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Growth in very preterm children: a longitudinal study.

The knowledge about the long-term growth of very preterm children in relation to gestational age at birth is incomplete. Therefore, a retrospective study of longitudinal growth from birth to 7 y of age in 52 of 56 surviving children who were born at a gestational age of <29 wk between 1988 and 1991 to mothers resident in the city of Göteborg, Sweden, was performed. A majority of the children had an initial decrease in weight during the first months of life, followed by an increase, with a maximum weight gain occurring at 36-40 wk postmenstrual age. After a period of decreased weight and length velocity, a second increase in weight velocity was demonstrated from 6 mo to 2 y of corrected age. A corresponding increase in length velocity was found from 2 to 12 mo of corrected age. A later catch-up growth period was found at 4-5 y of age. At 7 y of age, all but two had reached the normal height range of the population. This long-term catch-up in height was established later in those who were born at an earlier gestational age. We conclude that all preterm infants had an initial period of poor growth, which rendered them growth retarded during the first years of life. It took approximately 4-7 y to overcome what the very preterm child lost in growth during the first months of life. However, as a group, they did reach normal height, weight, and weight for height before puberty.

Adult↗

Bronchopulmonary dysplasia is not associated with ultrasound-defined cerebral white matter damage in preterm newborns.

Bronchopulmonary dysplasia (BPD) and cerebral white matter damage (WMD) are neonatal disorders that occur most commonly in those who are born much before term. In a large multicenter database, we sought to determine whether the two disorders occur together more frequently than expected and whether BPD and other neonatal respiratory characteristics are more common among infants who develop ultrasound-defined WMD than among those who do not. In a sample of 904 infants who were born before the 30th week of gestation and survived until 36 wk postmenstrual age, we did not find a co-occurrence of BPD and WMD above what would be expected by chance. Confounding does not seem to account for this lack of association between WMD and BPD. In conclusion, our findings do not support the hypothesis that BPD contributes to the occurrence of sonographically defined WMD.

Brain Diseases↗

Cerebral structure and metabolism and long-term outcome in small-for-gestational-age preterm neonates.

In the present study, we compared brain development and metabolism of small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) infants using proton magnetic resonance spectroscopy ((1)H-MRS). We tested the hypothesis that intrauterine growth retardation caused by placental insufficiency is associated with changes in cerebral metabolism and is followed by an adverse neurodevelopmental outcome at the age of 2 y. Twenty-six AGA and 14 SGA (birth weight <P 2.3) preterm infants with no major ultrasound abnormalities were enrolled prospectively. At 32 and 41 wk postmenstrual age, (1)H-MRS and magnetic resonance imaging were performed. For (1)H-MRS, a volume of interest was placed in the basal ganglia and in the periventricular white matter. Using echo times of 31 and 144 ms N-acetylaspartate/choline (NAA/Cho), lactate/Cho, myo-inositol/Cho (mI/Cho), and glutamate-glutamine-gamma-aminobutyric acid/Cho (Glx/Cho) ratios were compared between AGA and SGA groups. Griffiths' developmental quotient (DQ) values were assessed at 24 mo corrected age. Griffiths' DQ (AGA, 104 +/- 10; SGA, 99 +/- 9) and brain development assessed using magnetic resonance imaging showed no significant differences between both AGA and SGA groups, and NAA/Cho, Lac/Cho, mI/Cho, and Glx/Cho ratios were not significantly different between the groups. NAA/Cho ratios increased from 32 to 41 wk, whereas mI/Cho ratios decreased in both groups. No differences in cerebral metabolism, brain development, and DQ values between AGA and severely SGA infants could be demonstrated.

Birth Weight↗

The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome.

