Throughout most of the previous century, vitamin D deficiency and rickets were predominantly perceived as problems of industrialized countries at northern latitudes, where insufficient exposure to sun and intake of vitamin D were linked to inadequate intestinal absorption of calcium and impaired skeletal mineralization (¹). However, since vitamin D status has become readily estimable based on serum/plasma 25-hydroxyvitamin D concentration [25(OH)D] (²), epidemiologic research aimed at identifying previously-uncharacterized at-risk populations and characterizing novel disease associations with vitamin D status has been greatly facilitated. Thus, vitamin D deficiency has re-emerged as a global public-health concern and is now presumptively linked to a range of infectious, inflammatory and neoplastic diseases throughout the life course and around the world (¹).

Low 25(OH)D is surprisingly common in South Asia, where systemic vitamin D deficits would be expected to be prevented by cutaneous vitamin D synthesis stimulated by exposure to sun at relatively low latitudes (³). Few studies on vitamin D status in infancy have been conducted in South Asia (Table 1). In Bangladesh, two published reports on childhood 25(OH)D are available but neither reported 25(OH)D in early infancy (Table 1).

Knowledge of the vitamin D status of young children and infants is needed to design studies targeting the aetiologic mechanisms and potential health implications of deficiency. A case-control study on the association between acute lower respiratory tract infection (ALRI) and vitamin D status in infants and young children conducted in Zakiganj subdistrict of Sylhet district in Bangladesh, during January-February 2008, provided an opportunity to gain preliminary insights into the vitamin D status of infants in northeastern rural Bangladesh (⁴). Here, we aimed to describe the vitamin D status of the source population and briefly review the potential determinants of low infant 25(OH)D in this setting.

This preliminary study in Sylhet during the winter dry season revealed that the vitamin D status of young infants in rural Bangladesh might be poor enough to put many at risk of rickets and other potential vitamin D-related health consequences. Applying a very conservative definition of vitamin D deficiency [25(OH)D <25 nmol/L], we estimated that about one-third of infants aged 1-6 months may be vitamin D-deficient. To our knowledge, this is the first report of vitamin D status in young infants in Bangladesh. However, the causes and consequences of low 25(OH)D in this setting remain to be determined.

To put these findings in a global context, it is first useful to draw a comparison with what is perhaps the only young infant ‘reference’ group studied at the equator where vitamin D status would be expected to be optimal throughout the year in the absence of dietary supplementation or fortification. In a sample of infants in Oyem, Gabon (1°N), the mean 25(OH)D was 110 nmol/L (SD 43) at birth, 149 nmol/L (SD 54) at three months of age, and 151 nmol/L (SD 64) at six months of age (¹⁶). These values suggest a very wide variation but that most infants in that setting were well above the 25(OH)D threshold currently considered optimal (>80 nmol/L) (¹⁷). The present findings from Bangladesh were somewhat intermediary between the results of two other studies in South Asia. In Karachi, Pakistan (25°N), 38 breastfed infants aged less than six months had a mean 25(OH)D of 25 nmol/L (18 SD), and 71% of infants (12/17) aged less than three months, had 25(OH)D <40 nmol/L (¹¹). Further south, in Mumbai, India (18°N), 35 breastfed infants at three months of age had a mean 25(OH)D of 49 nmol/L (SD 24), and 51% had values of <37.5 nmol/L (¹³). In the United Arab Emirates (UAE), at latitude 24°N (about the same as Bangladesh), 78 breastfed term infants aged 1-4 months, born to women with low milk intake and a habitual practice of covering the skin entirely when outdoors, had a median 25(OH)D of only 11.5 nmol/L, and 82% had 25(OH)D <25 nmol/L (¹⁸).

In Iowa, USA (41°N), in a longitudinal study of predominantly white infants who were all exclusively breastfed and not receiving supplements, the mean 25(OH)D at about three and half months of age was 33 nmol/L for those assessed in the summer (50% at <27.5 nmol/L) and 17 nmol/L in the winter (79% at <27.5 nmol/L); at approximately six months of age, the mean 25(OH)D increased to 45 nmol/L in the summer (32% at <27.5 nmol/L) but remained at 17 nmol/L for those measured in the winter (82% <27.5 nmol/L) (¹⁹). An exogenous vitamin D source is recommended for all infants in North America. So, it is worthwhile noting that, among formula-fed or vitamin D-supplemented infants (mean vitamin D intake of ∼370 IU per day) aged 1-6 months (n=37) enrolled in a hospital-based study during the winter in Alberta, Canada (53°N) (²⁰), the mean 25(OH)D was 78 nmol/L (Roth D et al. unpublished observations). Although there was a wide variation (17-152 nmol/L), only one infant aged 1.3 months had 25(OH)D <40 nmol/L, demonstrating the real-world effect of supplementation/fortification policies.

