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doi:10.1111/jpc.12847
ORIGINAL ARTICLE
Vitamin D in preterm infants: A prospective observational study Kieran Pinto,1 Carmel T Collins,1,2 Robert A Gibson2,3 and Chad C Andersen4,5 1 School of Paediatrics and Reproductive Health, 3School of Agriculture, Food and Wine, 5The Robinson Research Institute, The University of Adelaide, 2Child Nutrition Research Centre and FOODplus Research Centre, Women’s and Children’s Health Research Institute, Women’s and Children’s Hospital, Flinders Medical Centre, and 4Department of Neonatal Medicine, Women’s and Children’s Hospital, Adelaide, South Australia, Australia
Aim: Preterm infants are at increased risk of vitamin D deficiency as a result of both maternal deficiency and inadequate supplementation. The quantity and effectiveness of vitamin D supplementation in preterm infants are unclear. The aim of this study was to evaluate the natural history of vitamin D status in preterm infants and the effectiveness of the hospital’s nutritional practices in meeting current supplementation recommendations. Methods: A prospective observational study was undertaken in the Neonatal Unit at the Women’s and Children’s Hospital, Adelaide. Enrolled infants received a standardised nutrition protocol with emphasis on vitamin D supplementation. The main outcome measure was a comparison of the proportion of vitamin D-deficient infants (25(OH)D < 50 nmol/L) at birth versus 36 weeks post-menstrual age/discharge. Results: Twenty-eight infants born between 30 and 36 weeks gestation were enrolled. The proportion of vitamin D-deficient infants decreased from initial to final measurement (32.1% vs. 7.1%, P = 0.016), whereas mean (standard deviation) 25(OH)D3 increased over the same period (58.4 (18.4) versus 82.9 (29.2) nmol/L, P < 0.001). Mean vitamin D intake was 643.6 (285.3) IU/day. Conclusions: Current nutritional practices are effective in meeting recommendations regarding vitamin D intake and result in a lower proportion of deficient infants at 36 weeks post-menstrual age/discharge. Key words:
neonatology; nutrition; preterm; vitamin D.
What is already known on this topic
What this paper adds
1 Preterm infants are at increased risk of vitamin D deficiency as a result of both maternal deficiency and inadequate supplementation. 2 The quantity and effectiveness of vitamin D supplementation in preterm infants are unclear.
1 Vitamin D deficiency is common in preterm infants at birth. 2 The proportion of vitamin D deficient infants is altered with the feeding and supplementation protocol. 3 Adoption of a simple feeding protocol resulted in vitamin D intakes consistent with American Academy of Paediatrics but lower than the European Society of Paediatric Gastroenterology, Hepatology and Nutrition recommendations.
Vitamin D deficiency is a significant perinatal health problem in Australia,1 with preterm infants being at particular risk of deficiency from both maternal deficiency and inadequate supplementation. Vitamin D deficiency is associated with a range of consequences in the newborn including bone disease, growth impairment and electrolyte disturbances. The quantity and effectiveness of vitamin D supplementation in preterm infants remain unclear. Recommendations vary from 200–400 (American Academy of Paediatrics (AAP) Committee on Nutrition) to 800–1000 IU/day (European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)).2,3 Correspondence: Dr Chad C Andersen, Department of Neonatal Medicine, Women’s and Children’s Hospital, 72 King William Road, North Adelaide, SA 5006, Australia. Fax: (08) 81617654; email: chad.andersen@ health.sa.gov.au Conflict of interest: None to declare. Accepted for publication 30 December 2014.
It was therefore the purpose of this study to evaluate the effectiveness of current supplementation practices by measuring the pattern and quantity of supplementation and the proportion of vitamin D-deficient preterm newborns at 36 weeks postmenstrual age (PMA)/discharge.
Methods Population Infants born between 30 and 36 weeks gestation were eligible. Those with major congenital malformations were excluded. Infants were enrolled following parental informed consent.
Study description Serum measurements of vitamin D and other bone biomarkers were measured at fixed time intervals from birth to 36 weeks PMA or discharge home (whichever occurred first). There was no alteration to routine management of infants.
Journal of Paediatrics and Child Health 51 (2015) 679–681 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
679
Vitamin D in preterm infants
K Pinto et al.
