 weeks. Rats treated with 10 micrograms dexamethasone per day lost weight at a rate of 10 g per week. Lower doses caused a significant reduction in weight gain compared with controls. Renin, aldosterone, plasma sodium and potassium concentrations were unaffected by dexamethasone treatment. Plasma atrial natriuretic peptide (ANP) concentrations were decreased by 40-50% by dexamethasone. These decreases were negatively correlated with increases in systolic blood pressure and haematocrit. Glucocorticoid-induced decreases in ANP contrast with ANP increases in response to mineralocorticoid treatment in rats with deoxycorticosterone-induced hypertension. Plasma concentrations of the endogenous glucocorticoid, corticosterone, were suppressed to the same very low levels by 5 and 10 micrograms dexamethasone per day; 1 and 2 micrograms doses were less effective. Unlike mineralocorticoid-induced hypertension, the pressor effects of dexamethasone were ameliorated but not abolished by dietary sodium restriction and were unaffected by sodium loading. Two micrograms of dexamethasone reduced plasma ANP in rats on either high- or low-sodium diets by 29 and 34%, respectively. We conclude that low-dose infusions (less than 5 micrograms/day) of dexamethasone are suitable for studying glucocorticoid-induced hypertension without the complications of weight loss that have been reported by others or of the mineralocorticoid-like side effects which endogenous glucocorticoids may exhibit.
Ten patients received a 30-min infusion of amikacin (30 mg/kg) on day 1 and 15 mg/kg on day 2. Mean serum creatinine was 1.1 +/- 0.3 (standard deviation) mg/dl before and 1.0 +/- 0.3 mg/dl 3 days after the second infusion. Mean serum amikacin concentrations before, at the end of infusion, and 1, 6, 12, and 24 h after 30 and 15 mg/kg were 0, 157, 79, 31, 16, 5, 5, 85, 51, 19, 12, and 5 mg/liter, respectively. Five strains each of Staphylococcus aureus, Staphylococcus epidermidis susceptible and resistant to oxacillin, Streptococcus (Enterococcus) faecalis, corynebacterium sp. strain JK, Listeria monocytogenes, Mycobacterium fortuitum (three strains), Klebsiella pneumoniae, Serratia marcescens, Acinetobacter calcoaceticus, and Pseudomonas aeruginosa were tested. Serum bactericidal activities (SBAs) were greater than or equal to 1:8 in greater than or equal to 80% of the sera 1 and 6 h after 30 mg/kg and in greater than or equal to 60% of the sera 1 and 6 h after 15 mg/kg against Staphylococcus aureus and Staphylococcus epidermidis susceptible to oxacillin, A. calcoaceticus, and K. pneumoniae. L. monocytogenes, Serratia marcescens, and P. aeruginosa had lower SBAs. Very low or no activity was observed against oxacillin-resistant staphylococci and Streptococcus faecalis. The study of the killing rate in serum confirmed these results. Postantibiotic effect was studied by incubating a strain from each species in serum samples obtained 1 and 6 h after both regimens for 0.5, 1, or 2 h. The duration of postantibiotic effect depended on the duration of contact and the concentration of amikacin for the following organisms: oxacillin-susceptible staphylococci, L. monocytogenes, P. aeruginosa, A. calcoaceticus, K. pneumoniae, and Serratia marcescens. M. fortuitum was killed after 30 min of contact. No postantibiotic effect was observed with Streptococcus faecalis, Corynebacterium sp. strain JK, or oxacillin-resistant staphylococci. Amikacin at 30 mg/kg provided high levels and SBAs against susceptible pathogens. Prolonged postantibiotic effects were observed. No signs of nephrotoxicity occurred.
The postantibiotic effect (PAE) is the suppression of bacterial growth that persists after limited exposure of organisms to
antimicrobial agents. Wedemonstrated and standardized the in vivo PAE in a thigh infection model in neutropenic mice. Inhibitors
of protein and nucleic acid synthesis induced PAEs of 1.4–7.5 h against aerobic gram-negative bacilli, whereas β-lactam antibiotics
did not induce significant PAEs. Against aerobic gram-positive cocci, cell wall-active agents and inhibitors of protein and
nucleic acid synthesis induced PAEs of 1.2–7.1 h, except for penicillins, which did not induce PAEs against streptococci.
