Antenatal glucocorticoid treatment is not associated with long-term metabolic risks in individuals born before 32 weeks of gestation.

BACKGROUND: A single course of maternal glucocorticoid treatment is effective in reducing neonatal mortality after preterm birth. However, in animals, maternal glucocorticoid treatment is associated with lifelong hyperglycaemia and hypertension, and impaired nephrogenesis in offspring. Findings from studies in humans on this topic are highly contradictory due to a number of methodological flaws, and renal function after glucocorticoid exposure has never been assessed. OBJECTIVES: To assess in individuals born <32 gestational weeks whether antenatal glucocorticoid treatment for preterm birth is associated with long-term metabolical risks, including renal function, in adulthood. DESIGN: Birth cohort study. SETTING: Multicentre study. PATIENTS: 412 19 year olds born <32 gestational weeks from the Project On Preterm and Small-for-gestational-age infants (POPS) cohort. INTERVENTIONS: Maternal betamethasone 12 mg administered twice with a 24 h interval. MAIN OUTCOME MEASURES: Body composition, insulin resistance, the serum lipid profile, blood pressure and estimated renal function. RESULTS: We did not find any long-term adverse effects of antenatal betamethasone, with the exception of an effect on glomerular filtration rate (GFR). In 19-year-old survivors, GFR was lower after betamethasone: -5.2 ml/min (95% CI -8.9 to -1.4) per 1.73 m(2). CONCLUSIONS: The reduction in neonatal mortality associated with a single course of maternal betamethasone is not accompanied by long-term metabolical risks in survivors of preterm birth. The only adverse effect found was lower GFR. Although this difference was not clinically relevant at 19 years, it might predict an increased risk of chronic renal failure in prematurely born individuals who were exposed antenatally to betamethasone.

Modulation of calcium oxalate monohydrate crystallization kinetics by urine of preterm neonates.

Preterm neonates frequently develop nephrocalcinosis (NC). However, the cause has not yet been elucidated. This study focuses on the effects of urine from preterm neonates on crystallization kinetics. Urine samples were collected and renal ultrasound examinations of preterm neonates (gestational age < 32 weeks) were performed during the first weeks of life, at term, and ages 6, 12, and 24 months. The effect of urine on crystallization was determined using a seeded crystal growth system, which measures the square root of solubility product ( radicalLc), percentage of growth inhibition (GI), and agglomeration inhibition ([tm]) of calcium oxalate crystals. Data for preterm neonates in the first weeks of life (n = 19) were compared with those for full-term neonates (n = 17) and healthy adults. Moreover, the correlation between [tm] and urinary (U)citrate level was studied. Mean radicalLc (0.27 +/- 0.1 versus 0.36 +/- 0.08 mmol/L) and mean [tm] (81 +/- 32 versus 143 +/- 97 minutes) were lower and mean Ucalcium-creatinine (2.20 +/- 1.74 versus 0.46 +/- 0.73 mol/mol) and Uoxalate-creatinine ratios (0.39 +/- 0.21 versus 0.16 +/- 0.09 mol/mol) were greater in preterm neonates in the first weeks of life compared with full-term neonates (p < 0.05). Furthermore, [tm] was less than the lower limit for healthy adults for all but one preterm neonate; [tm] increased and Ucalcium-creatinine and Uoxalate-creatinine ratios decreased with age (p < 0.005). There was a correlation between [tm] and citrate excretion (coefficient of 38; P < 0.001). Patients with and without NC at term did not differ statistically in mean radicalLc, percentage of GI, or [tm]. In conclusion, urine from preterm neonates in the first weeks of life is highly supersaturated and has a defective ability to inhibit calcium oxalate crystal agglomeration. This ability improves with age and is citrate mediated. We suggest that both the high level of supersaturation and defective ability to inhibit calcium oxalate crystal agglomeration contribute to the high incidence of NC.

