Calciuria and aminoaciduria in very low birth weight infants fed a high-mineral premature formula with varying levels of protein.

To assess the influence of protein intake on renal excretion of calcium and amino acids and on bone mineralization in preterm infants, we randomly selected within weight group strata 27 infants who weighed < 1500 gm at birth (nine per group) to be fed a high-mineral (calcium, 940 mg/L; phosphorus, 470 mg/L) premature formula with one of the following protein contents: formula A, 3.0 gm/100 kcal; formula B, 2.7 gm/100 kcal; and formula C, 2.2 gm/100 kcal. Mean (+/- SD) daily weight gain was greater in infants receiving the higher protein intakes for the first 30 days (formula A, 24.8 +/- 5.1 gm; formula B, 20.5 +/- 3.8 gm; formula C, 16.2 +/- 5.9 gm (analysis of variance: p < 0.01; C < A, p < 0.05)). Bone mineral content did not differ at any time point, and all groups had a high prevalence of generalized aminoaciduria (4 weeks: formula A, 56%; formula B, 71%; formula C, 75%). Urinary calcium corrected for creatinine (in milligrams per milligram) increased as protein content decreased (2 weeks: formula A, 0.16 +/- 0.10; formula B, 0.20 +/- 013; formula C, 0.44 +/- 0.33 (C > A, C > B, p < 0.05); 4 weeks: formula A, 0.23 +/- 0.15; formula B,0.34 +/- 0.47; formula C, 0.49 +/- 0.22 (C > A, p < 0.01). We conclude that the high mineral content and other components of premature formulas result in a higher growth rate and may increase protein requirements. Failure to meet protein requirements may result in underutilization of absorbed calcium and increased renal excretion of calcium. In preterm infants, higher protein intake probably supports rather than jeopardizes bone mineral accretion, and reduces rather then increases calciuria.

Measurement of true absorption, endogenous fecal excretion, urinary excretion, and retention of calcium in term infants by using a dual-tracer, stable-isotope method.

A dual-tracer, stable-isotope method was used to measure the percentage of true calcium absorption (alpha), true calcium absorption rate (Va), endogenous fecal calcium excretion rate (Vf), urinary calcium excretion rate (Vu), and calcium retention rate (Vr). Twenty-seven infants with a mean gestation of 30.6 +/- 1.7 weeks and a mean birth weight of 1.4 +/- 0.21 kg were studied at 2 or 3 weeks of age, or both, during feedings of human milk (HM), fortified human milk (HMF), and commercially available formula (20 or 24 calories per ounce) for premature infants (EPF-20/780 and EPF-24/940) (part 1 of our study). Of 13 additional infants with a mean (+/- SD) birth weight of 1.26 +/- 0.25 kg and gestation of 29.6 +/- 2.5 weeks, 11 completed a crossover-design study at 2 and 3 weeks of age, receiving two identical formulas containing calcium, 940 mg/L, and phosphorus, 470 mg/L (EPF-24/940 formula) or calcium 1340 mg/L, and phosphorus, 680 mg/L (EPF-24/1340 formula) (part 2 of our study). The alpha value was higher in infants receiving HM (76.4 +/- 15.1%) or HMF (68.0 +/- 7.8%) than in those receiving EPF-20/750 formula (54.1% +/- 5.6%) or in previously reported infants fed standard formula (47.1% +/- 11.5%); those given EPF-24/940 formula had intermediate values (63.9% +/- 13.9%, part 1; 56.1% +/- 16.5%, part 2). No significant differences existed among groups for either Vu or Vf per kilogram. In the crossover study (part 2), no significant differences were seen between formulas for alpha and for Va, Vf, or Vr per kilogram. However, Vu per kilogram was significantly decreased in infants receiving the higher mineral formula (EPF-24/940: 3.6 +/- 2.3; EPF-24/1340: 2.9 +/- 2.3 mg/kg per day; p = < 0.005). With all feedings, alpha, Vu per kilogram, and Vf per kilogram were not related to gestational age, age at study, calcium intake, or each other. However, Vf per kilogram was inversely related to birth weight. Thus, alpha, Vu, and Vf appear to be independent and may be differentially affected by factors altering calcium dynamics. We conclude that increasing formula mineral content does not ensure increased retention; careful monitoring of individual infants remains indicated.

Mineral and vitamin D adequacy in infants fed human milk or formula between 6 and 12 months of age.

