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Arab preterm infants often have less than 10 ng of vitamin D - 2010


High Prevalence of moderately severe vitamin D deficiency in Pre-Term Infants

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.

Introduction
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.

Methods
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.

Results
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.

Discussion
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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References

1 Holick MF. Vitamin D deficiency. N Engl J Med. 2007; 357: 266-81.
2 Oyatsi DP, Musoke RN, Wasunna AO. Incidence of rickets of prematurity at Kenyatta National Hospital, Nairobi. East Afr Med J. 1999; 76: 63-6.
3 Ryan S. Nutritional aspects of metabolic bone disease in the newborn. Arch Dis Child Fetal Neonatal Ed. 1996; 74: F145-8.
4 Fewtrell MS, Cole TJ, Bishop NJ, Lucas A. Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease? J Pediatr. 2000; 137: 668-73.
5 Karatekin G, Kaya A, Salihoglu O, Balci H, Nuhoglu A. Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers. Eur J Clin Nutr. 2009; 63: 473-7.
6 McNally JD, Leis K, Matheson LA, Karuananyake C, Sankaran K, Rosenberg AM. Vitamin D deficiency in young children with severe acute lower respiratory infection. Pediatr Pulmonol. 2009.
7 Dawodu A, Wagner CL. Mother-child vitamin D deficiency: an international perspective. Arch Dis Child. 2007; 92: 737-40.
8 Greer FR. Fat-soluble vitamin supplements for enterally fed preterm infants. Neonatal Netw. 2001; 20: 7-11.
9 Zeghoud F, Vervel C, Guillozo H, Walrant-Debray O, Boutignon H, Garabedian M. Subclinical vitamin D deficiency in neonates: definition and response to vitamin D
supplements. Am J Clin Nutr. 1997; 65: 771-8.
10 Dawodu A, Agarwal M, Hossain M, Kochiyil J, Zayed R. Hypovitaminosis D and vitamin D deficiency in exclusively breast-feeding infants and their mothers in summer: a justification for vitamin D supplementation of breast-feeding infants. J Pediatr. 2003; 142:169-73.
11 Salle BL, Glorieux FH, Delvin EE, David LS, Meunier G. Vitamin D metabolism in preterm infants. Serial serum calcitriol values during the first four days of life. Acta Paediatr Scand. 1983; 72: 203-6.
12 Markestad T, Aksnes L, Finne PH, Aarskog D. Vitamin D nutritional status of premature infants supplemented with 500 IU vitamin D2 per day. Acta Paediatr Scand.
1983; 72: 517-20.
13 Delmas PD, Glorieux FH, Delvin EE, Salle BL, Melki I. Perinatal serum bone Gla- protein and vitamin D metabolites in preterm and fullterm neonates. J Clin Endocrinol Metab. 1987; 65: 588-91.
14 Backstrom MC, Maki R, Kuusela AL, et al. Randomised controlled trial of vitamin D supplementation on bone density and biochemical indices in preterm infants. Arch Dis Child Fetal Neonatal Ed. 1999; 80: F161-6.
15 Delvin EE, Salle BL, Claris O, et al. Oral vitamin A, E and D supplementation of pre-term newborns either breast-fed or formula-fed: a 3-month longitudinal study. J Pediatr Gastroenterol Nutr. 2005; 40: 43-7.
16 Amirlak I, Ezimokhai M, Dawodu A, et al. Current maternal-infant micronutrient status and the effects on birth weight in the United Arab Emirates. In press. East Mediterr Health J. 2009.
17 Seino Y, Ishii T, Shimotsuji T, Ishida M, Yabuuchi H. Plasma active vitamin D concentration in low birthweight infants with rickets and its response to vitamin D treatment. Arch Dis Child. 1981; 56: 628-32.
18 Cooke R, Hollis B, Conner C, Watson D, Werkman S, Chesney R. Vitamin D and mineral metabolism in the very low birth weight infant receiving 400 IU of vitamin D. J Pediatr. 1990; 116: 423-8.
19 Wagner CL, Greer FR. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008; 122: 1142-52.
20 Hollis BW, Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr. 2004; 79: 717-26.
21 Fraser DR. Vitamin D-deficiency in Asia. J Steroid Biochem Mol Biol. 2004; 89-90:491-5.
22 Koo WW, Krug-Wispe S, Neylan M, Succop P, Oestreich AE, Tsang RC. Effect of three levels of vitamin D intake in preterm infants receiving high mineral-containing milk. J Pediatr Gastroenterol Nutr. 1995; 21: 182-9.
23 Taylor SN, Wagner CL, Fanning D, Quinones L, Hollis BW. Vitamin D status as related to race and feeding type in preterm infants. Breastfeed Med. 2006; 1: 156-63.