Etiology of nephrocalcinosis in preterm neonates: association of nutritional intake and urinary parameters.

BACKGROUND: Nephrocalcinosis (NC) in preterm neonates has been described frequently, and small-scale studies suggest an unfavorable effect on renal function. The etiologic factors have not yet been fully clarified. We performed a prospective observational study to identify factors that influence the development of NC. METHODS: The study population consisted of 215 preterm neonates with a gestational age <32 weeks. Clinical characteristics and intake in the first four weeks of calcium, phosphorus, vitamin D, protein, and ascorbic acid were noted. Serum calcium, phosphate, vitamin D, magnesium, uric acid, creatinine, urea and urinary calcium, phosphate, oxalate, citrate, magnesium, uric acid, and creatinine were assessed at four weeks of age and at term. Renal ultrasonography (US) was performed at four weeks and at term. At term was defined as a postconceptional age of 38 to 42 weeks. RESULTS: NC was diagnosed by means of US in 33% at four weeks and in 41% at term. Patients with NC at four weeks had a significantly higher mean intake of calcium (P < 0.05), phosphorus (P < 0.05), and ascorbic acid (P < 0.01) than patients without NC. They had a higher mean serum calcium (2.55 vs. 2.46 mmol/L, P < 0.01) and a higher mean urinary calcium/creatinine ratio (2.6 vs. 2.1 mmol/mmol, P < 0.05). Patients with NC at term had a lower birth weight (1142 vs. 1260 g, P < 0.05) and a lower gestational age (28.8 vs. 29.4 weeks, P < 0.05), were treated significantly longer with furosemide, dexamethasone, theophylline, and thiazides, developed chronic lung disease more frequently (40 vs. 16%, P < 0.001), and had a higher mean urinary calcium/creatinine ratio (2.7 vs. 2.3 mmol/mmol, P < 0.05) and a lower mean urinary citrate/calcium ratio (1.1 vs. 1.7 mmol/mmol, P = 0.005). CONCLUSIONS: NC develops as a result of an imbalance between stone-inhibiting and stone-promoting factors. A high intake of calcium, phosphorus, and ascorbic acid, a low urinary citrate/calcium ratio, a high urinary calcium/creatinine ratio, immaturity, and medication to prevent or treat chronic lung disease with hypercalciuric side effects appear to contribute to the high incidence of NC in preterm neonates.

Ceftazidime pharmacokinetics in preterm infants: effects of renal function and gestational age.

OBJECTIVE: The objectives of this study were (1) to determine the effects of gestational age on ceftazidime pharmacokinetics in the preterm infant, (2) to relate these effects to changes in glomerular filtration rate (GFR), and (3) to establish appropriate dosage recommendations for preterm infants on day 3 of life. METHODS: Multiple-dose pharmacokinetics of ceftazidime (administered twice daily in a 25 or 50 mg/kg body weight intravenous dose) were evaluated in 136 preterm infants on day 3 of life. Blood samples were collected from an arterial catheter 0, 1/2, 1, 2, 4, 8, and 12 hours after the intravenous dose. An HPLC method was used to determine ceftazidime concentrations in serum. The GFR was studied simultaneously by means of the 24-hour continuous inulin infusion technique. RESULTS: The total body clearance, volume of distribution, and elimination serum half-life of ceftazidime (mean +/- SD) were 55.7 +/- 34.4 ml/hr (37.3 +/- 11.9 ml/hr/kg), 496 +/- 228 ml (350 +/- 96 ml/kg), and 6.95 +/- 2.32 hours, respectively. The mean +/- SD peak and trough levels were 114.9 +/- 39.4 and 33.9 +/- 17.8 mg/L. All infants had a serum trough level above 5 mg/L. Clearance and volume of distribution of ceftazidime and GFR increased significantly with increasing gestational age, whereas serum trough levels and serum half-life of ceftazidime decreased significantly with increasing gestational age. Ceftazidime clearance increased significantly with increasing GFR. Prenatal exposure to indomethacin resulted in significantly lower GFR values and ceftazidime clearances. CONCLUSIONS: Dosage recommendations for ceftazidime administration in preterm infants during the first week of life should be based on gestational age and GFR. Additional adjustments in dosage are indicated in preterm infants who are exposed prenatally to indomethacin.

