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American Journal of Clinical Nutrition, Vol. 80, No. 6, 1589-1594, December 2004
© 2004 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Low plasma retinol concentrations increase the risk of developing bronchopulmonary dysplasia and long-term respiratory disability in very-low-birth-weight infants1,2,3

Karen Spears, Carrie Cheney and Joan Zerzan

1 From the Nutritional Science Program, School of Public Health and Community Medicine, University of Washington, Seattle (KS and CC), and the University of Washington Medical Center, Neonatal Intensive Care Unit, Seattle (JZ)

2 CC is deceased.

3 Address reprint requests to K Spears, 10300 Baltimore Boulevard, Building 307B, Room 138, BARC-East, Beltsville, MD 20705. E-mail: spearsk{at}ba.ars.usda.gov.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The effect of inadequate vitamin A during the neonatal period on lung status is still unknown.

Objective: We tested the hypothesis that low plasma retinol concentrations during the first month of life are independently associated with bronchopulmonary dysplasia (BPD) and long-term respiratory morbidity at 6 mo gestationally corrected age (ie, the age the infant would be had the pregnancy gone to term).

Design: Respiratory outcome information was obtained to 6 mo corrected age for a historical cohort of very-low-birth-weight neonates (<1250 g) who were admitted to intensive care over a 7-y period. Neonates with one or more plasma measurements of retinol concentrations < 0.35 µmol/L (<100 µg/L) on days 1–28 were classified as having low vitamin A. BPD was defined at day 28 by clinical and radiologic criteria and by use of supplemental oxygen at 36 wk postmenstrual age (PMA). Dependence on supplemental oxygen was used to identify long-term respiratory disability at 6 mo corrected age. Multivariate logistic regression analyses were conducted.

Results: Of the 350 study infants, 192 (55%) had low vitamin A status. BPD occurred in 52% of survivors at day 28 (173/331) and at 36 wk PMA (147/285). Fourteen percent (33/244) required oxygen support at 6 mo corrected age. Adjusted odds ratios of BPD with low vitamin A were 3.5 (95% CI: 1.7, 7.2) at day 28 and 1.7 (1.0, 2.7) at 36 wk PMA. At 6 mo corrected age, the adjusted odds ratio was 2.6 (1.1, 6.4) for respiratory disability with low vitamin A.

Conclusion: Poor vitamin A status during the first month of life significantly increased the risk of developing BPD and long-term respiratory disability.

Key Words: Vitamin A • retinol • bronchopulmonary dysplasia • chronic lung disease • premature infants • preterm infants


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Bronchopulmonary dysplasia (BPD) is the consequence of abnormal lung growth and healing from injury (1–3). Despite advancements in neonatal intensive care, BPD continues to affect 13–38% of surviving infants born weighing <1500 g (4) at a cost of approximately $2.4 billion per year (1).

Poor vitamin A status is a possible factor in the pathogenesis of BPD (1, 5–7). Vitamin A is involved in the regulation of lung alveolar septation and surfactant production and supports the integrity and regeneration of respiratory epithelial cells (5, 6). Animal models made deficient in vitamin A manifest lung necrosis and keratinizing squamous metaplasia of the epithelium, which are similar to the histologic alterations seen in BPD (5, 6). These lesions are reversed by the restoration of vitamin A status (8). Adequate tissue concentrations of vitamin A may offer protection from infection and the toxic effect of oxygen free radicals (5, 6, 9).

Most preterm infants are born with low vitamin A stores and low plasma concentrations (5, 7). Compounding the problem, the provision of exogenous vitamin A is problematic in this population owing to the poor bioavailability of intravenous vitamin A and delays in the initiation and attainment of full enteral nutrition support (7, 10, 11). Furthermore, a low concentration of vitamin A carrier proteins, which is common in preterm infants, may hinder the mobilization of vitamin A stores (7, 12).

The findings of clinical studies are inconsistent. Initial observational studies found significantly lower vitamin A status in infants who developed BPD than in infants without BPD (12, 13). However, others have not substantiated these findings (14–18). Likewise, in randomized controlled intervention trials, high-dose vitamin A therapy did not consistently reduce the risk of BPD (19–24). The largest randomized intervention trial, which was conducted by Tyson et al (24), found a modest yet significant decrease in the risk of BPD with administration of vitamin A intramuscularly 3 times per week over 4 wk (relative risk: 0.85; 95% CI: 0.73, 0.98). The invasiveness of repeated intramuscular injections limits the widespread acceptance of this administration route (4, 23).

