Willem B. de Vries

Reduced life expectancy in rats after neonatal dexamethasone treatment.

The glucocorticoid dexamethasone (Dex) is widely used in preterm infants for the prevention of chronic lung disease. However, major concern has arisen about the long-term sequelae of this therapy. Here we report that neonatal treatment with dexamethasone significantly shortens the lifespan by 25% of male rats (28.6 ± 1.1 to 21.3 ± 0.8 mo) and by 18% of female rats (26.9 ± 1.8 to 22.0 ± 0.7 mo). Histopathological examination indicated end-stage cardiac and renal failure as the cause of premature death. Furthermore, Dex- treated rats showed symptoms of hypertension at young adult age, which worsened with increasing age. Thus, a brief period of glucocorticoid treatment during early life results in untimely death presumably due to cardiovascular and renal disease later in life. These serious, adverse long-term consequences call for prudence with glucocorticoid treatment of human preterm infants and careful follow-up of young adults with a history of neonatal glucocorticoid treatment.

Long-term effects of neonatal hydrocortisone treatment for chronic lung disease on the developing brain and heart

Despite modern perinatal intensive care techniques, chronic lung disease remains a problem in preterm-born infants. The most commonly and almost exclusively prescribed drug to treat this disorder is dexamethasone. Corticosteroids improve short-term respiratory function; however, many side-effects have been reported and the adverse long-term effects of dexamethasone on neurodevelopment are particularly alarming. Hydrocortisone could be a suitable alternative for dexamethasone, if equally effective with fewer side-effects. This review evaluates the current literature on neonatal hydrocortisone treatment for chronic lung disease with regards to long-term neurodevelopmental outcome and cardiovascular effects. The neurodevelopmental studies do not show any adverse effects of hydrocortisone on neurocognitive and motor outcome, nor on incidence of brain abnormalities on magnetic resonance imaging or on long-lasting programming effects on the hypothalamus-pituitary-adrenal axis. At school age, cardiovascular stress response was the same in hydrocortisone-treated children compared with a reference group. Hydrocortisone seems a safe alternative to dexamethasone, but more double-blind randomised studies are needed.

Effects of Antenatal Glucocorticoid Therapy on Hippocampal Histology of Preterm Infants

Objective To investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn. Patients and Methods Included were consecutive neonates with a gestational age between 24 and 32 weeks, who were born between 1991 to 2009, who had died within 4 days after delivery and underwent brain autopsy. Excluded were neonates with congenital malformations and neonates treated postnatally with glucocorticoids. The brains were routinely fixed, samples of the hippocampus were stained with haematoxylin and eosin and sections were examined for presence or absence of large and small neurons in regions of the hippocampus. Additional staining with GFAP, neurofilament and vimentin was performed to evaluate gliosis and myelination. The proliferation marker Ki67 was used to evaluate neuronal proliferation. Staining with acid fuchsin-thionin was performed to evaluate ischemic damage. Results The hippocampi of ten neonates who had been treated with antenatal glucocorticoids showed a lower density of large neurons (p = 0.01) and neurons irrespective of size (p = 0.02) as compared to eleven neonates who had not been treated with glucocorticoids. No difference was found in density of small neurons, in myelination, gliosis, proliferation or ischemic damage. Conclusion We found a significantly lower density of neurons in the hippocampus of neonates after antenatal glucocorticoid treatment. Although the pathophysiological and clinical interpretations of these findings are not clear, they are consistent with those from experiments in mice and rhesus monkeys.

Antenatal Glucocorticoid Treatment Affects Hippocampal Development in Mice

Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function.