VitaminDWiki Pregnancy pages with PRETERM of PRE-TERM in title (61 as of May 2022)

This list is automatically updated

Items found: 62
Title Modified
4.4 X more likely to have a preterm birth if low vitamin D while pregnant - May 2022 23 May, 2022
Arab preterm infants often have less than 10 ng of vitamin D - 2010 15 May, 2022
Preterm birth interventions – 4 studies found possible vitamin D benefit – Cochrane – Nov 2018 15 May, 2022
Preterm birth might be prevented by Vitamin D, Omega-3, etc. (International survey) – Jan 2019 15 May, 2022
Preterm Births - promising preventions – anti-oxidants, Vitamin D, Omega-3, Zinc, etc. – Jan 2019 15 May, 2022
Preterm birth chance reduced – with 17P or Vitamin D – June 2015 15 May, 2022
Preterm birth reduction by nutrients - Vitamin D is the best, Omega-3 is next best – May 2022 15 May, 2022
Omega-3 supplementation reduced preterm birth rate by 4X – RCT July 2020 10 Apr, 2022
Preterm birth rate of pregnant smokers cut in half if take Omega-3 – RCT May 2017 20 Feb, 2022
Preterm birth varies with season: 25 percent more likely if conception in autumn – Feb 2022 04 Feb, 2022
Pre-term birth rate cut in half with 1000 milligrams of Omega-3 (if initially low) – RCT May 2021 04 Jun, 2021
Preterm birth risk increased 16 pcnt if heat wave (perhaps outside less) - Nov 2020 16 Nov, 2020
Preterm birth associated with many genes, including the Vitamin D Receptor again – Jan 2020 30 Jan, 2020
Preterm birth 8X more likely if poor Vitamin D Receptor – Dec 2019 31 Dec, 2019
8 percent fewer preterm births if adequate Selenium from food – Aug 2019 24 Dec, 2019
Pregnant women in Australia to take Omega-3 when told of reduction in preterm births – Dec 2019 19 Nov, 2019
Preterm birth 9 X more likely if fetus had a poor Vitamin D Receptor and previous miscarriage – Aug 2017 12 Nov, 2019
Preterm birth rate not vary with vitamin D level (when all are less than 30 ng) – Oct 2019 17 Oct, 2019
Extreme preterm infants helped somewhat by 800 IU of vitamin D – RCT Jan 2018 01 Oct, 2019
Preterm Births reduced by Omega-3, Zinc, and Vitamin D – Aug 2019 09 Aug, 2019
Preterm birth increases risk of heart disease by 1.5 X by age 40 – June 2019 06 Aug, 2019
Preterm Births decreased by Omega-3 (analysis of 184 countries) – April 2019 27 Apr, 2019
Preterm birth 3X more likely if low vitamin D – Oct 2018 07 Feb, 2019
Omega-3 index of 5 greatly decreases the risk of an early preterm birth – Dec 2018 04 Jan, 2019
Preterm birth cost for employers approximately 50,000 dollars – Oct 2017 28 Sep, 2018
Preterm births 12 X more likely if poor Vitamin D Receptor (white infants in Italy) – meta-analysis Aug 2018 27 Aug, 2018
Third trimester Vitamin D levels were lower if pre-term labor was expected – March 2018 24 Mar, 2018
Preterm birth 4X more likely if very low Vitamin D (Chinese) - Feb 2018 28 Feb, 2018
Preterm birth rates increased in 15 European countries – Oct 2013 23 Dec, 2017
Vitamin D intervention reduces preterm births and low birth weight by 60 percent – Cochrane Reviews – Nov 2017 07 Dec, 2017
Preterm birth rate increased 60 percent in 50 years (US) 26 Nov, 2017
