Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994.

OBJECTIVES: The purposes of this study were to report the neurodevelopmental, neurosensory, and functional outcomes of 1151 extremely low birth weight (401-1000 g) survivors cared for in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network, and to identify medical, social, and environmental factors associated with these outcomes. STUDY DESIGN: A multicenter cohort study in which surviving extremely low birth weight infants born in 1993 and 1994 underwent neurodevelopmental, neurosensory, and functional assessment at 18 to 22 months' corrected age. Data regarding pregnancy and neonatal outcome were collected prospectively. Socioeconomic status and a detailed interim medical history were obtained at the time of the assessment. Logistic regression models were used to identify maternal and neonatal risk factors for poor neurodevelopmental outcome. RESULTS: Of the 1480 infants alive at 18 months of age, 1151 (78%) were evaluated. Study characteristics included a mean birth weight of 796 +/- 135 g, mean gestation (best obstetric dates) 26 +/- 2 weeks, and 47% male. Birth weight distributions of infants included 15 infants at 401 to 500 g; 94 at 501 to 600 g; 208 at 601 to 700 g; 237 at 701 to 800 g; 290 at 801 to 900 g; and 307 at 901 to 1000 g. Twenty-five percent of the children had an abnormal neurologic examination, 37% had a Bayley II Mental Developmental Index <70, 29% had a Psychomotor Developmental Index <70, 9% had vision impairment, and 11% had hearing impairment. Neurologic, developmental, neurosensory, and functional morbidities increased with decreasing birth weight. Factors significantly associated with increased neurodevelopmental morbidity included chronic lung disease, grades 3 to 4 intraventricular hemorrhage/periventricular leukomalacia, steroids for chronic lung disease, necrotizing enterocolitis, and male gender. Factors significantly associated with decreased morbidity included increased birth weight, female gender, higher maternal education, and white race. CONCLUSION: ELBW infants are at significant risk of neurologic abnormalities, developmental delays, and functional delays at 18 to 22 months' corrected age.

Mineral nutrition and bone mineralization in full-term infants.

Bone mineralization is an intricate and tightly regulated process. Calcium, magnesium and phosphorus are the main minerals and play a principal role in skeletal mineralization. The following conclusions can be derived from different clinical studies. The large differences in Ca/P ratio between different formulas and between formulas and human milk suggest that most healthy full-term infants can adjust to a wide range of Ca/P ratio in their diet. The differences in serum levels of mineral and of mineral-regulating hormones are rarely clinically significant and most probably reflect continued compensatory mechanisms activated in response to dietary differences to maintain these levels within clinically normal ranges. Thus in most cases, these compensatory mechanisms are sufficient to reverse both short-term and long-term consequences and to prevent clinical disease. In the case of neonatal tetany, the compensatory mechanisms are overwhelmed, resulting in clinical signs and disease. Vitamin D is known to play an essential role in bone mineralization. Our studies have shown significant differences in vitamin D status in breast-fed infants with and without vitamin D supplementation and in infants fed various "humanized" formulas, whether cow milk-based or soy protein-based. The major variables affecting bone mineralization are Ca/P ratio and mineral-regulating hormones. However, factors such as season, geography (i.e. sun exposure), race and sex may have a significant long-term influence on bone mineralization and mineral metabolism. Some biological differences such as differences in serum vitamin D metabolite level may directly effect Ca/P absorption and retention and thus bone mineralization and growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Fractures and rickets in very low birth weight infants: conservative management and outcome.

Fractures and rickets (F/R) often occur in very low birth weight (VLBW less than 1500 g) infants who are acutely ill. However, there are no prospective longitudinal studies of the clinical course of F/R in these infants. In a prospective study of 78 VLBW infants during the first year after birth, radiographic evidence of healing and remodeling of F/R was noted in affected infants (n = 25) concurrent with increased enteral intake and physical growth, and regardless of whether specific orthopedic treatment was initiated. Skeletal maturation as indicated by the development of ossification centers at the wrists was directly related to weight gain, and was similar to term infants by 1 year. No infant had skeletal deformities on follow-up examination. We suggest that VLBW infants with F/R can be managed "conservatively," with emphasis on nutritional intake to achieve weight gain.

