Adekunle Dawodu, MBBS, FRCPCH1, Ravi Nath, FRCPCH2
1Global Health Center, Cincinnati Children’s Hospital Medical Center
2Department of Pediatrics, Al-Ain Hospital, Al-Ain, United Arab Emirates
Adekunle Dawodu, MD Cincinnati Children’s Hospital Medical Center. 3333 Burnet Avenue, MLC 2048. Cincinnati, OH 45229 adekunle.dawodu at cchmc.org
Background: The recommended dose of vitamin D (vD) supplementation of preterm infants is based on data from populations in which severe vD deficiency is uncommon and may be inadequate for infants in high risk population. However, data on vD status of preterm infants in high risk populations, such as Middle Eastern countries is scarce.
Aim: Investigate the vD status of Arab mothers and their preterm infants.
Method: Maternal serum and cord blood 25(OH)D, Ca, P and ALP were measured at delivery. Serum 25(OH)D was measured by HPLC while the other biochemical parameters were measured by standard autoanalyzer.
Results: Thirty-four preterm infants were studied. The mean gestational age was 31.4 weeks and birth weight was 1667g. The median serum 25(OH)D of 17.0 nmol/L in 28 mothers and 14.5 nmol/L in 34 cord blood samples were low. The median maternal and cord blood Ca, P and ALP levels were within normal range. Fifteen (44%) of the infants had moderately severe vD deficiency (serum 25 (OH)D levels <12.5 nmol/L). The median serum 25(OH)D levels of mothers who had reportedly taken prenatal vD supplementation and those who had not were similar (17.3 vs 16.3) nmol/L. The mean serum 25(OH)D levels among preterm infants in this study were low when compared to levels in Caucasians preterm infants on which the current vD recommendations are based. Conclusion: The high prevalence of moderately severe vD deficiency in Arab preterm infants provides a justification to investigate vD requirement of preterm infants in this and other high risk populations.
Vitamin D is important for maintenance of calcium and phosphorus homeostasis and bone mineralization and has also been shown to play a role in innate immune and autoimmune responses1. Vitamin D deficiency may play a role in metabolic bone disease, which is a common clinical problem in pre-term infants in developed and developing countries2, 3, and which could lead to poor long-term linear growth4. Furthermore, recent studies show that sub-clinical vitamin D deficiency in infancy and premature birth are associated with severe acute lower respiratory tract infection requiring hospitalization and intensive care5, 6. Therefore, maintenance of vitamin D sufficiency in infancy especially among prematurely born infants requires urgent attention.
It is generally accepted that the vitamin D status of newborn infants born at term or prematurely is dependent on the vitamin D status of the mother during pregnancy. Many studies have shown that vitamin D deficiency is more common in the Middle East and Asian countries during pregnancy and, therefore results in lower vitamin D status and higher prevalence of vitamin D deficiency in infants when compared to results from western countries7. Most studies, which have evaluated the vitamin D requirement of pre- term infants are from western countries where maternal vitamin D status is typically higher and, therefore, prevalence of vitamin D deficiency in newborns is lower than in the Middle Eastern and Asian countries8. In addition, studies from western countries indicate that the response to vitamin D supplementation in term infants is dependent on the baseline vitamin D status9. Therefore, data on vitamin D requirement in preterm infants should include studies of preterm infants from high risk population, in which vitamin D deficiency is more common. Clinical experience suggests that many institutions in the Arab countries use the recommended vitamin D supplementation of preterm infants from North America, which theoretically may not be sufficient to meet the vitamin D requirement of preterm infants in populations with high rates of severe vitamin D deficiency.
However, we are not aware of studies of vitamin D status of pre-term infants born to Arab mothers, who are at high risk of vitamin D deficiency. This study was therefore, designed to investigate the vitamin D status of Arab mothers and their preterm infants at delivery as measured by serum 25-hydroxy vitamin D 25(OH)D concentrations. We hypothesize that because of high prevalence of maternal vitamin D deficiency7, the prevalence and severity of vitamin D deficiency in pre-term infants born to Arab mothers would be higher than reported in preterm infants born to Caucasian mothers. The results will provide initial data on vitamin D status of preterm infants and their mothers at delivery and provide a guide to whether the currently recommended vitamin D supplementation is applicable to preterm infants in high risk population.
