Maturational changes in the in vivo activity of CYP3A4 in the first months of life.

OBJECTIVE: To document maturational changes of the in vivo activity of CYP3A4 in the first months of life. METHODS: The contribution of tramadol (M), O-demethyl tramadol (M1, CYP2D6-mediated) and N-demethyl tramadol (M2, CYP3A4-mediated) to the overall elimination of tramadol and the log M/M2 was assessed in 24-hour urine collections during continuous intravenous tramadol administration. Correlations with perinatal characteristics (postnatal age (PNA) and postmenstrual age (PMA)) were studied. RESULTS: Of the total amount of tramadol administered in a 24-hour interval to 25 neonates and young infants (PMA 25 - 53 weeks), 34.5% (SD 6.1) were retrieved in the urine as parent compound or metabolite in a 24-hour interval. This retrieved material consisted primarily of tramadol 79% (SD 18), M1 10% (SD 17) and M2 3% (SD 3.4). The contribution of M (r2 = -0.53), M1 (r2 = 0.46) and M2 (r2 = 0.16) to overall M elimination correlated with increasing PMA. The mean log M/M2 was 1.44 (SD 0.46) and there was an inverse correlation between the log M/M2 ratio and PMA (r2 = -0.43, 95% CI for r = -0.84 to -0.34, p = 0.0006) and PNA (r2 = -0.25, 95% CI for r = -0.78 to -0.16, p = 0.008). The maturational half-life of the log M/M2 ratio was 16 - 20 weeks. In a multiple regression model, PMA was the only significant variable accounting for the interindividual variability in log M/M2. CONCLUSIONS: PMA was found to be the most important maturational change determing the in vivo activity of CYP3A4. The activity of CYP3A4 is relatively delayed in the first months of life compared to the developmental changes in CYP2D6 activity described earlier, however, the overall weak correlations reflect that PMA explains only in part the interindividual variability observed.

Cryotherapy versus laser photocoagulation for threshold retinopathy of prematurity: impact on early postoperative clinical recovery.

In a retrospective study in preterms treated with either cryotherapy (n= 16, 2000-2001) or laser photocoagulation (n= 19, 2002-2005) for threshold retinopathy, a significant decrease in duration of postoperative ventilation, in postoperative administration of analgesics and in time until regain of full enteral feeding was documented in infants who received laser photocoagulation. We therefore conclude that - compared to cryotherapy - laser treatment for threshold retinopathy is associated with a faster clinical postoperative recovery.

Ibuprofen and cerebral oxygenation and circulation.

The effect of prophylactic administration of ibuprofen on the cerebral circulation in preterm babies was measured with near infrared spectroscopy. No significant difference in the change in cerebral blood volume, change in cerebral blood flow, or tissue oxygenation index was found between administration of ibuprofen or placebo.

Clinical pharmacology of non opioid analgesics in neonates.

An integrated approach of neonatal analgesia starts with the systematic evaluation of pain and should be followed by effective interventions, mainly based on the appropriate (i.e. safe and effective) administration of analgesics. In contrast to the more potent opioids, data on the pharmacokinetics and -dynamics of non-opioid analgesics in this specific population are still rare or even lacking. We therefore evaluated various aspects of developmental pharmacology of non-opioid analgesics (paracetamol, ibuprofen, acetylsalicyl acid) in neonates. We first performed a single dose propacetamol study in preterm and term neonates. Based on these preliminary findings, a repeated dose administration scheme was developed and tested and maturational aspects from preterm till teenage were documented. Although non-selective COX-inhibitors might be effective in the treatment of postoperative or inflammatory pain syndromes in neonates, potential efficacy should be balanced against the drugs' safety profile. Neonatal renal clearance strongly depends on glomerular filtration rate (GFR) and GFR itself strongly depends on the vaso-dilatative of prostaglandins on the afferent arterioli. We therefore evaluated the impact of the administration of ibuprofen or acetylsalicylic acid on renal clearance in preterm infants and hereby used amikacin clearance as a surrogate marker. We hereby documented the negative effect of ibuprofen on glomerular filtration rate in preterm infants up to 34 weeks and we were able to show that ibuprofen and acetylsalicylic acid had an equal impact on the glomerular filtration rate.

Properties of growth hormone and prolactin hypersecretion by the human infant on the day of birth.