Clara cell 10-kD protein (CC10) is a potent anti-inflammatory protein that is normally abundant in the respiratory tract. CC10 is deficient and oxidized in premature infants with poor clinical outcome (death or the development of bronchopulmonary dysplasia). The safety, pharmacokinetics, and anti-inflammatory activity of recombinant human CC10 (rhCC10) were evaluated in a randomized, placebo-controlled, double-blinded, multicenter trial in premature infants with respiratory distress syndrome. A total of 22 infants (mean birth weight: 932 g; gestational age: 26.9 wk) received one intratracheal dose of placebo (n = 7) or 1.5 mg/kg (n = 8) or 5 mg/kg (n = 7) rhCC10 within 4 h of surfactant treatment. Pharmacokinetic analyses demonstrated that the serum half-life was 11.6 (1.5 mg/kg group) and 9.9 h (5 mg/kg group). Excess circulating CC10 was eliminated via the urine within 48 h. rhCC10-treated infants showed significant reductions in total cell count (p < 0.0002), neutrophil counts (p < 0.001), and total protein concentrations (p < 0.01) and tended to have decreased IL-6 (p < 0.07) in tracheal aspirate fluid collected over the first 3 d of life. Infants in all three groups showed comparable growth. At 36 wk postmenstrual age, five of seven infants were still hospitalized and two of seven infants were receiving oxygen in the placebo group compared with two of seven hospitalized and one of seven receiving oxygen in the 1.5-mg/kg group and four of six hospitalized and three of six receiving oxygen in the 5-mg/kg group. A single intratracheal dose of rhCC10 was well tolerated and had significant anti-inflammatory effects in the lung. Multiple doses of rhCC10 will be investigated for efficacy in reducing pulmonary inflammation and ameliorating bronchopulmonary dysplasia in future studies.

Anti-Inflammatory Agents↗

Development of cerebral blood flow volume in preterm neonates during the first two weeks of life.

To investigate the postnatal development of cerebral perfusion in preterm neonates with normal brains over the first 2 wk of life, a prospective longitudinal study was designed. Quantitative measurement of cerebral blood flow (CBF) volume was performed using ultrasound flowmetry of the extracranial, brain-feeding arteries in 32 preterm infants of 28-35 wk gestational age. Measurements were done in the internal carotid and vertebral arteries of both sides on d 1, 2, 3, 7, and 14 after birth. A 10.0-MHz linear transducer of a computed sonography system (Acuson 128/XP10) was used. Intravascular flow volumes were calculated as the product of angle-corrected time-averaged flow velocity and the cross-sectional area of the vessel. Mean CBF volume increased markedly over the first 2 wk. One-third of this rise already occurred from the first to the second postnatal day, thereafter there was a continuous increase from d 2 to d 14 of life. Whereas the absolute level of CBF volume was primarily determined by postmenstrual age, the pattern of postnatal changes in CBF volume was found to be independent of gestational age. Arterial carbon dioxide tension, mean arterial blood pressure, and hematocrit had no influence on the development of CBF volume. The pronounced increase of CBF volume from d 1 to d 2 is likely to represent a normal adaptive response of the cerebral circulation to postnatal life. The data presented here may serve as the basis for further studies to investigate whether deviations from this adaptive response are associated with an increased risk of brain injury.

Analysis of Variance↗

Partitioning of airway and parenchymal mechanics in unsedated newborn infants.

The recent trend toward development of noninvasive methods that can accurately evaluate the lung periphery has particular relevance for the predominantly parenchymal nature of neonatal respiratory disease. Concerns regarding the safety of sedating newborn (especially preterm) infants have also stimulated a drive toward measurements obtained during natural sleep. This study aimed to adapt existing methodology for the low-frequency forced oscillation technique to obtain partitioned measurements of airway and parenchymal mechanics during unsedated, quiet sleep in newborn infants without a history of previous respiratory disease. A face mask was positioned over the infant's mouth and nose and a brief (4-5 s) breathing pause was induced by evoking the Hering-Breuer reflex via end-inspiratory occlusion at raised lung volume (airway opening occluded at 2 kPa). Airway opening pressure and flow were measured while a pseudorandom noise (2-14 Hz) was applied to the airway. Acceptable pulmonary impedance data were collected in 11 of the 12 infants studied (34.1-42.6 wk postmenstrual age, 1.9-3.9 kg body weight) on 17 (total of 20) occasions. Airway parameters (resistance and inertance) and respiratory tissue parameters were calculated from the resultant impedance spectra. Tissue resistance and tissue elastance decreased with increasing body length albeit at different rates such that hysteresivity (tissue resistance/tissue elastance) also decreased. There was a trend toward reduction in airway resistance with increasing length. Measurements of lung function are feasible in the unsedated newborn infant using low-frequency forced oscillations and confirm the important contribution of tissue resistance to lung mechanics in the developing lung.