BPD is a multifactorial disease. Yet, small sample sizes have prohibited most investigations from adjusting for biochemical variables and other potential BPD risk factors. For example, glucocorticoid steroid use, infection, and malnutrition have been reported as predictors of BPD (2) and they influence retinol concentrations (6, 7, 25–29). Glucocorticoids increase retinol concentrations (6, 7, 28, 29), whereas infection and malnutrition can reduce concentrations of retinol and retinol carrier protein (7, 25–27). No study has evaluated the relation between early low plasma retinol concentrations and pulmonary sequelae beyond 2 mo of age, nor has any study assessed multiple variables for confounding and interactions in the vitamin A-BPD relation.

We obtained historical vitamin A concentrations from a large, 7-y cohort of preterm infants to determine whether low plasma retinol concentrations increase the risk of developing BPD, long-term pulmonary dysfunction, and poor outcome (death or BPD) after adjustment for other BPD risk factors.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Infants admitted to the University of Washington regional level III neonatal intensive care unit (NICU) between 1 January 1993 and 31 December 1999 weighing ≤1250 g at birth and surviving for >72 h with any retinol concentration in the first 28 d of life were eligible. Participants were recruited from July 1999 through September 2000 through a letter of introduction and a follow-up phone call. The Human Subjects Review Committee at the University of Washington and the Institutional Review Board of Children's Hospital approved the study. Data were obtained from medical records and infants' guardians.

Neonatal medical and nutritional management in the NICU were under the direction of the attending physician. Standard care included ongoing nutrition assessment and monitoring by a neonatal dietitian; this assessment incorporated a comprehensive blood nutrition panel containing retinol concentrations. No infants received vitamin A treatments above the standard dosage in the first 4 wk of life.

MVI Pediatric by Astra Pharmaceutical (Wayne, PA) was added to parenteral nutrition solutions providing 690 IU retinol to infants weighing <1000 g and 1496 IU retinol for those weighing 1000–3000 g. Infants fed enterally received vitamin A in breast milk, fortified breast milk, or preterm infant formulas. An oral multivitamin for low-birth-weight infants was initiated on discontinuation of parenteral nutrition support; the multivitamin provided 750–1500 IU vitamin A/d.

Blood samples were collected by NICU nursing staff as part of routine care. The timing and frequency of blood sampling were at the discretion of the medical team. Plasma retinol concentrations were measured by reversed phase HPLC (laboratory reference range: 1.05–2.79 µmol/L) (30). Infants having one or more retinol concentrations <0.35 µmol/L (<100 µg/L) in the first 4 wk of life were categorized as having low or poor vitamin A status. Other investigators have used this concentration as an indictor of vitamin A deficiency in adults and children (27, 31). Serum protein concentrations were analyzed by standardized methods (32; retinol binding protein and transthyretin nephelometric kit insert, Behring Diagnostics, Inc, San Jose, CA). The cutoffs for laboratory tests for group classification were based on 1) the lower limit of the laboratory reference range [<0.021 g/L for retinol-binding protein (RBP) and <0.08 g/L for transthyretin (TTR)], 2) the cohort median (<0.45 for the retinol:RBP molar ratio), and 3) a value indicative of severe protein depletion (<21 g/L for albumin) (28) or marginal vitamin A deficiency (<0.36 for the RBP:TTR molar ratio) (33).

BPD was defined at day 28 by clinical and radiologic evidence according to the 4 criteria of Bancalari and et al (34): mechanical ventilation during the first week of life, use of oxygen support at 28 d of age, and clinical and radiographic evidence of respiratory disease. Need for continuous supplemental oxygen defined BPD at 36 wk postmenstrual age (PMA). Poor long-term pulmonary outcome was distinguished by use of intermittent or continuous oxygen support >21% within 2 wk of the time the infant reached a gestationally corrected age of 6 mo (ie, the age the child would be if the pregnancy had gone to term: corrected age = chronologic age – no. of weeks or months premature). Demographic and medical history information were recorded. All data were extracted from medical records by a single investigator (KS).