With few exceptions the in vivo PAE correlated well with the PAE reported in prior in vitro studies. Residual drug in thigh
tissue did not cause the PAE. Theoretically, the presence of a PAE may allow antimicrobial agents to be given more intermittently
without organism regrowth after drug levels fall below the minimal inhibitory concentration.
Forty-five mostly elderly patients with serious infections were treated in a prospective, comparative and randomized pharmacokinetic study with amikacin 11.0 or 15.0 mg/kg administered in a single daily dose as an intravenous, short-term infusion or with amikacin 7.5 mg/kg administered twice daily in the same way.
The results indicate that administration of amikacin 15 mg/kg in a single daily dose should be a practical and safe principle of administration. However elderly patients often have reduced creatinine clearance and should preferably be given a lower dose of 11 mg/kg bw.
The risk of nephrotoxicity did not increase, but conclusions on ototoxicity and clinical efficacy cannot be drawn from this limited study. This should be considered as an initial part of a future multicentre trial.
Single, large, daily aminoglycoside doses in animals are less toxic than conventional dosing, and higher drug concentrations
in vitro produce more-rapid bacterial killing. Thus, we compared various aminoglycoside dosing schedules in neutropenic (n = 153)and nonneutropenic (n = 192) guinea pigs with Pseudomonas aeruginosa pneumonia. Equivalent tobramycin dosages were given: 5 mg/kg every 4 h or 30 mg/kg every 24 h. Animals were serially killed
during therapy, and quantitative lung cultures were performed. Bacterial titers in lungs dropped rapidly in all tobramycin-treated
animals, both neutropenic and nonneutropenic, during the initial 16 h of therapy. In nonneutropenic guinea pigs, lung titers
remained constant despite continued 4-h dosing. With subsequent 24-h dosing, titers continued to drop, and by 72 h there were
a significant number of animals with sterile lungs (P < .01). In neutropenic guinea pigs given tobramycin every 24 h, bacterial regrowth occurred; thus, therapy was ineffective.
Adding mezlocillin, however, suppressed regrowth; thus, combination therapy was superior (P < .05).
This investigation examined the effects of Streptozotocin diabetes in pregnancy on several parameters of glucocorticoid action in the rat placenta. Pregnant diabetic rats showed reduced body weight, increased adrenal weight and serum corticosterone concentrations. Glucocorticoid receptors in placental cytosol of labyrinthine zone, measured in the absence of MoO4Na2 were similar in control and diabetic rats, but after addition of MoO4Na2 receptor number were moderately, but significantly reduced in diabetic placentas (P less than 0.01). No changes in affinity were detected in saturation analysis. Furthermore, transformation of the receptor assessed by its capacity for binding to DNA-cellulose, was enhanced in diabetic animals, suggesting increased efficiency of the receptor-bound hormone. Since the function of the glucocorticoid receptor of rat placenta may be the inhibition of local progesterone production (Heller and De Nicola, J. steroid Biochem. 19 (1983) 1339-1343), we determined progesterone synthesis in vitro and found that diabetic placentas synthesized significantly less progesterone than control tissue (P less than 0.05). Lastly, we found that the metabolism of corticosterone to 11-dehydrocorticosterone, while declining in control placentas as pregnancy advanced, it was sustained in diabetic pregnancy. It is suggested that diabetic rat placentas showed increased activity towards the glucocorticoid receptor, resulting in reduction in progesterone synthesis and sustained catabolism of corticosterone. The latter may possibly constitute a compensatory mechanism to protect the fetal compartment from high levels of maternal glucocorticoids.
Tobramycin 5.1 mg/kg/day was administered for 9 days to 20 healthy human volunteers to determine the potential vestibulotoxicity of once daily versus thrice daily treatment regimens. Vestibular function was tested carefully before, during, and following drug administration, using a battery of postural and caloric tests.