Specimen collection and measurement Study specimens (blood and urine) were collected as soon as possible after birth/enrolment, then fortnightly until 36 weeks PMA/discharge. Blood specimens were collected and centrifuged at 3500 rpm for 10 min at 4°C, then frozen for later batch analysis. Serum 25(OH)D3 was measured using isotope dilution liquid chromatography/tandem mass spectrometry (PathWest Laboratory Medicine in Perth, Western Australia, Australia). The intra- and inter-assay coefficients of variation were 2.1– 3.7% and 4.9–6.8%, respectively. Serum total calcium and alkaline phosphatase were measured using automated methods. Urine samples were collected, on the same day, for measurement of the calcium/creatinine ratio.
Local nutrition protocol Infants requiring parenteral nutrition were commenced on intravenous fat emulsion by day 2 of life at 0.5 g/kg/day and increased daily to 3.5 g/kg/day. Enteral nutrition was commenced as soon as possible (aiming for day 1–2) with intake increased by 30 mL/kg/day up to 180 mL/kg/day. Breast milk (BM) was fortified at an enteral intake of 150 mL/kg/day.
Vitamin D nutritional supplementation
were evaluated using t-tests. Comparisons between rates of vitamin D deficiency were made using McNemar’s test. Bivariate associations were assessed using Pearson’s correlation coefficient. Results were considered statistically significant if P < 0.05. Statistical analysis was undertaken using IBM SPSS Statistics, Version 20 (IBM Corporation, Armonk, NY, USA).
Ethics approval The study was approved by the Women’s and Children’s Health Network Human Research Ethics Committee.
Results Twenty-eight infants were enrolled in the study. Fourteen (50%) were male; the mean (standard deviation (SD)) gestational age was 32.0 (1.3) weeks, birthweight 1.63 (0.36) kg and maternal age 31.2 (6.1) years.
Vitamin D and other bone biomarkers Vitamin D and other biomarkers of bone status are shown in the Table 1. There was a significantly lower proportion of infants with vitamin D deficiency at 36 weeks PMA/discharge compared with birth (7.1 vs. 32.1%, P = 0.016). There was no relationship between initial 25(OH)D status and either maternal age, sex, birthweight or gestational age at birth. There was a weak but significant correlation between final serum 25(OH)D and admission duration (r = 0.378, P < 0.04) but not initial 25(OH)D status.
A standardised compound fat emulsion of Clinoleic 20%, Soluvit N and Vitalipid N Infant (Fresenius Kabi, Bad Homburg, Germany) containing a final vitamin D2 concentration of 8 IU/mL was used in infants requiring parenteral nutrition. Enteral feeding practice comprised BM (estimated vitamin D3: 25 IU/L) and/or preterm formula (Karicare Aptamil Gold, Nutricia, Groupe Danone, Paris, France, vitamin D3: 1.2 IU/mL) and/or term formula (S26, Pfizer, New York, NY, USA, vitamin D3: 0.48 IU/mL). The amount of BM per breastfeed was estimated from the previous gavage feed. BM was fortified with Nutriprem Breast Milk Fortifier (Nutricia; vitamin D3: 2.025 IU/ mL). In addition, infants received Penta-vite Infant supplementation (Bayer, Leverkusen, Germany, 400 IU/dose) once established on all milk feeds.
The mean (SD) vitamin D intake (Fig. 1) over the first week of admission was 88.6 (71.5) IU/day. This increased to 632.8 (242.4) IU/day by week two. Subsequently, intakes ranged from 800 to 900 IU/day for the remainder of study duration. The mean (SD) vitamin D intake was 643.6 (285.3) IU/day with 25 infants (89.3%) averaging >400 IU/day. There was a very strong correlation with the cumulative vitamin D intake and admission duration (r = 0.965, P < 0.001) and moderate correlation with the final 25(OH)D (r = 0.530, P = 0.004).
