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Keywords:

  • vitamin D;
  • pregnancy;
  • lactation

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. VITAMIN D REQUIREMENTS DURING PREGNANCY
  5. VITAMIN D REQUIREMENTS DURING LACTATION
  6. REFERENCES

The current recommended dietary requirement for vitamin D intake (200 IU/d) during pregnancy and lactation is based on little, if any, scientific evidence, and as a result is clinically irrelevant with respect to maintaining nutritional vitamin D status during these demanding human conditions. Current research has shown that the actual dietary requirement during pregnancy and lactation may actually be as high as 6000 IU/d. Current data on which these new recommendations could be based are presented.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. VITAMIN D REQUIREMENTS DURING PREGNANCY
  5. VITAMIN D REQUIREMENTS DURING LACTATION
  6. REFERENCES

The primary goal of this presentation is to discuss and begin to reassess the adequate intake (AI) for vitamin D during pregnancy and lactation and hopefully establish a meaningful dietary reference intake (DRI) for this important nutrient. This reassessment is critical because the currently recommended AI of 200 IU/d for vitamin D is useless for maintaining nutritional vitamin D status, yet alone improving it.[1] This is especially true in populations of people of color living in northern latitudes.[2] Clinical studies to date with respect to vitamin D supplementation during pregnancy and lactation are largely dated and grossly inadequate, and as a result, very little clinical information can be derived from them. Animal studies have not yielded any insight into the vitamin D requirement during pregnancy and lactation with respect to humans. Conversely, vitamin D toxicity studies in experimental animal models have shown no relevance to normal human physiology and have induced paranoia with respect to vitamin D use.[3] The need for modern clinical trials on these populations is imperative.

VITAMIN D REQUIREMENTS DURING PREGNANCY

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. VITAMIN D REQUIREMENTS DURING PREGNANCY
  5. VITAMIN D REQUIREMENTS DURING LACTATION
  6. REFERENCES

At no point in human nutrition is it more critical to ensure adequate nutrient intake than during the state of pregnancy. One only needs to look back at the data involving folate intake during pregnancy and its role in the development of neural tube defect as a stark example.[4, 5] The lack of clinical investigation into meaningful dietary vitamin D supplementation during pregnancy can be traced back to post-World War II Britain. Because of the British experience with idiopathic infantile hypercalcemia attributed to hypervitaminosis D, a terribly inaccurate association occurred that had a profound effect on the potential of vitamin D supplementation, not only during infancy, but also during pregnancy. In 1963, Black and Bonham-Carter[6] recognized that elfin facies observed in patients with severe idiopathic infantile hypercalcemia resembled the peculiar facies observed in patients with supravalvular aortic stenosis (SAS) syndrome. Shortly thereafter, Garcia et al.[7] documented the occurrence of idiopathic hypercalcemia in an infant with SAS who also had peripheral pulmonary stenosis, mental retardation, elfin facies, and an elevated blood concentration of vitamin D. This is an interesting observation because, in 1964, when the article was published, there were no quantitative means of assessing circulating concentrations of vitamin D. In fact, at that time, it was not even proven that vitamin D was further metabolized within the body. By 1966, vitamin D was viewed by the medical community as the cause of SAS syndrome.[8, 9] As a result of the theory that maternal vitamin D supplementation during pregnancy caused SAS syndrome, animal models were developed to show that toxic excesses of vitamin D during pregnancy would result in SAS.[10, 11] In these earlier cases, vitamin D had nothing to do with the etiology of SAS. What was described as vitamin D–induced SAS syndrome is now known as Williams syndrome.[12] Unfortunately, a low vitamin D intake during pregnancy is still mistakenly associated with SAS.

Williams syndrome is a severe genetic affliction related to elastin gene disruption[13] that is caused by deletion of elastin and contiguous genes on chromosome 7g11.23. This syndrome is characterized by multiorganic involvement (including SAS), dysmorphic facial features, and a distinctive cognitive profile.[13] Such patients often exhibit abnormal vitamin D metabolism, which makes them susceptible to bouts of idiopathic hypercalcemia.[14-18] This relation was suspected as early as 1976.[19] Subsequently, it was shown that children with Williams syndrome exhibit an exaggerated response of circulating 25(OH)D to orally administered vitamin D.[14] Recently, Williams Syndrome transcription factor (WSTF) has been shown to be involved in vitamin D–mediated transcription and replication as a component of two distinct ATP-dependent chromatin remodeling complexes.[20] In essence, what was thought to be SAS caused abnormal vitamin D metabolism and not visa versa. Thus, the fear of vitamin D–induced SAS is based on studies that are no longer valid yet continue to be cited.

A few years ago, The Cochrane Library issued a review of vitamin D supplementation during pregnancy[21] and identified six studies on this topic,[22-27] only four of which reported clinical outcomes.[22, 23, 25, 26] The Cochrane Review concluded that there was not enough evidence to evaluate the requirements and effects of vitamin D supplementation during pregnancy. Presented below are the clinically relevant studies offered by The Cochrane Review plus three additional studies not included in their report.[28-30] These studies have been listed in Table 1.

