Vitamin D Deficiency and Critical Care in the Neonatal Period

Abstract

Neonates in critical care constitute a vulnerable group, and vitamin D status in this group is the subject of extensive research. Studies suggest that critically ill neonates and children have lower mean vitamin D levels than healthy ones, and there is evidence linking vitamin D deficiency to an increased risk of mortality, illness severity, and complications in these patients. Vitamin D deficiency in neonates and children with congenital heart disease (CHD) undergoing corrective surgical treatment has attracted particular attention. Overall, studies show high prevalence rates of vitamin D deficiency in this group. Moreover, several studies report significant associations between low vitamin D levels and unfavorable findings, such as increased requirements for vasoactive support and mechanical ventilation and prolonged ICU stays. Available data suggest vitamin D deficiency as a risk factor in neonatal and pediatric critical illness, specifically in CHD patients undergoing surgical treatment. Clinical trials have been proposed to examine the beneficial effect of preoperational vitamin D supplementation on the outcome in this group. However, for now, vitamin D supplementation should be considered in critically ill neonates, particularly those undergoing surgery for CHD, aiming to maintain vitamin D at safe levels over the threshold of vitamin D deficiency.

1. Introduction

The traditional roles of vitamin D in skeletal dynamics, renal calcium reabsorption, and intestinal calcium absorption have long been known, as are the effects of vitamin D deficiency on skeletal abnormalities such as rickets [1], but in recent years, our understanding of vitamin D functions has rapidly evolved, and the list of roles attributed to this compound in the body is greatly expanded. Basic science studies have demonstrated the presence of vitamin D receptors on a wide range of cell types in the body, from myocytes to white blood cells, implying a physiological role for vitamin D in these organs. Similarly, laboratory animal studies have shown that a large number of diseases can occur in genetically modified, vitamin D receptor knockout mice and also in normal animals with nutritionally-induced vitamin D deficiency. In humans, vitamin D deficiency is now linked to various disorders, from unfavorable pregnancy outcomes to an increase in all-cause mortality, cardiovascular and cerebrovascular events, infectious and autoimmune diseases, and numerous cancers [2]. As a result, vitamin D is now studied as a crucial substance with potential effects on the initiation, progression, and outcome of a wide range of pathological conditions.

The possible links between vitamin D status and outcomes in critically sick patients are fascinating subjects of current research. It has been hypothesized that vitamin D deficiency may have a negative impact on the outcome in critically ill patients due to a variety of roles that this vitamin plays in vital organs and life processes [3]. Several studies have found a link between vitamin D deficiency and the risk of death in people receiving critical care, and clinical trials are conducted to look at the potential positive effect of supplemental vitamin D in this population of patients [4]. Neonates and infants in critical care constitute a particularly vulnerable group, and a considerable amount of research is focused on vitamin D status in this group. Studies suggest that neonates and children who are critically ill have lower mean vitamin D levels than healthy ones, and there is evidence linking vitamin D deficiency to an increased risk of mortality, illness severity, and complications in these patients [5, 6]. In this chapter, we look into the ongoing research on this exciting topic.

2. Defining vitamin D deficiency

Experts generally agree that 25-hydroxyvitamin D [25(OH)D] concentration should be used to evaluate vitamin D status because it captures the contribution from both diet and dermal synthesis [7], but there has been much debate regarding the suggested thresholds (cut-offs) to define vitamin D deficiency. The Endocrine Society Task Force on Vitamin D in the US has recommended that people with serum 25(OH)D levels of less than 50 nmol/L be classified as vitamin D-deficient [8], while an international expert panel assembled by the European Society for Pediatric Endocrinology has suggested serum 25-hydroxyvitamin D levels of 30–50 nmol/L as vitamin D insufficiency and levels <30 nmol/L as deficiency [9].