During the latter half of an infant's first year, adequate mineral and vitamin D intakes may be important not only for the prevention of rickets but also for the attainment of optimal adult peak bone mass. Ingestion of 400 IU vitamin D per day, either as a supplement or contained in formula or table milk, will result in normal serum concentrations of vitamin D,25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D. Human milk from a vitamin D-sufficient mother provides a marginal amount, less than 100 IU/L/day of total vitamin D activity from the vitamin D and 25-hydroxyvitamin D. Infants exclusively fed human milk of vitamin D-deficient mothers, who do not receive additional vitamin D or adequate exposure to sunlight, are at significant risk for vitamin D-deficiency rickets. The low concentration of phosphorus in human milk is adequate for most term infants but probably compounds any vitamin D deficiency. Intake of phosphorus from formula or table milk is more than adequate, and the addition of baby foods increases this mineral's intake to generous levels. Calcium is well absorbed and adequate in human milk if vitamin D is sufficient, but concern exists about calcium intake from infant formulas for this older group. My colleagues and I have conducted studies of bone mineral content and mineral homeostasis in term infants fed human milk (300 mg/L calcium), standard cow milk formula (440/mg/L calcium), or a soybean formula (600 mg/L calcium); our findings suggest that all three types of feedings provided comparable bone mineralization and normal indicators of mineral homeostasis. Mean calcium retentions at 6 months, 9 months, and 12 months in all three groups were between 138 and 205 mg/day, substantially more than the 130 mg/day estimated to be needed from body composition data. Estimates for phosphorus were similarly generous. The questions of whether higher calcium intakes will result in further increases in bone mineral content and of the effect of beikost on calcium absorption from different milks require further study.

Bone mineral content in term infants fed human milk, cow milk-based formula, or soy-based formula.

Bone mineral content (BMC) of the midportion of the humerus was measured with the Norland model 278 bone densitometer in 31 term infants fed human milk (9 inants), cow milk-based formula (11 infants), or soy protein-based formula (11 infants) over the first year of life. Serum and urine minerals, vitamin D, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were measured to ensure that intake of minerals and vitamin D was not limiting. Mineralization was similar in all three groups. Over the first year, BMC had a significantly positive slope. However, BMC appeared to increase during the first 4 months, plateau at 6 months, and then resume an increasing pattern. Bone width (BW) increased steadily over the first year; therefore the BMC/BW ratio actually dropped at around 6 months. The BMC was also correlated with body length. "Average density," which was calculated by the formula BMC/pi (BW/2)2, showed a steady decline as age increased. The ratio of BMC to body length over the first year may be an option for comparing individual data to normal data when growth is abnormal. Uncorrected BMC is recommended as a measurement for the infant growing normally; attempts to calculate average density are discouraged.

Vitamin D metabolism, mineral homeostasis, and bone mineralization in term infants fed human milk, cow milk-based formula, or soy-based formula.

The purpose of this study was to evaluate mechanisms of mineral homeostasis and mineralization in term infants with recommended vitamin D intakes. Infants fed human milk (nine), cow milk-based formula (11), or soy-based formula (11) were studied at 2 weeks and at 2, 4, 6, 9, and 12 months of age. While receiving 400 IU of vitamin D, all infants maintained serum vitamin D concentrations higher or equal to normal adult concentrations, and serum 25-hydroxyvitamin D levels were maintained at or above normal adult levels. Serum 1,25-dihydroxyvitamin D concentrations were higher than those of adults in the formula-fed but not in the human milk-fed infants. Serum calcium and phosphorus values were similar in all groups; however, urine phosphorus excretion and urine calcium excretion were adjusted to intakes. Serum parathyroid hormone values were normal in all groups. Bone mineral content significantly increased with age similarly in all groups; however, an apparent plateau occurred at 6 months of age in all groups. Bone width steadily increased with age. Taken as a whole, these data suggest that the vitamin D-sufficient term infant fed human milk, cow milk-based formula, or the soy-based formula studied can regulate mineral metabolism within acceptable physiologic limits to attain similar levels of serum minerals and bone mineral content.

Absorption, dosage, and effect on mineral homeostasis of 25-hydroxycholecalciferol in premature infants: comparison with 400 and 800 IU vitamin D2 supplementation.

Because the efficiency of vitamin D absorption or hepatic uptake and 25-hydroxylation appears decreased in very premature infants, the routine use of 25-hydroxycholecalciferol (25-OHD3) supplementation has been suggested. Absorption studies of a 3 micrograms/kg orally administered dose of 25-OHD3 showed peak serum 25-hydroxyvitamin D2 and -vitamin D3 (25-OHD) concentrations at 4 to 8 hours similar in timing but of lesser magnitude to those seen in adults. Administration of 1 microgram/kg birth weight/day of 25-OHD3 corrected moderately low, but not very low serum (25-OHD) concentrations, and 2 micrograms/kg BW/day resulted in rapid and sustained increase in serum 25-OHD. Administration of 800 IU ergocalciferol (D2) also produced significantly higher serum 25-OHD concentrations than those in infants given 400 IU vitamin D2, but increases in serum 25-OHD were more gradual than in infants given 25-OHD3. In treatment trials with infants weighing less than 1500 gm, those given 800 IU D2, compared with those given 400 IU D2, had higher serum calcium concentrations and less frequent moderate or severe hypomineralization. Infants given 2 micrograms/kg BW 25-OHD3 had a significant increase in serum phosphorus values, but a decrease in serum calcium and magnesium concentrations, and parathyroid hormone also was suppressed to low normal values. The frequency of moderate to severe hypomineralization remained the same as in infants given 400 IU D2. In a subgroup of infants, serum 1,25-dihydroxyvitamin D was elevated over adult values, both in infants given 25-OHD3 (68.5 +/- 8.4 pg/ml) and in infants given vitamin D2 (60 +/- 6.7 pg/ml). Serum vitamin D concentrations were undetectable in four of six infants receiving 25-OHD3, but were elevated (5 to 31 ng/ml) in four infants receiving vitamin D2. Although 800 to 1000 IU D2 can be recommended as routine vitamin D supplementation in very premature infants fed standard formula, the use of 25-OHD3 requires further study.