Chi square tests and chi-square tests for trend identified potential confounding factors and were used to compare inclusion and exclusion groups. Primary hypothesis testing was by multivariate logistic regression analyses with a backward elimination model strategy. Two-way interactions between terms of interest were removed simultaneously from the initial model and were evaluated by likelihood ratio test (chunk test) (35). Variables that substantially changed the odds ratio for low vitamin A when removed from the model were retained in the final model. BPD prevalence instead of incidence was reported because outcome data were not available for the full cohort. With an expected 45% prevalence of BPD in the low vitamin A group and a 30% prevalence in the high vitamin A group at day 28, a sample size of 324 subjects was needed for an alpha level of 0.05 and a power of 80%. All statistical analyses were performed by using SPSS 10.05 for WINDOWS (SPSS Inc, Chicago).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study cohort
During the 7-y admission period, 369 preterm infants met the study entry criteria. Of these, 350 were included in the study cohort. Infants were excluded because their guardians declined study entry (n = 17) or outcome data were not available at 28 d (n = 2). Overall, the study cohort and exclusion group were similar. Within the study cohort, outcome data were available for 89% of the infants at 36 wk PMA (310/350) and for 80% at 6 mo corrected age (281/350). Outcome information was not located for some of the infants who moved outside the University of Washington and Children's Hospital medical system. On average, parenteral nutrition therapy was started on day 3 (median: 3; range: 0–7) and discontinued on day 25 (median: 21; range: 4–150). Initiation of enteral therapy that was sustained for ≥5 d occurred between days 1 and 40 ( ± SD: 9 ± 6.7).

Clinical outcome
Fifty-five percent (192/350) of the study cohort infants experienced a poor outcome (BPD or death by any cause) at day 28. Nineteen infants died before day 28 and 52% of the survivors met all 4 criteria for BPD diagnosis at day 28. By 36 wk PMA, 25 infants had died, 52% required supplemental oxygen (147/285), and the prevalence of poor outcome (BPD or death) remained at 55% (172/310). Thirty-seven infants died by 6 mo corrected age, 14% (33/244) of survivors were dependent on supplemental oxygen, and 25% (70/281) experienced a poor outcome (use of oxygen support or death).

Biochemical findings
Fifty-five percent of infants (192/350) were classified as having low vitamin A status. Current observations confirmed the influence of steroid administration on retinol concentrations reported in previous research (17, 29). Within each week, the mean retinol concentration of infants exposed to steroids was significantly higher than that of infants not exposed to steroids (P < 0.001–0.08; data not presented).

Potential risk factors
The occurrence of BPD at day 28 among survivors (n = 331) in relation to exposure to potential risk factors is shown in Table 1Go. Race and sex were not associated with BPD.


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  		TABLE 1. Factors associated with risk of bronchopulmonary dysplasia in infants at day 281

 
BPD and long-term oxygen support dependence outcome
Eleven covariables that were significantly associated with the risk of BPD at day 28 were included in the initial logistic regression model (gestational age, admittance year, surfactant administration and steroid use before day 14, duration of parenteral therapy, respiratory distress syndrome-hyaline membrane disease, patent ductus arteriosus, sepsis, pulmonary infection, low albumin, and low TTR). Significant highly colinear variables that had similar representation in the equation, such as birth weight and enteral therapy, were not entered in the equation. All two-way interactions (chunk test P = 0.19) and nonconfounding variables (P = 0.4–0.9) were eliminated from the final model (Table 2Go). The odds of developing BPD at day 28 was 3.5 times higher for infants having retinol concentrations <0.35 µmol/L (<100 µg/L) during the first 4 wk of life than for infants with concentration ≥0.35 µmol/L (≥100 µg/L), after adjustment for confounding (95% CI: 1.7, 7.2; Table 2Go).


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  		TABLE 2. Results of multiple logistic regression of low vitamin A status (retinol < 0.35 µmol/L) and bronchopulmonary dysplasia outcome at day 281

 
Retinol concentrations analyzed as a continuous variable showed a dose-response relation. Using the lowest retinol concentration during the 4-wk time period for each infant, a decline in retinol concentration of 0.17 µmol/L (50 µg/L) increased the odds of BPD by 35% given similar gestational age (95% CI: 1.1, 1.7). With application of the same modeling procedure, the corresponding adjusted odds ratios for dependence on oxygen support were 1.7 (95% CI: 1.0, 2.7) at 36 wk PMA and 2.6 (95% CI: 1.1, 6.4) at 6 mo corrected age.

