The mother is the major source of circulating 25-OHD concentrations in the young infant. Thus maternal vitamin D status is an important factor in determining the vitamin D status of the infant and his/her risk of developing vitamin D deficiency and infantile nutritional rickets. There is evidence that the supplementation recommendations, particularly for pregnant and lactating women, may be inadequate to ensure vitamin D sufficiency in these groups. Thus there needs to be a wide spread and concerted effort to ensure daily supplementation of breastfed and other infants at high risk with vitamin D 400 IU from birth and pregnant women in high risk communities with at least 600 IU. Future studies are required to determine the optimal doses of vitamin D supplementation needed during pregnancy and lactation; and for normalizing vitamin D stores in infancy to reduce the prevalence of infantile nutritional rickets. Furthermore, operational research studies need to be conducted to understand the best methods of implementing supplementation programs and the factors that are likely to promote their success.
Infantile nutritional rickets is re-emerging as a worldwide health problem despite having been nearly eradicated in many countries, including the United States, in the 1930s and 1940s with the introduction of foods fortified with vitamin D, such as milk. The resurgence of vitamin D deficiency and rickets in developed countries and its continued presence in many developing countries have raised considerable concern and questions about the epidemiology and prevention of vitamin D deficiency rickets during infancy.
Vitamin D fortification of food and/or milk (including infant milk formulas) and the provision of vitamin D supplements had eradicated the problem in North America and many parts of Europe but the immigration of large numbers of dark-skinned families, and the emphasis on exclusive breastfeeding and “breast is best”, have led to a rising incidence of vitamin D deficiency in most developed countries. Other reasons for the resurgence of rickets include the use of sunscreens to reduce the risk of the later development of skin malignancies from ultraviolet (UV) radiation and religious/social practices that limit adequate sun exposure in pregnant and lactating mothers and their young children.
Developing countries have also not been spared. Rapid urbanization and the movement of rural families into overcrowded shanty towns associated with increased atmospheric pollution are some of the factors that have seen a continuation of or increase in the prevalence of rickets in young children.
Over the last 20 years, there has been an increasing realization of the role played by maternal vitamin D status during pregnancy and lactation in influencing the vitamin D status of the newborn and young infant.
This article briefly describes the pathophysiology of vitamin D homeostasis in the mother-infant pair and the interrelationship between maternal vitamin D status and infantile nutritional rickets, and discusses ways of improving maternal vitamin D status and thus reducing the prevalence of vitamin D deficiency in the young infant.
Cause and epidemiology of infantile nutritional rickets
The clinical picture of nutritional rickets was first described by Whistler (1645) and Glisson (1650), who reported that the disease rarely occurred before 6 months of age and was most prevalent between 6 months and 2.5 years of age. Although the classic features of vitamin D deficiency rickets are most commonly seen during this period, studies have shown that symptomatic vitamin D deficiency can develop early in infancy. In Turkey, for example, in a 2-year period, 42 infants less than 3 months of age were diagnosed with vitamin D deficiency and/or nutritional rickets, and isolated cases of congenital rickets have been described from countries such as Greece and India.
As the clinical features of vitamin D deficiency may be absent or not pathognomonic of rickets in early infancy, there may be an underestimation of the real prevalence of vitamin D deficiency in many studies.
