Folic acid supplementation and dietary folate intake, and risk of preeclampsia.

BACKGROUND/OBJECTIVES: Folic acid supplementation has been suggested to reduce the risk of preeclampsia. However, results from few epidemiologic studies have been inconclusive. We investigated the hypothesis that folic acid supplementation and dietary folate intake before conception and during pregnancy reduce the risk of preeclampsia. SUBJECTS/METHODS: A birth cohort study was conducted in 2010-2012 at the Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. A total of 10,041 pregnant women without chronic hypertension or gestational hypertension were enrolled. RESULTS: Compared with nonusers, folic acid supplement users had a reduced risk of preeclampsia (OR=0.61, 95% CI: 0.43-0.87). A significant dose-response of duration of use was observed among women who used folic acid supplemention during pregnancy only (P-trend=0.007). The reduced risk associated with folic acid supplement was similar for mild or severe preeclampsia and for early- or late-onset preeclampsia, although the statistical significant associations were only observed for mild (OR=0.50, 95% CI: 0.30-0.81) and late-onset (OR=0.60, 95% CI: 0.42-0.86) preeclampsia. The reduced risk associated with dietary folate intake during pregnancy was only seen for severe preeclampsia (OR=0.52, 95% CI: 0.31-0.87, for the highest quartile of dietary folate intake compared with the lowest). CONCLUSIONS: Our study results suggest that folic acid supplementation and higher dietary folate intake during pregnancy reduce the risk of preeclampsia. Future studies are needed to confirm the associations.

Randomized trial of enteral protein and energy supplementation in infants less than or equal to 1250 g at birth.

OBJECTIVE: To determine if enteral protein and energy supplementation would significantly improve weight gain as compared with energy supplementation alone in or=14 days, diet of >or=75% enteral nutrition (fortified human milk or formula) and either failure to regain BW or weight gain<15 g kg(-1) per days. Infants were randomized to a multinutrient supplement that provided increased protein and energy (P/E) intake or energy alone (medium chain triglyceride oil, MCT). Growth rates were compared at the end of the 4-week study period. RESULT: Of 30 eligible infants, 23 were enrolled, 12 received MCT (BW=862+/-252 g, mean+/-s.d.) and 11 received P/E (BW=879+/-241 g). Significantly higher protein intake (P/E=3.5+/-0.3 g kg(-1) per day, MCT=3.0+/-0.5 g kg(-1) per day) and better growth (P/E=17.0+/-2.4 g kg(-1) per day, MCT=11.5+/-4.8 g kg(-1) per day) were observed in the P/E group. CONCLUSION: These data are consistent with the importance of providing additional daily protein intake to achieve increased postnatal growth in very low birth weight infants experiencing slow growth.

Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial.

OBJECTIVES: Infants of

Neonatal auditory activation detected by functional magnetic resonance imaging.

The objective of this study was to detect auditory cortical activation in non-sedated neonates employing functional magnetic resonance imaging (fMRI). Using echo-planar functional brain imaging, subjects were presented with a frequency-modulated pure tone; the BOLD signal response was mapped in 5 mm-thick slices running parallel to the superior temporal gyrus. Twenty healthy neonates (13 term, 7 preterm) at term and 4 adult control subjects. Blood oxygen level-dependent (BOLD) signal in response to auditory stimulus was detected in all 4 adults and in 14 of the 20 neonates. FMRI studies of adult subjects demonstrated increased signal in the superior temporal regions during auditory stimulation. In contrast, signal decreases were detected during auditory stimulation in 9 of 14 newborns with BOLD response. fMRI can be used to detect brain activation with auditory stimulation in human infants.

Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.

BACKGROUND: Vitamin A supplementation may reduce the risk of chronic lung disease and sepsis in extremely-low-birth-weight infants. The results of our pilot study suggested that a dose of 5000 IU administered intramuscularly three times per week for four weeks was more effective than the lower doses given in past trials. METHODS: We performed a multicenter, blinded, randomized trial to assess the effectiveness and safety of this regimen as compared with sham treatment in 807 infants in need of respiratory support 24 hours after birth. The mean birth weight was 770 g in the vitamin A group and 769 g in the control group, and the respective gestational ages were 26.8 and 26.7 weeks. RESULTS: By 36 weeks' postmenstrual age, 59 of the 405 infants (15 percent) in the vitamin A group and 55 of the 402 infants (14 percent) in the control group had died. The primary outcome - death or chronic lung disease at 36 weeks' postmenstrual age - occurred in significantly fewer infants in the vitamin A group than in the control group (55 percent vs. 62 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.99). Overall, 1 additional infant survived without chronic lung disease for every 14 to 15 infants who received vitamin A supplements. The proportions of infants in the vitamin A group and the control group who had signs of potential vitamin A toxicity were similar. The proportion of infants with serum retinol values below 20 microg per deciliter (0.70 micromol per liter) was lower in the vitamin A group than in the control group (25 percent vs. 54 percent, P<0.001). CONCLUSIONS: Intramuscular administration of 5000 IU of vitamin A three times per week for four weeks reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in extremely-low-birth-weight infants.

Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: has the dose been too low? The NICHD Neonatal Research Network.

OBJECTIVE: Inconsistent effects of vitamin A supplementation on prevention of bronchopulmonary dysplasia have been reported. Meta-analysis of these reports resulted in a relative risk of 0.69-1.02 for death or bronchopulmonary dysplasia associated with vitamin A supplementation. Effective dosage regimens or serum retinol concentrations have not been determined in previous reports. The purpose of this pilot study was to define a vitamin A regimen that produces serum retinol concentrations of 25-55 micrograms/dl. STUDY DESIGN: In this three-phase study, 91 infants (mean birth weight 799-864 g) were enrolled. Vitamin A was administered three times/week for 4 weeks at an average daily dose of 986-2143 IU/day. Physical examinations were performed and serum retinol specimens were collected weekly to assess clinical signs of toxicity. RESULTS: The majority of serum retinol concentrations remained < 25 micrograms/dl until an intramuscular vitamin A dose of 5000 IU/dose three times/week was used. No clinical signs of toxicity were associated with the higher dosage and higher serum concentrations of vitamin A. CONCLUSION: A large clinical trial of vitamin A supplementation with 5000 IU/dose three times/week (25-114% more than the dose used in the three published clinical trials) is needed to assess whether vitamin A supplementation safely reduces the risk of bronchopulmonary dysplasia in very-low-birth-weight infants.

Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants.

DESIGN AND METHODS: We hypothesized that treatment with recombinant human erythropoietin (r-HuEPO) would stimulate erythropoiesis and would thereby reduce the need for erythrocyte transfusions in preterm infants. We treated 157 preterm infants born at 26.9 +/- 1.6 weeks of gestation who weighed 924 +/- 183 g at birth with either subcutaneous r-HuEPO (100 U/kg/d, 5 days per week) or placebo for 6 weeks in a randomized, double-blind, controlled clinical trial. All patients received oral iron and were managed according to uniform conservative transfusion guidelines. RESULTS: Treatment with r-HuEPO was associated with fewer erythrocyte transfusions (1.1 +/- 1.5 per infant in the r-HuEPO group versus 1.6 +/- 1.7 per infant in the placebo group; P = .046) and with a reduction in the volume of packed erythrocytes transfused (16.5 +/- 23.0 mL versus 23.9 +/- 25.7 mL per infant; P = .023). Overall, 43% of the infants in the r-HuEPO group and 31% of placebo-treated infants were transfusion-free during the study (P = .18). The volume of blood removed for laboratory tests and the need for respiratory support at the start of treatment had major effects on transfusion requirements independent of r-HuEPO. Reticulocyte counts were higher during treatment in the r-HuEPO group (P = .0001), and r-HuEPO-treated infants had higher hematocrit values at the end of the study (32% versus 27.3% in the placebo group; P = .0001). We found no differences in the incidence of major complications of prematurity between the treatment groups. CONCLUSION: We conclude that treatment with r-HuEPO at a weekly dose of 500 U/kg stimulates erythropoiesis, moderates the course of anemia, is associated with a reduction in erythrocyte transfusions, and appears safe in very low birth weight preterm infants who are receiving iron supplements. Conservative transfusion criteria, minimization of phlebotomy losses, and treatment with r-HuEPO are complementary strategies to reduce erythrocyte transfusions in these infants.

Selenium absorption and retention by very-low-birth-weight infants: studies with the extrinsic stable isotope tag 74Se.

Measurements of dietary selenium absorption and retention were obtained after administration of a single dose of the extrinsic stable isotope tag 74Se in 20 appropriate for gestational age premature infants with birth weights between 720 and 1,630 g and gestational ages between 26 and 33 weeks. Infants were assigned randomly to receive a standard premature formula (1.34 microgram of Se/dl) or a selenium-supplemented version of that formula (2.03 micrograms of Se/dl). Each study consisted of one feeding that had been extrinsically labeled with 74Se (1.03 microgram/kg) and a timed stool and urine collection. The percent 74Se absorption was 91.2 +/- 5.4% (mean +/- SD) from the standard formula and 86.2 +/- 3.0% from the selenium-supplemented formula (p less than 0.05), but the percent of the absorbed 74Se retained was not different, i.e., 96.6 +/- 2.1% and 95.0 +/- 2.8%, respectively. The percent net absorption and net retention were also not different between the standard and selenium-supplemented formulas; net absorption was 72.7 +/- 18.1% vs. 67.8 +/- 18.8% and net retention was 57.2 +/- 17.6% vs. 53.3 +/- 20.2%, respectively. The percent 74Se absorption and true selenium absorption were significantly correlated with the percent net selenium absorption and net selenium absorption, respectively. We conclude that an extrinsically administered dose of 74Se can be used to study selenium nutrition in growing premature infants.

