Vitamin D, known as the ‘sunshine vitamin’, is made in the skin in response to ultraviolet B (UVB) radiation, and once activated in the body to the hormone calcitriol (1,25 dihydroxy-vitamin D), it regulates a wide variety of processes; the most important of which being intestinal calcium and phosphate absorption (Wacker and Holick, 2013). Calcium – phosphate crystals (hydroxyapatite) – are the main building blocks for bone mineralisation and are therefore essential to maintain adequate bone hardness and strength. Hence, lack of vitamin D can lead to inadequate mineralisation resulting in osteomalacia in adults and children, and rickets in growing children (Uday and Högler, 2018a).
Vitamin D status is measured by serum concentration of 25-hydroxyvitamin D (25OHD) which is the most stable form (Nair and Maseeh, 2012). 25OHD concentration below 30 nmol/L (12ng/L) is classed as deficiency (Rosen et al, 2012; Munns et al, 2016). Prolonged severe rickets/osteomalacia in girls during growth can later result in obstructed labour which worsens with subsequent pregnancies (Konje and Ladipo, 2000). Vitamin D deficiency has also been implicated in gestational diabetes mellitus, pre-eclampsia and preterm labour (Mulligan et al, 2010). The deficiency state in the mother is naturally passed on to the fetus and the newborn whose 25OHD levels are about 50%–78% of the mother's (VioStreym et al, 2013; O'Callaghan et al, 2018). Vitamin D supplementation during pregnancy is associated with higher 25OHD concentrations, greater birth weight and birth length in the neonate (Pérez-López et al, 2015).
The infant born with a low-25OHD reserve due to lack of maternal supplementation, who does not receive infant vitamin D supplementation from birth, can experience devastating health consequences ranging from hypocalcaemic seizures and rickets to cardiac failure and sudden cardiac death (Uday et al, 2018). Considering that the implications of vitamin D deficiency reach far beyond skeletal effects and are easily remediable through monitored supplementation programmes, preventing deficiency should be among the major public health priorities (Uday and Högler, 2018b).
The pathophysiology of vitamin D
Calcitriol (active vitamin D) as a hormone is unique in that it originates from the biologically inert vitamin D synthesised in the skin from 7-dehydrocholesterol in response to UVB radiation in sunlight (see Figure 1a) (Wacker and Holick, 2013). Dietary sources of vitamin D are limited and humans therefore rely on sunlight, supplements or fortified food to achieve the recommended daily intake of vitamin D (Bates et al, 2014). Ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) are metabolised in the liver to calcidiol (25 hydroxyvitamin D), the stable form, and then in the kidneys to calcitriol (1.25 dihydroxyvitamin D), the only biologically active form of vitamin D (Uday and Högler, 2019).
Calcitriol aids intestinal calcium and phosphate absorption. Lack of calcitriol leads to calcium deprivation secondary to poor intestinal absorption. In response to even the smallest drop in serum calcium below the set-point (see Figure 1b), the chief cells in the parathyroid gland release parathyroid hormone (PTH) in order to avoid hypocalcaemia. High PTH in the initial stages maintains normal serum calcium levels by 1) releasing stored calcium from the bones 2) increasing calcitriol synthesis through increased renal 1-hydroxylation and 3) increasing renal calcium reabsorption (Atapattu et al, 2013). These compensation mechanisms will eventually fail and result in low phosphate (hypophosphataemia) as high PTH also reduces renal phosphate reabsorption. Phosphate is essential for apoptosis of mature growth plate chondrocytes, a process which initiates bone mineralisation (Tiosano and Hochberg, 2009). Hence, lack of phosphate results in defective mineralisation. The defective mineralisation of growth plates and metaphyses (in growing children) results in rickets and that of pre-formed osteoid (in existing bone of adults and children) results in osteomalacia (Uday and Högler, 2018a). It is the hypophosphataemia that causes rickets and osteomalacia, and not the hypocalcaemia which occurs only once PTH compensation fails. Individuals with long standing or severe vitamin D deficiency, or dietary calcium deficiency can therefore manifest with features of hypocalcaemia (eg seizures, tetany, heart failure) and/or hypophosphataemia (eg rickets, osteomalacia, muscle weakness).