Symptoms of hypocalcemia itself are frequently the presenting features of symptomatic vitamin D deficiency in infants less than 6 months of age, and asymptomatic hypocalcemia may be missed. At this early stage, radiographs generally do not show the typical features of rickets, although there may be some bone demineralization. The development of symptomatic hypocalcemia, which occurs before any radiological changes, has been attributed to the high demand for calcium during the rapid growth characteristic of early infancy. Ladhani and colleagues have reported that the ages of infants/children presenting with symptomatic hypocalcemia correlate with periods of rapid growth ( Fig. 1 ). During childhood before the pubertal growth spurt, the slower bone growth and thus lower calcium demands allow the body to avoid symptomatic hypocalcemia by drawing on bone stores of calcium through secondary hyperparathyroidism in situations of vitamin D deficiency. Symptomatic hypocalcemia in young infants caused by vitamin D deficiency has been reported from several countries, including the United Kingdom, Turkey, where the infants were exclusively breastfed, and Australia, where hypocalcemia was the mode of presentation in 50% of patients presenting at less than 6 months of age. In the last study, hypocalcemic seizures were more common in the winter and spring months than in summer and autumn months. In an Indian study of 13 exclusively breastfed infants presenting with hypocalcemic seizures secondary to proven vitamin D deficiency, the youngest was 2 months old and the oldest 6 months old. As is typical of this group of infants, none had received vitamin D supplements and all the mothers had low circulating 25-hydroxyvitamin D (25-OHD) concentrations. It is clear from the literature that there is an increasing awareness among health practitioners of vitamin D deficiency presenting as hypocalcemic seizures during the first 6 months of life. Whether or not the incidence is increasing is unclear as most studies are case reports.
Adequate endogenous synthesis of vitamin D is essential to establish and maintain vitamin D sufficiency and to prevent rickets in most children, as few foods, unless fortified, contain adequate amounts of vitamin D to maintain vitamin D sufficiency. The cutaneous production of vitamin D (cholecalciferol or vitamin D 3 ) depends on the amount of skin exposed and the dose of UV radiation with a wavelength of between 290 and 315 nm. Thus time of day, season, latitude, length of sunlight exposure, percentage of body surface exposed to sunlight (clothing), and skin pigmentation are all important factors influencing vitamin D formation. The amount of UV-B radiation available for vitamin D synthesis is reduced in early morning, late evening, in the winter, and at latitudes greater than 37° N or S. Evidence shows that 1 erythemal dose of sunlight, which is equivalent to a healthy young or middle-aged adult being on a sunny beach and obtaining enough sun to cause a slight pinkness to the skin, synthesizes approximately 20,000 IU D 3 . It has been suggested that for white infants to maintain vitamin D sufficiency, 2 hours of sunlight exposure per week are the minimum required if only the face is exposed, or 30 min/wk if the upper and lower extremities are exposed. Dark-skinned persons are more at risk of vitamin D deficiency than light-skinned persons because increased melanin content of the skin absorbs more UV radiation. Dark-skinned persons require 5 to 10 times the exposure of sunlight to produce the same amount of vitamin D 3 in their skin as does a white person with light skin. Preventable factors and practices that are perceived to be health beneficial but detrimental to cutaneous vitamin D synthesis include limiting skin exposure to sunshine by avoiding direct sunlight, ensuring good skin coverage by clothing, and the use of sunscreens to prevent UV radiation penetrating the skin. Religious and cultural practices may also limit vitamin D synthesis, for example, purdah (seclusion of women from public observation) and veiling are primarily responsible for vitamin D deficiency in Muslim women and their infants, and the practice of zuo yuezi or “doing the month” (confinement of new mothers and their babies to their beds) in China predisposes children to developing rickets.
The burden and prevalence of infantile nutritional rickets have been reported in studies in the past few decades from developing regions such as the Middle East and Asia, and from developed countries such as the United States, United Kingdom, Canada, Australia, and Greece. Common factors that seem to be important in most of the studies include maternal vitamin D deficiency, being breastfed, birth during winter and spring, and increased skin pigmentation. In Canada, the overall confirmed cases of vitamin D deficiency were 2.9 cases per 100,000 children less than 7 years of age in a 2-year period and in the United Kingdom the annual incidence rate was 7.5 per 100,000 children less than 5 years of age. Both studies observed higher rates of vitamin D deficiency among darker-skinned and black African or African Caribbean individuals. Furthermore, pregnant South Asian women (of Indian and Bangladeshi origin) residing in the United Kingdom have a high incidence of hypovitaminosis D, which is exacerbated by the low availability of overhead sun together with the risk factors of darker skin pigmentation, low amounts of outdoor activity, and excessive skin coverage by clothing. A high prevalence of hypovitaminosis D has also been observed in Northern India, a tropical country with abundant sunshine, among pregnant Asian women and their newborns not observing purdah. Despite the sunshine in Greece, mothers and their exclusively breastfed infants were found to be vitamin D deficient, especially during the winter and spring months. Other risk factors in Greece included a lack of vitamin D enriched foods and use of sun-block creams, as well as women in urban areas spending little time outdoors because of indoor jobs. Studies performed in the United States suggest that hypovitaminosis D affects healthy children of all ages and all races/ethnicities even although it is more common in dark-skinned infants and their mothers and those living in the northern states. A study of 200 black and 200 white newborns in Pittsburgh, Pennsylvania found that 9.7% of white compared to 45.6% of black neonates had 25-OHD concentrations less than 15 ng/mL (classified by the authors as vitamin D deficiency), while approximately a half of black and white neonates had 25-OHD levels between 15 and 32 ng/mL (classified as insufficiency). There was no seasonal effect on vitamin D status in black neonates, which probably reflects the low vitamin D status of their mothers throughout the year. Maternal vitamin D deficiency during pregnancy has been documented in many recent reports ( Table 1 ); these studies raise the concern that most infants are being born with limited vitamin D reserves and in many, circulating 25-OHD concentrations indicate vitamin D deficiency.