Histopathological Changes of the Heart After Neonatal Dexamethasone Treatment: Studies in 4-, 8-, and 50-Week-Old Rats

Dexamethasone (Dex), for prevention of chronic lung disease in preterm infants, showed potential negative long-term effects. Studies regarding long-term cardiovascular effects are lacking. We investigated possible histopathological myocardial changes after neonatal Dex in the young and adult rat heart. Rats were treated with Dex on d 1, 2, and 3 (0.5, 0.3, and 0.1 mg/kg) of life. Control-pups received saline. At 4, 8, and 50 wk after birth rats were killed and anatomic data collected. Heart tissue was stained with hematoxylin and eosin, Cadherin-periodic acid schiff, and sirius red for cardiomyocyte morphometry and collagen determination. Presence of macrophages and mast cells was analyzed. Cardiomyocyte length of the Dex-treated rats was increased in all three age groups, whereas ventricular weight was reduced. Cardiomyocyte volumes were increased at 50 wk indicating cellular hypertrophy. Collagen content gradually increased with age and was 62% higher in Dex rats at 50 wk. Macrophage focus score and mast cell count were also higher. Neonatal Dex affects normal heart growth resulting in cellular hypertrophy and increased collagen deposition in the adult rat heart. Because previous studies in rats showed premature death, suggesting cardiac failure, cardiovascular follow-up of preterm infants treated with glucocorticoids should be considered.

B-type natriuretic peptide and rebound during treatment for persistent pulmonary hypertension.

OBJECTIVE To investigate whether serum B-type natriuretic peptide (BNP) is a useful biomarker in evaluating the course of persistent pulmonary hypertension of the newborn (PPHN) and the effectiveness of treatment. STUDY DESIGN Prospective follow-up study of infants with clinical and echocardiographic signs of PPHN, who were treated with inhaled nitric oxide (iNO). Of 24 patients with PPHN who were treated, serum BNP levels were determined longitudinally in 21. BNP levels were compared between infants with (n = 6) and without rebound PPHN (n = 15). RESULTS BNP levels in all infants with PPHN were not significantly different at the initial start of iNO. BNP levels decreased in both groups during iNO treatment. In the infants in whom rebound PPHN developed after weaning from iNO, a significantly higher increase was found in BNP (283 pmol/L to 1232 pmol/L) compared with that in infants without rebound (98 pmol/L to 159 pmol/L). This occurred before the onset of clinical deterioration. BNP again decreased significantly after iNO treatment was restarted. CONCLUSIONS BNP, a biomarker of cardiac ventricular strain, proved to be useful in evaluating the efficacy of PPHN treatment, and moreover, BNP helps to predict a rebound of PPHN.

Neonatal glucocorticosteroid treatment causes systolic dysfunction and compensatory dilatation in early life : Studies in 4-week-old prepubertal rats

Glucocorticosteroid treatment is widely used to prevent chronic lung disease in premature infants. Recent studies in adult rats, treated with dexamethasone in the neonatal period, report negative long-term effects on the heart and severely reduced life expectancy. We treated neonatal rats with dexamethasone and studied cardiac function after 4 wk (prepubertal age) to investigate whether the late effects as previously described are preceded by detectable alterations in cardiac function at a younger age. Male rat pups (n = 12) were injected intraperitoneally with dexamethasone on d 1, 2, and 3 (0.5, 0.3, and 0.1 μg/g) of life. Control pups (n = 10) received saline. At 4 wk the animals were anesthetized, and a pressure-conductance catheter was introduced into the left ventricle to measure pressure-volume loops. Cardiac function was measured and pressure-volume relations were determined to quantify intrinsic systolic and diastolic function. Subsequently, hearts were excised for histologic examination. Compared with saline-treated animals, dexamethasone-treated rats had a reduced ventricular weight (270 ± 40 versus 371 ± 23 mg, p < 0.001) and reduced systolic function (end-systolic elastance: 1.24 ± 0.43 versus 2.50 ± 1.39 mm Hg/μL, p = 0.028). Cardiac output was maintained and end-diastolic volume was increased (84 ± 23 versus 59 ± 19 μL, p = 0.012) indicating a state of compensatory dilatation. Heart rate, diastolic function, and systemic vascular resistance were unchanged. Neonatal dexamethasone treatment causes cardiac alterations that can be detected in the prepubertal period and that may precede severe cardiac dysfunction later in life. If our findings are confirmed in humans, this may have consequences for a large patient population and cardiac screening at young age may be indicated to enable secondary prevention.