While there are inherited forms of rickets and osteomalacia, the most common cause of rickets worldwide is environmental-solar vitamin D deficiency and/or dietary calcium deficiency. Given the natural lack of nutritional vitamin D, specifically the near complete lack in breastmilk, the term ‘nutritional rickets’ used for both causes is misleading (Uday and Högler, 2019). Solar vitamin D deficiency predominates in high-income countries and dietary calcium deficiency predominates in low- and middle-income countries (Uday and Högler, 2018b).
Risk groups
The elements which predispose an individual to nutritional rickets and osteomalacia include:
The most vulnerable groups remain the resident (Uday and Högler, 2018b) and immigrant black, Asian and minority ethnic population in high latitude countries of whom pregnant women and infants are at highest risk (Robinson et al, 2006; Omand et al, 2014; Munns et al, 2016; Thacher et al, 2016). A study from Italy demonstrated that the prevalence of severe vitamin D deficiency was higher in migrant mothers and their infants (48.4% and 76.2%, respectively), compared to native Italian counterparts (38% and 18%, respectively) (Cadario et al, 2015).
UK studies of women of a childbearing age group have also highlighted the increased prevalence of deficient state in South Asian women year-round compared to Caucasian women (Darling et al, 2013). Lower 25OHD concentrations in the UK South Asian population is multi-factorial and has been attributed not only to darker skin but also to lower oral intake of vitamin D and reduced sun exposure (Kift et al, 2013; Darling et al, 2018). Maternal vitamin D deficiency is a global health problem (Saraf et al, 2016) even in sunshine abundant countries owing to sun avoidance and lack of supplementation (Schoenmakers et al, 2015).
Clinical manifestations of nutritional rickets and osteomalacia
The clinical manifestations of nutritional rickets and osteomalacia at different stages of life are detailed in Table 1. The discussion below will focus specifically on the consequences in pregnancy and infancy.
| Age group | Clinical presentation and manifestations |
|---|---|
| Pregnancy | Obstructed labour |
| Birth | Neonatal hypocalcaemia, low-birth weight |
| Infant | Craniotabes (soft skull), poor feeding, restlessness, irritability, seizures, dilated cardiomyopathy leading to heart failure and rarely cardiac death |
| Child | Muscle weakness, delayed development and dentition, swelling of wrists and ankles, rachitic rosary, leg bowing deformities, fractures |
| Adolescent | Hypocalcaemic seizures, tetany, bone pain, muscle weakness, fractures |
| Young adults including women of child bearing age group | Fatigue, bone pain, muscular pain and weakness, difficulty rising from seated position, waddling gait |
| Old age | Fatigue, malaise, muscle weakness, muscle pain, falls, fractures |
Pregnancy
For adequate fetal bone development, a fetus must be provided with approximately 30 g of calcium during gestation which requires increased resorption of maternal bone and increased intestinal calcium absorption (Bishop et al, 2012). The third trimester is the time where most fetal phosphorus and calcium deposition occurs (Bishop et al, 2012). For these reasons, preterm infants are specifically at increased risk of mineral deficiency.
There is no doubt that severe or prolonged maternal vitamin D deficiency affects the fetus, leading to congenital rickets (Erdeve et al, 2007; Paterson and Ayoub, 2015; Elidrissy, 2016) and hypocalcaemic seizures in the newborn (Basatemur and Sutcliffe, 2015). Infants with congenital rickets present with comorbidities including perinatal asphyxia, low-birth weight and pathological fractures (Innes et al, 2002). Newborn babies with congenital rickets can present with craniotabes (soft skull) or an enlarged fontanelle. A 2015 review of all published cases of congenital rickets found 25 cases, 24 of which were associated with maternal vitamin D deficiency, demonstrating that maternal deficiency can affect the fetal skeleton before birth (Paterson and Ayoub, 2015).