| Country | Percentage |
|---|---|
| United Kingdom | 18 |
| United Arab Emirates | 25 |
| Iran | 80 |
| North India | 42 |
| New Zealand | 61 |
| Netherlands | 60–84 of non-Western women |
The pathogenesis of rickets in the Middle East is multifactorial, but maternal vitamin D deficiency plays a major role. In Turkey, rickets is a disease of the underprivileged, strongly correlated with poor social background and insufficient exposure to sunlight, and a lack of vitamin D supplementation seems to be decisive for the development of the disease. Recent findings by Ozkan and colleagues confirmed that 89% of patients with rickets had veiled mothers whose bodies were not directly exposed to sunlight. Overcrowding, smaller houses, lower family incomes, and lower parental education levels were all correlated with the prevalence of nutritional rickets. Andiran and colleagues have also emphasized that in Turkey the 2 most important risk factors for a low serum 25-OHD level in a newborn are maternal 25-OHD concentrations less than 25 nmol/L (odds ratio [OR] = 15.2, P = .002), and a covered mother (OR = 6.8, P = .011). Among maternal factors, interlude to the next pregnancy, prenatal care, physician visits, nutrition during nursing, and exposed body surface were all lower in mothers of infants with rickets. Sociocultural practices of mothers seem to be more important than nutritional factors in the pathogenesis of infantile nutritional rickets.
Robinson and colleagues reported on the re-emerging burden of rickets in Sydney, Australia, which is a modern city with good nutritional health standards and high sunlight hours. These investigators implicated the immigration trends from North African, Middle Eastern, and Asian countries as the cause for the increasing prevalence of vitamin D deficiency. In their study, immigrant infants or first-generation offspring of immigrant parents with maternal vitamin D deficiency and exclusive or prolonged breastfeeding were prominent factors. It is likely that the vitamin D status of immigrant women deteriorated after arriving in Australia, as less time was probably spent outdoors.
In developing and developed countries, vitamin D deficiency has resurfaced. Despite adequate sunshine in certain regions, the fortification of food and dairy products in many countries and preventive strategies, the prevalence and burden of vitamin D deficiency are probably not diminishing and may be increasing. The major worldwide problems are lack of sun exposure, breastfeeding without vitamin D supplementation, and maternal vitamin D deficiency.
Vitamin D and calcium homeostasis in the mother-infant pair during pregnancy and lactation
Major changes in maternal calcium homeostasis take place during pregnancy and lactation, as the mother must provide enough calcium for fetal development during pregnancy and to meet breast milk calcium concentrations during lactation. In the nonpregnant and nonlactating woman, vitamin D sufficiency is essential to maintain normal calcium and bone homeostasis. However, during pregnancy and lactation, the vitamin D endocrine system probably plays little role in the physiologic alterations in maternal calcium homeostasis. In utero, the fetus too probably does not require the transplacental transfer of vitamin D to maintain normal calcium homeostasis as the placental transfer of calcium between mother and fetus is independent of vitamin D. It is only after birth that the infant’s dependency on vitamin D becomes evident, at least with respect to calcium metabolism and skeletal health in the infant.