Ceftazidime pharmacokinetics in preterm infants: effect of postnatal age and postnatal exposure to indomethacin.

1. The effects of postnatal age and postnatal exposure to indomethacin on the pharmacokinetic parameters of ceftazidime (CAZ) were investigated in 23 preterm infants (gestational age 28.7 +/- 1.7 weeks; weight 1086 +/- 311 g) on day 3 and day 10 after birth. 2. CAZ (25 mg kg-1) was administered by intravenous bolus injection. Blood samples were drawn from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after the dose and CAZ concentrations in serum were determined by h.p.l.c. CAZ pharmacokinetics followed a one-compartment open model. 3. The glomerular filtration rate (GFR) of all infants was studied by means of the 24 h continuous inulin infusion technique. 4. The total body clearance of CAZ (34.7 +/- 9.2 vs 50.6 +/- 19.6 ml h-1, P < 0.05; 30.7 +/- 5.9 vs 41.6 +/- 9.0 ml h-1 kg-1, P < 0.05) and GFR (0.72 +/- 0.11 vs 0.91 +/- 0.15 ml min-1, P < 0.05) increased, whereas the apparent volume of distribution (425 +/- 147 vs 352 +/- 108 ml, P < 0.05; 363 +/- 59 vs 292 +/- 44 ml kg-1, P < 0.005) and the elimination half-life (8.7 +/- 2.8 vs 5.0 +/- 0.9 h, P < 0.005) decreased significantly between day 3 and day 10 after birth. Clearance of CAZ increased with increasing GFR (r = 0.81, P < 0.001). 5. In infants with postnatal exposure to indomethacin the changes in CAZ pharmacokinetics were markedly reduced. 6. These results indicate that the dosage regimen of CAZ should be adjusted after the first week of life except in infants who were postnatally exposed to indomethacin.

The effect of asphyxia on the pharmacokinetics of ceftazidime in the term newborn.

The multiple-dose pharmacokinetics of ceftazidime (CAZ) (administered twice daily in a 50 mg/kg of body weight i.v. dose) were studied in 10 severely asphyxiated term infants with suspected septicemia on d 3 of life. Nine term infants with suspected septicemia but without asphyxia served as controls. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an i.v. bolus injection. A high performance liquid chromatography method was used to determine CAZ concentrations from serum. CAZ pharmacokinetics followed a one-compartment open model. The GFRs of all infants were simultaneously studied by means of the 24-h continuous inulin infusion technique. Elimination serum half-life (5.86 +/- 1.13 h versus 3.85 +/- 0.40 h) and serum trough concentrations (46 +/- 14 mg/L versus 23 +/- 7 mg/L) of CAZ were significantly (p < 0.001) increased in the asphyxiated newborn, whereas total body clearance of CAZ (128.4 +/- 25.1 mL/h versus 205.7 +/- 55.4 mL/h), CAZ clearance per kg (40.9 +/- 6.1 mL/h/kg versus 60.8 +/- 8.3 mL/h/kg), and the GFR expressed in mL/min (3.14 +/- 0.43 versus 4.73 +/- 0.89) were significantly (p < 0.001) decreased in the asphyxiated newborn. We conclude that twice daily administration of 50 mg/kg of body weight CAZ given to asphyxiated term newborns in the first days of life results in significantly higher serum trough levels in comparison with control infants. The impaired CAZ clearance is a result of a significantly decreased GFR.

Once-daily versus twice-daily administration of ceftazidime in the preterm infant.