Zinc and copper nutritional studies in very low birth weight infants: comparison of stable isotopic extrinsic tag and chemical balance methods.

Measurements of dietary zinc and copper absorption obtained after administration of a single dose of the extrinsic stable isotopic tags 70Zn and 65Cu were compared to measurements made with standard chemical balance methods in 41 appropriate for gestational age premature infants [body wt 1267 +/- 258 g, gestational age 29.8 +/- 1.9 wk (mean +/- SD), 4 to 83 postnatal d of age]. Fifty studies were performed; 33 with premature formula, five with term formula, seven with preterm human milk (PTHM), and five with fortified-PTHM. The percentages of net zinc and 70Zn absorption were found to be significantly greater from PTHM (66.4 +/- 15.2, 68.6 +/- 9.8) than from premature formula (14.0 +/- 29.9, 31.6 +/- 22.4), and term formula (23.6 +/- 18.5, 17.6 +/- 5.6). The percentages of net copper and 65Cu absorption were also found to be significantly greater from PTHM (61.5 +/- 14.0, 69.8 +/- 14.0) than from premature formula (16.6 +/- 20.6, 39.6 +/- 21.6) and term formula (20.6 +/- 24.1, 26.5 +/- 6.9). The percentages of net zinc and 70Zn absorption (35.9 +/- 29.1, 48.4 +/- 9.6) and net copper and 65Cu absorption (38.7 +/- 10.2 and 57.4 +/- 13.1) from fortified PTHM were similar to values from PTHM. Absorption of zinc and copper determined with extrinsic stable isotopic tag and standard nutrient balance methods were significantly correlated. Estimates of endogenous fecal losses of zinc and copper were substantial with each diet, but lower with PTHM. Stepwise, multiple linear regression analysis accounted for, at most, 58% of the variability in the measures of zinc and copper availability. We conclude that extrinsic 70Zn and 65Cu tags can be used to study absorption of dietary zinc and copper by very low birth wt infants.

Nutrient balance studies in premature infants fed premature formula or fortified preterm human milk.

This report compares fat, nitrogen, calcium, phosphorus, zinc, and copper absorption and retention data from 13 nutritional balance studies performed in 12 appropriate-for-gestational-age premature infants with birth weights less than or equal to 1,600 g fed a proprietary premature formula or their own mother's preterm human milk (PTHM) fortified with a powdered protein-mineral supplement. At the time of each balance study, each infant had a stable condition, was tolerating feedings, and was gaining weight steadily. Stool and urine were collected separately; doses of carmine red given 72 h apart were used to define dietary intake and the stool and urine collections. The balance studies were performed at an average age of 36 postnatal days. Both diets were found to support weight gain and nutrient retention at similar rates. Balance studies (n = 7) with premature formula demonstrated a weight gain of 16.8 +/- 5.2 g/kg/day, with a net fat absorption of 6.36 +/- 0.97 g/kg/day, net nitrogen retention of 427.9 +/- 47.1 mg/kg/day, net calcium retention of 95.0 +/- 14.1 mg/kg/day, net phosphorus retention of 56.7 +/- 5.9 mg/kg/day, net zinc retention of 208 +/- 903 micrograms/kg/day, and net copper retention of 26.4 +/- 30.8 micrograms/kg/day (mean +/- SD). Comparison balance studies (n = 6) with fortified PTHM demonstrated a weight gain of 17.2 +/- 7.1 g/kg/day, net fat absorption of 5.60 +/- 1.55 g/kg/day, net nitrogen retention of 366.0 +/- 84.0 mg/kg/day, net calcium retention of 82.2 +/- 10.8 mg/kg/day, net phosphorus retention of 58.6 +/- 5.9 mg/kg/day, net zinc retention of 685 +/- 363 micrograms/kg/day, and net copper retention of 67.3 +/- 37.2 micrograms/kg/day. These rates of weight gain and of fat, nitrogen, zinc, and copper retention approximate those of the third trimester of intrauterine life; only calcium and phosphorus retention approached the lower range of estimated in utero accretion.

Symptomatic zinc deficiency in a breast-fed, premature infant.

Hypozincemia and clinical features of acrodermatitis enteropathica developed in a breast-fed, premature infant at 6 months of age. Maternal breast milk zinc levels were normal at birth and at the time of appearance of zinc deficiency in the infant. Zinc supplementation administered orally resulted in rapid improvement. Seven premature infants with hypozincemia and transient symptomatic zinc deficiency have been previously described. In contrast with this case, the other infants received feedings with low zinc content.