Death or BPD outcome
At day 28, the adjusted odds ratio for death by any cause or BPD was significantly greater with low vitamin A status [odds ratio (OR): 2.7; 95% CI: 1.33, 5.42]. The relation of low vitamin A status to death by any cause or BPD at 36 wk PMA was complicated by an interaction between low TTR and gestational age. The data were therefore stratified on these variables. To maintain ample sample size, gestational age was categorized into 2 groups: <27 wk gestation and ≥27 wk gestation. Among infants <27 wk gestation, the adjusted odds for death or BPD was not significantly associated with low vitamin A regardless of TTR status (OR: 1.5; 95% CI: 0.80, 2.73 for low TTR, and OR: 1.0; 95% CI: 0.48, 2.26 for high TTR). For more mature infants, the adjusted OR was 1.8 (95% CI: 1.03, 3.13) in the low TTR group and 1.6 (95% CI: 0.86, 3.11) in the high TTR group. The 1.2 greater odds for death or use of oxygen support at 6 mo corrected age with low vitamin A status was not significant (95% CI: 0.62, 2.23).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study showed that low plasma retinol concentrations during the first month of life are significantly associated with an increased risk of developing BPD in very-low-birth-weight infants (<1250 g) after adjustment for confounding factors. Moreover, the adverse effect on the respiratory system extended to 6 mo corrected age. The adjusted odds for needing long-term oxygen support was significantly greater for infants with low vitamin A status than for those having higher vitamin A status. For the combined outcome (death or BPD), having a low plasma retinol concentration significantly increased an infant's odds of poor outcome at day 28. The present study also showed a significant dose-response relation between retinol concentrations and BPD at day 28 when retinol concentrations were analyzed as a continuous variable.

Although the plasma retinol concentration is the most commonly used index for vitamin A status, its limitations are well recognized (27, 31). Researchers have proposed adding the modified-relative-dose-response assay or RBP:TTR molar ratio as biochemical measures of vitamin A status (6, 16, 26, 31, 33, 36, 37). Because of the observational nature of the present study, modified-relative-dose-response data were not available. The RBP:TTR molar ratio offers advantages as a test for vitamin A status during inflammation or infection because RBP is reduced by both inflammation and vitamin A deficiency, whereas TTR is reduced only by inflammation (26, 33). Only 13 of the 350 infants in the present study had an RBP:TTR <0.36 (which is considered indicative of marginal vitamin A status), and of these, 4 had plasma retinol concentrations ≥0.35 µmol/L. RBP:TTR may not be useful in very-low-birth-weight infants. We observed a molar excess of RBP compared with retinol and TTR. This could account for the low prevalence of RBP:TTR < 0.36. About 80–90% of circulating RBP is bound to retinol-RBP, which quickly associates with TTR, forming a retinol:RBP:TTR triad (1:1:1 molar ratio) (27). In this sample, most retinol:RBP ratios (95%) showed a high degree of apo-RBP (retinol-free RBP) in the plasma, defined by ratio <0.82. The mean (±SD) retinol:RBP in this cohort (0.53 ± 0.21) was within the range reported in premature infants (0.39–0.60) (36–39). Renal immaturity might explain the higher retinol to RBP molar concentration. After holo-RBP delivers its retinol to target tissues, the resulting apo-RBP has a lower affinity for TTR and is rapidly catabolized by the kidneys (27). Others have postulated that the rate of TTR synthesis in premature infants may be a limiting factor in the transport of retinol, more so than the rate of RBP synthesis (39).

It is possible that the low plasma retinol concentrations observed are the result of BPD or other factors that accompany the development of BPD. The utilization of retinol may be increased for growth and repair of respiratory epithelial cells, or the release of retinol by the liver may be insufficient. The molar surplus of RBP in relation to retinol and the ability of premature infants to mount a response to the relative dose response test provide evidence that the liver can synthesize RBP and mobilize retinol in the face of infection or protein-energy malnutrition (36–38).

A major strength of the present study is the robust study design. The logistic regression model allowed us to consider a multivariable problem in describing the vitamin A:BPD relation. We were able to analyze a relatively large cohort (n = 350) and adjust for several known BPD risk factors and variables indicative of protein-energy malnutrition and immaturity. Most previous studies were case-control or cohort designs that treated vitamin A as the dependent variable rather than evaluating the association of vitamin A status with the likelihood of BPD (12–18). Four prior cohort studies published sufficient data to calculate relative risk and CIs for BPD and poor outcome with low vitamin A exposure (11, 12, 17, 40). Our findings agreed with most (11, 12, 17, 40) but not all (40) of these 4 studies. Differences in population characteristics, sample size, the classification of low retinol, and the handling of covariates could account for the discrepancies.