In addition to clinical care guidelines, the question of vitamin D deficiency has been addressed from the population health perspective. Some expert bodies tasked with developing dietary recommendations for vitamin D propose 50 nmol/L as the concentration of serum 25(OH)D that would satisfy the physiological vitamin D requirement of nearly all “normal healthy persons” [7]. The Institute of Medicine (IOM) in the US chose calcium absorption, bone mineral density (BMD), and two well-studied clinical conditions- rickets in children and osteomalacia in adults- as indicators for developing their vitamin D recommendations, known as Dietary Reference Intakes (DRI) [7]. The DRI committee developed the Recommended Dietary Allowance (RDA) based on the estimate that serum 25(OH)D concentration of 50 nmol/L (15 μg/day for those aged 1 to 70 and 20 μg/day for those over 70) would satisfy the needs of nearly all (i.e., 97.5%) of “normal healthy persons” [7]. Likewise, the Scientific Advisory Committee on Nutrition (SACN) in the UK chose musculoskeletal status (rickets, osteomalacia, falls, muscle strength, and function) for developing their vitamin D recommendations, known as Dietary Reference Values (DRV). They believe that the evidence overall suggests the risk of poor musculoskeletal health increases at serum 25(OH)D concentrations below 20–30 nmol/L [10]. Based on this reasoning, SACN chose a serum 25(OH)D target of 25 nmol/L as the “population protective level” in order to safeguard the musculoskeletal health of people in the UK throughout the year. They suggest a Reference Nutrient Intake (RNI) of 10 μg/day for those aged 4 years and older [10].

Overall, according to guidelines, serum 25(OH)D concentrations above 50 nmol/L indicate vitamin D sufficiency for the majority of people, whereas concentrations between 50 and 30 nmol/L indicate a risk of vitamin D inadequacy or deficiency for some people [7]. Even though there is not yet universal agreement on what constitutes vitamin D deficiency, it is generally accepted that we do not want people in our populations to have 25(OH)D concentrations below 25/30 nmol/L. Preventing such vitamin D deficiency is a public health priority.

3. Vitamin D deficiency in neonates and infants

Vitamin D deficiency is one of the most significant dietary deficits in children worldwide. The International Osteoporosis Foundation (IOF) estimates that vitamin D deficiency affected 84% of pregnant women and 96% of babies in 2009 [11]. A 2016 systematic review considered 25(OH)D concentrations in neonates and pregnant women worldwide from 1959 to 2014. Results showed that the mean maternal 25(OH)D concentrations ranged from 13 to 130 nmol /L, while the mean neonatal 25(OH)D concentrations ranged from 5 to 77 nmol/L. Around 54% of pregnant women and 75% of newborns had vitamin D deficiency, defined as a serum 25(OH)D concentration below 50 nmol /L, and 18% of pregnant women and 29% of newborns had severe vitamin D deficiency, defined as a serum 25(OH)D concentration below 25 nmol/L. There was a wide variation in vitamin D levels between WHO regions. In the Eastern Mediterranean region, the average maternal 25(OH)D concentration was <25 nmol /L, while it ranged from 75 to 100 nmol/L in the African region. In the Americas, the average newborn 25(OH)D concentration was >75 nmol/L, but it was <25 nmol/L in the Eastern Mediterranean. Similarly, 79% of pregnant women in the Eastern Mediterranean region had severe vitamin D deficiency. The prevalence of severe vitamin D insufficiency among pregnant women in the Americas, Western Pacific, and Europe were much lower (9%, 13%, and 23%, respectively). The prevalence of vitamin D deficiency in neonates from the South-East Asian region was very high (96%), while in the Americas, 30% of neonates were vitamin D deficient [12].

