Tibor Ertl

Postnatal development of renin-angiotensin-aldosterone system, RAAS, in relation to electrolyte balance in premature infants.

Summary: In an attempt to provide information about the role of RAAS in development of late hyponatremia in low-birthweight neonates, simultaneous measurement of plasma renin activity, (PRA), plasma aldosterone concentration (PA), and urinary aldosterone excretion (UAE) was made using RIA methods along with determination of Na and K balance weekly up to the 6th week of life. Seven healthy male infants with mean birthweight of 1580 g, range: 1160–1850 g, and mean gestational age of 31 weeks, range: 30–32 weeks, were selected for the study.Due to the increased urinary Na loss, negative Na balance developed in the first 2 weeks followed by positive balance thereafter. PRA, PA, and UAE increased tremendously from the initially high values of 18.2 ± 4.1 ng/ml/hr, 1.7 ± 0.5 ng/ml, and 2.6 ± 0.4 μg/day, mean and SEM, to their maximum of 78.6 ± 18.1 ng/ml/hr, P < 0.01,6.8 ± 3.7 ng/ml, P < 0.05, and 26.4 ± 2.9 μg/day, P < 0.01, in the 3rd week, respectively. Later on, gradual declines occurred, however, PRA, PA, and UAE remained highly elevated even at the 6th week with values of 45.5 ± 15 ng/ml/hr, 1.6 ± 0.5 ng/ml, and 14.5 ± 1.4 μg/day, respectively.It is suggested that late hyponatremia of premature infants is due to tubular unresponsiveness to aldosterone and not to inadequate response of RAAS to stimulation.Speculation: The initially high urinary sodium excretion in premature infants is coupled with low urinary potassium excretion indicating limited renal sodium reabsorption in exchange for potassium. Later on, progressive increase in renal sodium-potassium exchange occurs and the plasma sodium and potassium concentrations gradually approach the normal values.On the basis of these observations, one can assume the physiologic role of both the increasing activity of RAAS and also the increase in renal tubular responsiveness to aldosterone with advancing postnatal age.

Relationship between Hyperglycemia and Retinopathy of Prematurity in Very Low Birth Weight Infants

Retinopathy of prematurity (ROP) is a multifactorial vasoproliferative retinal disorder that increases in incidence with decreasing gestational age. Recently, an association between hyperglycemia and severe ROP was found in extremely low birth weight infants (ELBWI). The purpose of this study was to evaluate the possible relation between hyperglycemia and ROP at any stage in very low birth weight infants (VLBWI). We analyzed the data of 201 VLBWI. The incidence of ROP and hyperglycemia was detected and the χ2 test was applied to investigate the association between the two variables. The Clinical Risk Index for Babies (CRIB) score was attributed as a marker of illness severity. The incidence of ROP and hyperglycemia in VLBWI was 35.3 and 19.4%, respectively. ROP developed more frequently in hyperglycemic infants (p < 0.001). The gestational age, birth weight, and Apgar scores were significantly lower, the CRIB score was higher in ROP patients. In hyperglycemic ROP patients the CRIB score was significantly higher compared to euglycemic ROP patients (mean (SD) 8.1 (4.2) vs. 5.5 (3.3); p < 0.01). A logistic regression model revealed that gestational age (OR 0.59; 95% CI 0.46–0.76; p < 0.001) and hyperglycemia (OR 3.15; 95% CI 1.12–8.84; p < 0.05) are independent risk factors in ROP development. When ELBWI were analyzed separately, gestational age (OR 0.38; 95% CI 0.20–0.72; p < 0.01) and CRIB score (OR 1.58; 95% CI 1.02–2.45; p < 0.05) were found as significant contributors. Further studies are needed to elucidate the pathophysiological role of hyperglycemia in the development of vasoproliferative retinal disorder.

Postnatal Changes of Leptin Levels in Full-Term and Preterm Neonates: Their Relation to Intrauterine Growth, Gender and Testosterone

The present study was carried out to investigate leptin levels in arterial and venous cord serum and in amniotic fluid in full-term infants at birth and on the 5th postnatal day to define the relationship of leptin to intrauterine growth rate, gender and early postnatal life. The relation of weight gain to serum leptin levels in male preterm infants was determined measuring leptin concentration weekly in the first 5 postnatal weeks. Testosterone levels were determined simultaneously to explore a possible relationship between leptin and testosterone concentrations.Fifty-three term newborn infants with mean birth weight and gestational age of 3,419 g (range 2,150–4,480) and 38.9 weeks (range 36–41) and 19 preterm male infants (mean birth weight and gestational age were 1,416 g (770–1,800) and 30.2 weeks (26–35) were enrolled into the study. Leptin and testosterone levels were determined by radioimmunoassay. It was demonstrated that serum leptin levels were markedly elevated in the cord blood without discernible arteriovenous differences. Cord blood leptin was found to correlate with birth weight (r = 0.40, p < 0.002), weight to length ratio (r = 0.40, p < 0.002) and body mass index (r = 0.35, p < 0.005). It was significantly lower in boys as opposed to girls (p < 0.01) and there was an apparent fall by the 5th postnatal day (p < 0.001). Amniotic fluid contained leptin in much less concentration than cord blood and it proved to be independent of intrauterine growth or gender. Serum leptin concentration in preterm infants at 1 week of age was significantly lower compared with term infants (p < 0.002) and it increased progressively with age (p < 0.01). An inverse relationship was found between leptin and testosterone level (r = –0.358, p < 0.01) and a positive correlation between leptin level and weight/height ratio (r = 0.674, p < 0.01).It is concluded that leptin derived either from placenta or fetal adipose tissue may be involved in regulating fetal growth and development and it may be related to energy intake, storage and expenditure. In preterm male infants serum leptin concentration increases with postnatal weight and testosterone may suppress leptin synthesis.

