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Affiliations: DK Dror is with USDA ARS Western Human Nutrition Research Center, Davis, California, USA. LH Allen is with the USDA ARS
Western Human Nutrition Research Center, Davis, California, USA.
Correspondence: DK Dror, Allen Lab, USDA ARS Western Human Nutrition Research Center, 430 West Health Sciences Dr., Davis, CA 95616,
USA. E-mail: dkdror@ucdavis.edu, Phone: +1-530-752-5276, Fax: +1-530-752-5271.
Key words: inadequacy, pregnancy, vitamin D
doi:10.1111/j.1753-4887.2010.00306.x
Nutrition Reviews® Vol. 68(8):465–477 465
enzyme 25-hydroxylase rapidly converts vitamin D to fetal kidney, may contribute to the production of fetal
25-hydroxy-D [25(OH)D], the main circulating and 1,25(OH)2D. However, based on studies of infants with
storage form of the vitamin and that which is accepted as renal agenesis, it appears that most of the 1,25(OH)2D in
being a biomarker of vitamin D status. In the kidney and fetal plasma is synthesized in the fetal kidney.19 Little is
a wide range of other target tissues, the 1-a-hydroxylase known regarding placental transfer of cholecalciferol in
CYP27B1 converts 25(OH)D to the active form of humans, though its contribution to fetal status is likely
vitamin D, 1,25(OH)2D. Both 25(OH)D and 1,25(OH)2D minor given that 25(OH)D is the main circulating form
are catabolized to more polar metabolites by vitamin D of the vitamin.
24-hydroxylase CYP24A1, a mitochondrial cytochrome Maternal concentrations of 1,25(OH)2D double or
P450 enzyme. triple starting in the first trimester of pregnancy.18 This
The circulating 25(OH)D concentration sufficient rise may be attributed to increased expression of 1-a-
to meet the physiological needs of humans is an hydroxylase and VDR in placental and decidual cells of
ongoing subject of debate. In adults, optimal circulating early pregnancy20,21 as well as placenta-specific methyla-
25(OH)D has often been defined as the concentration tion in the promoter region of the CYP24A1 gene result-
that maximally suppresses serum parathyroid hormone ing in decreased expression of the catabolic enzyme
(PTH), a criterion grounded in the fact that hyperpar- 24-hydroxylase.22 It is notable that PTH, the usual stimu-
athyroidism promotes bone loss. A serum 25(OH)D lus for increased renal hydroxylation of 25(OH)D, may
level of <37.5 nmol/L in adults is defined as deficient by actually fall to the lower end of the normal range during
the Centers for Disease Control and Prevention based pregnancy.18,23
on this criterion.15 However, the concentrations of
25(OH)D that have been found to suppress PTH
actually vary from 20 to 110 nmol/L, in part because VITAMIN D, CALCIUM, AND BONE HOMEOSTASIS
PTH concentrations are influenced by diet, time of DURING PREGNANCY
day, renal function, and physical activity in addition
to vitamin D status.16 As research in the field of vitamin During gestation, the fetus accrues an average of 30 g of
D nutrition has developed, other outcomes such as bone calcium, 99% of which is contained in the skeleton.18 An
mineral density, calcium absorption, dental health, increased efficiency of maternal calcium absorption from
and risk of falls, fractures, and colorectal cancer have approximately 35% in the nonpregnant state to approxi-
been used to determine optimal circulating 25(OH)D mately 60% during the third trimester of pregnancy
concentrations. A review of randomized controlled appears to be the primary mechanism to support fetal
studies evaluating threshold concentrations of 25(OH)D calcium accretion.23 The near doubling of intestinal
associated with these health outcomes concluded that calcium absorption has commonly been attributed to the
advantageous serum concentrations begin at 75 nmol/L similar rise in 1,25(OH)2D during pregnancy; however,
and are best between 90 and 100 nmol/L.16 Many vitamin D-deficient or VDR-null animal models have
experts are of the opinion that 25(OH)D levels demonstrated an upregulation in calcium absorption
<50 nmol/L should be considered deficient and similar to controls.18,24 It has been hypothesized that
51–74 nmol/L insufficient.17 Overall, evidence is lacking prolactin and placental lactogen stimulate intestinal
regarding appropriate cut-points to define vitamin D calcium absorption independently of 1,25(OH)2D during
status during pregnancy.18 pregnancy.18
Although maternal bone resorption may contribute
MATERNAL-FETAL VITAMIN D NUTRITION to fetal calcium accretion, the evidence is inconclusive.