Airway Resistance↗

ADHD deficit as measured in adolescent boys with a continuous performance task is related to antenatal maternal anxiety.

Antenatal maternal anxiety has been shown to be related to infant temperament, childhood disorders, and impulsivity in adolescence. This study prospectively investigated whether antenatal maternal anxiety is associated with performance on a continuous performance task. Sixty-four adolescents (mean age, 15 y; 34 boys, 30 girls) were examined with a computerized continuous performance task (CPT) measuring sustained attention. Results showed that the CPT performance of boys of mothers with high levels of state anxiety during the 12th to 22nd postmenstrual week of pregnancy declined as the task progressed: their processing speed became slower and the variability in their reaction times increased. The study controlled for the possible confounding influences of postnatal maternal anxiety, the parents' educational level, and intelligence. Establishing a link between antenatal maternal anxiety and an objective measure of sustained attention/self-regulation, our results extend the growing evidence for an association between antenatal maternal anxiety and the neurobehavioral development of the offspring up into adolescence.

Adolescent↗

Sonographic maturation of third-trimester cerebellar foliation after birth.

The development of cerebellar folia of third-trimester preterms has not been described with ultrasound before. We set out to determine normal development of the pons and cerebellar folia for future measurements of hypoplasia and atrophy. Study sonograms were made in preterms admitted to the neonatal intensive care unit with postmenstrual age (PMA) from 25 wk until term. On a weekly basis, transcranial measurements were made in the axial and coronal planes at the asterion with high-frequency transducers (8.5 and 13 MHz). The axial images showed the pons and fourth ventricle. The coronal images showed cerebellar folia and white matter. In the same coronal plane, the depth of cerebellar fissures at the rostral cerebellar convexity could be observed. A total of 172 cranial sonograms were performed on 98 neonates. The development of folia could be measured with ultrasound through the asterion. We showed that pons area, mean of three fissure depths, hemisphere area, and number of folia in the horizontal fissure correlated significantly with PMA. Hemisphere area described the same trend of growth as the transverse cerebellar diameter used in fetal sonography.

Cerebellum↗

Noninvasive measurements of regional cerebral perfusion in preterm and term neonates by magnetic resonance arterial spin labeling.

Magnetic resonance arterial spin labeling (ASL) at 3 Tesla has been investigated as a quantitative technique for measuring regional cerebral perfusion (RCP) in newborn infants. RCP values were measured in 49 healthy neonates: 32 preterm infants born before 34 wk of gestation and 17 term-born neonates. Examinations were performed on unsedated infants at postmenstrual age of 39-40 wk in both groups. Due to motion, reliable data were obtained from 23 preterm and 6 term infants. Perfusion in the basal ganglia (39 and 30 mL/100 g/min for preterm and term neonates, respectively) was significantly higher (p < 0.0001) than in cortical gray matter (19 and 16 mL/100 g/min) and white matter (15 and 10 mL/100 g/min), both in preterm neonates at term-equivalent age and in term neonates. Perfusion was significantly higher (p = 0.01) in the preterm group than in the term infants, indicating that RCP may be influenced by developmental and postnatal ages. This study demonstrates, for the first time, that noninvasive ASL at 3T may be used to measure RCP in healthy unsedated preterm and term neonates. ASL is, therefore, a viable tool that will allow serial studies of RCP in high-risk neonates.

Cerebrovascular Circulation↗

Amiloride-sensitive nasal potential difference is not changed by estradiol and progesterone replacement but relates to BPD or death in a randomized trial on preterm infants.