A UK longitudinal study of children (n=198) born in 1991–1992 showed that maternal vitamin D deficiency in late pregnancy can have a long lasting adverse effect on the child's bone density at age nine years (Javaid et al, 2006). Moreover, maternal use of vitamin D supplements predicted 25OHD concentration (p=0.0110) and childhood bone mass (p=0.0267) (Javaid et al, 2006). A recent systematic review and meta-analysis concluded that maternal vitamin D deficiency in pregnancy is associated with increased risk of pre-eclampsia, gestational diabetes mellitus, preterm and small-for-gestational-age birth (Wei et al, 2013). A recent Cochrane review concluded that supplementing pregnant women with vitamin D alone probably reduces the risk of pre-eclampsia, gestational diabetes, low-birth weight and may also reduce the risk of severe postpartum haemorrhage (Palacios et al, 2019).
Infancy
Maternal vitamin D status is the most important predictor of vitamin D deficiency in infants at birth (Cadario et al, 2013; VioStreym et al, 2013). Infants are particularly susceptible to the effects of vitamin D deficiency due to high calcium demands from the growing skeleton. Nutritional rickets therefore has a peak incidence between 3–18 months of age (Ladhani et al, 2004). Infants younger than six months often present with symptoms of hypocalcaemia, such as seizures, irritability and dilated cardiomyopathy, with or without evidence of rickets on radiographs (Ladhani et al, 2004; Uday and Högler, 2017). The effects of hypocalcaemic cardiomyopathy can be grave resulting in cardiac arrest and failure, and also sudden cardiac death (Maiya et al, 2008; Uday et al, 2018).
While exclusively breastfed infants are deemed to be at highest risk (Jain et al, 2011), formula-fed infants are not fully protected from developing nutritional rickets (Ward et al, 2007; Gross et al, 2013; Basatemur and Sutcliffe, 2015). The amount of vitamin D in formula milk is not sufficient to mitigate the effects of long-standing deficiency from (before) birth, highlighting the need to supplement all infants (Munns et al, 2016; Uday et al, 2017).
Prevention of vitamin D deficiency: barriers and way forward
The fact that the required daily amount of vitamin D cannot be met through diet alone is well-established (Bates et al, 2014) and that holds true for many locations on earth where there is a lack of sunlight. Therefore, food fortification in the long-term and supplementation in the interim remain the two most sensible ways of optimising vitamin D intake to prevent the devastating health consequences.
Mandatory food fortification is not readily implemented in all countries, despite its successful adaptation to improve population vitamin D status in countries such as Canada and the US (Calvo and Whiting, 2013). The majority of developed countries have pregnancy and infant vitamin D supplementation policy in place however, its implementation and adherence rates vary widely (Uday et al, 2017). Using the UK as an example, we highlight how lack of clear consensus guidelines, robust monitoring and political support can lead to widespread prevalence of vitamin D deficiency and resurgence of rickets.
Current barriers
Currently in the UK, various organisations and committees make diverse recommendations for vitamin D supplementation and safe/reference intake which are detailed in Table 2. The existing UK recommendations are compared and contrasted to the evidence-based global consensus recommendations on prevention and treatment of nutritional rickets (Munns et al, 2016) which go in line with national recommendations of most European countries (Uday et al, 2017).