The neonatal period is the only interval in postnatal life characterized by physiologically elevated plasma concentrations of GH and PRL, two hormones of common origin. To study the secretion of GH and PRL on the day of birth, we obtained at regular intervals (every 20 min for 6 h) blood from seven polycythemic newborns (gestational age 34-41 weeks; birthweight 1600-3960 g; postnatal age 6-23 h) during a therapeutic, standardized, isovolumetric, partial exchange transfusion. Serum GH concentrations were measured by RIA and PRL levels by immunoradiometric assay. Deconvolution analysis of the profiles revealed that all infants displayed a pulsatile pattern of amplified GH release (range 9-191 micrograms/L). Bursts of GH secretion occurred at a median interval of 73 min. The median serum GH half-life was 18 min. All infants had continuously elevated serum PRL concentrations (range 86-191 micrograms/L) and none appeared to release PRL episodically. There was no significant cross-correlation between the secretion of GH and PRL. Mean serum GH concentrations during the 6-h study were higher than in cord serum at birth, whereas PRL and insulin-like growth factor-1 levels were lower than at birth. In conclusion, the neonatal hypersomatotropism appears to be characterized by high-amplitude, high-frequency, pulsatile secretion of GH without a prolonged GH half-life, whereas hyperprolactinemia seems to result from GH-independent, continuous PRL release. The immediate postnatal rise of GH secretion in the human newborn may be related to decreased inhibition by circulating insulin-like growth factor-1.

The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency.

The role of thyroid hormone in the human fetus is uncertain; a significant amount of T4 is transferred from the maternal to the fetal circulation. A mother-infant pair was found to be heterozygotic for a point mutation in codon 271 of the gene encoding Pit-1, a pituitary-specific transcription factor regulating somatotrope, lactotrope, and thyrotrope function. At birth, serum T4 was undetectable in mother and infant. The newborn presented with a striking delay of respiratory, cardiovascular, neurological, and bone maturation. Despite replacement therapy since birth, neurological development of the infant is impaired. Fetomaternal Pit-1 deficiency resulted in unmitigated fetal hypothyroidism that unmasked thyroid hormone as a potent endogenous drive of fetal maturation and revealed placental transfer of maternal T4 as a rescue mechanism for infants with congenital hypothyroidism, preventing fetal and neonatal symptoms of thyroid deficiency and safeguarding developmental potential.

Properties of thyroid-stimulating hormone and cortisol secretion by the human newborn on the day of birth.

Secretory activation of the thyroid and adrenal glands is a hallmark of the neonatal adaptation to extrauterine life. TSH and cortisol play key roles in these axes. The highest serum concentrations of TSH attained over the full span of human life are normally found shortly after birth. Serum cortisol is also known to be elevated in the immediate postnatal period. However, the dynamics of TSH and cortisol secretion have hitherto not been documented on the day of birth. To study the properties of neonatal TSH and cortisol secretion, we obtained arterial blood at regular intervals (every 20 min for 6 h) from nine polycythemic newborns (gestational age, 34-41 weeks) on the first and/or fourth days after birth during a therapeutic, standardized, isovolumetric, partial exchange transfusion. One premature infant had received betamethasone antenatally. The serum TSH level of an infant with congenital hyperthyroidism of transplacental origin was also measured at the postnatal age of 1 h. Deconvolution analysis of the profiles revealed that all infants displayed a combination of basal and pulsatile TSH release. Bursts of TSH secretion occurred at a median interval of 133 min. The median serum TSH half-life was 75 min. On the day of birth, basal TSH secretion and the amplitude of pulsatile TSH secretion were higher than 3 days later. Cortisol was secreted exclusively in a pulsatile fashion. Bursts of cortisol release occurred at a median interval of 69 min. The median serum cortisol half-life was 60 min. Cortisol secretion appeared to shift gradually from a high frequency, low amplitude pattern early on the first day toward a lower frequency, higher amplitude pattern 3 days later. TSH and cortisol secretion were low in the infant who received betamethasone prenatally. Serum TSH was undetectable in the infant with congenital hyperthyroidism. In conclusion, serum TSH concentrations in the human newborn appear to be elevated on the day of birth as a result of amplified basal and pulsatile TSH release, then fall rapidly through a mechanism that decreases the amplitude of TSH secretion and are affected by modulation of the fetal thyroid axis. From the day of birth onward, cortisol was found to be released in an exclusively pulsatile mode, with characteristics that appear to depend on postnatal age and prenatal glucocorticoid exposure.

Hormone synthesis and storage in the thyroid of human preterm and term newborns: effect of thyroxine treatment.