Postnatal replacement of placental estradiol (E2) and progesterone (P) in preterm infants may improve lung function, possibly mediated through enhanced epithelial Na(+) transport and alveolar fluid clearance. Preterm infants of <29 wk gestational age and <1000 g birth weight requiring mechanical ventilation within 12 h of birth were randomized to receive either 2.5 mg/kg E2 and 22.5 mg/kg P per day (E2/P), or vehicle placebo. Epithelial Na(+) transport was assessed in 29 infants by measuring total nasal potential difference (NPD) and amiloride-sensitive NPD (ASNPD) on postnatal days of life 1, 3, 5, and 7, and mean values of all four measurements were calculated. Bronchopulmonary dysplasia (BPD) was defined as need for supplemental oxygen (goal Sa(O2) 90%) or mechanical ventilation at 36 wk corrected postmenstrual age. Mean ASNPD was -6.5 +/- 2.8 mV in infants receiving E2/P and -6.1 +/- 2.6 mV in infants receiving placebo (not significant). NPD was -10.6 +/- 3.8 mV and -10.7 +/- 3.6 mV, respectively. The ASNPD was significantly higher in infants surviving without BPD (-7.1 +/- 2.5 mV) than in infants developing BPD or not surviving (-5.2 +/- 2.4 mV). In conclusion, ASNPD is not changed by postnatal replacement of E2 and P. Infants at high risk of developing BPD had lower ASNPD values in the immediate postnatal period.

Amiloride↗

Electrical potential difference across the nasal epithelium is reduced in premature infants with chronic lung disease but is not associated with lower airway inflammation.

Airway liquid content and insufficient absorptive airway ion transport at birth are potentially important factors in the development and severity of neonatal respiratory disease. The role of deficient absorptive airway ion transport in the development of chronic lung disease of prematurity is unknown. Additionally, lung inflammatory mediators modulate airway ion transport. Their effect on preterm lung ion transport and absorptive capacity is not established. We performed serial nasal potential difference studies and broncho-alveolar lavage in preterm infants born less than 30 wk postmenstrual age over the first four postnatal weeks. Our study aims were to: 1) compare nasal potential difference between preterm infants developing chronic lung disease and babies of similar gestation who do not; and 2) examine for an association between airway inflammation and ion transport parameters. We found that potential difference across the nasal epithelium increased with gestation, remained low and unchanged in infants developing chronic lung disease over the first four postnatal weeks, was significantly lower at four weeks in chronic lung disease infants, and was not associated with lower airway inflammation at any time point. We conclude that infants with chronic lung disease postnatally have a persistently reduced absorptive airway ion transport capacity.

Female↗

Vascular proliferation and vascular endothelial growth factor expression in the rhesus macaque endometrium.

The relationship between vascular endothelial growth factor (VEGF) expression and the pattern of vascular proliferation in the rhesus macaque endometrium has not been studied. In this report, we used in situ hybridization to evaluate VEGF, VEGF receptor type 1 and VEGF receptor type 2 mRNA expression during hormonally regulated menstrual cycles in ovariectomized macaques. Proliferating endothelial cells were identified by a double immunocytochemistry procedure that detected Ki-67 antigen and von Willebrand factor in the same endothelial cells. One and 2 d after progesterone withdrawal (premenstrual), VEGF mRNA was up-regulated in the glands and stroma of the superficial endometrial zones, a finding that supports our previous suggestion that VEGF may play a role in the menstrual induction cascade. During the postmenstrual repair phase, the healing surface epithelium showed a further, dramatic increase in expression of VEGF mRNA, accompanied by strong increases in signals for VEGF receptor types 1 and 2 in multiple profiles of small blood vessels immediately below the surface epithelium. This finding implicates VEGF in the early angiogenic processes associated with endometrial healing and regeneration. Vascular endothelial proliferation persisted throughout the cycle in the upper endometrial zones and showed a dramatic estrogen- dependent peak during the midproliferative phase. This proliferative peak coincided with a peak in VEGF expression in the endometrial stroma. Endothelial proliferation was also significantly correlated with the degree of stromal VEGF expression during the proliferative and secretory stages of the cycle. These results implicate VEGF of stromal origin in endometrial vascular proliferation.

Animals↗

Cardiovascular stress reactivity and mood during the menstrual cycle.

This study examined blood pressure and heart rate responses to a mental arithmetic task in a sample of 16 regularly menstruating women during the follicular (postmenstrual) and luteal (premenstrual) phases of their menstrual cycles. Self-reports of physical and psychological symptoms (mood) were obtained prior to testing. A control group of men was matched to the women with regard to age and yoked to the women's cycle phases. Both women and men were told the study involved "phases of the moon" in order to eliminate subjects' awareness of participating in a biological cycle study. Consistent with prior studies that have eliminated women's awareness of taking part in a study on menstrual phases, no phase differences in mood were evident nor did the women's mood ratings differ from those of men's. In addition, there were no phase differences in blood pressure and heart rate reactivity. These findings suggest that hormonal variations characteristic of the luteal and follicular phases do not assert an influence on common assessments of cardiovascular stress reactivity.

