Description of the condition
Vitamin D metabolism
Vitamin D is a fat-soluble vitamin which comes primarily from exposure to sunlight, and is found naturally only in a few foods, such as fish-liver oils, fatty fish, mushrooms, egg yolks, and liver (Holick 2007a; Holick 2008). There are two physiologically active forms of vitamin D collectively called calciferol: D2 and D3. Vitamin D2 (also called ergocalciferol) is synthesized by plants while vitamin D3 (also called cholecalciferol) is subcutaneously produced from 7-dehydrocholecalciferol upon exposure to ultraviolet light B (UVB) radiation (DeLuca 2004). Vitamin D in supplements is found as either vitamin D2 or D3. The latter could be three times more effective than vitamin D2 in raising serum concentrations of vitamin D and maintaining those levels for a longer time; also, its metabolites have superior affinity for vitamin D-binding proteins in plasma (Armas 2004; McCullough 2007). As vitamin D has a short half-life, adequate vitamin D intake is necessary in order to ensure sustained circulating levels.
Both D2 and D3 forms share a similar metabolism. They are first hydroxylated in the liver to form 25 hydroxyl vitamin D (25(OH)D or calcidiol), and then in the kidney to 1,25 di hydroxyl vitamin D (1,25-di(OH) D or calcitriol) in response to parathyroid hormone (PTH) levels. Calcitriol is considered an important pre-hormone with active metabolites that are involved in metabolic processes including bone integrity and calcium homeostasis (Wagner 2008).
The major sites of vitamin D action include the skin, intestine, bone, parathyroid gland, immune system, and pancreas as well as the small intestine and colon in the human fetus (Theodoropoulos 2003). Additionally, vitamin D helps maintain normal levels of glucose in the blood, by binding to its receptors in the pancreatic beta cells, to regulate the release of insulin in response to the level of circulating glucose (Clifton-Bligh 2008; Maghbooli 2008; Palomer 2008).
There is a unique relationship between vitamin D and calcium. The PTH is responsible for raising the calcium concentration in the blood through bone resorption, while calcitriol inhibits PTH and allows an increase of serum calcium concentration from sources other than the bone. In the presence of calcitriol, renal and intestinal calcium and phosphorus absorption is augmented leading to an improved calcium status.
Vitamin D status
Serum calcidiol or 25(OH)D can be used to assess vitamin D status, as it reflects the sum of the vitamin D produced cutaneously and that obtained from foods and supplements (Jones 2008). This metabolite is difficult to measure, with large variations between methods and among laboratories even when the same methods are used (Hollis 2004).
Currently, there is no consensus on the optimal levels of serum calcidiol for promoting health. In general, levels lower than 50 nmol/L (or lower than 20 ng/mL) are considered inadequate (Institute of Medicine 1997). Levels around 80 nmol/l (32 ng/ml) could be considered optimal, since they suppress PTH levels and lead to the greatest calcium absorption and the highest bone mass, reducing the rates of bone loss, falls, and fractures (Dawson-Hughes 2005; Dawson-Hughes 2008). Individuals with plenty of sun exposure have circulating calcidiol levels ranging from 54 to 90 ng/ml (135 to 225 nmol/L) (Haddock 1985). Whether the optimal levels proposed for non-pregnant adults are adequate for pregnant women remains uncertain.
Vitamin D status is affected by factors that regulate its production in the skin (i.e. skin pigmentation, latitude, dressing codes, season, aging, sunscreen use, and air pollution) and by factors affecting its absorption or metabolism (Holick 2007b; Maghbooli 2007). Melanin acts as a filter for ultraviolet (UV) rays hence reducing the skin production of vitamin D. Hispanic and black populations in the United States may have higher melanin content, and thus have reduced vitamin D photosynthesis (Clemens 1982), explaining the variation in vitamin D concentration among ethnic groups living in the same geographical areas (Brooke 1980; Egan 2008; Matsuoka 1991; Nesby-O'Dell 2002; Rockell 2005). Differences in latitude have also been shown to influence the concentration of vitamin D, and individuals from countries in high and low latitudes have lower vitamin D levels. The importance of UV rays is further shown by the seasonal variation in the concentration of vitamin D between summer and winter, with changes during the summer compared to the winter months (Holick 2007b; Levis 2005). Vitamin D metabolism is also affected in obese individuals, as vitamin D is deposited in body fat stores, making it less bioavailable (Arunabh 2003). It has been shown that low calcidiol levels are more prevalent among overweight and obese individuals compared to normal weight individuals (Vilarrasa 2007; Wortsman 2000). In the same context, sedentary activity is also associated with low vitamin D levels as it may be linked with diminished sunlight exposure (Ohta 2009).
