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 Table of Contents  
Year : 2015  |  Volume : 4  |  Issue : 1  |  Page : 1-7

Vitamin D and the neonate: An update

1 Department of Newborn Services, The George Washington University Hospital, Washington, DC, USA
2 Department of Neonatology, Mansoura University Children's Hospital, Mansoura, Egypt

Date of Web Publication10-Feb-2015

Correspondence Address:
Hany Aly
Department of Newborn Services, The George Washington University Hospital, 900 23rd Street, N.W., Suite G2092, Washington, DC 20037
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2249-4847.151155

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In this review, we aim to summarize available data on vitamin D in neonates critically. Vitamin D is a fat-soluble, steroid hormone with pleiotrophic effects not only on bone metabolism but also on optimal functioning of many organ systems. Deficiency is considered when 25-hydroxyvitamin D value is ˂20 ng/ml. Vitamin D deficiency is a global problem that prevales even in developed countries. Vitamin D deficiency is closely related to multiple disease states. It may influence obstetrical complications as preeclampsia, gestational diabetes, bacterial vaginosis, preterm birth, low-birth weight and cesarean section. Long-term outcomes in the offspring including asthma, multiple sclerosis, schizophrenia, abnormal neurocognitive outcome, type 1 diabetes mellitus, and insulin resistance can occur with vitamin D deficiency. Trials are needed to assess the effect of vitamin D supplementation and its dosage during pregnancy and lactation on clinical outcomes. The American Academy of Pediatrics recommends 400 IU/day of supplemental vitamin D for breastfed infants from the 1 st day of life. Preterm infants born <32 weeks are at a greater risk to develop vitamin D deficiency. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition has recommended higher intakes of vitamin D of 800-1000 IU/day for preterm infants. However, studies are needed to evaluate the dose and duration of vitamin D supplementation to preterm infants.

Keywords: 25-hydroxyvitamin D, infants, lactation, pregnancy outcome, premature, vitamin D deficiency

How to cite this article:
Aly H, Abdel-Hady H. Vitamin D and the neonate: An update. J Clin Neonatol 2015;4:1-7

How to cite this URL:
Aly H, Abdel-Hady H. Vitamin D and the neonate: An update. J Clin Neonatol [serial online] 2015 [cited 2023 Feb 2];4:1-7. Available from: https://www.jcnonweb.com/text.asp?2015/4/1/1/151155

  Introduction Top

Vitamin D is a fat-soluble vitamin that plays an important role in bone metabolism. It is also considered a steroid hormone with pleiotrophic effects and has important roles in the optimal functioning of many organ systems and may be a risk modifying factor for many chronic diseases, including osteomalacia, rickets, autoimmune disease, multiple sclerosis, schizophrenia, hypertension and heart disease, type 1 and type 2 diabetes and cancer. [1],[2],[3]

  Vitamin D Metabolism Top

There are 2 major forms of vitamin D, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is derived from plants, and some fish and vitamin D3 is obtained from either dietary sources or through the conversion of 7-dehydrocholesterol in the skin upon exposure to ultraviolet B radiation. [4]

The preformed vitamin D needs both 25- and 1 α -hydroxylation to become the active hormone 1,25-dihydroxivitamin D (1,25(OH) 2 D). 25-hydroxylases accomplish the 25-hydroxylation of vitamin D to 25(OH) D in liver cells. The second hydroxylation takes place mainly in the kidney, but it also occurs in skin, bone, cartilage and macrophages by 1 α-hydroxylase to 1,25(OH) 2 D, the biologically active form of vitamin D [1] [Figure 1].
Figure 1: Vitamin D metabolism in the liver, 25-hydroxylation of vitamin D occurs leading to 25(OH)D. In the kidney, a second hydroxylation takes place by 1 α-hydroxylase leading to the formation of 1,25-dihydroxivitamin 2D, the biologically active form of vitamin D

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  Physiology of Vitamin D Top