Decreased bone mineral content in infants of diabetic mothers.

The present study was conducted to test the hypothesis that infants of diabetic mothers (IDMs) have decreased bone mineral content at birth, and whether or not decreased infant bone mineral content in IDMs correlates with poor control of diabetes during pregnancy, maternal bone mineral content, and the development of neonatal hypocalcemia. Forty-five pregnant diabetic women and their infants were enrolled in a prospective trial. In addition, 55 normal newborn infants of nondiabetic mothers were used as controls. Bone mineral content was measured before delivery in all diabetic pregnant patients and at birth in all infants by photon absorptiometry. Bone mineral content was significantly decreased in infants of diabetic mothers compared with control infants and correlated inversely with mean first trimester maternal capillary blood glucose; it did not correlate with cord serum 1,25-dihydroxyvitamin D concentrations. By stepwise multiple regression analysis, in infants of diabetic mothers, bone mineral content correlated inversely with mean first trimester capillary blood glucose and maternal bone mineral content, but did not correlate with maternal blood glycosylated hemoglobin, infant gestational age, infant birthweight or weight percentile, or development of neonatal hypocalcemia.

Radiation dose to small infants from single-photon absorptiometry.

The radiation dose to the patient resulting from single-photon absorptiometry (SPA), now a widely used method for measuring bone mineral content (BMC) in vivo in infants and children, was evaluated. Lithium fluoride chips were placed on a phantom with a BMC in the small infant range (60 and 145 mg/cm). Measurement procedures mimicked the actual clinical sequence. The radiation exposure for a single BMC measurement is 46-70 mrad (460-700 microGy) to the forearm surface and 25-38 mrad (250-380 microGy) and 125-190 mrad (1,250-1,900 microGy) to the bone marrow and the bone, respectively. When eight repeated measurements are performed over a 1-year period, the radiation dose is about 368-560 mrad (3,680-5,600 microGy) to the forearm surface and 200-305 mrad (2,000-3,050 microGy) and 1,000-1,525 mrad (10.0-15.25 mGy) to the bone marrow and the bone, respectively. Even though the radiation dose is small, this method should be used only in well-designed clinical studies.

Bone mineral content measurement in small infants by single-photon absorptiometry: current methodologic issues.

Single-photon absorptiometry (SPA), developed in 1963 and adapted for infants by Steichen et al. in 1976, is an important tool to quantitate bone mineralization in infants. Studies of infants in which SPA was used include studies of fetal bone mineralization and postnatal bone mineralization in very low birth weight infants. The SPA technique has also been used as a research tool to investigate longitudinal bone mineralization and to study the effect of nutrition and disease processes such as rickets or osteopenia of prematurity. At present, it has little direct clinical application for diagnosing bone disease in single patients. The bones most often used to measure bone mineral content (BMC) are the radius, the ulna, and, less often, the humerus. The radius appears to be preferred as a suitable bone to measure BMC in infants. It is easily accessible; anatomic reference points are easily palpated and have a constant relationship to the radial mid-shaft site; soft tissue does not affect either palpation of anatomic reference points or BMC quantitation in vivo. The peripheral location of the radius minimizes body radiation exposure. Trabecular and cortical bone can be measured separately. Extensive background studies exist on radial BMC in small infants. Most important, the radius has a relatively long zone of constant BMC. Finally, SPA for BMC in the radius has a high degree of precision and accuracy.

Sequential bone mineral content in small preterm infants with and without fractures and rickets.

