We sought to determine the incidence of necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) in surviving extremely low-birth-weight (ELBW, <1000 g birth weight) infants and to establish the impact of NEC on outcomes by hospital discharge and at 18 to 22 months adjusted age in a large, contemporary, population-based practice. Hospital outcome data for all ELBW infants born in the greater Cincinnati region from 1998 to 2009 were extracted from the National Institute of Child Health Neonatal Research Network Database. Neurodevelopmental outcome at 18 to 22 months was assessed using Bayley Scales of Infant Development-II scores for Mental Developmental Index and Psychomotor Developmental Index. Multivariable logistic regression was used and adjusted odds ratios reported to control for confounders. From 1998 to 2009, ELBW infants accounted for 0.5% of the 352 176 live-born infants in greater Cincinnati. The incidence of NEC was 12%, with a 50% case-fatality rate. Death before discharge, morbid complications of prematurity and neurodevelopmental impairment were all increased among infants diagnosed with NEC. Infants with surgical NEC and SIP had a higher incidence of death, but long-term neurodevelopmental outcomes were not different comparing surviving ELBW infants with medical NEC, surgical NEC and SIP. Although ELBW infants comprise a very small proportion of live-born infants, those who develop NEC and SIP are at an increased risk for death, morbid complications of prematurity and neurodevelopmental impairment. No significant differences in neurodevelopmental outcomes were observed between the medical and surgical NEC and SIP groups.

OBJECTIVE:High-risk infant follow-up programs have the potential to act as multipurpose clinics by providing continuity of clinical care, education of health care trainees and facilitating outcome data research. Currently there are no nationally representative data on high-risk infant follow-up practices in the United States. The objective of this study is to collect information about the composition of high-risk infant follow-up programs associated with academic centers in the United States, with respect to their structure, function, funding resources and developmental assessment practices, and to identify the barriers to establishment of such programs.STUDY DESIGN:Staff neonatologists, follow-up program directors and division directors of 170 Neonatal Intensive Care Units (NICU) associated with pediatric residency programs were invited to participate in an anonymous online survey from October 2009 to January 2010.RESULT:The overall response rate was 84%. Ninety three percent of the respondents have a follow-up program associated with their NICU. Birth weight, gestational age and critical illness in the NICU were the major criteria for follow-up care. Management of nutrition and neurodevelopmental assessments was the most common service provided. Over 70% have health care trainees in the clinic. About 75% of the respondents have the neurodevelopmental outcome data available. Most of the respondents reported multiple funding sources. Lack of personnel and funding were the most common causes for not having a follow-up program.CONCLUSION:High-risk infant follow-up programs associated with academic centers in the United States are functioning as multidisciplinary programs providing clinical care, trainee education and facilitating outcomes research.

To evaluate the safety and immunogenicity of palivizumab, 55 children who received palivizumab in the IMpact-RSV trial received 5 monthly doses of 15 mg/kg palivizumab (Synagis) during the subsequent year. The single child with an antipalivizumab titer of >1/40 had no associated serious adverse events and had expected serum palivizumab trough concentrations. Second year palivizumab prophylaxis was safe and well-tolerated.

Background: Inhaled nitric oxide (INO) improved oxygenation and reduced the occurrence of death or extracorporeal membrane oxygenation in term and near-term hypoxic neonates. We report the results of neurodevelopmental follow-up of infants enrolled in the NINOS trial. Methods: Hypoxic infants greater than or equal to 34 weeks' gestation and <14 days of age were randomized to 20 ppm INO or 100% oxygen as control. Comprehensive neurodevelopmental assessment of survivors occurred at 18 to 24 months of age. Results: A total of 235 infants were enrolled in the original trial. There were 36 deaths, 20 of 121 infants in the control group and 16 of 114 infants in the INO-treated group. Of the 199 surviving infants, 173 (86.9%) were seen for follow-up (88 members of the control group and 85 members of the INO-treated group), and 135 infants were normal (69 [79.3%] members of the control group and 66 [77.6%] members of the INO-treated group). Twenty-two infants had sensorineural hearing loss (12 members of the control group and 10 members of the INO-treated group). Moderate to severe cerebral palsy occurred in 13 infants (7 infants in the control group and 6 infants in the INO-treated group). Mental developmental index scores (87 +/- 18.7 in the control group vs 85 +/- 21.7 in the INO-treated group) and psychomotor developmental index scores (93.6 +/- 17.5 in the control group vs 85.7 +/- 21.2 in the INO-treated group) were not different. A total of 29.6% of the control group compared with 34.5% of the INO-treated group had at least one disability. Infants with congenital diaphragmatic hernia, enrolled in a separate but parallel trial, had similar outcomes with a higher incidence of sensorineural hearing loss. Conclusion: Inhaled nitric oxide is not associated with an increase in neurodevelopmental, behavioral, or medical abnormalities at 2 years of age.