Adult↗

Impact of ibuprofen administration on renal drug clearance in the first weeks of life.

The administration of ibuprofen or any other nonselective cyclooxygenase (COX) inhibitor drug in early neonatal life is associated with a reduction of glomerular filtration, which reduces the elimination of drugs dependent on renal function for clearance. However, the relationship between COX inhibitor drug indication (prophylactic or therapeutic) and the magnitude of this effect remains unclear. Observations collected in two population pharmacokinetic studies, in preterm neonates, investigating amikacin and vancomycin were used to estimate: i) the impact of ibuprofen administration on the clearance of these drugs; and ii) the difference between prophylactic and therapeutic administration of ibuprofen on this clearance. Prophylactic administration of ibuprofen to preterm neonates on the first day of life to enhance closure of an asymptomatic patent ductus arteriosus (PDA) reduced amikacin clearance by 21% while coadministration of ibuprofen to induce closure of a symptomatic PDA resulted in an 18% reduction in vancomycin clearance in the first month of postnatal life. A significant and clinically relevant reduction in drug clearance is observed when ibuprofen is coadministered independent of indication, postmenstrual or postnatal age. Population modeling with covariate analyses can provide us with the tools to further disentangle the impact of nonselective COX-inhibitors on renal drug clearance.

Age Factors↗

Transient hypothyroxinemia of prematurity and histological chorioamnionitis.

BACKGROUND: Transient hypothyroxinaemia of prematurity (THOP) is a common condition of preterm infants whose causes remain unclear. We tested the hypothesis that THOP is associated with histological chorioamnionitis (HCA). METHODS: Whole blood T4 and TSH concentrations on day 4 and at 40 weeks' postmenstrual age (rtx-T4 and rtx-TSH), placental histology and illness severity were prospectively evaluated in 155 very low birth weight (VLBW) infants. RESULTS: HCA-positive infants showed significantly decreased blood total T4 concentrations on day 4, as compared to the HCA-negative population (P<0.0001), along with comparable TSH, rtx-T4, and rtx-TSH blood concentrations. None of the infants showed evidence of hypothyroidism during the study. A total T4 < or = 4.4 microg/dL on postnatal day 4 identified HCA-positive newborns with 90.8%, sensitivity, 94.7%, specificity, 96.7% positive predictive and 85.7% negative predictive values. HCA (OR: 32.19; 95% CI: 8.95-115.64), birth weight < or = 880 g (OR: 4.1; 1.15-14.64), and RDS (OR: 3.71, 95% CI: 1.13-12.25) were independently associated with evidence of hypothyroxinaemia on day 4. CONCLUSION: Our findings indicate a previously un-recognized relationship between HCA and THOP, hence suggesting a predominant role for a fetal systemic inflammatory response syndrome in the pathogenesis of THOP.

Age Factors↗

Postnatal glucocorticosteroid therapy for treatment and prevention of neonatal chronic lung disease.

Neonatal chronic lung disease (CLD) is a persistent complication, primarily of premature infants. Postnatal glucocorticoid therapy is widely used in the treatment and prevention of CLD. Most studies reveal acute improvement in the pulmonary status of infants treated with postnatal glucocorticoid therapy. Recent studies of 'earlier' intervention (< 14 days of age) demonstrated a reduction in mortality and in the occurrence of CLD between 28 days of age and 36 weeks postmenstrual age. Great concern remains, however, regarding the potential adverse outcomes, including growth inhibition, infection, catastrophic GI complications and CNS injury. Therefore, the use of postnatal glucocorticoid therapy remains controversial with respect to the clinical indications for initiating therapy, the dose, duration, onset and route of administration, as well as potential benefits and risks. Inhaled glucocorticoid therapy is increasingly used to treat and prevent CLD in order to avoid adverse effects of high dose systemic glucocorticoid therapy. Recent studies with inhaled glucocorticoid therapy show promise. Further work, however, for improving aerosol delivery and deposition, will be needed to refine their role in the prevention and treatment of CLD. Future studies enabling early, accurate identification of infants at greatest risk for CLD, coupled with a more comprehensive understanding of the different pathogeneses, will provide information regarding appropriate timing of onset, dosing, route of therapy and duration of intervention.