Leading causes of vitamin D deficiency in neonates include lower nutritional intake, exclusive breastfeeding when the mother has vitamin D deficiency, and decreased sun exposure due to seasonal changes. Maternal vitamin D deficiency is demonstrated to be a significant risk factor for newborns with vitamin D deficiency [11]. Neonatal 25(OH)D concentrations at delivery are generally lower than normal in babies born to mothers with deficient and insufficient vitamin D levels but not in babies of mothers with sufficient vitamin D status [13]. Infants in a disadvantaged socioeconomic position exhibit a higher rate of vitamin D deficiency. This could be explained by the likelihood of decreased calcium and vitamin D intake in these children. Likewise, preterm newborns are more susceptible to vitamin D deficiency due to diminished placental transfer, insufficient sun exposure, and lower vitamin D storage as a result of low-fat mass. Babies with nephrotic syndrome, cystic fibrosis, or malabsorption syndrome are also at higher risk of vitamin deficiency [14]. Drugs such as phenobarbital, carbamazepine, oxcarbazepine, and phenytoin can interfere with vitamin D metabolism [8]. The absorption, metabolism, or activation of vitamin D are also impacted by other medications, including corticosteroids and azole antifungals.

Secondary hyperparathyroidism, secondary hyperphosphatemia, and hypocalcemia are the main biochemical changes seen in babies with vitamin D deficiency [15]. Along with vitamin D deficiency, other factors that may contribute to hyperphosphatemia in this group include a decreased glomerular filtration rate, low intact parathyroid hormone (iPTH) levels, and renal tubular nonresponse to PTH, particularly in the first days after birth. It is possible that co-occurring metabolic bone disease—especially in preterm, small-for-gestational-age (SGA) neonates—also contributes to these biochemical alterations.

Clinically, vitamin D deficiency in infants presents as rickets in extreme situations, which can cause bowing of the knees, wrist widening, frontal bossing, spontaneous fractures, and skeletal abnormalities. In older children, it can cause short stature, muscle weakness, and pain. In addition to skeletal signs, vitamin D insufficiency can cause developmental delay, growth failure, and recurrent respiratory infections [14]. Early vitamin D insufficiency can go undetected without clinical symptoms and later proceed to florid rickets in older children if undiagnosed. In fact, in the neonatal age group, the symptoms of hypocalcemia, there may the only clinical manifestations of vitamin D deficiency.

To avoid the risk of later skeletal abnormalities and reduce pulmonary morbidity, vitamin D insufficiency must be promptly identified and treated in neonates and infants. A dosage of 400–1000 international units (IU) of vitamin D per day for 8 to 12 weeks is the recommended course of treatment for newborns with vitamin D insufficiency, while infants after the newborn stage need 1000–5000 IU of vitamin D per day for 8–12 weeks [15]. To treat vitamin D deficiency and prevent the hungry bone syndrome, which develops as a result of underlying hypocalcemia, vitamin D therapy is combined with appropriate calcium administration. To attain ideal serum levels, children with malabsorption syndromes and those taking anticonvulsants, glucocorticoids, antifungals, or antiretroviral drugs require longer and higher oral doses of vitamin D [16].

Dietary consumption and cutaneous production both contribute to the maintenance of vitamin D levels. Neonates and children have a greater potential to generate vitamin D from sunshine because they have a higher body surface area to volume ratio than adults [17]. A 10- to 15-minute period of direct sunshine exposure can generate 10,000 to 20,000 IU of vitamin D. It has been demonstrated that completely dressed infants exposed to sunlight for 2 hours each week can avoid severe vitamin D insufficiency [18]. However, it should be noted that exposure to direct sunshine is not recommended in infants younger than 6 months. Geographical latitude, degree of skin pigmentation, and the amount of skin exposed to sunlight are among the most critical variables that affect vitamin D synthesis from sunlight. Therefore, children with more skin pigmentation are at a higher risk of vitamin D deficiency. Compared to children with less skin pigmentation, these children need five to ten times more time in the sun for the same amount of 25(OH) vitamin D to be produced. Asian children need three times more sun exposure than white American children to maintain adequate vitamin D levels due to their darker complexion.

