Vitamin A supplementation in very-preterm or very-low-birth-weight infants to prevent morbidity and mortality: a systematic review and meta-analysis of randomized trials.

BACKGROUND: A previous systematic review showed that intramuscular vitamin A supplementation reduced the risk of bronchopulmonary dysplasia (BPD) in very-low-birth-weight (VLBW) infants. However, more recent studies have questioned this finding. OBJECTIVES: Our objective was to synthesize current evidence on vitamin A supplementation in very-preterm (<32 wk gestational age) or VLBW infants and investigate the factors that may modify its efficacy. METHODS: A systematic review was conducted using the Cochrane systematic review methodology. We included randomized controlled trials investigating vitamin A supplementation for reducing morbidity and mortality in very-preterm or VLBW infants. Certainty of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluation (GRADE) recommendations. Prespecified subgroup analyses assessed factors that may modify the effects of vitamin A supplementation. RESULTS: We included 17 studies (n = 2471) in the qualitative and 15 studies (n = 2248) in the quantitative synthesis. Moderate-certainty evidence suggested a beneficial effect of vitamin A for decreasing the risk of BPD at 36 wk postmenstrual age (RR: 0.83; 95% CI: 0.74, 0.93; numbers needed to treat for an additional beneficial outcome: 16; 95% CI: 9, 53; 9 studies, n = 1752; P = 0.002). Subgroup analysis suggested that the beneficial effect was limited to infants with baseline vitamin A intake <1500 IU · kg-1 · d-1. Both enteral and parenteral routes were effective. Vitamin A supplementation did not have adverse effects and did not alter mortality before discharge (12 studies, n = 1917) or neurodevelopmental outcomes at 18-22 mo (1 study, n = 538). CONCLUSIONS: The benefit of vitamin A supplementation for reducing BPD is likely to be limited to infants with baseline vitamin A intake <1500 IU · kg-1 · d-1 and is not affected by the route of administration.

Effect of Enteral Vitamin A on Fecal Calprotectin in Extremely Preterm Infants: A Nested Prospective Observational Study.

BACKGROUND: Vitamin A has anti-inflammatory and immune-modulating properties. We aimed to assess whether enteral water-soluble vitamin A supplementation in extremely preterm infants decreases fecal calprotectin, a marker of intestinal inflammation. METHODS: This was a prospective observational study nested in a randomized, double-blind, placebo-controlled clinical trial investigating enteral vitamin A (5,000 IU/day) for reducing the severity of bronchopulmonary dysplasia (BPD) in extremely preterm infants. Fecal calprotectin levels were measured using enzyme-linked immunosorbent assay after 28 days of Vitamin A or placebo supplementation. RESULTS: Fecal calprotectin was measured in 66 infants (Vitamin A: 33, Placebo: 33). The mean (standard deviation) gestational age (25.5 [1.55] vs. 25.8 [1.48]; p = 0.341) (week), birth weight (810 [200] vs. 877 [251]; p = 0.240) (gram), and factors influencing fecal calprotectin levels were comparable between the vitamin A versus placebo group infants. All infants were exclusively fed with mother's or donor's human breast milk if mother's milk was unavailable using a standardized feeding regimen and received prophylactic probiotic supplementation. Fecal calprotectin levels (median; 25th-75th centiles) (micrograms/gram of feces) were not significantly different between vitamin A (152; 97-212) and placebo groups (179; 91-313) (p = 0.195). Two infants in the vitamin A group developed definite necrotizing enterocolitis compared to none in the placebo group. Incidence of BPD at 36 weeks postmenstrual age was similar between the groups (vitamin A: 18/33, placebo: 13/33, p = 0.218). CONCLUSION: Enteral supplementation with water-soluble vitamin A did not affect fecal calprotectin levels in extremely preterm infants. Studies with a larger sample size are required to confirm the findings.

Enteral Vitamin A for Reducing Severity of Bronchopulmonary Dysplasia: A Randomized Trial.