Iodine and thyroglobulin concentrations, as well as iodine, T3, T4 and sialic acid contents of thyroglobulin, were measured in thyroid glands collected postmortem from 42 human premature or term newborns and infants. Three groups were considered: very preterm newborns (24-32 postmenstrual weeks, < 5 days postnatal life), preterm and term newborns (34-41 postmenstrual weeks, < 5 days postnatal life) and infants (born at term, postnatal age 1-8 months). Five very preterm and seven preterm newborns received a daily dose of 10 microg/kg L-T4 for at least 3 days. Thyroid weight and sialic acid content of thyroglobulin progressed with maturation. Intrathyroidal concentrations of iodine and thyroglobulin did not increase significantly before the 42nd week of postmenstrual age. The level of thyroglobulin iodination increased during the postnatal life, except in the very preterm neonates. T4 and T3 content of thyroglobulin was directly proportional to its degree of iodination and positively related to its sialic acid content. L-T4 treatment of preterm newborns increased thyroglobulin iodination and T4-T3 content, without increasing thyroglobulin concentration in the thyroid. It was concluded that the storage of thyroglobulin and iodine in the thyroid develops around term birth. This, associated with the resulting rapid theoretical turnover of the intrathyroidal pool of T4 in Tg, could be an important factor of increased risk of neonatal hypothyroxinemia in the premature infants. The L-T4 treatment of preterm newborns does not accelerate the maturational process of the thyroid gland.

Congenital eventration of the diaphragm: an unusual cause of intractable neonatal respiratory distress with variable etiology.

We describe two infants dying neonatally of respiratory failure despite all attempts at resuscitation. The most striking finding at autopsy was eventration and reduced muscle content of the diaphragm. Microscopic examination of the skeletal muscles, in combination with retrospective evaluation of the family history, disclosed severe X-linked centronuclear myopathy in the first patient and congenital myotonic dystrophy in the second. These disorders are probably more frequent than reported before. Their identification is important, not only for genetic counseling of the involved families but also for providing the neonatologist a sufficient explanation for the failure of resuscitation.

Opitz C syndrome and pseudohypoaldosteronism.

The C syndrome of multiple congenital anomalies is described in a male infant with pseudohypoaldosteronism. The association of these 2 rare autosomal recessive conditions is discussed.

The syndrome of diaphragmatic hernia, abnormal face and distal limb anomalies (Fryns syndrome): report of two sibs with further delineation of this multiple congenital anomaly (MCA) syndrome.

We describe 2 sibs with the syndrome of diaphragmatic hernia, abnormal face, and distal limb anomalies. Both infants died shortly after birth with severe respiratory distress. Postmortem examination showed gross internal anomalies: Dandy-Walker malformation, ventricular septal defect, and renal cystic dysplasia. This combination of anomalies, also termed the Fryns syndrome, appears to be a distinct MCA syndrome with variable expression and probable autosomal recessive inheritance. Prenatal ultrasonographic diagnosis was successful in both patients.

Congenital pulmonary lymphangiectasis with chylothorax: a heterogeneous lymphatic vessel abnormality.

We report on 7 perinatal autopsy cases of primary congenital pulmonary lymphangiectasis (CPL) with bilateral chylothorax. This study demonstrates that primary CPL is often complicated by chylous pleural effusions with ensuing pulmonary hypoplasia. Conversely, CPL appears to be a constant pathological finding in spontaneous congenital chylothorax. These observations indicate a common pathogenesis for both disorders. The basic defect is not an intrinsic lung abnormality, but a developmental error of the lymphatic system resulting in a pulmonary lymphatic obstruction sequence. The cause of CPL is heterogeneous. Apparently, most cases are sporadic occurrences. We report the second instance of CPL in sibs. This indicates that some cases are genetically determined with autosomal recessive inheritance. CPL may also be part of a multiple congenital anomalies (MCA) syndrome such as Noonan, Ullrich-Turner, and Down syndrome.

Diaphragmatic hernia in Denys-Drash syndrome.

We report on a newborn infant with male pseudohermaphroditism and glomerular lesions (Denys-Drash syndrome) but without Wilms tumor. A constitutional heterozygous mutation in the WT1 gene (366Arg to His) was identified. In addition the child had a large diaphragmatic hernia, so far not described in Denys-Drash syndrome. The expression of the WT1 gene in pleural and abdominal mesothelium and the occurrence of diaphragmatic hernia in transgenic mice with a homozygous WT1 deletion strongly suggests that the diaphragmatic hernia in this patient is part of the malformation pattern caused by WT1 mutations.