Magnitude of vitamin D deficiency (VDD)
it has been estimated that one billion people worldwide have vitamin D deficiency or insufficiency and about 40% to 100% of elderly men and women still living in the community in the United States and Europe are deficient in vitamin D (Holick 2007a). VDD is a common health problem both in children and adults, affecting an estimated 30% to 50% of the global population (Bandeira 2006; Holick 2007a). Low concentrations of vitamin D have been found in all age groups in various countries including some in the Middle East (Fuleihan 2001; Sedrani 1984), the United States (Gordon 2004; Lips 2001; Sullivan 2005; Tangpricha 2002), India (Farrant 2009; Marwaha 2005), Japan (Sato 2005) and Australia (McGrath 2001b).
In pregnancy, vitamin D deficiency or insufficiency is also thought to be common. A study in black and white pregnant women residing in the northern United States found that approximately 29% of black pregnant women and 5% of white pregnant women had VDD (defined as serum 25(OH)D less than 37.5 nmol/L); whereas 54% of black women and 47% of white women had vitamin D insufficiency (defined as serum 25(OH)D levels 37.5 to 80 nmol/lL) (Bodnar 2007). Similar results have been found in pregnant African-American adolescents (Davis 2010), in pregnant Asian women (Alfaham 1995), in Iranian pregnant women (Kazemi 2009), in veiled or dark-skinned pregnant women (Grover 2001), in Indian pregnant women (Sachan 2005), in non-Western pregnant women in the Netherlands (Van der Meer 2006), and in pregnant women from Pakistan, Turkey and Somalia (Madar 2009). Recent studies in white pregnant women also show high prevalence of VDD in the UK (Holmes 2009) and Ireland (O'Riordan 2008).
Seasonal variation increases the risk of VDD in pregnancy, with greater prevalence of VDD during the winter months compared to the summer months (Nicolaidou 2006; O'Riordan 2008). Differences in latitude have also been shown to influence the concentration of vitamin D in a majority of pregnant women (Sloka 2009).
Vitamin D status and health outcomes
Vitamin D status and hypertensive disorders during pregnancy
Maternal VDD in pregnancy has been associated with an increased risk of pre-eclampsia (new-onset gestational hypertension and proteinuria for the first time after 20 weeks of gestation), a condition associated with an increase in maternal and perinatal morbidity and mortality (Bodnar 2007; Holick 2008; Li 2000; MacKay 2001; Xiong 1999). Women with pre-eclampsia have lower concentrations of calcidiol compared with women with normal blood pressure (Diaz 2002; Frenkel 1991; Halhali 1995; Halhali 2000; Tolaymat 1994). The low levels of urinary calcium (hypo calciuria) in women with pre-eclampsia may be due to a reduction in the intestinal absorption of calcium impaired by low levels of vitamin D (August 1992; Halhali 1995). Additionally, pre-eclampsia and VDD are directly and indirectly associated through biologic mechanisms including immune dysfunction, placental implantation, abnormal angiogenesis, excessive inflammation, and hypertension (Bodnar 2007; Cardus 2006; Evans 2004; Hewison 1992; Li 2002).
Vitamin D status and other maternal conditions
Maternal VDD in early pregnancy has been associated with elevated risk for gestational diabetes mellitus, although findings are still not consistent (Farrant 2008; Zhang 2008). Poor control of maternal diabetes in early pregnancy is inversely correlated with low bone mineral content in infants, as is low maternal vitamin D status (Namgunga 2003). VDD may lead to a high bone turnover, bone loss, osteomalacia and myopathy in the mother in addition to neonatal and infant VDD (Glerup 2000; Lips 2001).
An adequate vitamin D status may also protect against other adverse pregnancy outcomes. For example, maternal VDD has been linked to cesarean section in a single recent study (Merewood 2009) but the mechanisms involved are unclear.
Low prenatal and perinatal maternal vitamin D concentrations can affect the function of other tissues, leading to a greater risk of multiple sclerosis, cancer, insulin-dependent diabetes mellitus, and schizophrenia later in life (McGrath 2001a).
Vitamin D status and preterm birth and low birthweight
The potential association between maternal vitamin D status and preterm birth (less than 37 weeks' gestation) has been reported (Dawodu 2010; Morley 2006). In comparison, not all the studies show significant associations between maternal calcidiol levels and any measure of the child's size at birth or during the first months of life (Bodnar 2010; Farrant 2009; Gale 2008; Morley 2006). There is not much information on maternal vitamin D status and low birthweight or preterm birth in children born from HIV-infected pregnant women (Mehta 2009).
Vitamin D status and postnatal growth
Some observational studies suggest that vitamin D levels during pregnancy influence fetal bone development and children's growth (Bodnar 2010; Brooke 1980; Mahon 2010; Morley 2006). While head circumference in children nine years of age has been significantly associated with maternal calcidiol levels (Gale 2008), there is still inconsistent information about the association of maternal vitamin D status and infants' bone mass (Akcakus 2006; Javaid 2006; Viljakainen 2010).
It is not clear if maternal VDD leads to neonatal rickets, since rickets is usually identified later in childhood. Early studies indicate a possible risk for neonatal rickets in the offspring of women with osteomalacia, abnormal softening of the bone by deficiency of phosphorus, calcium or vitamin D (Ford 1973). More recent studies have found that VDD (serum levels less than 25 nmol/L) was identified in 92% of rachitic Arab children and 97% of their mothers compared with 22% of nonrachitic children and 52% of their mothers (Dawodu 2005). A positive correlation was found between maternal and child vitamin D levels.