The placenta actively transports calcium (25–250 mg/d) ( Fig. 2 ) to the fetus, whose total and ionized serum calcium concentrations are maintained at about 1 mg/dL more than maternal levels. To meet the needs for fetal bone development and growth, maternal intestinal calcium absorption increases by approximately 33%, with the maximum rate occurring in the last trimester. These processes are mediated during pregnancy in part by increased 1,25-(OH) 2 D concentrations but also through the actions of other regulating factors such as parathyroid hormone-related protein (PTHrP), estradiol, placental lactogen, and prolactin.
Approximately 80% of fetal skeletal mineral is deposited between 25 weeks of gestation and term. At birth, neonatal total body calcium is approximately 30 g, of which 99% is in the skeleton.
Fetal plasma calcium and phosphorus concentrations are higher than those of the neonate after delivery, which in turn are higher than those of adults. The fetus has increased circulating levels of calcitonin and low levels of parathyroid hormone and the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH) 2 D). At birth, maternal transfer of calcium and phosphorus ceases when the umbilical cord is cut, with the result that parathyroid hormone levels increase during the first 24 to 48 hours of extrauterine life. By 24 to 36 hours serum total calcium concentrations reach their nadir of about 9.0 mg/dL (2.25 mmol/L), whereas ionized calcium levels reach a nadir of 4.9 mg/dL (1.2 mmol/L) by approximately 16 hours of life. The rapid decline in circulating calcium is believed to reflect continued incorporation of mineral substrate into bone in the face of a reduced influx caused by low dietary intakes and the absence of placental transfer in association with initially low levels of parathyroid hormone (PTH) and 1,25-(OH) 2 D. In the immediate postnatal period, the neonate becomes dependent on PTH and 1,25-(OH) 2 D to maintain calcium homeostasis; thus vitamin D deficiency in the neonate may cause a prolongation of the neonatal hypocalcemia and a more severe decrease in serum calcium concentrations postnatally.
During pregnancy 25-OHD readily crosses the placenta ( Fig. 3 ) such that cord blood 25-OHD levels are between 80% and 100% of maternal concentrations. Vitamin D and 1,25-(OH) 2 D do not cross the placenta into the fetus in appreciable amounts. Thus, the newborn is dependent on the maternal supply of 25-OHD to ensure an adequate vitamin D status at birth. As 25-OHD has a short half-life (2–3 weeks), newborn concentrations decrease rapidly during the neonatal period unless an exogenous source of vitamin D is provided. Thus if maternal vitamin D status is poor, the low 25-OHD concentrations in the neonate decrease rapidly into the deficient range.
The mechanism by which the increased demands for calcium during lactation are met by the mother is different from that which occurs during pregnancy. Maternal losses of calcium and phosphorus through breast milk are more than 4 times greater than those that are required by the fetus during pregnancy ( Fig. 4 ). During lactation the major source of calcium is the maternal skeleton, with 5% to 10% of bone mass being lost over the course of 6 months of lactation. As mentioned earlier, during pregnancy the increased calcium demands are met by an increase in intestinal calcium absorption, and bone mass changes little during pregnancy. The probable mechanism by which bone mineral is mobilized during lactation is through the production of PTHrP in breast tissue and its secretion into the maternal circulation, mobilizing bone mineral and suppressing maternal PTH secretion. Further, the low estrogen levels characteristic of lactation enhance skeletal mobilization. Although serum calcitonin levels are increased and may help to protect the calcium stores, these are insufficient to prevent rapid bone loss. Intestinal calcium absorption during lactation returns to normal from the increased rate that occurs during pregnancy. Neither habitual calcium intake nor calcium supplementation influences the rate or extent of maternal bone loss during lactation. In general, maternal bone mass recovers to prepregnancy values within 3 to 6 months following the cessation of lactation by mechanisms that are unclear at present.