1,25-dihydroxivitamin D regulates calcium metabolism by enhancing intestinal calcium absorption and mobilizing calcium from the skeleton and has an array of effects on the body's organs. [2],[4] 1,25(OH) 2 D has pleomorphic roles in both nervous system health and disease; it is involved in proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission and neuroplasticity. It exerts its biological function not only by influencing cellular processes directly, but also by influencing gene expression through vitamin D response elements. [5] There is overwhelming experimental evidence that vitamin D has an important role in the regulation of both the innate and adaptive immune systems. [6] It Influences innate immune responses by enhancing the chemotaxis and phagocytosis by macrophages and production of anti-microbial proteins such as cathelicidin LL37. [7] 1,25(OH) 2 D also modulates antigen presenting cells causing indirect shift in T cell polarization from a TH1 and TH17 phenotype toward a TH2 phenotype. [8] It inhibits B-lymphocyte function and modulates the humoral immune response, resulting in a diminished secretion of immunoglobulin E. [9]

  Vitamin D Deficiency Top

A recent institute of medicine (IOM) report defines "inadequate vitamin D" when serum concentrations of 1,25(OH)D are <20 ng/ml. [10] A recent task force of the Endocrine Society defines vitamin D "deficiency" as a 25(OH) D value below 20 ng/ml, "insufficiency" as a 25(OH) D value between 20 and 30 ng/ml, and recommended target of treatment should be to achieve a 25(OH) D above 30 ng/ml. [11] To date, specific range for neonates is not available.

Vitamin D inadequacy and deficiency are global problems, and their prevalence is high even in developed and sunny countries. [12],[13],[14] The prevalence of vitamin D insufficiency is increasing globally. Although the reason for the increase in vitamin D deficiency is unclear, a combination of a change in lifestyle, liberal use of sunscreens in some parts of the world, adoption of covered attire in some societies and global environmental pollution might have contributed to the widespread increase in vitamin D deficiency. [15] Risk factors for vitamin D deficiency and rickets in early life include breastfeeding without vitamin D supplementation, dark skin pigmentation, race, season, latitude and maternal vitamin D deficiency. [16]

  Maternal Vitamin D Status and Neonatal Outcome Top

There is a high prevalence of vitamin D deficiency in pregnant and lactating mothers especially nonwestern immigrants in countries at higher latitude. [16],[17] Evidence from observational studies shows higher rates of preeclampsia, [18] gestational diabetes, [19] bacterial vaginosis, [20] preterm birth [21] and cesarean section [22] in women with low vitamin D levels; all of which have potentially adverse effects on the neonate. However, other studies found no associations with the same outcomes. [23],[24] Contradictory results can be explained by methodological, genetic, ethnic and racial differences as well as latitude of residence and season.

The relationship between maternal vitamin D status and fetal birth weight has been studied in randomized controlled trials (RCTs) [25],[26] and a number of observational studies [27],[28],[29] with mixed results. The presence of multiple confounding factors such as, maternal nutritional status, calcium and phosphorus intake, prepregnant body mass index and socioeconomic status could explain the inconsistent findings. There is a strong correlation between maternal and infant cord blood 25(OH) D concentrations. [30] However, in utero, skeletal mineralization is primarily independent of maternal vitamin D status; consequently, the blood calcium, calciotropic hormones and skeleton are normal at birth in the offspring of mothers who are severely vitamin D deficient. [31],[32] No systemic studies have examined the effect of maternal vitamin D status on neonatal skeletal mineral content. Only few studies [33],[34],[35] reported contradictory results. Therefore, the importance of maternal vitamin D status to fetal skeletal development is not sufficiently investigated.

25-hydroxy vitamin 2D induces more than 2000 genes, many of which have a role in fetal development. [36] Therefore, 1,25(OH) 2 D may be relevant to the "fetal programming hypothesis" in which environmental factors such as 1,25(OH) 2 D influence the genomic programming of the fetus and neonate and influence disease risk in later life. [37] Decreased concentrations of 1,25(OH) 2 D in pregnant women is associated with the development of many disease states in their offspring. Such diseases include wheezing and asthma, [38] multiple sclerosis, [39] schizophrenia, [40] abnormal neurocognitive outcome, [41] type 1 diabetes mellitus and insulin resistance [42] [Figure 2]. This suggests a role for vitamin D in intrauterine programming of fetuses. However, the current evidence is insufficient to support the hypothesis that supplementing vitamin D during pregnancy would have positive effects on mothers or children. [43] There is a great need for RCTs evaluating the effect of maternal supplementation with vitamin D during pregnancy on such outcomes.{Figure 1}
Figure 2: Diseases and conditions associated with vitamin D deficiency