BACKGROUND Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants. MEDI-493 (palivizumab) is a humanized monoclonal antibody to the fusion protein of RSV and is active in animal models for prevention of pulmonary RSV replication. OBJECTIVE To describe the safety, tolerance, immunogenicity and pharmacokinetics of repeat intravenous doses of MEDI-493 in premature infants or infants with bronchopulmonary dysplasia. DESIGN Phase I/II multicenter, randomized, double blind, placebo-controlled, dose escalation trial. PATIENT POPULATION Infants born prematurely (< or = 35 weeks of gestation) who were < or = 6 months of age and infants with bronchopulmonary dysplasia who were < or = 24 months of age were eligible for study participation. STUDY AGENTS: Participants received 3, 10 or 15 mg/kg MEDI-493 or 0.9% saline intravenously every 30 days for up to five doses. RESULTS MEDI-493 was safe and well-tolerated and did not induce a specific anti-MEDI-493 response. The mean half-life of 20 days was comparable with that of other immunoglobulin G preparations. Mean trough serum concentrations 30 days after Infusion 1 were 6.8, 36.1 and 60.6 microg/ml for the 3-, 10- and 15-mg/kg dose groups, respectively. After Infusion 2 the trough concentrations were 11.9, 45.2 and 70.7 microg/ml. After subsequent doses the mean trough values ranged from 14 to 18 microg/ml in those given 3 mg/kg and were > 40 microg/ml for patients who received 10 or 15 mg/kg MEDI-493 (46 to 72 microg/ml and 88 to 96 microg/ml, respectively). CONCLUSIONS MEDI-493 was safe and well-tolerated in this high risk pediatric population. Mean serum concentrations of MEDI-493 that have been shown to produce a 2-log reduction in pulmonary RSV titer in cotton rats were maintained when 10 or 15 mg/kg MEDI-493 was given every 30 days to pediatric patients at high risk for serious RSV disease. Monthly doses of 15 mg/kg maintained concentrations of > 40 microg/ml for the majority of patients.

Background, Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in infants and children. MEDI-493 (palivizumab, Synagis(R)) is a humanized monoclonal IgG1 antibody to the fusion protein of RSV, and it is highly active in vitro against RSV A and B strains.Objective, To describe the safety, tolerance, immunogenicity and pharmacokinetics of monthly intramuscular injections of MEDI-493 among premature infants and children with bronchopulmonary dysplasia and to compare these data with information previously obtained with intravenous dosing,Design. A Phase I/II multicenter, opera label, escalating dose clinical trial,Patient population and dosing regimen. Children (n = 65) born prematurely at less than or equal to 35 weeks of gestation who were less than or equal to 6 months of age (n = 41) and children with bronchopulmonary dysplasia who were less than or equal to 24 months of age (n = 24) were enrolled, From 1 to 5 monthly injections were given at doses of 5 mg/kg (n = 11), 10 mg/kg (n = 6) and 15 mg/kg (n = 48). Serum was collected before administration of each dose, 30 days after the last dose, and 2, 7 and 14 days after the first and second doses for measurement of MEDI-493 concentrations by enzyme-linked immunosorbent assay,Results, The pharmacokinetics of MEDI-493 were similar to those of other human IgG1 antibodies. Mean serum MEDI-493 concentrations were 91.1 mu g/ml (range, 52.3 to 174.0)2 days after the initial dose of 15 mg/kg and 49.2 mu g/ml (range, 13.5 to 132.0) at 30 days. Monthly dosing of 15 mg/kg maintained mean trough concentrations of similar to 70 mu g/ml. These concentrations were similar to previously published trough concentrations after iv administration. MEDI-493 injections were well-tolerated. Only three children had adverse events judged to be possibly related to MEDI-493. Ten children had transient, low titer anti-MEDI-493 binding titers (1:10 to 1:40) which were not associated with a pattern of specific adverse events or alterations of MEDI 493 concentrations. Two patients in the 5-mg/kg dose group were hospitalized for RSV; no RSV hospitalizations were found in the higher dose groups,Conclusions. MEDI-493 was safe and well-tolerated, Monthly intramuscular doses of 15 mg/kg maintained mean trough serum concentrations that were above 40 mu g/ml (the value associated with 99% reduction of pulmonary RSV in the cotton rat model), These concentrations were similar to those previously reported with iv administration of MEDI-493.