Mineral homeostasis in very premature infants: serial evaluation of serum 25-hydroxyvitamin D, serum minerals, and bone mineralization.

This study was designed to evaluate the role of vitamin D sufficiency, as reflected in serum 25-hydroxyvitamin D (25-OHD) concentrations, on serum minerals and bone mineralization in very premature infants. Seventy-two infants (mean +/- SD gestation 30.1 +/- 2.5 weeks, mean +/- SD birth weight 1178 +/- 278 gm) were observed serially for the first 3 months of life. Mean serum calcium and phosphorus values, but not magnesium, remained low prior to 12 weeks. The percentage of infants with moderate to severe hypomineralization was 75% at 3 weeks, 55% at 6 weeks, 54% at 9 weeks, and 15% at twelve weeks. Low serum calcium and phosphorus values, high alkaline phosphatase activity, and moderate-severe hypomineralization were more frequent in infants weighing less than 1000 gm and in those with lower mineral intake. With a 400 IU vitamin D supplement, 45% of infants could maintain an initially normal serum 25-OHD concentration or increase low concentrations, whereas 55% had falling or persistently low (less than or equal to 15 ng/ml) 25-OHD concentrations. Birth weight and mineral intakes were comparable in these two groups, yet the group with the lower serum 25-OHD concentration had lower serum calcium and higher alkaline phosphatase values, and a higher percentage of moderate to severe hypomineralization. Regardless of birth weight, mineral intake, or 25-OHD concentration, increases in serum calcium and phosphorus values and in mineralization were seen at postconception term (12 weeks in most infants, nine weeks in those weighing 1250 to 1600 gm). At 12 weeks of age, but not before, serum 25-OHD concentration was directly correlated with serum calcium (r = 0.47, P less than 0.01) and serum phosphorus (r = 0.47, P less than 0.01) and inversely correlated with alkaline phosphatase values (r = -0.71, P less than 0.01). Mineral availability and 25-OHD sufficiency both appear to be important and to act synergistically, with neither totally compensating for the other.

Effect of calcium therapy in the sick premature infant with early neonatal hypocalcemia.

Twenty-seven sick premature infants with serum calcium concentrations less than 6.0 mg/dl during the first day of age were enrolled in a prospective controlled study involving two treatment regimens--calcium given as a bolus or a drip--or no treatment. Mean total calcium concentration was 5.5 +/- 0.8 mg/dl, and ionized calcium was 3.1 +/- .3 mg/dl, with no significant difference between treatment groups. By 24 hours, in all groups total calcium had increased to greater than 6.0 mg/dl (bolus 6.5 +/- 1.1, drip 7.0 +/- 0.4, control 6.6 +/- 0.4) and ionized calcium to greater than 3.5 mg/dl (bolus 3.9 +/- 0.3, drip 3.6 +/- 0.6, control 3.6 +/- 0.3). Ionized and total calcium concentrations were significantly correlated (r = 0.562; P less than 0.001), but total calcium did not predict ionized calcium in any group. These data support the concept that, even in sick infants, early neonatal hypocalcemia is a physiologic phenomenon that may not require treatment.

Elevation of postmortem triiodothyronine in sudden infant death syndrome and in infants who died of other causes: a marker of previous health.

