Description of the condition

Breastfeeding is the optimal source of nutrition for infants under six months of age. The World Health Organization (WHO) recommends exclusive breastfeeding for the first six months of life, followed by continued breastfeeding with complementary food until two years of age and beyond (WHO 2003). Exclusive breastfeeding means that no other fluid or food is given to the infant. It is recommended that for the duration of exclusive breastfeeding a mother's breast milk alone is sufficient to meet the energy and nutrition requirements of her infant (Butte 2001). However, there are concerns that breastfed infants may not maintain adequate vitamin D status from sunshine or their mother’s milk (Dawodu 2003; Lovell 2016). This is in part contributed by low maternal vitamin D levels (Andiran 2002), and limited exposure of infants to sunlight (NHS 2017).

It is widely accepted that vitamin D levels are low in breast milk (Hollis 1981; við Streym 2016). The reported prevalence of vitamin D insufficiency or deficiency in term breastfed infants without vitamin D supplementation ranges from 0.6% at seven months of age in Nepalese infants (Haugen 2016), to 40% at four months of age in infants in the USA (Merewood 2012), and even as high as 83% at one month of age in Qatari infants (Salameh 2016). The vast differences seen are likely to be caused by multiple factors, including geographical factors (latitude and season during measurement), skin pigmentation of the population studied, use of covered clothing and methodological differences (Kasalová 2015; Matsuoka 1992; Munns 2016).

Serum 25(OH)vitamin D (calcidiol) is the generally accepted marker of vitamin D sufficiency (IOM 2011). Though there is no universal consensus, most guidelines report that 25(OH)vitamin D of at least 50 nmol/L is adequate (EFSA 2016; IOM 2011; Munns 2016). A 25(OH)vitamin D level of 30 to 50 nmol/L is considered insufficient, while a level lower than 30 nmol/L is considered deficient (Munns 2016). (Note: 1 nmol/L = 0.4 ng/mL; IOM 2011).

Vitamin D deficiency in an infant can result in a number of bone‐related as well as 'non‐bone'‐related conditions (Wharton 2003). The bony condition resulting from vitamin D deficiency in children is nutritional rickets. Nutritional rickets is characterised by deficient mineralization of cartilage and bone, growth failure and skeletal deformity (Shore 2013a). The 'non‐bone' conditions resulting from vitamin D deficiency include seizure, myopathy and myelofibrosis (Wharton 2003). Nutritional rickets results from vitamin D deficiency, primary calcium deficiency, or both (Pettifor 2004). Two reviews on the epidemiology of nutritional rickets worldwide found that calcium deficiency may also be a major etiology of nutritional rickets in some African, Middle Eastern and Asian countries (Creo 2017; Prentice 2013). For this Cochrane Review, the term 'nutritional rickets' refers to vitamin D‐deficient nutritional rickets.

Infants with nutritional rickets often present at between three to 18 months of age, when exclusive or partial breastfeeding is predominant (Creo 2017). Prior to three months, the infant is relatively protected by placental transfer of vitamin D (Shore 2013b).

The progression of nutritional rickets can be described in three stages. Initially, low circulating calcium (hypocalcaemia) occurs as a result of reduced absorption from the gastrointestinal tract and reabsorption from bones. The hypocalcaemia is often transient, but in infants can be prolonged enough for the infant to become symptomatic, presenting with tetany or seizures. Subsequently, direct feedback to the parathyroid gland producing secondary hyperparathyroidism results in normalisation of serum calcium, but this is also accompanied by hypophosphataemia and hyperphosphaturia. If vitamin D deficiency continues, the raised parathyroid hormone (PTH) can no longer maintain calcium levels and rickets becomes more severe (Fraser 1967).

Diagnosis of rickets is made from a combination of clinical features, radiological findings and biochemical abnormalities. The radiological (x‐ray) findings that are most diagnostic of rickets are those that demonstrate disordered mineralization and ossification of the physes, described as metaphyseal splaying. These are best seen in the metaphysis of fast‐growing bones, such as the distal ulnar and radius, distal femur, proximal and distal tibia, proximal humerus and anterior ends of middle ribs. Other findings include osteopenia and deformities (Shore 2013b). Due to increased bone activity, raised alkaline phosphatase (ALP) and PTH are commonly found. Hypocalcaemia may not be present as this is dependant on the stage of rickets development (Fraser 1967). Specifically for vitamin D‐deficient rickets, the 25(OH)vitamin D levels are less than 30 nmol/L (Munns 2016).

Nutritional rickets can be treated by replacement of vitamin D and calcium (Misra 2008). However in the case of nutritional rickets, much of the damage caused by the deficiency, such as the skeletal deformity, is not correctable. Therefore, it is important to prevent nutritional rickets in vulnerable groups, such as breastfed infants.

Other than bone health, vitamin D has also been implicated in other conditions, such as improving immunity, prevention of cardiovascular disease, prevention of certain types of malignancies and mental health protection (Pludowski 2013). However, it is beyond the scope of this Cochrane Review to consider these outcomes.