4. Vitamin D deficiency and neonatal and pediatric health outcomes

In addition to its well-defined classical functions related to calcium homeostasis and bone development, the relationship between vitamin D levels and health outcomes in infancy has also attracted exceptional attention in the scientific community. We begin our review of possible links between vitamin D status and health outcomes with pregnancy outcomes. Despite its critical importance, it is still unclear whether maternal vitamin D status plays a role in proper fetal and placental development and consequently in pregnancy outcomes. One recent review found no clear evidence to suggest that low vitamin D levels in early pregnancy are associated with adverse pregnancy outcomes, mainly preeclampsia, fetal growth restriction, preterm birth, and stillbirths [19]. In contrast, another review concluded that pregnant women with low 25(OHD) levels had an increased risk of gestational diabetes, preeclampsia, small for gestational age infants, and lower birth weight infants but no association with delivery by cesarean section [20]. Aghajafari et al. reviewed five randomized controlled trials and suggested a protective effect of vitamin D supplement during pregnancy on low birth weight (LBW) but no effect on preterm delivery [21].

The relationship between maternal vitamin D levels and particular child health outcomes, such as infections, has been investigated. Evidence suggests a relationship between maternal vitamin D levels and infants’ predisposition to infection. One study found a significantly higher risk of respiratory infections (colds, cough, whooping cough, chest infection, and ear infection) by 3 months of age among infants with cord blood levels of 25(OH)D less than 25 nmol/L [22]. In contrast, a cohort study followed-up children at the age of 9 months and found that mothers in the top quartile of 25 (OH) D statuses in late pregnancy were significantly more likely to report their children having been diagnosed with pneumonia or bronchiolitis compared with those in the bottom quartile [23]. One recent study showed an association between early-onset neonatal sepsis and low maternal vitamin D levels in term infants [24]. Studies have also suggested that vitamin D pathways may be involved in the susceptibility to and outcome of Hepatitis B Virus infection acquired early in life [25].

The epidemiological evidence of the link between maternal vitamin D levels and infection is inconclusive, but vitamin D has a direct role in the production of antimicrobial peptides such as cathelicidin, which may help prevent infection during pregnancy and early childhood. This mechanism suggests a plausible biological basis for the relationship between maternal vitamin D levels and infection in infancy. Preventive measures in pregnant women aim to ensure that they have enough vitamin D, either from sunlight exposure or the right vitamin D supplements, and protect the newborn against possible adverse effects of vitamin D deficiency.

5. Vitamin D deficiency in neonatal and pediatric critical care

Accumulating evidence from various parts of the world points to a high prevalence of vitamin D deficiency among children admitted to neonatal and pediatric critical care units. Babies in the neonatal period are particularly vulnerable to a range of diseases requiring NICU hospitalization, and the study of vitamin D status in this group has attracted considerable interest in recent years. In a study by Bhimji et al. in Tanzania, about 80% of newborns admitted to the NICU of a tertiary care hospital showed vitamin D insufficiency [26]. A study from the U.S. discovered vitamin D inadequacy or insufficiency in 80% of preterm newborns with birth weights under 1500 g [27]. Another study from Australia found such conditions in 35.7% of preterm neonates admitted to NICU [28]. To determine the prevalence of vitamin D deficiency, Chacham et al. carried out an observational study on infants aged equal to or younger than 1 year at a tertiary care facility in Northern India. Neonates comprised 80% of the population under study and had a 79% prevalence of vitamin D insufficiency [29]. According to a recent study from Iran, 37% of neonates hospitalized in the NICU had vitamin D deficiency, while 58% had vitamin D insufficiency. Thus, 95% of neonates had abnormal vitamin D levels at admission [30]. Kim et al. studied vitamin D status in very-low-birth-weight neonates in Korea and reported a mean serum vitamin D level of 13.4 ± 9.3 ng/mL, with 79.8% of the subjects being vitamin D deficient. They found a higher prevalence of respiratory morbidities, such as bronchopulmonary dysplasia and respiratory distress syndrome in preterm neonates, that had severe vitamin D deficiency. Moreover, vitamin D deficiency was associated with a longer NICU stay [31].