BACKGROUND AND OBJECTIVES: Evidence suggests that intramuscular vitamin A reduces the risk of bronchopulmonary dysplasia (BPD) in preterm infants. Our objective was to compare enteral water-soluble vitamin A with placebo supplementation to reduce the severity of BPD in extremely preterm infants. METHODS: We conducted a double-blind randomized controlled trial in infants <28 weeks' gestation who were to receive either enteral water-soluble vitamin A (5000 IU per day) or a placebo. Supplementation was started within 24 hours of introduction of feeds and continued until 34 weeks' postmenstrual age (PMA). The primary outcome was the severity of BPD, assessed by using the right shift of the pulse oximeter saturation versus the inspired oxygen pressure curve. RESULTS: A total of 188 infants were randomly assigned. The mean ± SD birth weight (852 ± 201 vs 852 ± 211 g) and gestation (25.8 ± 1.49 vs 26.0 ± 1.39 weeks) were comparable between the vitamin A and placebo groups. There was no difference in the right shift (median [25th-75th percentiles]) of the pulse oximeter saturation versus inspired oxygen pressure curve (in kilopascals) between the vitamin A (11.1 [9.5-13.7]) and placebo groups (10.7 [9.5-13.1]) (P = .73). Enteral vitamin A did not affect diagnosis of BPD or other clinical outcomes. Plasma retinol levels were significantly higher in the vitamin A group versus the placebo group on day 28 and at 34 weeks' PMA. CONCLUSIONS: Enteral water-soluble vitamin A supplementation improves plasma retinol levels in extremely preterm infants but does not reduce the severity of BPD.

Saliva for Assessing Vitamin A Status in Extremely Preterm Infants: A Diagnostic Study.

BACKGROUND: Salivary measurement of hormones and vitamins is gaining prominence as a minimally invasive procedure with the negligible potential for harm. We aimed to assess the utility of saliva for assessing vitamin A status in extremely preterm infants. METHODS: Paired saliva and blood samples were collected at 4 weeks of age from infants born <28 weeks of gestation using a proprietary polymer swab. Plasma retinol was measured using high-performance liquid chromatography, and salivary retinol was measured using enzyme-linked immunosorbent assay. RESULTS: Thirty infants were recruited with a median (IQR) gestation and birth weight of 26.2 weeks (24.8-27.2) and 865 g (718-1,002), respectively. An adequate volume of saliva (>50 µL) was obtained in 68%. There was no significant correlation (Spearman's correlation coefficient = 0.16, p = 0.3) between individual plasma and salivary retinol levels. Bland-Altman analysis showed wide limits of agreement (-113 to +119%) between individual plasma and salivary retinol levels. CONCLUSION: Individual vitamin A status cannot be determined reliably from saliva in extremely preterm infants using current collection materials and analysis techniques.

Inter-rater reliability of amplitude-integrated EEG for the detection of neonatal seizures.

BACKGROUND: Amplitude-integrated electroencephalogram (aEEG) is being used increasingly for seizure detection in neonates. However, data regarding inter-rater reliability among neonatologists for the use of aEEG for the detection of neonatal seizures is lacking. METHODS: Term and late-preterm infants at risk of seizures were monitored simultaneously with 24-h video-electroencephalography (vEEG) and aEEG. vEEG was interpreted by an experienced neurologist. Five neonatologists with experience in aEEG interpretation from four different neonatal units interpreted aEEG recordings independently. The Brennan and Prediger kappa coefficient and Intra-class Correlation Coefficients (ICC) were used to assess inter-rater reliability between the neonatologists. RESULTS: Thirty-five infants at risk of seizure with gestational age at birth 35-42 weeks were recruited for the study after informed parental consent. vEEG detected seizures in seven infants with a total of 169 individual seizure episodes. Neonatologists detected seizures in 10 to 15 infants on aEEG. The sensitivities for the detection of individual seizures by neonatologists ranged from 18% to 38%. The inter-rater reliability for detection of: individual seizure was "fair" (kappa = 0.37; 95% CI: 0.32-0.42), infant with seizure was "moderate" (kappa = 0.60; 95% CI: 0.44-0.75), duration of individual seizure (ICC: 0.22; 95% CI: 0.18-0.28) and total duration of seizures in an infant (ICC: 0.46; 95% CI: 0.30-0.63) was "poor". The neonatologists missed 77-90% of the duration of seizures. CONCLUSION: The inter-rater reliability of aEEG for the detection of neonatal seizures was suboptimal. Even when interpreted by experienced and trained clinicians, seizure detection with aEEG has limitations and can miss large number and duration of seizures.