| Infancy Vitamin D μg (IU)/day | Childhood Vitamin D μg (IU)/day | Pregnancy Vitamin D μg (IU)/day | High risk population Vitamin D μg (IU)/day | |
|---|---|---|---|---|
| Global consensus recommendations (Munns et al, 2016) | 10 (400) universal supplements, irrespective of mode of feeding | 15 (600) diet and/or supplements | 15 (600) supplements | 15 (600) supplements |
| Royal College of Paediatrics and Child Health guide (2019) | 8.5−10 (340−400) birth to 1 year unless they are consuming >500 ml formula milk a day | Children aged between 1−4 years should receive a daily vitamin D supplement of 10 mcg. Parents should consider giving the same dose to children over 4 years, particularly through the winter months | No recommendations | No recommendations |
| Royal College of Obstetricians and Gynaecologists (2014) | No recommendations | No recommendations | Supplements 10 (400) in all, 25 (1 000) in high risk and 20 (800)+ calcium if risk of pre-eclampsia | No recommendations |
| Scientific Advisory Committee on Nutrition (2016) | 8.5−10 (340−400) safe intake | 10 (400) 1 to <4 years: safe intake >4 years: reference nutrient intake | 10 (400) reference nutrient intake | 10 (400) reference nutrient intake |
| Public Health England advice (2016) | 8.5−10 (340−400) supplements if consuming <500 ml/day of formula feed | 10 (400) supplements if consuming <500 ml formula/day (1−4 years) | 10 (400) consider taking supplements | 10 (400) consider taking supplements |
Due to increasing concerns over vitamin D deficiency in the UK risk population, in 2012 the UK chief medical officers (CMOs) issued a letter emphasising the need for supplementation of all risk groups (including pregnant/breastfeeding women and children aged under five years) (UK CMO, 2012). The Royal College of Obstetricians and Gynaecologists ([RCOG], 2014) concurred with the CMOs' recommendation of 10 μg (400 IU) daily for all pregnant women and, in addition, proposed a higher dose of 25 μg (1 000 IU) for at-risk women (women with increased skin pigmentation, reduced exposure to sunlight, or those who are socially excluded or obese) and a dose of 20 μg (800 IU) combined with calcium for those at risk of pre-eclampsia (RCOG, 2014). Similarly, since 2014, the Royal College of Paediatrics and Child Health (RCPCH) have also endorsed the CMOs' recommendations. However, it was added that exclusively breastfed infants should commence supplementation at birth; and these guidelines have recently been revised to recommend supplementation of infants consuming <500 ml formula per day (RCPCH, 2019).
In 2014, the National Institute for Health and Care Excellence ([NICE], 2014) updated their guidelines to detail the at-risk groups. NICE also made recommendations to increase availability and uptake of vitamins by risk groups and highlighted the need to clarify the current guidelines which hinder uptake in infants (NICE, 2014). The 2016 ‘Vitamin D and Health’ report by the Scientific Advisory Committee on Nutrition ([SACN], 2016) set safe and reference nutrient intake for vitamin D and acknowledge the difficulty in meeting needs via diet alone but did not commit to recommending supplements or fortification (SACN, 2016). On the basis of the 2016 SACN report, Public Health England (2016) provided advice to the adult public that the daily requirement of vitamin D ie 10 μg (400 IU) should be met through diet in the low-risk population and high-risk population should ‘consider’ taking supplements.
The advice for infants, the most susceptible group, by all organisations is extremely complex and also lacks commitment and clarity on daily requirements, with supplement dose and age of commencement depending largely on whether they are breast- or formula-fed and the amount of formula consumed (Table 2). The ‘Healthy start’ scheme which provides free vitamins to families on income support has a very complex delivery system resulting in very poor uptake (Jessiman et al, 2013; McFadden et al, 2015), not to mention its lower than recommended vitamin D content. These complex guidance and specifically the lack of accountability hinders implementation (Uday et al, 2017). It is therefore not at all surprising that many health professionals (GPs, health visitors and midwives) refrain from advising vitamin D supplementation routinely to their patients due to uncertainty about which patients to target and what doses to recommend (Jain et al, 2011).
Consequences of poor public health policies
Strategies required
Based on a survey of vitamin D supplementation policies and implementation strategies across 29 European countries, we propose the following evidence-based strategies (Uday et al, 2017) to tackle the resurgence of rickets in the UK:
Prevention of rickets and improving adherence to supplementation programmes is a multi-task operation and as many of the above factors as possible should be incorporated into national policies. A group of relevant healthcare professionals (midwives, health visitors, GPs, and paediatric and obstetric specialists) should be held accountable for implementing and monitoring adherence to supplementation policies. Political support is crucial in implementing and sustaining changes (Uday and Högler, 2018b).
Conclusion
Vitamin D deficiency in pregnancy can have devastating health consequences in the newborn and infant including hypocalcaemic seizures, dilated cardiomyopathy, heart failure and death. All health consequences of nutritional rickets and osteomalacia are easily prevented with vitamin D supplementation. Lack of robust supplementation policies and implementation has led to the resurgence of nutritional rickets and a high prevalence of vitamin D deficiency in ethnic risk groups in certain high-income countries. Long-term strategies, such as mandatory food fortification, should be pursued.