Vitamin D status and immune response
Vitamin D has direct effects on both adaptive and innate immune systems (Miller 2010; Walker 2009). In children vitamin D insufficiency is linked to autoimmune diseases such as type 1 diabetes mellitus, multiple sclerosis, allergies and atopic diseases (Bener 2009; Miller 2010; Pierrot-Deseilligny 2010). Various studies have also shown that vitamin D deficiency is strongly associated with tuberculosis, pneumonia, and cystic fibrosis (Chocano-Bedoya 2009; Hall 2010; Williams 2008) and both prenatal and perinatal vitamin D deprivation might influence early-life respiratory morbidity as this vitamin is important for lung growth and development. (Devereux 2007; Litonjua 2009).
Vitamin D may have positive effects on the immune system by up-regulating the production of the antimicrobial peptides by macrophages and endothelial cells (Wang 2004), which may inactivate viruses and suppress inflammation (Cantorna 2008), which may reduce the severity of infections.
Vitamin D toxicity
There has been little toxicity reported in adults taking doses as high as 10,000 IU/d (250 µg/d) of vitamin D (Hathcock 2007; Heaney 2008; Vieth 1999), although toxicity becomes generally present at 20,000 IU/d (500 µg/d). Vitamin D toxicity leads to hypercalcaemia (serum calcium higher than 10.6 mg/L), hypercalciuria (fasting urinary calcium/creatinine ratio of higher than 0.16 ng/mg) and an upper limit of serum 25(OH)D levels of 200 nmol/L (Aloia 2008). Hypercalciuria has been associated with renal and kidney stones (Heaney 2008).
Description of the intervention
Many health organizations recommend vitamin D supplementation during pregnancy and lactation. However, there are some variations in the recommended dose for supplementation ranging from 200 to 400 IU/d (Canadian Paediatric Society 2007; Hollis 2004; Institute of Medicine 1997; UK Department of Health 2009; WHO/FAO 2004) and some authors have suggested that requirements could be even greater (Hollis 2004). The American Academy of Pediatrics (Wagner 2008) suggests that healthcare professionals who provide obstetric care should consider monitoring maternal vitamin D status by measuring its concentrations in pregnant women.
The intake of vitamin D necessary to achieve a blood concentration considered optimal (80 nmol/l or 32 ng/ml) is greater than current recommendations. The debate on adequate values stems from the variability in baseline serum calcidiol levels and the laboratory techniques used. Studies have found that to increase serum calcidiol levels in 1.2 nmol/l, a supplemental dose of vitamin D of 400 IU/d is needed in those with low serum calcidiol levels, while those with better baseline levels have smaller increments with the same dose. It has been suggested that a supplemental dose of vitamin D of 1000 to 1600 IU might be necessary (Dawson-Hughes 2005). However, the dose of vitamin D needed to have an effect during pregnancy or to prevent or treat VDD is not clear. Some have suggested that doses around 1000 IU/d may be needed in order for pregnant women to maintain a blood concentration of vitamin D of more than 50 nmol/l (Heaney 2003; Hollis 2004; Hollis 2007; Vieth 2001). Others have suggested providing vitamin D as a weekly dose of 5000 IU (125 ug/wk) (Utiger 1998) or a single dose of 200,000 IU or greater (Mallet 1986; Sahu 2009; Yu 2009).
Since vitamin D can also be synthesized by the skin upon exposure to sunlight, increasing casual sun exposure for reaching the optimal serum levels (Holick 2002) has been recommended. However, since excessive UV radiation is a carcinogen, it might be better to obtain additional vitamin D from foods or supplements.
How the intervention might work
Vitamin D supplementation improves maternal vitamin D status during pregnancy (Delvin 1986; Yu 2009), which in turn has direct influence on the fetal and neonatal supply of vitamin D (Brooke 1980). The potential effect of gestational vitamin D supplementation in preventing preterm birth (less than 37 weeks' gestation) and low birthweight (less than 2500 g) has been suggested (Maxwell 1981); although there is not much information on the additional benefit of vitamin D supplementation over other nutritional interventions during pregnancy such as iron and folic acid supplementation on the risk of low birthweight (Christian 2003). There is also a potential effect of maternal vitamin D supplementation on neonatal growth (Marya 1988). In addition to adequately exposing the infant to sunlight, vitamin D supplementation during pregnancy may be necessary to assure adequate concentration of vitamin D in breast milk during lactation (Butte 2002).
Some agencies have indicated that ensuring adequate vitamin D status with conventional prenatal vitamin D supplements should be encouraged as gestational vitamin D deficiency is common (Arden 2002; Namgunga 2003; Specker 1994; WHO/FAO 2004).
Why it is important to do this review
This review will update a previously published review (Mahomed 1999) and will incorporate new evidence on the effects and safety of vitamin D supplementation in pregnancy for the well being of the mother and newborn.