Although subjects receiving the once daily regimen performed better on the postural tests, we feel this does not necessarily indicate an adverse effect in either group. The caloric test was the primary measure of vestibular function in this experiment, and this test appeared to demonstrate a slight adverse effect during drug administration of equal magnitude in both treatment groups.
The results of this experiment indicate that there is no significant difference in the risk of adverse vestibular effects between once daily and thrice daily tobramycin administration.
The kinetics of entry and release of gentamicin was investigated in fluids and tissues of the inner ear of the rat, as well as in renal cortex, and in organs that do not share susceptibility to the toxic effects of aminoglycosides. Various modes of administration were used to achieve different patterns of drug plasma concentrations. Electrophysiological and histological examinations were performed to correlate pharmacokinetics and ototoxicity. Results show that: the uptake of the drug by the inner ear tissues is dose dependent and manifests a rapid saturation kinetics with a concentration plateau of about 1 micrograms/mg of protein. The low ratio of the perilymph and endolymph to plasma concentrations argues against the concept of an accumulation of the drug in the inner ear over drug levels in plasma, which has been considered as the basic mechanism of ototoxicity. In renal cortex, the kinetics appears similar to that of the inner ear but the concentrations achieved are 10-fold higher than in cochlear tissues. In other organs (liver, heart, lung, and spleen), no saturation could be demonstrated within the duration of the experiment. Ototoxicity seems to be related to the penetration of the drug into compartment(s) from which the half-life of disappearance is extremely slow. Rapid uptake, early saturation, and long exposure of the tissues to the drug may account for the development of toxicity in inner ear and kidney.
The effect of chronic ethanol intake during gestation was studied in rats fed a liquid diet in which ethanol provided 36% of the total calories. The animals were chronically alcoholised before mating, and the body weight gain and nutritional status during pregnancy were noted. Blood ethanol levels were measured during pregnancy and parturition. Specifically, we have shown that chronic ethanol intake during pregnancy lengthens the gestation period, decreases foetal viability, increases the placental weight and diminishes foetus, liver and brain weights, as well as the protein and DNA content of foetal brain. The reduced body weight of rats prenatally exposed to alcohol continued for the first two months of the postnatal period and was most apparent during lactation.
Extract: A constant infusion of 14C-cortisol and 3H-cortisone for 4 hr was given to six pregnant women, at term, at the time of elective cesarean section. Radioactive and nonradioactive cortisol (F) and cortisone (E) concentrations were determined in maternal and cord plasma at the time when the concentration of the radioactive steroids had reached a plateau. Metabolic clearance rates (MCR), plasma levels of endogenous F and E, blood production rates (BP), conversion ratios (Cr), and transfer constants ([ρ]BB values) were calculated and compared with those obtained in eight nonpregnant women, half of whom took contraceptive medication (subjects taking “the pill”) and half of whom did not (control subjects).
The present survey of aminoglycoside nephro- and ototoxicity covers approximately 10,000 patients reported on in clinical trials published between 1975 and 1982. Included in the survey were clinical trials with at least 15 patients evaluable for nephro and/or ototoxicity provided relevant data were given on methodology, patient material and aminoglycoside dosage. Each publication was evaluated by both investigators and relevant data entered into a chart. One hundred and forty-four published trials were surveyed; 139, 63 and 34 for renal, cochlear and vestibular side effects, respectively. Frequencies were calculated as number of patients with side effect of total number of evaluated patients. In the average overall figures toxicity labelled by respective authors as 'definitely', 'probably' and 'possibly' related to study drug is included. When available, frequencies of toxicity 'definitely' and 'probably' related to study drug were analysed separately. The average daily dosages of gentamicin, tobramycin, netilmicin and amikacin were 3.9, 3.8, 5.2 and 15.4 mg/kg, respectively. The average frequencies of nephrotoxicity for gentamicin and tobramycin were 14.0 and 12.9%, respectively, and of netilmicin and amikacin 8.7 and 9.4%, respectively. The average frequency of cochlear toxicity was 13.9% for amikacin, 8.3 and 6.1% for gentamicin and tobramycin, respectively, and 2.4% for netilmicin. The material available for evaluation of vestibular toxicity was considerably smaller. The average frequencies for gentamicin, tobramycin and amikacin were similar (3.2 to 3.7%) while netilmicin again exhibited a somewhat lower figure (1.4%). The overall figures and the clinical ranking that they imply were basically substantiated when prospective comparative trials were analysed separately. However, some inconsistencies go unexplained: for example the frequency of gentamicin nephrotoxicity was markedly higher in trials where it was compared to tobramycin (20 trials) than when it was compared to netilmicin (16 trials).