Seventy-four infants with birth weights 1009 +/- 28 grams and gestational age 28.6 +/- 0.3 weeks (M +/- SEM) were studied prospectively to test the hypotheses that bone mineral content (BMC) measured by photon absorptiometry, would be: (1) lower in very low birth weight (VLBW) infants with radiographic evidence of fractures and/or rickets (F/R), and (2) will continue to be lower over the first year when compared to VLBW infants without F/R. BMC and bone width (BW) of the distal one-third of left radius and ulna were measured at 5 weeks (n = 8), 14 weeks (n = 61), 26 weeks (n = 58), 40 weeks (n = 59), and 1 year (n = 52). Standardized radiographs of both forearms, and weight, length, and head circumference were also determined at each study age. Investigators and technicians involved in the photon absorptiometry measurements were unaware of the radiographic findings and vice versa. Twenty-three of 74 infants were found to have F/R. BMC of studied infants remained markedly below our previously determined range of "intrauterine bone mineralization," even at 26 weeks after birth. There was no significant difference in BMC or BW between infants with and without F/R, either at the time of confirmation of F/R or during early follow-up; however, BMC was lower at greater than or equal to 6 months and BW was lower at greater than or equal to 9 months in infants with F/R. We suggest that the extremely low BMC measurements in early infancy predispose all VLBW infants to fractures and rickets.

Bone mineralization and growth in term infants fed soy-based or cow milk-based formula.

The purpose of this study was to evaluate the adequacy of a soy protein-based formula versus a cow milk protein-based formula for body growth and skeletal mineralization in the first year of life. Thirty-six healthy, term, appropriate for gestational age infants were assigned randomly and prospectively to one of two feeding groups and observed longitudinally over the first year of life. Group 1 infants (n = 18) were fed soy protein isolate-based formula (Isomil with Iron); group 2 infants (n = 17) were fed a cow milk protein-based formula (Similac with Iron). All infants were given the formula within the first 24 hours of life, and were fed the study formula through the first year of life. Weight, length, and head circumference were recorded; bone mineral content (BMC) and bone width (BW) were measured at one-third distal length (midshaft) of the left radius and ulna during the first 18 days of life, and again at 6 weeks, and 3, 6, 9, and 12 months postnatally. Baby food was provided to all infants, and except for type of formula, food intake was similar for all infants. Weight, length, and head circumference were normal in all infants and not different between groups. BMC and BMC/BW were similar for both groups at entry into the study. Group 1 infants had significantly lower BMC and BMC/BW at 3, 6, 9, and 12 months of age (P less than 0.05 to P less than 0.0001) compared with group 2 infants, but their values were similar to those in previously studied infants receiving human milk with vitamin D supplementation. The long-term implication of differences in bone mineralization in early infancy for long-term skeletal mineralization remains to be determined.

Vitamin D requirement in infants receiving parenteral nutrition.

The adequacy of low dose vitamin D (25 IU/dl) parenteral nutrition (PN) solution was studied in 18 infants. All infants had surgical indications for PN. The birth weights were 2810 +/- 135 g and gestational ages 37.4 +/- 0.5 wk (mean +/- SEM). Duration of study ranged from 5 to 175 days. Thirteen infants were studied for up to 6 weeks and five infants for 71 to 175 days. Results showed that studied infants maintained growth along normal percentiles for weight, length, and head circumference. Vitamin D status as indicated by serum 25 hydroxyvitamin D (25 OHD) rose from 15 +/- 1.9 ng/ml to 26 +/- 2.8 ng/ml, mean +/- SEM (p less than 0.001) after 9 days, and remained normal up to 6 months. Five infants with biochemical liver dysfunction also had normal serum 25 OHD concentrations, indicating the hepatic 25 hydroxylation process was not severely impaired. Serum total and ionized calcium, phosphorus, and vitamin D-binding protein concentrations were normal. Serum magnesium was mildly elevated in five infants (2.6 to 3 mg/dl) on one occasion and resolved spontaneously. Serum alkaline phosphatase (AP) concentrations rose above baseline values in 12 of 17 infants, but remained within normal range (less than 400 IU/liter at 30 degrees C). Another infant with markedly elevated AP values died from liver dysfunction. Radiographs of the forearms were normal except for marked demineralization in one infant in spite of normal 25 OHD concentrations. We conclude that 25 IU vitamin D/dl of nutrient infusate is adequate to maintain normal vitamin D status, as indicated by normal serum 25 OHD concentrations in infants receiving PN for as long as 6 months.

Breastfeeding the low birth weight preterm infant.