Small sample size (n = 56) limited the ability of Tammela et al (40) to detect a statistically significant relation between BPD and vitamin A status and could explain the disagreement with our findings. Those authors estimated that a sample size of 308 infants (similar to our study size) would be needed to detect statistical significance at the 5% type I and 20% type II error levels (40). In addition, the study by Tammela et al probably did not distinguish infants who were truly depleted in vitamin A. Because only 2 infants had retinol concentrations <0.7 µmol/L at birth, the investigators selected <1.05 µmol/L as the cutoff for low vitamin A status (40). The value of 0.7 µmol/L is generally accepted as the lower level of adequacy in adults, and <0.35 µmol/L, as used in this study, is generally accepted as indicating vitamin A depletion (27, 31).

Regarding the combined outcome of BPD or death at day 28 and 36 wk PMA, our findings confirmed prior results by Inder et al (17). Inder et al used logistic regression and controlled for gestational age and antenatal steroid use. However, they did not include two-way interaction and carrier protein assessment in their logistic regression analysis; thus, the interaction of gestational age and TTR status that we detected at 36 wk PMA cannot be confirmed (17). The interaction maybe a product of multiple testing or an unknown physiologic mechanism.

As seen in the present cohort and in others (11, 17, 41), current nutritional practices were unable to prevent low vitamin A status in very-low-birth-weight infants. Fifty-five percent of the study infants had one or more serum retinol concentrations <0.35 µmol/L during the first month of life. This was probably due to the prolonged need for parenteral nutrition support. Half of the surviving cohort infants (122/244) still relied on parenteral nutrition support or a combination of parenteral and enteral nutrition support at day 28. Studies have shown a 75–80% loss of intravenous vitamin A due to photodegradation and adhesion of the vitamin to plastic tubing (10). In randomized controlled trials, administration of vitamin A intramuscularly (2000 IU or 5000 IU 3 times/wk for 4 wk) to populations with a high baseline frequency of low vitamin reduced the incidence of BPD (21, 24). The benefit of intramuscular vitamin A treatments was not shown where <5% of the baseline very-low-birth-weight population had retinol concentrations <0.35 µmol/L (20, 22).

Generalization of the present findings may be limited by the high prevalence of low vitamin A status and BPD. Because we used the retinol concentration nadir during the first month of life instead of values on a single day (eg, values at birth or on day 4), 55% of infants had retinol concentrations <0.35 µmol/L, which exceeds previously published rates (0–45%) (11–13, 15–17, 20, 22–24, 38, 40). The reported incidence of BPD ranges from 20% to 50% for infants with birth weights <1500 g (2). The present study enrolled only infants weighing ≤1250 g ( ± SD: 950 ± 194 g), and 52% of survivors developed BPD at day 28 or 36 wk PMA.

Limitations existed in the chart review process. Information on the use of antenatal steroids, which can affect neonatal retinol concentrations (17, 29), was not obtained and additional data to confirm diagnoses of confounding diseases were not extracted from the medical record (eg, laboratory confirmation of pulmonary infection).

In conclusion, this research adds to the evidence that poor vitamin A status, defined as a retinol concentration <0.35 µmol/L in the first month of life, may be a contributing factor in the complex pathogenesis of BPD. Low vitamin A status was associated with an increased risk of developing BPD and of poor pulmonary outcome at 6 mo corrected age after control for neonatal diseases, carrier protein concentration, steroid and surfactant administration, and duration of parenteral therapy. Further exploration into the role of the carrier protein TTR in the vitamin A status of premature infants is warranted.


   ACKNOWLEDGMENTS
 
This work is dedicated to the memory of one of the authors, Dr. Carrie Cheney, who died on 14 March 2003.

KS developed the study design, collected and analyzed the data, and wrote the manuscript. CC provided significant advice on the study design, analysis of data, and written manuscript. JZ provided consultation on the nutrition support of NICU infants, assisted in identifying potential study subjects, and participated in the review of the manuscript. None of the authors had a conflict of interest.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication April 19, 2004. Accepted for publication July 12, 2004.




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