Statistical analysis
Discussion
Deficiency was defined according to Australian classifications (i.e. 25(OH)D < 50 nmol/L).4 Differences between mean values
This is the one of the first Australian studies to evaluate the vitamin D status of preterm infants. The only source of vitamin
Vitamin D intake
Table 1 Serum biomarkers of 25(OH)D status
Chronologic age, days (median (IQR)) Gestational age, weeks Serum 25(OH)D3, nmol/L n (%) deficient Ca, nmol/L ALP, IU/L Urinary calcium/creatinine ratio
Initial assessment
Final assessment
P-value
3 (2–3) 32.4 (1.3) 58.4 (18.4) 9 (32.1) 2.3 (0.3) 201.5 (49.7) 0.89 (1.26)
27 (21–32) 35.7 (0.9) 82.9 (29.2) 2 (7.1) 2.6 (0.7) 236.8 (79.6) 1.61 (1.07)
NA NA 250 nmol/L.4,5 While no infants recorded a level >250 nmol/L, four infants (14.3%) recorded final vitamin D levels > 125 nmol/L. No infants showed any signs of potential harm associated with vitamin D toxicity. It is interesting to note the elevated urine calcium/creatinine ratio raising the possibility of hypercalciuria. Unfortunately, without a control group, it is not possible to unravel the relative contributions of maturity, fortification and vitamin D supplementation to this finding.
Acknowledgements We thank the families who participated in the study and the nursing and medical staff at WCH for their assistance. Funds were provided by the Child Nutrition Research Centre, Women’s and Children’s Health Research Institute (University of Adelaide). Research fellowships were provided by the National Health and Medical Research Council of Australia (APP1046207) and The MS McLeod Research Fund of the Women’s and Children’s Hospital Foundation, supported by CRE in Foods for Future Australians (APP1035530).
References 1 De Laine KM, Matthews G, Grivell RM. Prospective audit of vitamin D levels of women presenting for their first antenatal visit at a tertiary centre. Aust. N.Z. J. Obstet. Gynaecol. 2013; 53: 353–7. 2 Abrams SA. Calcium and vitamin d requirements of enterally fed preterm infants. Pediatrics 2013; 131: 1676–83. 3 Agostoni C, Buonocore G, Carnielli VP et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J. Pediatr. Gastroenterol. Nutr. 2010; 50: 85–91. 4 Paxton GA, Teale GR, Nowson CA et al. Vitamin D and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a position statement. Med. J. Aust. 2013; 198: 142–3. 5 Institute of Medicine (IOM). Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press, 2011.
Journal of Paediatrics and Child Health 51 (2015) 679–681 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
681
doi:10.1111/jpc.12847
ORIGINAL ARTICLE
Vitamin D in preterm infants: A prospective observational study Kieran Pinto,1 Carmel T Collins,1,2 Robert A Gibson2,3 and Chad C Andersen4,5 1 School of Paediatrics and Reproductive Health, 3School of Agriculture, Food and Wine, 5The Robinson Research Institute, The University of Adelaide, 2Child Nutrition Research Centre and FOODplus Research Centre, Women’s and Children’s Health Research Institute, Women’s and Children’s Hospital, Flinders Medical Centre, and 4Department of Neonatal Medicine, Women’s and Children’s Hospital, Adelaide, South Australia, Australia
Aim: Preterm infants are at increased risk of vitamin D deficiency as a result of both maternal deficiency and inadequate supplementation. The quantity and effectiveness of vitamin D supplementation in preterm infants are unclear. The aim of this study was to evaluate the natural history of vitamin D status in preterm infants and the effectiveness of the hospital’s nutritional practices in meeting current supplementation recommendations. Methods: A prospective observational study was undertaken in the Neonatal Unit at the Women’s and Children’s Hospital, Adelaide. Enrolled infants received a standardised nutrition protocol with emphasis on vitamin D supplementation. The main outcome measure was a comparison of the proportion of vitamin D-deficient infants (25(OH)D < 50 nmol/L) at birth versus 36 weeks post-menstrual age/discharge. Results: Twenty-eight infants born between 30 and 36 weeks gestation were enrolled. The proportion of vitamin D-deficient infants decreased from initial to final measurement (32.1% vs. 7.1%, P = 0.016), whereas mean (standard deviation) 25(OH)D3 increased over the same period (58.4 (18.4) versus 82.9 (29.2) nmol/L, P < 0.001). Mean vitamin D intake was 643.6 (285.3) IU/day. Conclusions: Current nutritional practices are effective in meeting recommendations regarding vitamin D intake and result in a lower proportion of deficient infants at 36 weeks post-menstrual age/discharge. Key words:
neonatology; nutrition; preterm; vitamin D.
What is already known on this topic
What this paper adds
1 Preterm infants are at increased risk of vitamin D deficiency as a result of both maternal deficiency and inadequate supplementation. 2 The quantity and effectiveness of vitamin D supplementation in preterm infants are unclear.