Table Table 1.. Summary of Vitamin D Supplementation Studies During Pregnancy
  1. * It is very likely that the wrong dose of supplementation was given or the assay for 25(OH)D was invalid. The response observed is one that would be expected after supplementation with 10,000 IU/d vitamin D3 for 3 mo.[1]

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Initial vitamin D supplementation studies during pregnancy were carried out in the early 1980s. Brooke et al.,[22] who studied British mothers of Asian descent, found a greater incidence of small-for-gestational-age infants born to mothers who received placebo than in mothers who received 1000 IU (25 μg) vitamin D2/d during the final trimester of pregnancy. Neonates in the placebo group also had a greater fontanelle area than did the supplemented group. It must be noted that the placebo group in this study showed profound hypovitaminosis D. Follow-up studies by Brooke et al.[25] were conducted in Asian mothers who again were provided with either placebo or 1000 IU vitamin D2/d during the last trimester of pregnancy. The follow-up data provided evidence that, during the first year of life, the infants of the maternal placebo group gained less weight and had a lower rate of linear growth than did the infants of the maternal supplemented group.

Cockburn et al.[23] undertook a large vitamin D supplementation study of >1000 pregnant subjects in the United Kingdom who were supplemented with 400 IU (10 μg) vitamin D2/d or received a placebo from week 12 of gestation onward. At this level of supplementation, serum concentrations of 25(OH)D in the supplemented group were only slightly higher than those in the placebo group. A defect in dental enamel formation was observed in a higher proportion of the children at 3 yr of age in the maternal placebo group. Maxwell et al.[26] conducted a double-blind trial of vitamin D (1000 IU/d) during the last trimester of pregnancy in Asian women living in London. They found that the supplemented mothers had greater weight gains and, at term, had significantly higher plasma concentrations of retinol-binding protein and thyroid-binding prealbumin, which indicated better protein-calorie nutrition. Almost twice as many infants of the unsupplemented group weighed <2500 g at birth and had significantly lower retinol-binding protein concentrations than did infants of the supplemented mothers. Brunvand et al.[28] followed 30 pregnant Pakistani women who were free of chronic disease and had uncomplicated pregnancies. Nearly all of the women had low (<15 ng/ml) circulating 25(OH)D concentrations, and nearly 50% exhibited secondary hyperparathyroidism. The maternal circulating PTH concentration was inversely related to the neonatal crown-heel length. These authors concluded that maternal vitamin D deficiency affected fetal growth through an effect on maternal calcium homeostasis.

How does vitamin D supplementation during pregnancy affect the nutritional vitamin D status in both mother and fetus? This is an important question that is being addressed in our laboratory and clinics with the aid of an NIH-sponsored study (R01-HD043921) to study high-dose vitamin D supplementation during pregnancy. In the United States, the current AI for vitamin D during pregnancy is 200 IU/d.[31] However, supplementation of mothers with 400 IU/d during the last trimester of pregnancy did not significantly increase circulating 25(OH)D in the mother or their infants at term.[23] This finding agrees with current data in healthy men published by Heaney et al.[1] Supplementation with 1000 IU (25μg) vitamin D/d during the last trimester of pregnancy has produced mixed results. The initial study by Brooke et al.[22] described a dramatic increase, 50–60 ng/ml, in circulating 25(OH)D in both mothers and neonates at term. However, these results are highly suspect in light of later and current work and are consistent with a dose response obtained after consumption of 10,000 IU (250 μg) vitamin D/d for 3 mo.[1] There also is possibility that the 25(OH)D assay method used in this study was flawed, as was common during this early period of investigation.

Mallet et al.[29] reported that vitamin D supplementation (1000 IU/d, or 25 μg/d) during the last trimester of pregnancy resulted in an increase in circulating 25(OH)D concentrations of only 5–6 ng/ml in maternal and cord serum. In the most recent study, by Datta et al.,[30] 160 pregnant minority women in the United Kingdom were provided with 800–1600 IU (20–40 μg) vitamin D/d for the duration of their pregnancy. Using modern assay technology for the measurement of circulating 25(OH)D concentrations,[32] these investigators found a mean increase in circulating 25(OH)D concentrations of from 5.8 ± 0.9 (SD) ng/ml at the beginning of pregnancy to 11.2 ± 6.3 ng/ml at term after vitamin D supplementation. In other words, mothers who were vitamin D deficient at the beginning of their pregnancy were still deficient at the end of their pregnancy after being supplemented with 800–1600 IU vitamin D/d throughout their pregnancy. The results of this study again point out that the AI for vitamin D during pregnancy is grossly inadequate, especially in ethnic minorities. Clearly from the studies listed in Table 1, one can conclude that there is a dearth of data with respect to vitamin D supplementation during pregnancy. Current work by our group will provide data needed for the redefinition of the AI for vitamin D during pregnancy and hopefully establish a DRI. This work is generously sponsored by NIH (R01-AD043921) and involves supplementation with up to 4000 IU/d vitamin D3 from 12 wk of gestation. Primary parameters being assessed include infant and maternal skeletal growth and ability to achieve optimal nutritional vitamin D status. Many secondary outcomes are being assessed, including dental parameters and susceptibility to infection.