Results of longitudinal studies of BMD during pregnancy
Based on direct evidence from animal studies and cor- are conflicting; while some have shown decreases in bone
relations between cord and maternal blood concentra- density in the spine, hip, and ultradistal radius,25–30 others
tions of 25(OH)D in humans, it is known that 25(OH)D have shown no change31–34 or even an increase in bone
readily crosses the human placenta and that the vitamin density at cortical sites.29 Bone resorption markers are
D pool of the fetus is entirely dependent on that of the modestly increased during pregnancy18 while osteocalcin,
mother.19 Concentrations of 25(OH)D in cord blood at a marker of bone formation, is decreased from mid-
delivery range from 68 to 108% of maternal concentra- pregnancy through delivery.35,36 In vitamin D-deficient
tions according to numerous investigators.20 At physi- rats, skeletal mineral content was shown either to
ological concentrations, there is inconsistent evidence of increase37 or to decrease38 during pregnancy. No human
transplacental transfer or correlation between maternal studies have focused specifically on the relationship
and fetal concentrations of 1,25(OH)2D. The placenta between vitamin D status during pregnancy and maternal
itself contains 1-a-hydroxylase and, in addition to the bone turnover.
RISK FACTORS FOR VITAMIN D DEFICIENCY Numerous studies have estimated the prevalence of
DURING PREGNANCY vitamin D deficiency and insufficiency amongst pregnant
women in various ethnic populations and living at
In addition to conditions that predispose the general different latitudes (Table 1). Though direct comparisons
population to hypovitaminosis D, including darker pig- between studies are not possible due to inconsistent defi-
mentation, sunscreen use, clothing coverage, latitude of nitions of deficiency and insufficiency, there is a disturb-
residence, urban pollution, and poor intake, several ingly high prevalence of hypovitaminosis D amongst
risk factors have a particular significance in relation to pregnant women in nearly all of the populations studied.
pregnancy. This is true despite the fact that pregnant women in most
Seasonal variation in serum 25(OH)D is a well- countries are encouraged to take a daily prenatal vitamin-
established phenomenon due to reduction in UVB pen- mineral supplement containing 400 IU of vitamin D. In
etration through the atmosphere during the winter “high-risk” pregnant populations consisting of highly
months when the sun’s zenith angle is increased.101 pigmented or veiled women, the prevalence of vitamin D
Because pregnancy traverses several seasons, it is evident deficiency and insufficiency is generally greater than in
that maternal status at a given point in pregnancy is influ- lighter skinned or less covered women living at the same
enced by season of measurement as well as other envi- latitude.
ronmental and physiological factors. It has been Although it has been assumed that cut-points for
speculated that the timing of vitamin D deficiency during defining vitamin D deficiency and insufficiency in preg-
gestation may be pivotal in predicting health outcomes in nancy are the same as in the general population, few
the offspring.84 Several studies of vitamin D status in studies have compared circulating 25(OH)D in pregnant
pregnancy have shown higher rates of deficiency at term women and in nonpregnant controls. A recent longitu-
in women delivering in spring and winter months.4,5,7,11 dinal study of vitamin D deficiency and insufficiency in
Only one study published to date has compared seasonal Caucasian pregnant women and age-matched non-
variations in vitamin D status between pregnant women pregnant controls in Northern Ireland (54–55°N) found
and nonpregnant controls living in the same commu- that 96, 96, and 75% of pregnant women were classified
nity.7 Because all women participating in the study were as vitamin D insufficient (plasma 25(OH)D <50 nmol/L)
recruited at the same time of year, it remains to be eluci- at 12, 20, and 35 weeks of gestation, respectively. At the
dated whether progressively poorer vitamin D status in same time points, which corresponded to winter, spring,
pregnant women compared with controls was due to dif- and summer measurements, 92, 74, and 42% of non-
ferential effects of season in pregnant and nonpregnant pregnant women were vitamin D insufficient. The
women or to the physiological demands of pregnancy authors speculate that lower vitamin D status after 12
itself. weeks gestation may be due to increased fetal demand
Multiple studies have demonstrated that circulating for the nutrient.7 Because all pregnant women in this
25(OH)D concentrations are lower in obese than lean study conceived in late fall or early winter and delivered
individuals, including several studies conducted during in summer, interpretation of results is complicated by
pregnancy.46,52,102–106 Proposed mechanisms include the confounding effect of season. Ardawi et al.107 col-
sequestration of vitamin D in adipose tissue105 or sub- lected blood from 40 pregnant Saudi Arabian women in
cutaneous fat,106 enhanced production of calcitriol with each trimester, at delivery, and 6 weeks postpartum. A
negative feedback on hepatic synthesis of 25(OH)D,102 single blood sample was collected from nonpregnant
avoidance of sun exposure,104 or lower vitamin D controls. Serum 25(OH)D3 levels in pregnant women
intake.52 In a subset of subjects participating in a pro- decreased significantly from the first trimester
spective pregnancy cohort study in Pittsburgh, Pennsyl- (54 ⫾ 10 nmol/L) to the third trimester (33 ⫾ 8 nmol/L)
vania, Bodnar et al.103 demonstrated that pregravid obese and remained depressed at delivery and postpartum.