We measured serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse T3, free T4, thyroid-stimulating hormone, and cortisol in 62 victims of sudden infant death syndrome (SIDS) in 30 infants who died of known causes and in 15 living controls. The mean T3 value was elevated in 69% of those with SIDS. 37% of the others who died, and in no control infants. After excluding those who died of known cause who had abnormal thyroid function (abnormal postmortem concentrations of T4, free T4, or reverse T3), the T3 values were elevated in 63% of those remaining. When the data were analyzed on the basis of case histories and autopsy findings, those infants who were in good health and died suddenly of accidental causes had an elevation in mean T3 similar to that seen in SIDS victims; those who died under conditions known to alter thyroid metabolism did not. The T4, free T4, reverse T3, thyroid-stimulating hormone, and cortisol values were not useful in differentiating those with SIDS from the living controls, or those who were healthy at the time of death. We were unable to find any difference in T3 serum concentrations between the total group who had SIDS and those who had SIDS with minor infections, with petechiae on intrathoracic organs, with premature birth, or those who were resuscitated. Our data point out the importance of using appropriate controls when evaluating SIDS. The normal reverse T3 values in SIDS, as well as confirmation of the normal T4 and free T4 values, constitute evidence against chronic persistent alveolar hypoventilation or prolonged episodes of hypoxia immediately preceding death from SIDS.

Diagnosis, treatment, and follow-up of neonatal mepivacaine intoxication secondary to paracervical and pudendal blocks during labor.

Seven infants developed mepivacaine intoxication secondary to accidental injection during paracervical or pudental blocks or both. All presented with unexplained neonatal depression at birth, tonic seizures (often with apnea) within six hours, and characteristic neurologic findings. Twenty-four-hour urinary excretion produced 12.7 to 37.4 mg, exchange transfusions less than 1.02 to 3.5 mg, and gastric drainage or lavage or both 0.63 to 1.26 mg of mepivacaine. Thus promotion of urinary excretion is the treatment of choice. All six survivors are seizure free and neurologically and developmentally normal at one to 4 1/2 years. With early diagnosis and prevention of severe perinatal hypoxia, the prognosis from intoxication alone is very good.

Serum concentrations of 25-hydroxyvitamin D in rickets of extremely premature infants.

Nine premature infants developed radiographic and biochemical rickets at a mean +/- SD of 12.6 +/- 2.8 weeks of age. Serum 25-hydroxyvitamin D concentrations were all low, with a mean of less than 3.6 +/- 2.1 ng/ml. The mean average daily intake of vitamin D since birth had been 300 +/- 181 IU, and the mean average daily intake during the week of diagnosis was 587 +/- 313 IU. All of the infants were extremely premature (mean weight 948 +/- 153 gm, mean gestation 27.7 +/- 1.1 weeks), and were being fed either a low-calcium "human milk-like" formula or a soy formula. It is postulated that low-calcium intake may have increased 25-OHD utilization in the face of a decreased ability of the extremely premature infant to produce 25-OHD. Because of multiple factors leading to both decreased production and possible increased utilization of 25-OHD, such infants have an increased requirement for vitamin D to maintain normal serum 25-OHD concentrations, and daily intakes of at least 400 IU vitamin D orally must be assured. Serum 25-OHD measurements and radiographs may be important in following infants at risk.

Clinical pharmacology of hexachlorophene in newborn infants.

Bathing with soap containing hexachlorophene was instituted during two major staphylococcal epidemics in a Neonatal Intensive Care Unit. Infants who weighed less than 1,200 gm, those with a postconceptional age of less than 35 weeks, and those with large areas of abraded skin were at highest risk to achieve elevated blood HCP concentrations. T 1/2 of HCP ranged from 6.1 to 44.2 hours and appeared to follow first order kinetics. Time of peak blood concentrations of HCP following a bath ranged from 6 to 10 hours. One infant with liver disease achieved a concentration of HCP of 4,350 ng/ml after seven baths and developed clinical symptoms consistent with HCP toxicity.

Perinatal vitamin D metabolism. II. Serial 25-hydroxyvitamin D concentrations in sera of term and premature infants.

Serial concentration values of 25-hydroxyvitamin D (25-OHD) were determined in the sera of term, premature, and twin infants. In infants born at term with normal concentrations of 25-OHD in cord blood, serial concentrations of 25-OHD remained normal; in infants born at term with low concentrations of 25-OHD in cord blood, serial concentrations of 25-OHD increased. In premature infants with normal concentrations of 25-OHD in cord blood, serial concentrations of 25-OHD decreased; in premature infants with low values of 25-OHD in cord blood, serial concentrations of 25-OHD did not increase until a postconceptual age of 36 to 38 weeks. The concentrations of 25-OHD in the sera of twin infant pairs followed parallel courses. Oral and intravenous supplementation of vitamin D did not significantly increase the concentrations of 25-OHD in serum of premature infants. These findings suggest that a decreased rate of 25-hydroxylation of vitamin D may be a factor impairing homeostasis of 25-OHD in premature infants.

Brain tissue levels in a fatal case of neonatal mepivacaine (Carbocaine) poisoning.

A fatal case of mepivacaine poisoning in a newborn infant is reported. Regional brain tissue concentrations of mepivacaine were determined by a sensitive and specific gas chromatographic-mass spectrometric method. The brain tissue levels in this patient were higher than those previously reported, possibly due to alkalosis occurring several hours prior to the infant's death.