Child morbidity patterns in two tropical seasons and associated mortality rates.

Cross-sectional morbidity recorded during two successive quarterly survey rounds and subsequent 27-months mortality were studied in a random sample of 4238 preschool children in a rural Zairian area. Analysis focuses on morbid patterns, i.e. any combination of the principal signs and symptoms encountered in tropical areas (oedema, marasmus, cough, fever, diarrhoea and tachypnoea). Almost half the children (45-48%) had signs of morbidity, a very high rate. The 3-6 month age group emerged as particularly vulnerable with the highest prevalences of all morbid patterns except for isolated fever. Isolated cough was more prevalent in the dry season probably as an effect of nightly indoor woodburning. All other morbid patterns were significantly more prevalent in the rainy season. Diarrhoea with cough was found to constitute half of all cases of diarrhoea. The results show that with a few simple questions on major symptoms and a brief examination by paramedical health workers, children with an increased risk of death can be identified. The method can be applied at under-5 clinics. Prognosis is particularly bad in severe malnutrition, especially when associated with diarrhoea, in diarrhoea with cough, cough with fever/tachypnoea and for children who are found sick both in the rainy and the subsequent dry season.

PIP: Cross-sectional morbidity in 2 successive quarterly survey rounds and subsequent 27-months mortality were studied in a random sample of 4238 preschool children in the rural health zone of Bwamanda in northern Ubangi, Zaire. 45-48% of the subjects displayed signs of morbidity such as oedema, marasmus, cough, fever, diarrhea, and tachypnoea. Being particularly vulnerable, children aged 3-6 months exhibited the highest prevalences of all morbid patterns except for isolated fever. Further, while isolated cough was more prevalent in the dry season and probably attributable to nightly indoor woodburning, all other morbid patterns were significantly more prevalent in the rainy season. Diarrhea with cough constituted half of all diarrhea cases. The authors continue by concluding that children at increased risk of death may be readily identified by posing a few simple questions on major symptoms and a brief examination by paramedical health workers. The method could be employed at under-5 clinics. Prognosis, however, is particularly bad in severe malnutrition, especially when associated with diarrhea, in diarrhea with cough, cough with fever/tachypnoea, and for children who are found sick both in the rainy and the subsequent dry season.

Iron supplementation in preterm infants: a study comparing the effect and tolerance of a Fe2+ and a nonionic FeIII compound.

The more widely used divalent forms of iron (Fe2+) supplementation often lead to gastrointestinal symptoms in preterm infants although little is known about the use of nonionic trivalent iron preparations (FeIII) in these patients. It is especially under this nonionic form that dietary iron is available. For this reason, a randomized controlled study was undertaken to compare the efficacy and the extent of possible side effects in two groups of preterm infants. In one group, the elemental iron was given in the Fe2+ form, while the other group received a nonionic trivalent iron (FeIII) complexed with polysaccharides of low molecular weight. Both groups received 7.5 mg elemental iron daily. Measured parameters in the two study groups did not differ significantly throughout the study period of 14 weeks. Both forms of iron supplementation were well tolerated. However, vomiting, diarrhea, or constipation occurred slightly more often in the group receiving iron supplementation in the Fe2+ form without reaching statistical difference. The authors found a nonionic trivalent polysaccharide-iron complex given as iron supplementation as effective as the generally more favored ferrous sulphate. Since iron therapy is mandatory in the preterm infant, the use of trivalent iron complexes can be considered as a good alternative.

Fetal cardiac tamponade due to an intrapericardial teratoma.

A case of an intrapericardial tumor diagnosed in utero at 26 weeks of gestation is presented. The prenatal echocardiographic follow-up of an incipient hydrops fetalis determined the management and the emergency surgical treatment. Histologically, the tumor appeared to be a benign teratoma, grade I. In the postoperative period an unexpected mediastinal tumor was found and removed later. This tumor also appeared to be a benign teratoma, grade 0. Both teratomas were independent and therefore primary.

Threshold retinopathy at threshold of viability: the EpiBel study.