The recent increase in the use of human milk in feeding low birth weight (LBW) preterm infants has stimulated new research questions in infant nutrition, especially in regards to the nutritional adequacy and nutrient composition of milk from mothers of mature and preterm infants. The current state of knowledge on the effect of feeding human milk with or without nutritional supplements on growth of the low birth weight infant is summarized. Recommendations and guidelines for feeding human milk and/or supplementing human milk in LBW infants are discussed and appropriate handling of human milk and feeding schedules are outlined.

Parenteral nutrition for infants: effect of high versus low calcium and phosphorus content.

Calcium (Ca) and phosphorus (P) homeostasis were determined in 18 infants (birth weight, 2,810 +/- 135 g; gestational age, 37.4 +/- 0.5 weeks; mean +/- SEM) who received high or low Ca and P content (Ca, P) parenteral nutrition (PN) with a fixed, low dose of vitamin D (25 IU/dl). Nine infants were randomized into low (standard) Ca, P (20 mg Ca and 15.5 mg P/dl) and nine into high Ca, P (60-80 mg Ca and 46.5-62 mg P/dl) PN, and then were studied for up to 6 weeks. The high Ca, P group had stable serum 1,25 dihydroxyvitamin D [1,25(OH)2D], which consistently remained within the normal range (less than 116 pg/ml). Tubular reabsorption of phosphorus (TRP) also was stable and remained consistently less than 90%. The low Ca, P group had elevated and higher 1,25(OH)2D (p = 0.03) than the high Ca, P group. The mean serum 1,25(OH)2D concentration rose from 32 to 112, 115, and 133 pg/ml over a period of 6 weeks. TRP also was higher (p = 0.02) and remained consistently greater than 90%. There were no significant differences between groups in serum parathyroid hormone, calcitonin, Ca, Mg, P, alkaline phosphatase, vitamin D binding protein, and 25 hydroxyvitamin D concentrations; urine Ca/creatinine and Mg/creatinine ratios, and fractional excretion of sodium (Na). Thus, a "high" Ca (60 mg/dl) and P (46.5 mg/dl) content in PN solutions can result in stable serum 1,25(OH)2D and TRP, presumably reflecting minimal stress to Ca and P homeostatic mechanisms without further increase in urinary Ca excretion.

Elevated serum calcium and osteocalcin levels from calcitriol in preterm infants. A prospective randomized study.

The hypothesis of this study was that pharmacologic doses of calcitriol (1,25-dihydroxyvitamin D3) would result in elevated levels of serum osteocalcin, the major noncollagenous bone protein, and calcium in infants of very low birth weight (less than 1500 g). Twenty-four infants of very low birth weight but of the appropriate weight for gestational age were matched in 250-g weight ranges and randomized into calcitriol treatment and control groups on the first day after birth. Treated infants received 4 micrograms/kg of calcitriol intravenously on entry and on the second and third study days. Controls did not receive calcitriol. Four infants from each group were hypocalcemic (serum calcium level, less than 7.0 mg/dL [less than 1.75 mmol/L]) on entry (five to 20 hours after birth) to the study. Seven infants received calcium replacement; data analyses with and without these infants were similar. Of the remaining 17 infants, eight were in the treatment group and nine were in the control group. Calcitriol significantly increased serum calcium and osteocalcin concentrations on days 2, 3, and 4 after birth compared with the control group. None of eight treated infants manifested hypocalcemia after calcitriol vs eight of nine controls. There were no acute changes in heart rate, respiratory rate, systolic blood pressure, or urinary calcium loss nor were there changes at the infusion site, but the diastolic blood pressure increased with treatment. Although high doses of calcitriol may elevate serum calcium concentrations in infants of very low birth weight, we suggest that the long-term or subtle biologic effects of high doses of calcitriol remain to be studied and that its routine use not be recommended at present.

Aluminum in parenteral nutrition solution--sources and possible alternatives.