VITAMIN D REQUIREMENTS DURING LACTATION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. VITAMIN D REQUIREMENTS DURING PREGNANCY
  5. VITAMIN D REQUIREMENTS DURING LACTATION
  6. REFERENCES

Scientific data pertaining to vitamin D supplementation during lactation in the human is even scarcer than data on vitamin D supplementation during pregnancy. As during pregnancy, an arbitrary AI has been set at 200 IU/d.[31] This level of supplementation will do nothing to increase or even sustain the nutritional vitamin D status of mothers or their breastfeeding infants. We believe that vitamin D supplementation of lactation mothers has a dual purpose: (1) to increase the nutritional vitamin D status of the mother and (2) to improve the vitamin D nutrition of her breastfeeding infant. A maternal intake of 200 IU/d will accomplish neither of these goals.

We are aware of only four prospective studies that examined vitamin D supplementation during lactation.[33-35, 37] These studies are listed in Table 2. The first study was conducted in 1985.[33] Lactating mothers were supplemented with 1000 IU/d vitamin D3. This study showed that, at this level of maternal supplementation, nursing infants could not achieve adequate circulating levels of 25(OH)D. The second study conducted by this same group in 1986 was somewhat more positive.[34] In this study, lactating mothers were supplemented with either 1000 or 2000 IU/d vitamin D3 for 15 wk. Increases in circulating 25(OH)D concentrations were observed in both mother and nursing infant, with the more pronounced effect in the higher intake group. Neither of these previous studies quantitated the vitamin D content of the mother's milk. Our group has conducted the only two other prospective studies to date.[35, 37] Our first study involved supplementing mothers with either 2000 or 4000 IU/d vitamin D2 for a period of 3 mo.[35] Although these treatments increased the nutritional vitamin D status of both mother and nursing infant, the increases were small and disappointing.

Table Table 2.. Summary of Vitamin D Supplementation Studies During Lactation
  1. * Milk anti-rachitic activity was calculated from summing vitamin D and 25(OH)D levels in milk and assigning biological activity as previously described.[39, 40]

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The relative lack of effect was deemed to be because of the use of vitamin D2 as the supplement. It has recently been shown that vitamin D2 is much less effective than vitamin D3 at improving nutritional vitamin D status in humans.[37] At these levels of vitamin D2 supplementation, we observed little increase in either maternal or infant circulating 25(OH)D levels, as well as limited increase in the anti-rachitic activity of the mother's milk.[35] In our most recent study, we supplemented lactating mothers with either 400 or 6400 IU/d vitamin D3 for 6 mo with remarkable results.[37] Not only did maternal vitamin D status markedly improve, but the mother secreted large amounts of vitamin D3 into her milk, and in doing so supplied her nursing infant with enough endogenous vitamin D to significantly increase their nutritional vitamin D status. This relationship is displayed in Figs. 1 and 2. It is important to note that it is the parent compound in the circulation, vitamin D3, that is responsible for supplying the majority of vitamin D activity to human milk (Figs. 1 and 2). This observation enlightens a new function for the importance of maintaining circulating vitamin D3, the parent vitamin, during lactation. In all other human conditions that are known, the key to optimal nutritional vitamin D status is simply maintaining optimal circulating 25(OH)D levels. In lactation, however, maintaining both circulating 25(OH)D and vitamin D are important because vitamin D3 is what is quantitatively transferred into mother's milk as opposed to circulating 25(OH)D, which is transferred on a very limited basis into milk.[38] Because of its short circulating half-life, a supplement of vitamin D3 would have to be taken on a daily basis to ensure steady circulating levels of the parent vitamin and thus an adequate milk supply. It is also apparent that a 400 IU/d vitamin D3 intake will not increase the circulating levels of vitamin D3 and thus the content of vitamin D3 in milk (Figs. 1 and 2). Our group is now conducting a study in a large cohort of lactating mothers and their nursing infants with the aid of a current award from NIH (R01HD047511) in hopes of resolving this important nutritional topic. Similar parameters are being assessed in this study as we have previously described for our pregnancy study.

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Figure FIG. 1.. Maternal circulating vitamin D3 levels as a function of a 400 or 6400 IU vitamin D3/d supplementation regimen (Reprinted with permission from reference 36).

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Figure FIG. 2.. Milk anti-rachitic activity as a function of a 400 or 6400 IU vitamin D3/d supplementation regimen (Reprinted with permission from reference 36).

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REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. VITAMIN D REQUIREMENTS DURING PREGNANCY
  5. VITAMIN D REQUIREMENTS DURING LACTATION
  6. REFERENCES
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