1 Vitamin D deficiency is common in preterm infants at birth. 2 The proportion of vitamin D deficient infants is altered with the feeding and supplementation protocol. 3 Adoption of a simple feeding protocol resulted in vitamin D intakes consistent with American Academy of Paediatrics but lower than the European Society of Paediatric Gastroenterology, Hepatology and Nutrition recommendations.
Vitamin D deficiency is a significant perinatal health problem in Australia,1 with preterm infants being at particular risk of deficiency from both maternal deficiency and inadequate supplementation. Vitamin D deficiency is associated with a range of consequences in the newborn including bone disease, growth impairment and electrolyte disturbances. The quantity and effectiveness of vitamin D supplementation in preterm infants remain unclear. Recommendations vary from 200–400 (American Academy of Paediatrics (AAP) Committee on Nutrition) to 800–1000 IU/day (European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN)).2,3 Correspondence: Dr Chad C Andersen, Department of Neonatal Medicine, Women’s and Children’s Hospital, 72 King William Road, North Adelaide, SA 5006, Australia. Fax: (08) 81617654; email: chad.andersen@ health.sa.gov.au Conflict of interest: None to declare. Accepted for publication 30 December 2014.
It was therefore the purpose of this study to evaluate the effectiveness of current supplementation practices by measuring the pattern and quantity of supplementation and the proportion of vitamin D-deficient preterm newborns at 36 weeks postmenstrual age (PMA)/discharge.
Methods Population Infants born between 30 and 36 weeks gestation were eligible. Those with major congenital malformations were excluded. Infants were enrolled following parental informed consent.
Study description Serum measurements of vitamin D and other bone biomarkers were measured at fixed time intervals from birth to 36 weeks PMA or discharge home (whichever occurred first). There was no alteration to routine management of infants.
Journal of Paediatrics and Child Health 51 (2015) 679–681 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
679
Vitamin D in preterm infants
K Pinto et al.
Specimen collection and measurement Study specimens (blood and urine) were collected as soon as possible after birth/enrolment, then fortnightly until 36 weeks PMA/discharge. Blood specimens were collected and centrifuged at 3500 rpm for 10 min at 4°C, then frozen for later batch analysis. Serum 25(OH)D3 was measured using isotope dilution liquid chromatography/tandem mass spectrometry (PathWest Laboratory Medicine in Perth, Western Australia, Australia). The intra- and inter-assay coefficients of variation were 2.1– 3.7% and 4.9–6.8%, respectively. Serum total calcium and alkaline phosphatase were measured using automated methods. Urine samples were collected, on the same day, for measurement of the calcium/creatinine ratio.
Local nutrition protocol Infants requiring parenteral nutrition were commenced on intravenous fat emulsion by day 2 of life at 0.5 g/kg/day and increased daily to 3.5 g/kg/day. Enteral nutrition was commenced as soon as possible (aiming for day 1–2) with intake increased by 30 mL/kg/day up to 180 mL/kg/day. Breast milk (BM) was fortified at an enteral intake of 150 mL/kg/day.
Vitamin D nutritional supplementation
were evaluated using t-tests. Comparisons between rates of vitamin D deficiency were made using McNemar’s test. Bivariate associations were assessed using Pearson’s correlation coefficient. Results were considered statistically significant if P < 0.05. Statistical analysis was undertaken using IBM SPSS Statistics, Version 20 (IBM Corporation, Armonk, NY, USA).
Ethics approval The study was approved by the Women’s and Children’s Health Network Human Research Ethics Committee.
Results Twenty-eight infants were enrolled in the study. Fourteen (50%) were male; the mean (standard deviation (SD)) gestational age was 32.0 (1.3) weeks, birthweight 1.63 (0.36) kg and maternal age 31.2 (6.1) years.
Vitamin D and other bone biomarkers Vitamin D and other biomarkers of bone status are shown in the Table 1. There was a significantly lower proportion of infants with vitamin D deficiency at 36 weeks PMA/discharge compared with birth (7.1 vs. 32.1%, P = 0.016). There was no relationship between initial 25(OH)D status and either maternal age, sex, birthweight or gestational age at birth. There was a weak but significant correlation between final serum 25(OH)D and admission duration (r = 0.378, P < 0.04) but not initial 25(OH)D status.