Administration, Inhalation↗

Cortical pain responses in human infants.

Despite the recent increase in our understanding of the development of pain processing, it is still not known whether premature infants are capable of processing pain at a cortical level. In this study, changes in cerebral oxygenation over the somatosensory cortex were measured in response to noxious stimulation using real-time near-infrared spectroscopy in 18 infants aged between 25 and 45 weeks postmenstrual age. The noxious stimuli were heel lances performed for routine blood sampling; no blood tests were performed solely for the purpose of the study. Noxious stimulation produced a clear cortical response, measured as an increase in total hemoglobin concentration [HbT] in the contralateral somatosensory cortex, from 25 weeks (mean Delta[HbT] = 7.74 micromol/L; SE, 1.10). Cortical responses were significantly greater in awake compared with sleeping infants, with a mean difference of 6.63 micromol/L [95% confidence interval (CI) limits: 2.35, 10.91 micromol/L; mean age, 35.2 weeks]. In awake infants, the response in the contralateral somatosensory cortex increased with age (regression coefficient, 0.698 micromol/L/week; 95% CI limits: 0.132, 1.265 micromol/L/week) and the latency decreased with age (regression coefficient, -0.9861 micromol/L/week; 95% CI limits: -1.5361, -0.4361 micromol/L/week; age range, 25-38 weeks). The response was modality specific because no response was detected after non-noxious stimulation of the heel, even when accompanied by reflex withdrawal of the foot. We conclude that noxious information is transmitted to the preterm infant cortex from 25 weeks, highlighting the potential for both higher-level pain processing and pain-induced plasticity in the human brain from a very early age.

Brain Mapping↗

Comparison of Infasurf (calf lung surfactant extract) to Survanta (Beractant) in the treatment and prevention of respiratory distress syndrome.

OBJECTIVE: To compare the relative safety and efficacy of Infasurf (calf lung surfactant extract; ONY, Inc, Amherst, NY, IND #27169) versus Survanta (Beractant, Ross Laboratories, Columbus, OH) in reducing the acute severity of respiratory distress syndrome (RDS) when given at birth and to infants with established RDS. DESIGN: A prospective, randomized, double-blind, multicenter clinical trial. SETTING: Thirteen neonatal intensive care units participated in the treatment arm: seven of these concurrently participated in the prevention arm. PATIENTS: The treatment arm enrolled infants of </=2000 g birth weight with established RDS, and the prevention arm enrolled infants of </=29 weeks' gestation with birth weights <1250 g. INTERVENTION: Infants were randomly assigned to receive Infasurf (n = 303, treatment arm; n = 180, prevention arm) or Survanta (n = 305, treatment arm; n = 194, prevention arm) in accordance with the Survanta package insert instructions. OUTCOME MEASURES: We projected a 25% reduction between groups in the need for a third dose of surfactant for infants with established RDS, and a 25% reduction in the need for a second dose of surfactant for infants who received prophylactic surfactant. Secondary outcomes included the severity of RDS measured by inspired oxygen concentrations and mean airway pressure, air leaks, complications associated with surfactant administration, and survival to 36 weeks' postmenstrual age without the need for oxygen supplementation. RESULTS: In the treatment arm, there was no difference between groups in the number of infants requiring more than two doses of surfactant. The interval between doses was significantly longer for Infasurf, suggesting an increased duration of treatment effect. The inspired oxygen concentration and mean airway pressure were lower in the Infasurf infants during the first 48 hours in the treatment arm. In the prevention arm, there were no differences with respect to the number of surfactant doses. The dosing intervals were longer for Infasurf infants after the second dose. No difference in inspired oxygen or mean airway pressure was noted during the first 72 hours. There were no significant differences in the incidence of air leaks, complications associated with dosing, complications of prematurity, mortality, or survival without chronic lung disease in the prevention or treatment arm. CONCLUSIONS: Infants treated with Infasurf have a modest benefit in the acute phase of RDS. Infasurf seems to produce a longer duration of effect than Survanta.

Age Factors↗