The extent of aluminum (Al) contamination in parenteral nutrition (PN) solutions for infants is not known. Aluminum was measured in 136 samples from various commercially available components that are used with PN. Results showed Al content varied widely among different components. The same chemical may have a different Al content depending on the manufacturer. However, Al contents were similar among lots from the same manufacturer for the same chemical. Aluminum contamination was arbitrarily classified as high (greater than 500 micrograms Al/liter), intermediate (51-500 micrograms Al/liter) or low (less than or equal to 50 micrograms Al/liter). The high group included most calcium and phosphorus containing salts, 1 multivitamin preparation, folic acid, ascorbic acid and concentrated (25%) albumin. The intermediate group included sodium lactate, potassium phosphates, zinc and chromium chloride, multitrace metal preparation, and 5% plasma protein. The low group included amino acids, sterile water and dextrose water, chloride salts of sodium, potassium, calcium, copper and chromium, sodium phosphates, magnesium sulphate, zinc sulphate, vitamin B12, vitamin K1, 1 multivitamin preparation, soybean oil emulsion and heparinized (2 U/ml) saline. PN solutions made from high Al components may contain up to 300 micrograms Al/liter. Calcium gluconate contributed greater than 80% of the total Al load from PN. Lowering of Al content in calcium gluconate in addition to use of specific low Al components offers the opportunity to significantly lower the Al concentration of the final PN solution and theoretically may achieve an Al content as low as 12 micrograms/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Response to aluminum in parenteral nutrition during infancy.

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.

Early neonatal hypocalcemia in extremely preterm infants. High incidence, early onset, and refractoriness to supraphysiologic doses of calcitriol.

Nineteen preterm infants born at or before 32 weeks of gestation were studied to determine the dose of calcitriol that would be effective in the prophylaxis of early neonatal hypocalcemia (serum calcium level, less than 7.0 mg/dL [less than 1.75 mmol/L]). In these infants the course of early neonatal hypocalcemia was not modified by calcitriol administration. Serum 1,25-dihydroxyvitamin D level rose in response to intramuscular administration of calcitriol. The incidence of hypocalcemia in these infants was 37% by 12 hours, 83% by 24 hours, and 89% by 36 hours. Thus, in extremely preterm infants, the incidence of early neonatal hypocalcemia is higher and the onset earlier than in larger preterm infants; furthermore, in these infants the hypocalcemia is refractory even to high doses of calcitriol.

Late infantile tetany and secondary hyperparathyroidism in infants fed humanized cow milk formula. Longitudinal follow-up.

Five full-term infants with birth weights appropriate for gestational age presented with hypocalcemic tetany at 5 to 9 days of age. All infants had been fed Similac 20, a cow milk formula. Initial mean serum calcium (Ca), phosphorus (P), and magnesium (Mg) levels of the tetanic infants were 6.8, 9.5, and 1.6 mg/dL, respectively. The mean serum parathyroid hormone (PTH) level was elevated at 79 mu LEq/mL (adult normal values, less than or equal to 57 mu LEq/mL). Following restoration of normocalcemia with Ca supplements, feeding was reinstituted with Similac 20 in two infants and Similac PM 60/40 in three infants. Serum biochemical and hormonal values were compared with those of 18 exclusively breast-fed infants followed up from three weeks to six months and 14 Similac 20-fed full-term infants followed up from one week to six months. In tetanic infants, serum Ca concentrations became elevated (10.4 +/- 0.05 mg/dL; mean +/- SEM) by six weeks (vs 9.2 +/- 0.3 mg/dL in breast-fed infants) (P less than .001) and serum Mg concentrations (2.26 +/- 0.01 mg/dL) by four weeks (vs 1.92 +/- 0.07 mg/dL in breast-fed infants) (P less than .01). Mean serum P concentrations declined progressively. Mean serum PTH concentrations were elevated and ranged from 74 to 143 mu LEq/mL at two to 16 weeks (vs mean 28 to 35 mu LEq/mL in breast-fed infants (P less than .0001). In 14 formula-fed-nontetanic full-term infants, serum PTH concentrations were intermediate between formula-fed-tetanic and breast-fed infants, mean serum Ca concentrations ranged from 10.2 to 10.4 mg/dL, and mean serum P concentrations declined from 8.3 to 7.1 mg/dL. We speculate that acute hypocalcemic tetany in the study infants was induced by the relatively high P load in cow milk formulas (vs human milk); with the continued P load, secondary hyperparathyroidism continued, maintaining P, Ca, and Mg homeostasis.