Ceftazidime pharmacokinetics in 28 preterm infants (gestational ages, 25.6 to 31.9 weeks) were studied on day 3 of life. Patients with suspected septicemia were randomized on day 1 of life in two groups. One group (n = 13) was administered 25 mg of ceftazidime per kg of body weight once daily, and the other (n = 15) was given 25 mg of ceftazidime per kg twice daily. Both groups also received 25 mg of amoxicillin per kg twice daily. Blood samples were collected on day 3 of life with an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an intravenous bolus injection. An additional blood sample was taken at 24 h from the group dosed once a day. High-performance liquid chromatography was used to determine serum ceftazidime concentrations. The pharmacokinetics of ceftazidime were best described by using a one-compartment model. The half-life for the elimination of the drug from serum, apparent volume of distribution, total body clearance of ceftazidime, and inulin clearance were not significantly different for both groups. The ceftazidime/inulin clearance ratio was 0.72 for both groups. However, trough concentrations in serum for the twice-daily group were significantly (P < 0.001) higher (42.0 +/- 13.4 mg/liter) than those for the once-daily group (13.1 +/- 4.7 mg/liter). The latter concentrations were all still substantially higher than the MIC of ceftazidime for major neonatal pathogens. We conclude that the currently recommended dosage of 25 mg of ceftazidime per kg twice daily for preterm infants with gestational ages below 32 weeks may be adjusted during the first days of life to one daily dose at 25 mg/kg, provided that for the empirical treatment of septicemia, amoxicillin at 25 mg/kg is also given twice daily.

Effects of prenatal exposure to betamethasone and indomethacin on the glomerular filtration rate in the preterm infant.

The effects of gestational age (GA), body weight, and prenatal exposure to betamethasone and indomethacin on the glomerular filtration rate (GFR) on d 3 of life in preterm infants were studied. GFR measurements were performed in 147 preterm infants with a GA between 23.4 and 37.0 wk by means of the continuous inulin infusion technique. Mean GFR values increased significantly with GA (r = 0.60, p < 0.001) and with body weight (r = 0.44, p < 0.001). Multivariate analysis indicated that GA was the most important determinant for this increase. Prenatal exposure to indomethacin resulted in significantly lower GFR values (-0.15 +/- 0.03 mL/min, p < 0.001) at d 3 after birth. Prenatal administration of betamethasone and indomethacin significantly (p < 0.001) increased the GFR in comparison with exposure to indomethacin alone to levels not different than those seen in patients who were not prenatally exposed to betamethasone or indomethacin. GFR measurements were repeated in 40 preterm infants on d 10 after birth. During this 7-d period, a significant increase in GFR values (0.17 +/- 0.03 mL/min, p < 0.001) was detected. This postnatal increase in GFR values was independent of GA and was not influenced by prenatal exposure to betamethasone or indomethacin. We conclude that prenatal exposure to betamethasone or indomethacin exerts significant effects on the renal function of preterm infants in the first days of life.

Persistent anuria, neonatal death, and renal microcystic lesions after prenatal exposure to indomethacin.

OBJECTIVE: The purpose of this study is to emphasize the high risk of renal failure and severe morphologic changes related to prolonged prenatal exposure to indomethacin. STUDY DESIGN: Referred renal specimens from six anuric neonates exposed in utero to indomethacin were studied. Clinical charts were retrospectively reviewed. Indomethacin dosages varied from 150 to 400 mg daily, and the drug was given for a 2- to 11-week period, until birth. RESULTS: All infants died in anuria, 4 of them after 7 to 39 days on peritoneal dialysis. In 5 infants cystic dilatations of superficial nephrons were associated with ischemic changes of the deep cortex. By immunohistochemical analysis intrarenal renin content was increased in 4 of 5 patients. CONCLUSION: Long-term indomethacin treatment during pregnancy may lead to the development of renal failure and irreversible renal damage with cystic dilatation of developing nephrons in an exposed fetus. Prior stimulation of the renin-angiotensin system may favor this complication.