Therefore, these data from rural Bangladesh, in combination with earlier findings from infants in urban Pakistan, India, and UAE, have demonstrated that the vitamin D status of young infants in South Asia and the Middle East may be no better than that of unsupplemented infants at much higher northern latitudes in North America, where guidelines support the provision of routine vitamin D supplementation to all breastfed infants (²¹,²²). This implies that a tropical climate does not necessarily protect against low 25(OH)D in early infancy. Although cutaneous pre-vitamin D3 synthesis is expected to occur year-round in South Asia on the basis of latitude (²³), there is a substantial seasonal variation in ultraviolet B irradiance (²⁴). In fact, a seasonal differential in vitamin D status was observed among Pakistani infants (¹¹). Therefore, the representativeness of our data is limited because they reflect vitamin D status during the winter, when ultraviolet radiation exposure is at its nadir, and when cutaneous vitamin D synthesis would be expected to be relatively minimal (²⁴). Moreover, in the Bengal region, the attenuation of actual summer-time ultraviolet radiation exposure due to monsoon cloud-cover (²⁴) may prevent sufficient endowment of vitamin D stores during the summer and, thus, further increase the risk of deficiency during the winter. Our cross-sectional observations suggest that 25(OH)D in Bangladeshi infants may rise within the first few months of life. However, these age-dependent differences may have been confounded by seasonal timing of gestation—a younger age implied that the third trimester coincided with the expected seasonal nadir of vitamin D synthesis, when maternal vitamin D stores might be relatively depleted and, thus, when transfer of vitamin D metabolites to the foetus may have been minimized.

To further explain the apparent ‘vitamin D paradox’ in South Asia (³), a range of hypothetical mechanisms can be proposed (Table 3). Young infants depend almost entirely on the transplacental transfer of vitamin D and 25(OH)D, which explains the consistent association between maternal and cord-blood 25(OH)D (²⁵) and the observation that maternal antenatal vitamin D supplementation augments both maternal and cord-blood 25(OH)D (²⁶). Therefore, the major reason that Bangladeshi infants start life with poor vitamin D stores is low maternal antenatal 25(OH)D, which has been documented in urban and rural Bangladeshi women of reproductive age (²⁷). Islam et al. recently studied female workers in a garment factory in Dhaka and speculated that their long day-time hours in indoors, brief exposure to low-intensity sunlight in the early morning, outdoor air pollution, and widespread sunscreen use, in combination with darkly-pigmented skin, may contribute to their poor vitamin D status (mean 25(OH)D of 37 nmol/L, and 15% of the participants had 25(OH)D <25 nmol/L) (²⁸). Conservative dress, including almost complete skin coverage by traditional veils or cloaks, has been emphasized as a contributor to vitamin D deficits in Muslim women in South Asia and the Middle East because it limits cutaneous vitamin D synthesis regardless of the intensity of ambient ultraviolet B (²⁹).

Inferences regarding the determinants of infant/toddlers’ vitamin D status in this study were limited, largely because of the small sample-size and substantial uniformity with respect to selected maternal clothing and dietary practices. We also acknowledge that pooling of ALRI cases and controls to maximize our available sample-size may have led to selection biases. However, the observation that mothers of infants with relatively low 25(OH)D seemed less likely to consume foods from animal sources (other than fish) deserves consideration in future studies. The amount of vitamin D in the local diet is unknown but low calcium intake (or reduced absorption of calcium due to high phytate intake), typical of low-income diets in Bangladesh (³⁰,³¹), may accelerate 25(OH)D use, leading to relatively-increased vitamin D demands (³²). Since the concentration of vitamin D metabolites in breastmilk is determined by maternal vitamin D status, maternal vitamin D deficiency during lactation may cause ongoing deficits in postnatal infants’ vitamin D intake (⁴²); yet, maternal factors cannot entirely account for the persistence of low 25(OH)D among toddlers (Table 1) who experience direct exposure to sun and should be unaffected by the conservative clothing practices of their mothers. Therefore, much remains to be learnt about the determinants of vitamin D status throughout infancy and childhood, particularly where 25(OH)D appears discrepant from that which would be expected based on latitude.