Maternal serum and cord blood calcium, phosphorus, alkaline phosphates and 25(OH)D levels were measured at delivery in a convenience sample of 34 Arab mothers and their infants born prematurely at 26-34 weeks of gestation. Serum 25(OH)D concentrations were determined by high-performance liquid chromatography after extraction with acetonitrile and purification with a C-18 column as previously reported 10. Serum calcium, phosphorus and alkaline phosphate concentrations were measured by standard autoanalyser.
Inclusion criteria were pre-term infants without congenital malformations. Infants born to mothers with conditions likely to affect vitamin D metabolism10 were excluded from the study. The gestational age of the infant was based on the date of the last menstrual period and confirmed using Ballard scoring system. The study was undertaken at a tertiary care institution in Al Ain, United Arab Emirates the year round during which there was an abundance of sunshine. The study was approved by the Institutional Review Board and mothers gave informed consent.
Data collected included maternal age and parity and self reported intake of prenatal vitamin D supplementation during the current pregnancy. The prenatal multivitamin
supplements available in the institution and in the medical district contain 200-400 IU of vitamin D per tablet. However, the exact amount of vitamin D intake by each subject was not determined. We compared the mother and infant biochemical parameters. We also compared the results with the vitamin D status of preterm infants reported from western countries. The data were analyzed using appropriate statistical tests and p-value < 0.05 was considered significant.
Thirty-four infants were studied. The mean (SD) maternal age and parity were 27.0 (5.5) years and 4.9 (3.7) respectively. This demography, and ethnicity (70% Arabs) and cultural background are similar to the general obstetric population in Al-Ain Medical District (unpublished observation). Gestational age was 31.4 (2.3) weeks and birth weight was 1667 (395) g. Only seventeen of the mothers reported taking prenatal vitamin D supplementation during the current pregnancy. The vitamin D and calcium homeostasis of mothers and infants with available results are summarized in Table 1. The numbers of biochemical results are lower than the number of subjects because blood samples were either insufficient or not available for tests. The results are presented as median and interquartiles range (IQR) since the biochemical parameters were not normally distributed and non-parametric statistical test, Mann-Whitney U was employed for analysis of differences between two groups and Spearman correlation coefficient was used for correlation analysis when indicated. The maternal and cord blood serum 25(OH)D concentrations are low and there was lack of significant correlation between maternal and cord blood values. The median maternal and cord blood Ca, P and ALP levels were within normal range. The cord blood phosphorus and ALP were significantly higher than the maternal levels. Of the infants, 15 (44%) have serum 25(OH)D levels less than 12.5 nmol/L. There was no significant difference between the median serum 25(OH)D levels of mothers who reported taking prenatal vitamin D and those who did not take supplementation (17.3 vs 16.3 nmol/L). The available sparse data from the literature on vitamin D status of preterm infants at birth are summarized in Table 2. The mean serum 25(OH)D level in infants in this study is low when compared to the reports from western countries.
The findings of this study confirm our hypothesis that the vitamin D stores of prematurely born Arab infants will be low because of high prevalence of maternal vitamin D deficiency. Similarly, low vitamin D stores had been reported in term infants in the same community16. It appears that there is a high prevalence of vitamin D deficiency in preterm infants in this population. Forty-four percent of the preterm infants were born with serum 25 (OH)D concentrations <12.5 nmol/L , which is compatible with metabolic bone disease17. We are not aware of reports of such high prevalence and severity of vitamin D deficiency in preterm infants at birth. The infants in this study are therefore, theoretically at risk of metabolic bone disease without an adequate vitamin D and mineral supplementation when compared to preterm infants in western countries (Table 2), where vitamin D stores at birth are generally higher8, 18. In addition, recent studies suggest that subclinical vitamin D deficiency (<50 nmol/L) in infancy and preterm births are risk factors for acute lower respiratory infection requiring hospitalization and intensive care,6 and it has been
suggested that serum 25(OH)D levels < 50nmol/L be regarded as vitamin D insufficiency in all infants and children19 .