Objective. To determine the safety and efficacy of prophylaxis with palivizumab in reducing the incidence of hospitalization because of respiratory syncytial virus (RSV) infection in high-risk infants. Methods. A randomized, double-blind, placebo-controlled trial was conducted at 139 centers in the United States, the United Kingdom, and Canada. During the 1996 to 1997 RSV season, 1502 children with prematurity (less than or equal to 35 weeks) or bronchopulmonary dysplasia (BPD) were randomized to receive 5 injections of either palivizumab (15 mg/kg) or an equivalent volume of placebo by intramuscular injection every 30 days. The primary endpoint was hospitalization with confirmed RSV infection. Children were followed for 150 days (30 days from the last injection). Those with hospitalization as a result of RSV infection were evaluated for total number of days in the hospital, total days with increased supplemental oxygen, total days with moderate or severe lower respiratory tract illness, and incidence and total days of intensive care and mechanical ventilation. The incidence of hospitalization for respiratory illness not caused by RSV and the incidence of otitis media were also evaluated. The placebo and palivizumab groups were balanced at entry for demographics and RSV risk factors. Ninety-nine percent of children in both groups completed the protocol and similar to 93% received all five scheduled injections. Results. Palivizumab prophylaxis resulted in a 55% reduction in hospitalization as a result of RSV (10.6% placebo vs 4.8% palivizumab). Children with prematurity but without BPD had a 78% reduction in RSV hospitalization (8.1% vs 1.8%); children with BPD had a 39% reduction (12.8% vs 7.9%). When gender, entry age, entry weight, BPD, and gestational age were included in a logistic regression model, the effect of prophylaxis with palivizumab remained statistically significant. The palivizumab group had proportionally fewer total RSV hospital days, fewer RSV hospital days with increased oxygen, fewer RSV hospital days with a moderate/severe lower respiratory tract illness, and a lower incidence of intensive care unit admission. Palivizumab was safe and well tolerated. No significant differences were observed in reported adverse events between the two groups. Few children discontinued injections for related adverse events (0.3%). Reactions at the site of injection were uncommon (1.8% placebo vs 2.7% palivizumab); the most frequent reaction was mild and transient erythema. Mild or moderate elevations of aspartate aminotransferase occurred in 1.6% of placebo recipients and 3.6% of palivizumab recipients; for alanine aminotransferase these percentages were 2.0% and 2.3%, respectively. Hepatic and renal adverse events related to the study drug were similar in the two groups. Conclusions. Monthly intramuscular administration of palivizumab is safe and effective for prevention of serious RSV illness in premature children and those with BFD.

Age- and sex-specific bone mineral measures have not been available for healthy preschool children. We determined bone mineral content (BMC) and bone width in 89 children 1 to 6 years of age using direct photon absorptiometry at the one-third distal radius site. The BMC increased significantly with age, and bone width increased slightly with age. After stratification by age, male and female children had similar BMC from 1 to 4 years of age, but female children had significantly lower BMC at 5 to 6 years of age.