The dosing frequency of aminoglycoside antibiotics may alter efficacy and toxicity independent of total daily dose. Once-daily
tobramycin dosing was compared with continuous infusion in three models of efficacy. Acute pneumonia due to Pseudomonas aeruginosa in guinea pigs responded better to once-daily dosing, and chronic pneumonia in rats and endocarditis in rabbits responded
equally to both regimens. Dogs given gentamicin, tobramycin, or netilmicin once daily, with maximum serum concentrations of
>100 mg/liter, had less nephrotoxicity than dogs given continuous infusions. Tobramycin was given once daily or continuously
to 52 patients with cystic fibrosis who in 10 days had no change in creatinine clearance or hearing despite maximum serum
tobramycin concentrations of 40 mg/liter. Intermittent dosing of aminoglycosides, causing infrequent large maximum serum concentrations,
may be less toxic and equally efficacious as frequent dosing.
Two hundred fifty-eight patients with suspected sepsis were treated with tobramycin or gentamicin in a prospective, randomized, double-blind trial. One hundred forty-six patients received nine or more doses, had serial determinations of serum creatinine, and were evaluated for nephrotoxicity; 91 were able to cooperate with audiometry and were evaluated for auditory toxicity. Auditory toxicity developed in five of 47 (10 per cent) given gentamicin and five of 44 (11 per cent) given tobramycin. Nephrotoxicity developed in 19 of 72 (26 per cent) given gentamicin and nine of 74 (12 per cent) given tobramycin (P less than 0.025). The severity of the nephrotoxicity was not different; the mean increase in creatinine was 1.3 mg per 100 ml (114.9 mumol per liter) in both groups. Both the tobramycin and gentamicin groups had a similar mean age, initial serum creatinine level, total dose, serum aminoglycoside level, and duration of therapy. We conclude that tobramycin causes nephrotoxicity less frequently than does gentamicin.
Low birthweight is associated with the subsequent development of common disorders of adult life, especially hypertension; maternal malnutrition has been suggested as the cause. We suggest an alternative aetiology—increased fetal exposure to maternal glucocorticoids. This hypothesis is supported by our findings that in rats decreased activity of the enzyme that acts as a placental barrier to maternal glucocorticoids (11 β-hydroxysteroid dehydrogenase) is associated with low birthweight. Furthermore, increased exposure of the fetus to exogenous glucocorticoids leads to low birthweight and subsequent hypertension in the offspring. Glucocorticoids acting during critical periods of prenatal development may, like other steroid hormones, exert organisational effects or imprint patterns of response that persist throughout life. Thus, the lifetime risk of common disorders may be partly determined by the intrauterine environment.
Postantibiotic effects
- Vogelman
- Bs
- Craig
- Wa
Vogelman BS, Craig WA. Postantibiotic effects. J Antimicrob Chemother 1985; 15 (suppl A): 37-46.
Aminoglycoside-induced hearing loss in humans Weight in infancy and death from ischaemic heart disease
- Brummett Re
- Fox
- Barker
- Osmond C Djp
- Pd Winter
Brummett RE, Fox KE. Aminoglycoside-induced hearing loss in humans. Antimicrob Agents Chemother 1989; 33: 797-800. REFERENCES 1. Barker DJP, Osmond C, Winter PD, Margetts B. Weight in infancy and death from ischaemic heart disease. Lancet 1989; ii: 577-80.
Maternal diabetes in rats: I, effects on placental growth and protein turnover
- Robinson
Fetal and placental size and risk of hypertension in adult life
- Barker
Prenatal exposure to prednisone in humans and animals retards intrauterine growth
- Reinisch