Unlike the pattern of vitamin D and its metabolite transfer across the placenta during pregnancy, when the major transferred metabolite is 25-OHD, during lactation it seems that the parent vitamin D crosses readily into breast milk, whereas only about 1% of maternal circulating 25-OHD and no 1,25-(OH) 2 D crosses. Thus breast milk contains the parent vitamins (D 2 and D 3 ) and small amounts of their 25-hydroxylation products (25-OHD 2 and 25-OHD 3 ) as well as other metabolites that are present in plasma. The small amount of maternal circulating 25-OHD that crosses into breast milk provides a steady supply of antirachitic activity that is resistant to daily fluctuations in vitamin D supply, although in most women the amount in breast milk is too small to prevent vitamin D deficiency in the breastfed infant. In contrast, 20% to 30% of maternal circulating vitamin D is expressed in breast milk. However, maternal circulating vitamin D concentrations are low unless the mother has recently been exposed to sunlight or vitamin D supplements ; thus in the normal urban situation the parent vitamin D content of breast milk is low, resulting in the characteristically low antirachitic activity of breast milk. It has been estimated that breast milk from an unsupplemented vitamin D replete mother contains the equivalent of 20 and 60 IU/L of antirachitic activity in the form of various metabolites, which is insufficient to meet the vitamin D requirements of the exclusively breastfed infant and contributes little to the infant’s vitamin D status ( Fig. 5 ). Using the Heaney regression model a maternal supplement of 400 IU/d vitamin D 3 during lactation would increase the maternal circulating 25-OHD concentration by 2.8 ng/mL following 5 months of supplementation, thus doing little to sustain the vitamin D status of the mother or her nursing infant. However, this calculation does not take into account the possible increase in circulating maternal vitamin D levels and thus the possible resultant increase in parent vitamin D transfer into breast milk.
The lower vitamin D activity in breast milk of African American women is well documented, and reflects the generally poorer vitamin D status of black women compared with white women in the United States. The cutaneous synthesis of vitamin D in individuals with darker skin pigmentation requires longer sun exposure or higher doses of UV-B radiation to produce comparable serum 25-OHD to that produced in individuals with lighter skin pigmentation. The high incidence of obesity in African American women may also play a role in reducing 25-OHD concentrations, as has been reported by Parikh and colleagues, who found a significant negative correlation between body mass index (calculated as weight in kilograms divided by the square of height in meters) or obesity and serum 25-OHD in African Americans.
The association between low maternal 25-OHD concentrations and poor vitamin D status in their breastfed infants has been noted in studies conducted in many different countries. This association probably reflects a combination of 2 major factors: first, the lack of adequate vitamin D activity in the breast milk of the vitamin D insufficient or deplete mother, and second, the exposure of the infant to similar social and environmental factors to those that induced vitamin D insufficiency in the mother (mainly a lack of sunlight exposure). This combination is highlighted in studies conducted in the Middle East, where there are large amounts of sunshine for most of the year. Despite the abundance of sunshine in the United Arab Emirates, exclusively breastfed, healthy, term infants and their mothers have a high prevalence of hypovitaminosis D without supplemental vitamin D. In this study, rachitic infants were almost all breastfed (92% compared with 58% in age-matched controls), were not on vitamin D supplements (92% vs 62%), had limited sunlight exposure (0 min/d vs 45 min/d), and their mothers had lower 25-OHD concentrations (5.3 ng/mL vs 9.6 ng/mL) than mothers of nonrachitic children. In a study from Johannesburg, South Africa, which has an average of more than 8 hours of sunshine per day throughout the year, low maternal 25-OHD concentrations (10.6 ng/mL) during the winter months were believed to be responsible for the low 25-OHD concentrations in exclusively breastfed young infants. Similarly in Pakistan, a high prevalence of vitamin D deficiency in breastfed infants (55%) and nursing mothers (45%) was observed. In Sydney, Australia, 91% of a pediatric cohort with rickets had a 25-OHD level of less than 8 ng/mL if they were breastfed by a vitamin D deficient mother (<20 ng/mL). All these studies highlight the importance of maternal vitamin D deficiency during lactation in the pathogenesis of rickets in breastfed infants. It is also important to ensure that the maternal vitamin D status during pregnancy is optimized so that the neonate starts life with a good 25-OHD concentration, as vitamin D stores in the neonate are limited because of the lack of passage of the parent vitamin D across the placenta. Thus, in early infancy, the vitamin D status of breastfed infants depends on the 25-OHD transferred across the placenta during intrauterine life. Thereafter, because of the short 3-week half-life of 25-OHD, either an exogenous supply of vitamin D through breast milk or infant supplementation or the endogenous production through sunlight exposure is necessary to maintain vitamin D sufficiency.