The response to aluminum loading from parenteral nutrition (PN) solutions was determined in 20 infants with gestational ages 29 to 41 weeks and birth weights 880 to 3630 gm. Mean duration of PN was 43 days (range 5 to 175 days). Ten infants received a high Al load (from an experimental high calcium- and phosphorus-containing PN solution, with a measured Al content of 306 +/- 26 micrograms/L (mean +/- SE), n = 11), for up to 6 weeks. Ten infants received a lower Al load (from standard Ca-P solutions, measured Al content 144 +/- 16 micrograms/L, n = 11). Five infants received PN with a low Al load for longer than 6 weeks. The mean urine Al/creatinine (Cr) ratio (micrograms/mg) increased threefold, from 0.3 +/- 0.09 to 0.97 +/- 0.17 during PN in the entire group (P less than 0.001), and was significantly higher in infants who received greater Al loading (P less than 0.001). There was no significant difference between preterm and term infants in the rate of change in urine Al/Cr during the study. Urine Al was calculated to account for less than 50% of Al load. During the study, serum Al concentrations ranged from 6 to 318 micrograms/L (median 37 micrograms/L, compared with the median 18 micrograms/L for normal infants and children). Serum Al concentrations were not significantly changed during the study, or between infants in high or lower Al loading groups. Vertebrae from autopsy of two infants who received the lower Al containing PN for 71 and 152 days, respectively, stained positive for Al at the bone mineralization front. Thus, currently used PN solutions are contaminated with Al, urine Al concentration is higher with higher Al loading, and is not different in term and preterm infants. We suggest that renal elimination of Al in infants is incomplete, as assessed by lower urine Al excretion versus load, elevated serum Al concentration, and bone deposition of Al.

High Ca, P fortified ‘premie’ formulas (FM) have been recommended as supplements to preterm infants fed own mother's milk (OMM) to prevent rickets. FM (20kcal/dl) when added to OMM in 1:1 ratio by volume and given 150ml/kg/d can deliver maximum Ca 78-113mg, P 44-59mg and vit D 42-79IU/kg/d. Two white females, birth wt 410g (P1), 660g (P2), gestation 23, 30 wks resp given FM alone, or, FM added to OMM or standard (20kcal/oz) formula (SM) who developed severe bone demineralization, rickets and fractures on x-ray at 15 and 13wks resp. Nutrition intake prior to diagnosis was: *Parenteral solution Ca 2hg, P 15mg/dl, vit D2 20 IU/kg/d. ** Daily Ca, P, vit D intake from FM alone, or, FM+OMM or SM. Additional 100-400 IU vit D2/d commenced at 63 and 14d resp. FM were shaken prior to each bolus gavage feed. P1 received 24 doses furosemide (1-2mg/kg) and 43d of phenobarbital (5mg/kg/d). P2 received 4 doses of furosemide (1-2mg/kg). At diagnosis, serum Ca and Mg were normal, P were 3.6 and 4.8mg/dl, and 25 hydroxyvitamin D (250HD) normal (61 and 38ng/ml). Rickets and fractures healed while Pl continued on FM and same drug therapy and P2 was fed OMM alone. We conclude 1) supplementation of OMM or SM with Ca, P fortified milk (1:1 vol/ vol) may not be sufficient to prevent rickets and fracture in extremely small infants (BW<800g); 2) 400 IU vit D2/d is sufficient to maintain normal serum 250HD. 3) Rickets may resolve “spontaneously” with age.

Infants of diabetic mothers have a higher incidence of neonatal hypocalcemia and hypomagnesemia. Decreased BMC has been reported in diabetic patients, with bone mineralization of IDM has not been; systematically evaluated. The present study was done to test the hypothesis that decreased neonatal BMC in IDMs is correlated with poor control of diabetes during pregnancy & with the development of neonatal hypocalcemia. 54 fullterm IDMs & 55 normal fullterm controls, infants of non-diabetic mothers were prospectively studied. Mothers of IDMs were classified prospectively in 3 groups: group 1-strict control of diabetes from the first trimester: group 2-customary control from the first trimester: group 1 & 2 were randomized; group 3-late entry (after first trimester) in the study. Maternal BMC was measured prior to delivery. Infant serum calcium was measured at age 24 & 72 hours, & infant BMC at age 3 days. Multiple regression analysis shows that: 1) infant's BMC is not correlated with maternal BMC, neonatal hypoglycemia, neonatal hypocalcemia & infant weight percentile; 2) IDMs from group 2 & 3 had significantly lower BMC than IDMs from group I (p<0.02); 3) IDMs from group 1 & controls had similar BMC. It appears that decreased BMC is observed in IDMs & may be prevented by strict control of diabetes during pregnancy. Decreased BMC in IDMs does not seem to play a role in the pathogenesis of neonatal hypocalcemia. We speculate that decreased BMC in IDMs might be in the diabetic pregnancy inappropriate calcium supply through the placenta.