Changes of Maternal Serum Leptin Levels during Pregnancy

Maternal leptin levels in serum and urine, their relations to maternal weight and body mass index, were examined in 9 healthy pregnant women from the 12th week of gestation until term. Serum leptin concentration was found to increase progressively during the first two trimesters followed by a slight decline thereafter. The peak value of 27.6 ± 15.3 ng/ml (mean ± SD) concentration was reached at the 28th week. Serum leptin levels during the first two trimesters correlated significantly with maternal weight (p = 0.002) and body mass index (p = 0.002) but such a relationship was absent during the third trimester. Leptin could be detected only in about half of urine samples; its concentrations proved to be independent of serum values. No correlation was found between maternal serum leptin levels and the birth weight of neonates. Maternal leptin levels appear to refer to alterations in maternal fat tissue mass that occur during pregnancy.

Hyponatremia and Sensorineural Hearing Loss in Preterm Infants

In a case-control study the role of hyponatremia in the hearing loss of preterm infants was investigated. One hundred and sixty-four premature infants treated at the neonatal intensive care unit were screened with transient evoked otoacoustic emission (TEAOE). In 32 infants TEAOE results indicated the need for further investigations. Auditory brainstem response was performed and 22 of 32 cases had bilateral hearing impairment (HI). The birth weight and gestational age in the HI group were 1,425 ± 528 g and 30.4 ± 3.7 weeks. The matched control group consisted of 25 infants with a mean birth weight and gestational age of 1,410 ± 280 g and 31.1 ± 2.1 weeks. Significant differences were found between the HI and control groups: Apgar score (p < 0.05), pH value (p < 0.01) and pO2 level (p < 0.05) were lower; the total dose of aminoglycosides (p < 0.01), furosemide usage (p < 0.01), the maximum pCO2 level (p < 0.01), incubator stay (p < 0.05) and hyponatremia (p < 0.01) were higher, and the duration of hyponatremia (p < 0.05) was longer in the HI group. Multivariate logistic regression revealed that aminoglycoside treatment and hyponatremia were the two most significant factors in the development of hearing impairment. These results suggest that hyponatraemia is an additional risk factor for hearing loss in preterm infants.

Male reproductive tract abnormalities: more common after assisted reproduction?

BACKGROUND In this era of increased use of assisted reproduction (AR) techniques, the prevalence rates of hypospadias, cryptorchidism, poor semen quality have been increasing in parallel with a rising incidence of testicular cancer. It is suggested that these problems result from the disruption of gonadal development during fetal life causing the testicular dysgenesis syndrome (TDS). AIM The aim of our study was to evaluate the influence of conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), on the development of male genital tract abnormalities. STUDY DESIGN AND SUBJECTS We analyzed a cohort of 15,206 neonates born from January 1, 1999 through December 31, 2008 at the Department of Obstetrics and Gynecology, Medical School, University of Pécs, including 890 children (5.9%) born after IVF or ICSI. We examined the association between these AR methods and developmental abnormalities of the genital tract (hypospadias, cryptorchidism), after controlling for potential confounding factors, such as prematurity, low birthweight and twinning. RESULTS Preterm birth and low birthweight are risk factors for hypospadias and cryptorchidism (p<0.001), twinning increases the risk of hypospadias (p<0.001). ICSI was revealed as a risk factor for hypospadias in singletons (OR: 3.190, 95%CI: 1.266-8.042) and in normal birthweight (>2500 g) infants (OR: 3.966, 95%CI: 1.193-13.181, respectively). Similar but not nonsignificant trends were seen for cryptorchidism. CONCLUSION IVF and ICSI, by increasing the risks of prematurity, low birthweight, and multiple gestation, are indirect risk factors for developing male genital malformations. In infants with normal birhtweight or from singleton pregnancies, ICSI is a specific risk factor for hypospadias.