Cardiovascular Follow-up at School Age After Perinatal Glucocorticoid Exposure in Prematurely Born Children: Perinatal Glucocorticoid Therapy and Cardiovascular Follow-up

OBJECTIVE To study whether antenatal or neonatal glucocorticoid therapy to reduce the incidence and severity of chronic lung disease in preterm infants is associated with long-term adverse cardiac effects and hypertension. DESIGN Retrospective matched-cohort study. SETTING Outpatient clinic of a tertiary care hospital. PARTICIPANTS One hundred ninety-three children aged 7 to 10 years who had been born prematurely between December 2, 1993, and September 15, 1997. Main Exposure Neonatal treatment with dexamethasone disodium phosphate(n = 48) or the clinically equally effective glucocorticoid hydrocortisone (n = 51), or only antenatal treatment with betamethasone disodium phosphate and betamethasone acetate (n = 51). These 3 groups were compared with a reference group of prematurely born children who had not been exposed to perinatal glucocorticoid therapy (n = 43). MAIN OUTCOME MEASURES General hemodynamic data (heart rate and blood pressure), cardiovascular function as assessed at echocardiography, intima-media thickness of the carotid arteries, and cardiac biochemical features as early markers of expansion and volume overload of the cardiac left ventricle (B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide). RESULTS No significant group differences were found for heart rate, blood pressure, biochemical features, intima-media thickness, or systolic or diastolic left ventricular function. CONCLUSIONS Although no differences were found in blood pressure and cardiovascular function at school age in children antenatally or neonatally treated with glucocorticoids, further cardiovascular follow-up may be advisable because cardiovascular dysfunction may become apparent only later in life.

Neonatal Dexamethasone Treatment in the Rat Leads to Kidney Damage in Adulthood

Recently, concern has been raised that corticosteroid treatment of preterm neonates might be associated with adverse effects later in life, including early development of hypertension. Here, we investigate the impact of neonatal dexamethasone (Dex) treatment on early renal cell proliferation and nephron number. We analyzed mitotic activity in renal cortex of rat pups neonatally treated with Dex. Nephron number was measured and possible renal damage was quantified by counting inflammatory foci, ED-1 positive cells (macrophages), and the desmin score (activated podocytes). Mitotic activity was 34 and 29% lower on d 2 and 4 in Dex-treated rats compared with saline-treated controls. The number of glomeruli was lower at 4 wk, but nephron size was unchanged after Dex treatment, as calculated from glomerular density and (lower) body- and kidney weight. At wk 50, the glomerular number was significantly lower in Dex-treated rats, whereas body and kidney weight were the same as in Sal controls. Dex rats also showed more kidney damage, manifested by a ∼3.5-fold increase in inflammation foci/mm2 and in ED-1 positive cells/mm2 and a ∼4.3-fold increased desmin score. Temporary suppression of mitotic activity during neonatal Dex treatment leads to reduction of nephron number and more kidney damage later in life.

Use of cardiac biomarkers in neonatology

Cardiac biomarkers are used to identify cardiac disease in term and preterm infants. This review discusses the roles of natriuretic peptides and cardiac troponins. Natriuretic peptide levels are elevated during atrial strain (atrial natriuretic peptide (ANP)) or ventricular strain (B-type natriuretic peptide (BNP)). These markers correspond well with cardiac function and can be used to identify cardiac disease. Cardiac troponins are used to assess cardiomyocyte compromise. Affected cardiomyocytes release troponin into the bloodstream, resulting in elevated levels of cardiac troponin. Cardiac biomarkers are being increasingly incorporated into clinical trials as indicators of myocardial strain. Furthermore, cardiac biomarkers can possibly be used to guide therapy and improve outcome. Natriuretic peptides and cardiac troponins are potential tools in the diagnosis and treatment of neonatal disease that is complicated by circulatory compromise. However, clear reference ranges need to be set and validation needs to be carried out in a population of interest.