Radiographic bone demineralization (BD), rickets (R) and fractures (F) have been noted anecdotally in VLBW infants but there is no prospective study of the course and outcome of the skeletal pathology. We hypothesized that BD, R and F are frequent in VLBW infants, but the lesions are self resolving with time. X-rays from 60 VLBW (birth wt <1500g) infants were taken prospectively. Birth wts were 580-1500g, gestation 24-34wks; 32B, 28W; 54 AGA and 6 SGA. Single view x-rays were taken of both forearms at 3, 6, 9 and 12mos. Other x-rays taken for clinical reasons also were reviewed. BD, R and F were determined using standard criteria. ‘Mild’ BD was regarded as normal. From 40 infants who completed the study BD occurred in 22.5%, R in 17.5%, F in 20%. BD was noted in all infants with R or F. All infants with R had F but only one infant had F without R. All abnormal x-rays were noted by 6mos, 75% by 3mos and one infant by 7wks. F occurred predominantly in extremities (8 radius and/or ulna, 3 humerus, 3 femur), 5 ribs; unusual sites included 1 scapula; 5 had multiple F. Prior to radiographic changes, 60% received parenteral nutrition (calcium 20mg, phosphorus 15.5mg/dl, vit D2 20IU/kg/d); 70% received own mother's milk or standard 20kcal/oz formula; 30% received high calcium and phosphorus formulas in varying quantities. By 9mos all F and R healed regardless of mode of therapy or diet. By 12mos, 1 infant only still had BD. We conclude 1) BD, R and F are present in 1 in 5 of VLBW infants; 2) infants with rickets are likely to have fractures; 3) if one fracture is noted other fractures are likely. Until definitive preventive measures become available, we suggest care be taken during physical manipulation of these infants.

Serum parathyroid hormone and total and ionized Ca, Mg, and P levels were determined serially from birth to 96 hr of age in 28 infants of diabetic mothers (IDM, 15 Class A, 13 Class B, C, D) and their respective mothers at the time of delivery. In spite of marked decreases in concentrations of serum total and ionized Ca from birth to 24 to 48 hr, there was an insignificant increase in serum PTH values over this period in infants of insulin-dependent mothers. Infants of Class A diabetic mothers had an equivocal PTH response. Nineteen term control infants were similarly examined and had a significant increase in serum PTH postnatally. Relatively higher values of serum ionized Ca at birth in IDM were followed by greater decreases in ionized Ca from birth to 24-48 hr of age, and by decreased neonatal parathyroid function. The data support functional hypoparathyroidism as a basis for the hypocalcemia and hyperphosphatemia of IDM. It is speculated that increased concentrations of serum ionized Ca in utero and suppression of activity in the fetal parathyroid glands may be a cause for the functional hypoparathyroidism.

Fifty-six diabetic mothers and their infants were studied prospectively from birth. Twenty-one of 56 IDM had serum Mg less than or equal to 1.5 mg/dl, on at least one occasion during the first 3 days. Serum Mg in these hypomagnesemic infants did not demonstrate the normal increase with postnatal age that was present in normomagnesemic infants. Decreased neonatal serum Mg was related to increased severity of maternal diabetes, young mothers, mothers for lower gravidity, and prematurity. Decreased serum Mg, alone or with decreased ionized or total Ca, did not correlate with neuromuscular irritability in the infants. Decreased serum Mg in IDM was associated with decreased maternal serum Mg, decreased neonatal ionized and total Ca, increased serum P, and decreased parathyroid function. Serum Mg was not related to dietary P intake, or urinary Ca or P excretion. Thus, transitory neonatal hypomagnesemia occurs in IDM; it is speculated that factors causing HM might include maternal HM or neonatal hyperphosphatemia, and that the HM is related to the hypocalcemia and functional hypoparathyroidism of IDM.