AIM: To describe incidence, co-morbidity characteristics, and risk factors associated with threshold retinopathy of prematurity (ROP) in survivors with a gestational age (GA) of < or =26 weeks at birth. METHODS: Retrospective analysis of perinatal data of all inborn survivors in all perinatal centres of Belgium in the period 1999-2000 (EpiBel cohort) believed to be between 22 and 26 weeks GA at time of delivery. Data on survivors who did and survivors who did not develop threshold ROP were compared (chi(2), Mann-Whitney U) and logistic regression was performed. RESULTS: Of 303 admitted infants 175 (58%) were discharged alive. Incidence of major retinopathy (> or =stage 3) and of threshold ROP was 25.5% and 19.8% in survivors. Associated central nervous abnormalities were documented in six (17%) and associated chronic lung disease in 19 (54%) threshold ROP infants. Threshold ROP without additional morbidity characteristics at discharge was documented in 14 (40%) infants. Besides often reported risk factors, renal insufficiency (creatinaemia>1.5 mg/dl) was a risk factor to develop threshold ROP (p<0.0015) (chi(2)). Days of respiratory support (OR 1.02; 95% CI 1.002 to 1.039), number of transfusions (OR 1.118; 95% CI 1.030 to 1.214), and renal insufficiency (OR 3.31; 95% CI 1.344 to 8.196) remained independent risk factors to develop threshold ROP in this cohort in a stepwise logistic regression model (MedCalc). CONCLUSIONS: Incidence of threshold ROP is high at the limits of viability. Renal insufficiency is a risk factor to develop threshold ROP in this cohort.

Calcium and phosphorus retention in the preterm infant during total parenteral nutrition. A comparative randomised study between organic and inorganic phosphate as a source of phosphorus.

The preterm infant fed parenterally is prone to some demineralisation due in part to insufficient Calcium (Ca) and Phosphorus (P) retention. In an attempt to augment Ca and P retention, we prepared a standardised parenteral solution containing calcium gluconate and glucose-1-phosphate (Phocytan) as source of phosphorus, yielding a daily supply of 75 mg/kg Ca and 45 mg/kg P. 28 very low birthweight infants were randomly assigned to receive either this solution (high Ca P ; n = 15) or a conventional formulation containing calcium gluconate and potassium mono- and dibasic phosphate delivering 42 mg/kg Ca and 36 mg/kg P daily (low Ca P ; n = 13). In the high Ca P daily retention was respectively 80% and 99% for Ca and P whereas in the low Ca P group, retention was 70% and 82%. Serum parathormone levels were significantly lower in the high Ca P group. We conclude that parenteral nutrition with a new high Ca P supplement results in an augmented Ca and P retention in very low birthweight infants. This may help to prevent neonatal bone demineralization.

Standard two-compartment formulation for total parenteral nutrition in the neonatal intensive care unit: A fluid tolerance based system.

The nutrient requirements of most (pre) term newborns receiving intensive care appear to be relatively fixed. The range of optimal fluid load however, is perceived as being quite narrow and highly variable in time. We designed four amino acid-dextrose mixtures for a standardized neonatal parenteral nutrition, delivering a fixed amount of nutrients in four dilutions with water and corresponding to a fluid load of 90, 110, 130 or 170 ml/kg per day. The addition of a lipid emulsion completes the TPN. In a pilot study, we followed the weight of 30 very low birthweight infants on this parenteral nutrition. After a stabilisation period, the weight gain was found to be similar to the normal fetal weight accretion in utero. We have now infused these solutions in to more than 1000 infants, without significant complications. These formulations proved to have substantial advantages compared to the individualized prescription in terms of availability, safety and time- and cost-effectiveness.

Pulmonary mechanics during respiratory distress syndrome in the prediction of outcome and differentiation of mild and severe bronchopulmonary dysplasia.

Pulmonary mechanics was prospectively and longitudinally studied in a cohort of 58 infants who suffered from respiratory distress syndrome. The aim was to determine if early compliance and resistance measurements had additional value to simple clinical variables in predicting poor outcome ie nonsurvival or severe bronchopulmonary dysplasia (BPD) at 28 days. Second, we wanted to determine whether and when the recently described type 1 (mild) BPD and type 2 (severe) BPD could be differentiated by means of lung function tests. In a logistic model, neither lung compliance nor pulmonary resistance at days 1 and 4 of life were selected as predictive variables. On the other hand, gestational age and the ventilatory index no. 1 (ventilator frequency x maximal inspiratory pressure) on day 3 were the best early predictors of poor outcome. Type 2 BPD was characterized by a lower lung compliance and a higher pulmonary resistance than type 1 BPD, although the differences were only significant at 28 days. In conclusion, pulmonary function tests were not helpful in the early prediction of poor outcome at 28 days. They might, however, be of value in the follow-up of BPD patients after 28 days.