Effect of low-dose dopamine infusion on prolactin and thyrotropin secretion in preterm infants with hyaline membrane disease

The effect of low-dose (2-4 micrograms/kg/min) and long-term (greater than or equal to 46 h) dopamine infusion on serum prolactin and thyrotropin concentrations was investigated in 8 preterm infants with hyaline membrane disease. Dopamine was administered for systemic hypotension and/or for impending renal failure. Serum prolactin decreased from 1,314.5 +/- 422.7 microU/ml to 489.9 +/- 464.1 microU/ml (p less than 0.005), while serum thyrotropin fell from 3.77 +/- 2.27 microU/ml to 1.01 +/- 0.25 microU/ml (p less than 0.025) during dopamine infusion. Our data indicate that exogenous dopamine exerts an inhibitory effect on the secretion of prolactin and thyrotropin even in the sick preterm neonate. The role of prolactin in fetal lung maturation and in regulation of the neonatal tissue water stores is discussed. The results of the present study are also useful in explaining the renal effects of long-term low-dose dopamine infusion in the sick preterm infant.

Plasma asymmetric dimethylarginine concentration during the perinatal period.

Experimental and clinical evidence has been accumulated to indicate that elevated plasma asymmetric dimethylarginine (ADMA) levels can be regarded as a marker of endothelial dysfunction that mediates cardiovascular morbidity by impairing NO-dependent vascular reactions; therefore, it may have a role in the cardiopulmonary adaptation of the neonate. The present study was undertaken to investigate the perinatal NO metabolism by measuring L-arginine, the NO synthase substrate, ADMA, the endogenous inhibitor of NO synthase, and symmetrical dimethylarginine (SDMA), the biologically inactive L-arginine metabolite in umbilical venous and arterial plasma and in peripheral plasma of the neonate. Measurements were done in ten healthy pregnant women at term delivery and in their newborn infants on the second day of life by using liquid chromatography-mass spectrometry method. It was demonstrated that cord blood L-arginine, ADMA, and SDMA levels were markedly elevated with a moderate, but consistent veno-arterial difference suggesting that they are mainly generated by the placental endothelium. L-Arginine and ADMA levels were found to fall significantly (p < 0.001) by the second postnatal day, whereas SDMA remained unaltered. This finding indicates accelerated enzymatic ADMA elimination and reduction in the inhibition of NO-synthase activity. It is concluded that ADMA may play a role in the control of feto-placental circulation and the circulatory adaptation of the neonate.

The effect of dopamine administration on the activity of the renin-angiotensin-aldosterone system in sick preterm infants

Nine premature infants with birth weight of 1150 to 2500 g and gestational age of 28 to 35 weeks were given dopamine in a dose of 2–4 μg/kg/min to treat cardiopulmonary distress.In addition to monitoring of blood gases, blood pressure, acid-base balance, urine flow and urinary sodium excretion, plasma renin activity (PRA) and plasma aldosterone concentration (PA) was also determined prior to and during dopamine therapy.The dopamine-induced increase in urine flow and urinary sodium excretion was associated with a significant increase of PRA from 18.2±5.1 ng/ml/h to 33.0±5.6 ng/ml/h (P<0.025), while PA and blood pressure remained unaltered by dopamine administration.It is suggested that the angiotensin II-stimulated aldosterone production is overridden by the inhibitory effect of dopamine.

Recombinant Bile Salt-Stimulated Lipase in Preterm Infant Feeding: A Randomized Phase 3 Study

Introduction Feeding strategies are critical for healthy growth in preterm infants. Bile salt-stimulated lipase (BSSL), present in human milk, is important for fat digestion and absorption but is inactivated during pasteurization and absent in formula. This study evaluated if recombinant human BSSL (rhBSSL) improves growth in preterm infants when added to formula or pasteurized breast milk. Patients and Methods LAIF (Lipase Added to Infant Feeding) was a randomized, double-blind, placebo-controlled phase 3 study in infants born before 32 weeks of gestation. The primary efficacy variable was growth velocity (g/kg/day) during 4 weeks intervention. Follow-up visits were at 3 and 12 months. The study was performed at 54 centers in 10 European countries. Results In total 415 patients were randomized (rhBSSL n = 207, placebo n = 208), 410 patients were analyzed (rhBSSL n = 206, placebo n = 204) and 365 patients were followed until 12 months. Overall, there was no significantly improved growth velocity during rhBSSL treatment compared to placebo (16.77 vs. 16.56 g/kg/day, estimated difference 0.21 g/kg/day, 95% CI [-0.40; 0.83]), nor were secondary endpoints met. However, in a predefined subgroup, small for gestational age infants, there was a significant effect on growth in favor of rhBSSL during treatment. The incidence of adverse events was higher in the rhBSSL group during treatment. Conclusions Although this study did not meet its primary endpoint, except in a subgroup of infants small for gestational age, and there was an imbalance in short-term safety, these data provide insights in nutrition, growth and development in preterm infants. Trial Registration ClinicalTrials.gov NCT01413581