Vitamin D and calcium homeostasis in the mother-infant pair during pregnancy and lactation
Major changes in maternal calcium homeostasis take place during pregnancy and lactation, as the mother must provide enough calcium for fetal development during pregnancy and to meet breast milk calcium concentrations during lactation. In the nonpregnant and nonlactating woman, vitamin D sufficiency is essential to maintain normal calcium and bone homeostasis. However, during pregnancy and lactation, the vitamin D endocrine system probably plays little role in the physiologic alterations in maternal calcium homeostasis. In utero, the fetus too probably does not require the transplacental transfer of vitamin D to maintain normal calcium homeostasis as the placental transfer of calcium between mother and fetus is independent of vitamin D. It is only after birth that the infant’s dependency on vitamin D becomes evident, at least with respect to calcium metabolism and skeletal health in the infant.
The placenta actively transports calcium (25–250 mg/d) ( Fig. 2 ) to the fetus, whose total and ionized serum calcium concentrations are maintained at about 1 mg/dL more than maternal levels. To meet the needs for fetal bone development and growth, maternal intestinal calcium absorption increases by approximately 33%, with the maximum rate occurring in the last trimester. These processes are mediated during pregnancy in part by increased 1,25-(OH) 2 D concentrations but also through the actions of other regulating factors such as parathyroid hormone-related protein (PTHrP), estradiol, placental lactogen, and prolactin.
Approximately 80% of fetal skeletal mineral is deposited between 25 weeks of gestation and term. At birth, neonatal total body calcium is approximately 30 g, of which 99% is in the skeleton.
Fetal plasma calcium and phosphorus concentrations are higher than those of the neonate after delivery, which in turn are higher than those of adults. The fetus has increased circulating levels of calcitonin and low levels of parathyroid hormone and the active metabolite of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH) 2 D). At birth, maternal transfer of calcium and phosphorus ceases when the umbilical cord is cut, with the result that parathyroid hormone levels increase during the first 24 to 48 hours of extrauterine life. By 24 to 36 hours serum total calcium concentrations reach their nadir of about 9.0 mg/dL (2.25 mmol/L), whereas ionized calcium levels reach a nadir of 4.9 mg/dL (1.2 mmol/L) by approximately 16 hours of life. The rapid decline in circulating calcium is believed to reflect continued incorporation of mineral substrate into bone in the face of a reduced influx caused by low dietary intakes and the absence of placental transfer in association with initially low levels of parathyroid hormone (PTH) and 1,25-(OH) 2 D. In the immediate postnatal period, the neonate becomes dependent on PTH and 1,25-(OH) 2 D to maintain calcium homeostasis; thus vitamin D deficiency in the neonate may cause a prolongation of the neonatal hypocalcemia and a more severe decrease in serum calcium concentrations postnatally.
During pregnancy 25-OHD readily crosses the placenta ( Fig. 3 ) such that cord blood 25-OHD levels are between 80% and 100% of maternal concentrations. Vitamin D and 1,25-(OH) 2 D do not cross the placenta into the fetus in appreciable amounts. Thus, the newborn is dependent on the maternal supply of 25-OHD to ensure an adequate vitamin D status at birth. As 25-OHD has a short half-life (2–3 weeks), newborn concentrations decrease rapidly during the neonatal period unless an exogenous source of vitamin D is provided. Thus if maternal vitamin D status is poor, the low 25-OHD concentrations in the neonate decrease rapidly into the deficient range.