women had significantly lower serum 25(OH)D concen- However, the mean 25(OH)D values at each time point
trations than lean women at 4–22 weeks of gestation were within the reference range obtained from non-
and at term after adjustment for race/ethnicity, season, pregnant controls, and the authors did not address the
gestational age, periconceptional vitamin use, precon- possible contribution of season to the variations seen
ception physical activity, and maternal age. Cord blood during pregnancy. Based on preliminary evidence, it
471
may be prudent to revisit the definition of vitamin D lating 25(OH)D to be obtained late in pregnancy and
sufficiency late in pregnancy, when most studies have studies should investigate the level of supplementation
measured circulating 25(OH)D. needed to reach this goal.
473
confirm a daily dose sufficient to ensure vitamin D 7. Holmes VA, Barnes MS, Alexander HD, McFaul P, Wallace JM.
adequacy in the majority of the pregnant population, Vitamin D deficiency and insufficiency in pregnant women:
a longitudinal study. Br J Nutr. 2009;102(6):876–881.
based on existing evidence it appears that this dose would
8. Kazemi A, Sharifi F, Jafari N, Mousavinasab N. High preva-
exceed 1,000 IU/day. Subsets of pregnant women who lence of vitamin D deficiency among pregnant women and
are at higher risk for hypovitaminosis D due to pre- their newborns in an Iranian population. J Womens Health.
pregnancy obesity, darker pigmentation, or winter/spring 2009;18:835–839.
due date may require higher-dose supplementation. 9. Lee JM, Smith JR, Philipp BL, Chen TC, Mathieu J, Holick MF.
Vitamin D deficiency in a healthy group of mothers and
newborn infants. Clin Pediatr. 2007;46:42–44.
CONCLUSION 10. Maghbooli Z, Hossein-Nezhad A, Shafaei AR, Karimi F,
Madani FS, Larijani B. Vitamin D status in mothers and their
newborns in Iran. BMC Pregnancy Childbirth. 2007;7:1.
The widespread global prevalence of hypovitaminosis D 11. Nicolaidou P, Hatzistamatiou Z, Papadopoulou A, et al. Low
during pregnancy and its implications for undesirable vitamin D status in mother-newborn pairs in Greece. Calcif
health outcomes in present and future generations is an Tissue Int. 2006;78:337–342.
area of growing concern. Because inadequate vitamin D 12. Sachan A, Gupta R, Das V, Agarwal A, Awasthi PK, Bhatia V.
status during gestation may have adverse effects on High prevalence of vitamin D deficiency among pregnant
women and their newborns in northern India. Am J Clin
maternal pregnancy as well as fetal and postnatal growth Nutr. 2005;81:1060–1064.
and development, an increasing number of experts 13. Weiler H, Fitzpatrick-Wong S, Veitch R, et al. Vitamin D defi-
are advocating changes to recommended vitamin D ciency and whole-body and femur bone mass relative to
intakes in pregnancy. Although the optimal circulating weight in healthy newborns. CMAJ. 2005;172:757–761.
25(OH)D concentration throughout pregnancy remains 14. Yu CK, Sykes L, Sethi M, Teoh TG, Robinson S. Vitamin D
deficiency and supplementation during pregnancy. Clin
the subject of debate, it is evident that prior levels used
Endocrinol. 2009;70:685–690.
to establish intake recommendations were too conserva- 15. Standing Committee on the Scientific Evaluation of Dietary
tive. In light of existing evidence, public health interven- Reference Intakes, Food and Nutrition Board, Institute of
tion to reduce the prevalence of hypovitaminosis D in Medicine. Dietary Reference Intakes for Calcium, Phospho-
pregnant women in the United States and worldwide is rous, Magnesium, Vitamin D and Fluoride. Washington, DC:
National Academies Press; 1997.
imminently desirable.
16. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T,
Dawson-Hughes B. Estimation of optimal serum concentra-
tions of 25-hydroxyvitamin D for multiple health outcomes.
Acknowledgment Am J Clin Nutr. 2006;84:18–28.
17. Merewood A, Mehta SD, Chen TC, Bauchner H, Holick MF.
Declaration of interest. The authors have no relevant Association between vitamin D deficiency and primary
interests to declare. cesarean section. J Clin Endocrinol Metab. 2009;94(3):940–
945.
18. Kovacs CS. Vitamin D in pregnancy and lactation: maternal,
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