Despite the current enthusiasm for vitamin D supplementation in the USA (²²), the effects of vitamin D deficits during early infancy are still not fully understood, and meaningful inflection points in 25(OH)D-outcome relationships have not been established. The most widely-accepted manifestation of severe vitamin D deficiency in infancy is rickets, the classical childhood metabolic bone disease associated with skeletal hypomineralization and deformities, muscle weakness, and growth impairment (¹). Young infants with severe congenital vitamin D deficiency may present with hypocalcaemic tetany or seizures, with absent or subtle skeletal pathology (⁴³–⁴⁵). Greer noted that there is no clear or consistent association between 25(OH)D and the risk of rickets or other functional outcomes (⁴⁶). Although 25(OH)D <25 nmol/L is typical of clinically-apparent rickets, early stages of the disease may occur at higher 25(OH)D (∼40 nmol/L) (⁴⁷), with declines in 25(OH)D occurring as the disease progresses and vitamin D stores are depleted. The frequent occurrence of 25(OH)D >25 nmol/L among toddlers and older children with rickets has been presumptively attributed to dietary calcium deficits (⁴⁸); however, rickets among breastfed infants with 25(OH)D >25 nmol/L (⁴⁹) suggests that factors other than calcium intake may be implicated.

In Bangladesh, rickets may be more common than previously thought, based on surveys of lower limb deformities in ambulating children (⁵⁰,⁵¹). Recent data from a nationwide survey suggest that about 0.6% of Bangladeshi children, aged 1-15 years, may have radiologic evidence of rickets, with the highest prevalence in Chittagong and Sylhet divisions (⁵¹). The incidence of symptomatic hypocalcaemia secondary to vitamin D deficiency in early infancy is unknown. Some investigators have played down the role of vitamin D in rickets in Bangladesh (¹⁰, ⁵²), instead blaming dietary calcium deficits or other mineral deficiencies or excesses, e.g. aluminum (⁵³). However, in case-control studies, dietary calcium intake between rickets-affected and unaffected households did not differ (⁵⁴) whereas the mean 25(OH)D in cases was significantly lower than in controls (¹⁰). A plausible hypothesis is that vitamin D deficiency acts synergistically with other causes of inadequate bone mineralization and that an individual's 25(OH)D concentration below which clinical signs emerge depends on the severity and multiplicity of other genetic and environmental factors.

Beyond rickets, speculation abounds regarding the potential extra-skeletal consequences of suboptimal vitamin D status during foetal development and infancy. The vitamin D receptor has been found within virtually every organ-system (⁵⁵), and the active metabolite of vitamin D is well-described as a potent mediator of cell proliferation and differentiation, particularly noted for its range of effects on immune function in laboratory models (⁵⁶). The case-control study for which the data for the present analysis were primarily collected revealed an inverse association between 25(OH)D and the odds of hospitalization for ALRI (⁴), corroborating the findings in neonates in Turkey (⁵⁷) and children in India (¹⁵). If vitamin D deficiency is confirmed as a risk factor for pneumonia, interventions to improve maternal-infant vitamin D status could reduce the global burden of ALRI, the single most important cause of early childhood death in the world (⁵⁸). Other postulated consequences of antenatal or infant vitamin D deficiency include growth faltering (⁵⁹,⁶⁰), type 1 diabetes (⁶¹), and asthma (⁶²). However, rigorous studies of the broad health benefits of interventions to improve the antenatal or postnatal vitamin D status in South Asian mothers and infants have yet to be reported.

The authors thank the participants and caregivers for their kind cooperation and also thank the study field staff, the Projahnmo Sylhet team, and personnel at the Zakiganj subdistrict hospital. They particularly thank Kazi Moksedur Rahman (Deputy Executive Director, SHIMANTIK), Dr. Arun Kumar Roy (Project Research Physician, Projahnmo), Dr. Daniel Hossain (Project Research Manager, Projahnmo), Dr. Sirajul Islam (Upazila Health and Family Planning Officer), and Dr. Jonme Joy Dutta Shankar (Medical Officer, Zakiganj subdistrict hospital). The authors are grateful to Dr. Bruce Hollis and Dr. Carole Wagner (Medical University of South Carolina, USA), Dr. Samir K. Saha (Bangladesh Institute of Child Health, Dhaka Shishu Hospital, Dhaka, Bangladesh), and the Department of International Health at the Johns Hopkins Bloomberg School of Public Health. D. Roth was supported by training grants from the Canadian Institutes for Health Research and the Alberta Heritage Foundation for Medical Research.