Vitamin D status has also been studied beyond the neonatal period and in the pediatric critical care setting. Rey et al. studied vitamin D levels of critically ill children in PICU and healthy kids in Spain. They found a nearly twofold higher rate of vitamin D deficiency in PICU patients compared to healthy controls [32]. In a multicenter study of critically ill children across Canada by McNally et al., the mean 25(OH)D levels (43 nmol/L) were much lower than the 67–75 nmol/L mean levels observed among healthy Canadian and US children. In patients who needed catecholamine infusions, required mechanical breathing, and received more than 40 ml/kg of fluid resuscitation, 25(OH)D levels were lower. Vitamin D deficiency was also independently associated with a 2-day increase in PICU stays [33]. The authors hypothesized that, during critical illness, sudden reductions in vitamin D levels might be more physiologically relevant than chronic deficiency because compensatory mechanisms are affected by inflammation and multiorgan failure in this setting. Similarly, in their study of a tertiary care PICU in India, Sankar et al. found a vitamin D deficiency prevalence of 74%. Furthermore, vitamin D deficiency was associated with a longer duration of PICU stay in this study [34].

A prospective study by Madden et al. at Boston Children’s Hospital’s pediatric intensive care unit (PICU) examined vitamin D levels at the time of admission. The study did not include patients undergoing heart surgery. The 25(OH)D deficiency was significantly associated with poorer clinical outcomes. In patients with vitamin D deficiency, the scores of illness severity were higher, and they were more likely to need vasopressor treatment. However, no association was discovered between 25(OH)D levels and the time spent on mechanical ventilation, and ionized serum calcium levels were normal in almost all cases [35]. The authors suggested that these findings were secondary to vitamin D’s function in immunological regulation, inflammation, and calcium homeostasis and not due to fluid shifts and hemodilution.

6. Vitamin D deficiency and critical care in congenital heart disease

Congenital heart disease (CHD) and its surgical treatment is one the conditions that necessitate ICU admission and critical care in neonates and pediatric patients. In recent years, a considerable amount of research has been dedicated to vitamin D status in children with cardiac disease and the relationship between vitamin D levels and treatment outcomes in this group. In the study by Rippel et al. on critically ill children, two-thirds of the patients were postoperative cardiac patients. The researchers found no association between 25(OH)D deficit and the requirement for mechanical ventilation, the need for vasoactive support, the length of hospital or ICU stays, the severity of disease scores, or mortality. However, the likelihood of being vitamin D deficient in patients with cardiac diseases was almost twice that of non-cardiac patients in this study (40% vs. 22%) [36].

In 2013, McNally et al. reported the findings of a prospective cohort study on the vitamin D status of 54 children with CHD who underwent open heart surgery at a mean age of 8.4 months and 4 children who had coarctation of the aorta and underwent closed heart surgery. Forty-two percent of patients had a preoperative 25OHD deficiency (<50 nM), with the mean value being 58.0 nM (SD, 22.4). Following surgery, there was a 40% reduction in mean 25OHD to 34.2 nM (SD, 14.5), with 86% of subjects having vitamin D deficiency. The open-heart surgery group’s decline in vitamin D levels was more remarkable. Intraoperative measurements showed a sudden drop in vitamin D with the start of cardiopulmonary bypass. Additionally, the authors investigated the need for catecholamines and discovered an association between lower postoperative- but not preoperative- vitamin D levels and the need for catecholamines [37]. A study of the vitamin D levels in 20 children with CHD having open heart surgery was published in 2017 by Abou Zahr et al. Prior to surgery, 40% of the patients had 25OHD deficiency, with values <20 ng/mL. After cardiac bypass surgery, the investigators found that the mean vitamin D level had significantly decreased [38]. Dohain et al. examined the vitamin D status of 69 CHD children following open heart surgery in 2020. Of the patients, 34 (49.5%) had vitamin D deficiency before surgery, and 63 (91.3%) after surgery. They found a 42.03% reduction in 25(OH)D after surgery and noted an association between decreased postoperative vitamin D levels and a rise in inotropic support requirement. These findings suggest a link between unfavorable circumstances and the postoperative decline in vitamin D levels [39]. In 2021, Ye et al. evaluated the relationship between preoperative vitamin D deficiency and the maximum vasoactive-inotropic score 24 hours after surgery in 900 children with CHD. The median total serum 25(OH)D level before surgery was 24.0 ng/mL, and 32.6% of the patients had vitamin D deficiency (25(OH)D < 20 ng/mL). They discovered an association between low vitamin D levels and the need for more postoperative inotropic support 24 hours after cardiac surgery [40].