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The exact amount of vitamin D required during pregnancy has not been defined. Current IOM guidelines recommend 600 IU/day, [44] the Endocrine Society recommends a dose from 600 IU/day to 1500-2000 IU/day, [11] the American College of Obstetricians and Gynecologists recommends 600 IU/day for the general population of pregnant women and doses up to 1000-2000 IU/day in vitamin D deficient pregnant women. [45] Vitamin D supplements <2000 IU/day does not effectively prevent vitamin D deficiency in pregnant women and their neonates. [25] Two recent RCTs were conducted to compare the efficacy of different vitamin D doses in pregnant women. The trial by National Institute for Child Health and Human Development compared doses of 400 IU/day, 2000 IU/day and 4000 IU/day; whereas the doses of 2000 IU/day and 4000 IU/day were used in the Thrasher Research Trial. [30],[46] A combined analysis of both trials suggests that vitamin D supplementation of 4000 IU/day is safe and allows to obtain adequate maternal and neonatal vitamin D levels while reducing the risk of preeclampsia and infections. [47] Another RCT confirmed that 4000 IU/day is the most effective dose to raise vitamin D levels in vitamin D deficient pregnant women and their offspring. [48]

According to the Endocrine Society report, lactating women require at least 200 IU/day of vitamin D and at least 1500-2000 IU/day of vitamin D may be needed to maintain a blood level of 25(OH) D >30 ng/ml. [11] It has been demonstrated that an intake of 400 IU/day vitamin D did not sustain adequate concentrations of circulating maternal 25(OH) D, whereas supplementation with high doses of vitamin D (6400 IU/day) allows the achievement of optimal 25(OH) D concentrations (>32 ng/ml) in the maternal and infant serum without any risk of hypervitaminosis D in the mother. [49] A recent systematic review demonstrated a strong positive correlation between maternal vitamin D intake during exclusive breastfeeding and infant serum 25(OH) D levels and concluded that when maternal vitamin D intake is sufficient, vitamin D transfer via breast milk is adequate to meet infant needs. In the reviewed studies, doses up to 10 times the current recommended daily intake of vitamin D were needed to produce sufficient transfer from mother to breastfed infant. [50] However, such high dose supplementation must be validated and demonstrated to be safe in larger RCTs.

  Vitamin D Supplementation in Neonates Top

Vitamin D supplementation seems to be necessary for breastfed infants. Based on available knowledge, breast milk does not contain adequate vitamin D to satisfy infants' requirements. [51] The recommended daily dosage of vitamin D for neonates is 400 units. [52] However, various daily doses of vitamin D, ranging from 100 IU to 1000 IU, have been recommended. [47],[51],[52],[53] In the past, the American Academy of Pediatrics (AAP) [51] as well as Canadian experts [54] indicated that 200 IU of vitamin D supplementation beginning during the first 2 months of life would be sufficient to prevent rickets. It has been observed, however, that despite a daily intake of 400 IU of vitamin D, some infants have a blood level of 25(OH) D <32 ng/ml in the winter, even in countries in which mothers have a vitamin D-fortified diet. [44] This resulted in the development of a new recommendation that supports a 400 IU daily dose of vitamin D, and an even higher dose in the northern areas, beginning in the first few days of life. [55]

Cranney et al. [56] summarized the published trials on the effect of vitamin D supplementation on circulating 25(OH) D concentrations. Interestingly, the daily doses of vitamin D2 used in all of these trials were < 400 IU. [53],[57] Zeghoud et al. Administered either 200,000 IU once at birth or 100,000 IU vitamin D3 at birth, 3 and 6 months. [58] They later compared daily doses of 500 IU versus 1000 IU. [59] Another trial demonstrated a dose-response relationship infants receiving daily vitamin D2 of 100, 200 and 400 IU. Authors suggested that 200 IU of vitamin D2 may not be enough to prevent vitamin D deficiency in some infants residing at northern latitudes. [57] Consistent dose-response to vitamin D supplementation is noted across trials, however infants who are vitamin D deficient may respond differently and require higher doses of vitamin D. [57]