Total lipid content and fatty acid composition of preterm human milk.

The total lipid content and fatty acid composition of preterm human colostrum and milk were analyzed from aliquots of 24-h collections of colostrum, transitional milk, and mature milk obtained from 21 women who had delivered premature infants with a mean birth weight of 1,049 +/- 38 g (mean +/- SEM) and a mean gestational age of 29 +/- 0.4 weeks. The total lipid content increased significantly with time of lactation (p less than 0.001), from 1.99 +/- 0.25 g/dl in colostrum to 3.89 +/- 0.28 g/dl in mature milk. With respect to the fatty acid pattern, the percentages of 12:0 and 14:0 increased significantly (p less than 0.001), while those of 16:0 (p less than 0.05) and 18:1 (p less than 0.001) decreased significantly with time of lactation. The percentages of 10:0, 16:1, 18:0, 18:2, and 18:3 did not vary significantly with the duration of lactation. Similar compositional changes have been described in term human colostrum and milk as the duration of lactation progresses.

Pharmacokinetics of a single intramuscular injection of vitamin E to premature neonates.

The pharmacokinetics of parenterally administered vitamin E (d, l-alpha tocopherol) in serum were developed using data from five premature neonates (1,500 +/- 100 gm) receiving a single 20 mg/kg intramuscular injection. Blood samples were obtained immediately prior to drug administration to establish baseline vitamin E concentrations: then further sampling was performed at various intervals for up to 7 days. It was assumed that dietary intake of vitamin E did not markedly alter serum concentration of vitamin E during the 7-day study and that the total intramuscular dose was absorbed. Although extensive sampling could not be performed in any one neonate, composite sampling from the study population made it possible to construct a pharmacokinetic profile of vitamin E in premature neonates. The half-life of elimination was 44 hours, the volume of distribution (V beta) was 0.41 liter/kg. and serum clearance was 6.5 ml/hr/kg. Vitamin E is an important biological antioxidant that may provide protection to the retinas and lungs of premature infants exposed to supplemental inspiratory oxygen. Therefore, if the pharmacokinetics of vitamin E observed in the present study can be generalized to the population of premature infants, a single 10 mg/kg intramuscular (IM) loading dose followed by 5 mg/kg every 48-72 hours should maintain serum concentration of 1.5 to 2.5 mg%--a level that has been associated with antioxidant protection.

Influence on retrolental fibroplasia of intramuscular vitamin E administration during respiratory distress syndrome.

The effect of vitamin E administered during the acute phase of therapy for respiratory distress syndrome (RDS) on the development of retinopathy of prematurity (ROP) was evaluated in a randomized double-masked study. One hundred neonates received either vitamin E or placebo intramuscularly within the first 24 hours of birth and at 24, 48, and 168 hours respectively. Additional doses were given twice weekly while the infant remained in an oxygen-enriched environment and could not tolerate feedings and vitamin supplements. Parenteral vitamin E-treated infants had significantly increased serum vitamin E levels compared to placebo-treated infants. Most placebo-treated patients attained normal serum vitamin E levels during the second week of life because of nutritional sources of vitamin E. Infants in both groups had RDS of similar severity. Seventy-four infants, 37 vitamin E-treated and 37 placebo-treated, survived longer than 10 days and had ophthalmologic examinations. Active changes of Stage I and Stage II ROP were noted in 17 of those patients; 9 (24.3%) vitamin E-treated and 8 (21.6%) placebo-treated patients (P = 0.572). No infants developed severe cicatricial changes, and their retinal findings regressed. The incidence of risk factors associated with ROP development occurred equally in the vitamin E-treated and placebo-treated infants that developed ROP. Thus, vitamin E-administration as described in this study did not result in any further reduction in the incidence of the active stages of ROP over that seen with standard neonatal care, which included daily oral Vitamin E supplements.

Amelioration of bronchopulmonary dysplasia after vitamin E administration. A preliminary report.

We studied the effect of vitamin E on the development of bronchopulmonary dysplasis in neonates with respiratory-distress syndrome. Twenty infants received vitamin E administered intramuscularly during the acute phase of the syndrome, and 20 infants served as controls. Administration of vitamin E significantly increased the serum vitamin E concentration. Nine vitamin-treated and 13 control patients required supplemental oxygen for longer than 250 hours; all were treated with positive-pressure ventilation and endotracheal continuous distending airway pressure. Six of those 13 controls had x-ray changes consistent with bronchopulmonary dysplasia, and four died. None of the nine vitamin-treated patients had changes characteristic of bronchopulmonary dysplasia (P = 0.046), and all survived. Administration of vitamin E during the acute phase of the respiratory-distress syndrome appears to modify the development of bronchopulmonary dysplasis.