Preterm births are VERY costly – Feb 2017 26 Nov, 2017
Preterm births strongly related to Vitamin D, Vitamin D Receptor, Iodine, Omega-3, etc 13 Nov, 2017
Vitamin D Receptor is associated with preeclampsia, gestational diabetes and preterm birth – Nov 2017 10 Nov, 2017
Preterm birth trend toward 2.5 X more likely if less than 10 ng of Vitamin D – Aug 2017 26 Aug, 2017
Preterm birth rate reduced by vitamin D – 78 percent if non-white, 39 percent if white – July 2017 27 Jul, 2017
Preterm birth more likely if dark skinned and low vitamin D (not white-skinned) – April 2017 06 Jul, 2017
Risk of preterm birth twice as likely when less than 10 ng of vitamin D – Nov 2016 13 Apr, 2017
Preterm labor 20 times more likely if low vitamin D, etc. (India) – Feb 2017 08 Mar, 2017
Preterm birth rate reduced by 43 percent with adequate Vitamin D supplementation – meta-analysis Feb 2017 02 Mar, 2017
Pre-term birth - many of risk factors are associated with low vitamin D 27 Feb, 2017
Preterm birth rate reduced 57 percent by Vitamin D – Nov 2015 23 Jan, 2017
Vitamin D Webinar - cost of pre-term birth etc- Baggerly Nov 2013 11 Dec, 2016
Preterm birth extended by 2 weeks with Omega-3 – Meta-analysis Nov 2015 10 Dec, 2016
Omega-3 supplementation during pregnancy reduce early preterm births (save 1500 USD per child) – Aug 2016 12 Oct, 2016
Zinc helps pregnancies – 14 percent fewer preterm births, etc. – Cochrane RCT Feb 2015 14 Jun, 2016
Preterm birth has become the leading cause of infant mortality (vitamin D not mentioned) – JAMA June 2016 07 Jun, 2016
Preterm birth 30 percent more likely if low vitamin D – meta-analysis May 2016 20 May, 2016
Asthmatic pregnant women had 30 percent more preterm births if air pollution (vitamin D not mentioned) – March 2016 09 Mar, 2016
Omega-3 helps pregnancy in many ways: preterm 26 percent less likely etc – review July 2012 08 Sep, 2015
Extreme preterm survival 30 percent less likely if little sunshine 23-28 weeks – June 2015 05 Sep, 2015
Magnesium (Sulfate) reduces risk of cerebral palsy for those at risk of pre-term births – Dec 2013 18 Aug, 2015
Respiratory distress after preterm birth is more likely if low vitamin D – review April 2015 05 Aug, 2015
Pre-term births reduced in half if 40 ng of vitamin D in 3rd trimester – Nov 2014 15 Mar, 2015
Chance of preterm birth is strongly associated with low vitamin D – Feb 2015 05 Feb, 2015
The more preterm the birth, the lower the vitamin D level (both mothers and infants) – Feb 2014 05 Feb, 2015
Preterm infants more likely to have vitamin D levels below 20 ng – Feb 2014 05 Feb, 2015
Decreased risk of preterm birth if have more than 36 ng of vitamin D – Jan 2015 09 Jan, 2015
Pre-term birth 3X more likely and C-section 4X if less than 20 ng of vitamin D – May 2012 13 Feb, 2014
Recurrent pre term birth and low vitamin D – Dec 2012 23 Jan, 2013
Blacks have more pre-term births due to low nutrients such as vitamin D – Sept 2011 14 Sep, 2011
Pre-term birth not associated with first tri-mester vitamin D – April 2011 21 Apr, 2011



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