More recently, Siafarikas et al. [60] and Holmlund-Suila et al.[61] performed RCTs to investigate vitamin D status in breastfed, term infants with measurement of calcium homeostasis and bone health. Siafarikas et al.[60] studied "low doses" of vitamin D supplementation, 250 versus 500 IU/day, Holmlund-Suila et al.[61] evaluated the effects of "high doses" of vitamin D supplementation with three dose groups (400, 1200 and 1600 IU/day) to identify the dose that ensures 25(OH) D status of at least 32 ng/ml without evidence of toxicity. In both studies, no vitamin D toxicity and no difference in markers of calcium homeostasis or bone health were appreciated among doses. Siafarikas et al.[60] concluded that 250 IU/day is adequate for breastfed infants and the Holmlund-Suila et al.[61] concluded that vitamin D supplementation up to 1600 IU/day safely maintains vitamin D sufficiency. Until more conclusive results are available, the AAP. [55] recommendation to provide 400 IU/day to all infants remains generally safe and efficacious in preventing rickets.

  Vitamin D Deficiency in Preterm Infant Top

Several studies have demonstrated that preterm infants born <32 weeks (and especially those <28 weeks) are at greater risk of developing vitamin D deficiency compared to more mature infants. [62],[63] Approximately 10% to 20% of extremely low-birth weight infants have radiological evidence of rickets with metaphyseal changes despite current nutritional practices. [64] Rickets in preterm infants is almost always attributable to decreased total absorbed calcium and phosphorus. [65] Phosphorus deficiency is at least as important, if not more important, than calcium deficiency in the etiology of this disease. [66],[67] Unfortified human milk, parenteral nutrition and infant formulas designed for full-term infants, do not contain enough calcium and phosphorus to meet the needs fully for bone mineralization in preterm infants. [68]

The contents of vitamin D in breast milk, full-term milk formula (20 kcal/oz), and transitional formula (22 kcal/oz) are not adequate for a growing premature infant. For example, a premature infant who weighs 1500 g and consumes 160 ml/kg/day will receive a total of 2.4, 110 and 125 IU/day respectively. However, fortified breast milk and premature formula (24 kcal/oz) will provide 280 and 400 IU/day respectively. There is no consensus regarding the dose of vitamin D supplementation required for preterm infants. [44],[55],[69] The European Society for Pediatric Gastroenterology, Hepatology and Nutrition has recommended higher intakes of vitamin D of 800-1000 IU/day for preterm infants. [70],[71] Although this vitamin D intake is likely safe, no data are available for very low-birth weight infants and especially infants with birth weight <1000 g to assess the safety of providing these vitamin D intakes. A recent clinical report from the committee on nutrition at the AAP recommended that breastfed preterm infants who are at home should receive 400 IU/day of vitamin D. [72] Formula-fed preterm infants receiving formulas designed for full-term infants or transitional formulas would generally not achieve an intake of 400 IU/day of vitamin D. Providing these infants with an additional 200-400 IU/day may be considered, but there are no data indicating any clinical benefit to this practice. The amount of vitamin D in the formula will be adequate when the weight of a premature infant reaches around 5 kg and consumes 800-1000 ml/day of formula. Our recommendations for vitamin D supplementation are summarized in [Table 1].
Table 1: Recommended vitamin D supplementation

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Routine evaluation of bone mineral status by using serum alkaline phosphatase activity (APA), calcium and phosphorus are indicated for infants with birth weight <1500 g at 4 weeks after birth and followed every 2 weeks until discharge. Infants with APA >500 IU/L at the time of discharge will need laboratory follow-up every 2-4 weeks until it normalizes. When APA is abnormally high, it is important to confirm its source not being the liver by checking gamma-glutamyl transferase once.

Randomized, controlled trials are necessary to evaluate the dose of vitamin D to be administered to preterm infants, as well as the duration of the period of supplementation and any side effects of the treatment. Pending further research, using the full-term infant vitamin D intake recommendation of 400 IU/day is appropriate for preterm infants born with birth weight >1500 g. Potential risks related to high 25(OH) D concentrations are unknown. The upper tolerable intake for healthy full-term infants is around 1000 IU/day. Upper intake for preterm infants is not known.

  Acknowledgment Top

We thank Pete Van Riper for drawing the figures of this article.

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