This study supports our hypothesis of low vitamin D status in Arab mothers, who delivered prematurely. The reason for lack of difference in the serum 25(OH)D levels between supplemented and non-supplemented mothers is not clear but could be that a daily intake of 200-400 IU of vitamin D supplementation generally recommended in the country is insufficient to elevate vitamin D status to show a significant difference between supplemented and non-supplemented group 20. Furthermore, the lack of correlation between maternal and cord blood 25(OH)D levels could be due to small sample size or low transplacental transfer because of very low maternal values as reported by other authors21.
The recommended vitamin D intake for preterm infants varies widely and range from 150-400 IU/kg/day in the US to 800-1600 IU/day in Europe8, 14. Many authors opined that with a high intake of calcium and phosphorus, an intake of up to 400 IU/day is adequate to maintain normal vitamin D levels in healthy preterm infants3, 8, 14, 17-18,22. Many of the studies from western countries on which the vitamin D recommendations were based, had baseline vitamin D stores which were higher than in the present study. The figures ranged from serum 25(OH)D levels of 29.2 ±11.8 nmol/L14 and 70± 6.8 nmol/L22 to 75± 25 nmol/L18. In a recent study of preterm infants, who were on current feeding regimen it was found that 400 IU/day vitamin D was insufficient to maintain baseline vitamin D levels by 1 month of age 23. The mean serum 25(OH)D concentration of 53.5 nmol/L at 7-8 days of age decreased to 42.5 nmol/L at 28-30 days of age 23. In an older study11, vitamin D intake of 2100 IU/day for 96 hours increased the serum 25(OH)D from a baseline value of 27.5±2.5 to a level of 67.5±12.5 nmol/L which was regarded as vitamin D replete. The authors in that study suggested that a dose of 400 IU/day of vitamin D would be insufficient to maintain vitamin D sufficiency11. Furthermore, in another recent study from France, the mean serum 25(OH)D level of 47.5 nmol/L at 3 days of age increased to 142.6 nmol/L at 3 months among preterm infants on 1000 IU /day vitamin D supplementation without hypervitaminosis D15. Clearly, further studies are needed to determine optimal vitamin D requirement of preterm infants in different geographical locations.
Judging by the high prevalence of vitamin D deficiency at birth in preterm infants in this study and the widespread vitamin D deficiency in Arab women of child bearing age,7 there is a justification to investigate vitamin D requirements to ensure vitamin D sufficiency in preterm infants in high risk and other populations. An important issue to resolve is the definition of vitamin D sufficiency in infancy and childhood. While the definition of vitamin D sufficiency in infancy and childhood is controversial, most vitamin D experts recommend maintaining serum 25(OH)D level above 50 nmol/L19. Based on the results of some published studies, and the lower baseline vitamin D status in preterm infants in this study, a higher vitamin D intake more than 400 IU/day currently recommended may be required to prevent vitamin D insufficiency 19 in preterm infants born to Arab and probably other high risk mothers11, 23. This premise needs to be investigated in a randomized controlled trial
(RTC). We are planning a RCT to evaluate vitamin D requirement of preterm infants in this high risk population. Such a study is urgently required in view of the association between subclinical vitamin D deficiency and history of premature births and severe lower respiratory infections in young children6.
Finally, in view of the high prevalence of vitamin D deficiency in the mothers at delivery and its possible adverse effects on the fetus and the contribution to low vitamin D in
infancy 7,20, it is important to include adequate maternal vitamin D supplementation during pregnancy as part of the strategies to maintain vitamin D sufficiency in mothers and their preterm infants. We are currently conducting a RCT of prenatal vitamin D supplementation to prevent vitamin D deficiency in Arab women and their newborn infants (Clinicaltrials.gov, No. 00610688).
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