A standardised compound fat emulsion of Clinoleic 20%, Soluvit N and Vitalipid N Infant (Fresenius Kabi, Bad Homburg, Germany) containing a final vitamin D2 concentration of 8 IU/mL was used in infants requiring parenteral nutrition. Enteral feeding practice comprised BM (estimated vitamin D3: 25 IU/L) and/or preterm formula (Karicare Aptamil Gold, Nutricia, Groupe Danone, Paris, France, vitamin D3: 1.2 IU/mL) and/or term formula (S26, Pfizer, New York, NY, USA, vitamin D3: 0.48 IU/mL). The amount of BM per breastfeed was estimated from the previous gavage feed. BM was fortified with Nutriprem Breast Milk Fortifier (Nutricia; vitamin D3: 2.025 IU/ mL). In addition, infants received Penta-vite Infant supplementation (Bayer, Leverkusen, Germany, 400 IU/dose) once established on all milk feeds.
The mean (SD) vitamin D intake (Fig. 1) over the first week of admission was 88.6 (71.5) IU/day. This increased to 632.8 (242.4) IU/day by week two. Subsequently, intakes ranged from 800 to 900 IU/day for the remainder of study duration. The mean (SD) vitamin D intake was 643.6 (285.3) IU/day with 25 infants (89.3%) averaging >400 IU/day. There was a very strong correlation with the cumulative vitamin D intake and admission duration (r = 0.965, P < 0.001) and moderate correlation with the final 25(OH)D (r = 0.530, P = 0.004).
Statistical analysis
Discussion
Deficiency was defined according to Australian classifications (i.e. 25(OH)D < 50 nmol/L).4 Differences between mean values
This is the one of the first Australian studies to evaluate the vitamin D status of preterm infants. The only source of vitamin
Vitamin D intake
Table 1 Serum biomarkers of 25(OH)D status
Chronologic age, days (median (IQR)) Gestational age, weeks Serum 25(OH)D3, nmol/L n (%) deficient Ca, nmol/L ALP, IU/L Urinary calcium/creatinine ratio
Initial assessment
Final assessment
P-value
3 (2–3) 32.4 (1.3) 58.4 (18.4) 9 (32.1) 2.3 (0.3) 201.5 (49.7) 0.89 (1.26)
27 (21–32) 35.7 (0.9) 82.9 (29.2) 2 (7.1) 2.6 (0.7) 236.8 (79.6) 1.61 (1.07)
NA NA 250 nmol/L.4,5 While no infants recorded a level >250 nmol/L, four infants (14.3%) recorded final vitamin D levels > 125 nmol/L. No infants showed any signs of potential harm associated with vitamin D toxicity. It is interesting to note the elevated urine calcium/creatinine ratio raising the possibility of hypercalciuria. Unfortunately, without a control group, it is not possible to unravel the relative contributions of maturity, fortification and vitamin D supplementation to this finding.
Acknowledgements We thank the families who participated in the study and the nursing and medical staff at WCH for their assistance. Funds were provided by the Child Nutrition Research Centre, Women’s and Children’s Health Research Institute (University of Adelaide). Research fellowships were provided by the National Health and Medical Research Council of Australia (APP1046207) and The MS McLeod Research Fund of the Women’s and Children’s Hospital Foundation, supported by CRE in Foods for Future Australians (APP1035530).
References 1 De Laine KM, Matthews G, Grivell RM. Prospective audit of vitamin D levels of women presenting for their first antenatal visit at a tertiary centre. Aust. N.Z. J. Obstet. Gynaecol. 2013; 53: 353–7. 2 Abrams SA. Calcium and vitamin d requirements of enterally fed preterm infants. Pediatrics 2013; 131: 1676–83. 3 Agostoni C, Buonocore G, Carnielli VP et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J. Pediatr. Gastroenterol. Nutr. 2010; 50: 85–91. 4 Paxton GA, Teale GR, Nowson CA et al. Vitamin D and health in pregnancy, infants, children and adolescents in Australia and New Zealand: a position statement. Med. J. Aust. 2013; 198: 142–3. 5 Institute of Medicine (IOM). Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: The National Academies Press, 2011.
Journal of Paediatrics and Child Health 51 (2015) 679–681 © 2015 The Authors Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
681