Description of the intervention

Vitamin D, also known as ‘the sunshine vitamin’ is a pro‐hormone rather than a ‘vitamin’. It has two physiologically active forms, vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol). Vitamin D₂ (VD2) is formed from ultraviolet (UV) radiation in plants and yeast (thus the source is from food), while vitamin D₃ (VD3) is synthesised in the skin (epidermis to dermis) from 7‐dehydrocholesterol. The synthesis of VD3 is a two‐step process, with the formation of pre‐VD3 using UVB (spectral range 290 to 320 nm) and subsequent thermal isomerization into VD3. Once formed it is bound to vitamin D‐binding protein for transport into the circulation (Holick 1980). Both VD2 and VD3 subsequently undergo similar metabolic pathways and are physiologically equivalent in function (Shore 2013a).

Vitamin D is considered a pro‐hormone because it requires further metabolism in order to function. VD2 and VD3 undergo hydroxylation in the liver to form 25(OH)vitamin D (calcidiol) and is further hydroxylated in the renal tubules to form of 1,25(OH)₂vitamin D (calcitriol), which is the active form of vitamin D (Shore 2013a). However, 25(OH)vitamin D (calcidiol) is the most plentiful and stable vitamin D metabolite in the human body and thus used for measurement of vitamin D level in the body (Adams 2010).

Vitamin D supplements come in two forms, either plant‐based VD2 or animal‐based VD3 (Wagner 2008). VD3 is frequently preferred over VD2 as it has greater efficacy in raising circulating levels of 25(OH)vitamin D and is more sustained (Armas 2004; Oliveri 2015). VD3 is extensively used as part of milk formula or food fortification (Holick 1992).

For infants, supplements are available either in combination with other vitamins or alone (Wagner 2008). Sole vitamin D supplements are preferable over combination vitamin preparations to allow adequate vitamin D dosing without overdose of other vitamins (Wagner 2008). The recommended dose for vitamin D supplementation of infants is between 340 IU and 400 IU per day, starting from birth up till one‐year age (Health Canada 2012; NICE 2014; Wagner 2008). At these amounts the risk of vitamin D toxicity is low (IOM 2011). As vitamin D is found in breast milk, it is possible to supplement the breastfeeding mother with vitamin D, thus indirectly supplementing the infant (Haggerty 2010). However, doses of about 6400 IU/day are needed in the lactating mother to have adequate excretion into human milk (Haggerty 2010).

Vitamin D toxicity has been defined as hypercalcaemia, a 25(OH)vitamin D level exceeding 250 nmol/L associated with hypercalcuria and suppressed PTH (Munns 2016). Clinically, it may result in growth retardation and symptoms of hypercalcaemia (IOM 2011). Toxicity only occurs with dietary intake, not sun exposure (Holick 1981).

How the intervention might work

Human bone is first formed as cartilage and, later, bone tissue is laid down to replace the cartilage. This process is called bone mineralization or ossification. As the infant grows, bones undergo longitudinal and radial growth and a process of modelling‐remodeling takes place (Clarke 2008). Vitamin D plays an important role in these processes. The primary action of vitamin D is to increase the absorption of calcium from the gastrointestinal tract (Elder 2014). It also mobilises calcium from bone with the help of PTH by way of increasing osteoclastic bone resorption (Shore 2013a). In addition, vitamin D also increases the kidney's distal tubules reabsorption of calcium together with the action of PTH (IOM 2011). The net action of vitamin D is to increase serum calcium levels.

Good bone mineralization during early childhood and adolescent is the foundation of stronger bones later in life preventing fractures and osteoporosis (Winzenberg 2013a). Aquisition of bone mineral content is greatest in the first year of life (Koo 2013). Therefore, it is hypothesised that prevention of vitamin D deficiency by supplementation of breastfed infants should lead to better bone health in future.

Why it is important to do this review

Vitamin D deficiency and nutritional rickets among breastfed infants are not uncommon. A review of the global incidence of nutritional rickets in the last 10 years found it is an important global health problem (Creo 2017). With increasing efforts to promote exclusive breastfeeding of infants from birth to six months old (WHO 2003), it is important the risk of vitamin D deficiency in these infants is addressed.

Vitamin D supplementation of term breast‐fed infants has been recommended by the American Academy of Pediatrics (AAP), Institute of Medicine, Canada Health and NICE Guidelines (Health Canada 2012; IOM 2011; NICE 2014; Wagner 2008). These guidelines state that breast‐fed infants should start supplements by one month of life. Adherence to these guidelines is influenced by the recommendations of individual physicians or other healthcare professionals (Crocker 2011; Taylor 2010; Umaretiya 2017). However, when surveyed, the most common reasons given for low adherence to guidelines by physicians or mothers included "breast milk has all the nutrients a baby needs" and "nutritional rickets is not an important disease" (Perrine 2010; Taylor 2010; Umaretiya 2017). Breastfeeding advocates have also expressed concerns that the suggestion that breast milk may be vitamin D‐deficient and thus require additional supplementation may imply that artificial feeding is superior to breastfeeding (Heinig 2003).

There are two Cochrane Reviews and a Cochrane protocol on vitamin D supplementation for children and pregnant women (De‐Regil 2016; Winzenberg 2010; Winzenberg 2013b). A review on interventions to prevent nutritional rickets in term‐born children reported few data specific to term breastfed infants (Lerch 2007). This review aims to focus on evidence from randomised controlled trials (RCTs), specifically for term breastfed infants for the role of vitamin D supplementation to prevent vitamin D deficiency and improve bone health.