A number of studies have focused on vitamin D status in neonates with CHD in critical care settings. In 2013, Graham et al. studied the vitamin D status of 70 neonates with CHD having open heart surgery. Before the procedure, 84% (59/70) of the subjects had vitamin D insufficiency. There was no significant decline in vitamin D levels after the operation. However, higher inotropic support was required when postoperative 25(OH)D levels were lower [41]. In 2022, Mosayebi et al. studied changes in vitamin D status in neonates with CHD having heart surgery. The study included 33 open-heart surgery patients and 13 patients with closed-heart surgery. This wide coverage allowed researchers to compare vitamin D status in the open- and closed-heart surgeries. Before the procedure, 66.7% of the patients were vitamin D deficient. This number rose to 84.4% after surgery. After surgery, vitamin D levels declined significantly in patients who had open heart surgery but not those who had closed heart surgery. A significant association was found between the rate of postoperative decrease in vitamin D levels and an unfavorable outcome while preoperative vitamin D levels did not demonstrate a link with the outcome and did not predict the rate of postoperative vitamin D decline. The authors suggested a sharp decrease in vitamin D levels after surgery as an indicator of an unfavorable outcome [6].

Citing the evidence that links vitamin D deficiency to poor outcomes in neonate and infant CHD surgery, in 2020, McNally et al. conducted a dose evaluation feasibility study in preparation for a clinical trial of vitamin D supplementation in children with CHD undergoing corrective surgery. They reported that supplementation with a daily high dose of vitamin D before surgery improved vitamin D status at the time of pediatric ICU admission. The authors recommended modifying the trial protocol and giving vitamin D supplements to patients for at least 1 month before surgery or considering a loading dose [42].

7. Conclusion

With the gradual recognition of the crucial role of Vitamin D status in many physiological and pathological processes, vitamin D deficiency has been proposed as a possible modifiable risk factor for ICU outcomes. The discovery of the role of vitamin D in stress response in the immune, cardiovascular, and respiratory systems has lent support to this possibility. Moreover, numerous clinical studies have identified a high prevalence of vitamin D deficiency among ICU patients.

Neonates and pediatric patients constitute a particularly vulnerable group, and the vitamin D status in this group in critical illness has come under increasing scrutiny in recent years. The studies have predominantly shown a high prevalence of vitamin D deficiency in critically ill neonates and pediatric patients, pointing to a potential role for vitamin D status in critical illness in these patients. Vitamin D deficiency in CHD patients undergoing corrective surgical treatment has attracted particular attention, and a number of studies have focused on this topic. Overall, these studies report high prevalence rates of vitamin D deficiency in this group of neonates and pediatric patients. Moreover, several studies report significant associations between low vitamin D levels and unfavorable findings, such as increased requirements for vasoactive support and mechanical ventilation and prolonged ICU stays, in these patients.

An evaluation of available data suggests vitamin D deficiency as a modifiable risk factor in neonatal and pediatric critical illness, specifically in CHD patients undergoing surgical treatment. Clinical trials have been proposed to examine the potential beneficial effect of preoperational vitamin D supplementation on the outcome of heart surgery in this group. Studies on this topic are still in progress. However, for now, vitamin D supplementation should be considered in critically ill neonates in general and in those undergoing surgery for CHD in particular. Such supplementation aims to maintain serum/plasma 25(OH)D concentrations at safe levels over the threshold of vitamin D deficiency.

Conflict of interest

The author declares no conflict of interest.