Maternal Vitamin D During Pregnancy and Its Relation to Immune-Mediated Diseases in the Offspring

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Maternal Vitamin D During Pregnancy and Its Relation to Immune-Mediated Diseases in the Offspring M. Erkkola,* B.I. Nwaru,† and H.T. Viljakainen ‡ Contents 240 241 241 241 245 246 246 247 248 248 248 249

I. Introduction II. Vitamin D A. Forms and sources of vitamin D B. Vitamin D metabolism C. Functions in the body D. Immunological functions E. Methods for assessing S-25-OHD III. Vitamin D Status During Pregnancy IV. Dietary Guidelines and Maternal Vitamin D Intake A. Dietary guidelines during pregnancy B. Maternal vitamin D intake from food and supplements C. Dietary assessment during pregnancy V. Maternal Vitamin D During Pregnancy and Disease Outcomes in the Offspring A. Allergic diseases and asthma B. Autoimmune diseases C. Infectious diseases D. Cancer VI. Conclusions References

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Abstract Vitamin D deficiency during pregnancy is fairly common in many parts of the world. However, currently there is no consensus on the optimal vitamin D intake during pregnancy. Vitamin D is known to be of great importance for the homeostatic functions within the immune system. Maternal vitamin D status during * Division of Nutrition, Department of Food and Environmental Sciences, University of Helsinki, Finland Tampere School of Public Health, University of Tampere, Finland Hospital for Children and Adolescents, HUS, Finland

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Vitamins and Hormones, Volume 86 ISSN 0083-6729, DOI: 10.1016/B978-0-12-386960-9.00010-1

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2011 Elsevier Inc. All rights reserved.

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pregnancy may therefore affect the developing immune system of the fetus, thus contributing to the later development of immune-mediated diseases. This chapter introduces the basics of vitamin D during pregnancy and discusses the role of maternal vitamin D intake in the development of asthma, allergic diseases, autoimmune diseases, cancer, and infections in the offspring. So far, the strongest observational evidence underlines the potential of maternal vitamin D intake during pregnancy to influence the likelihood of asthma and allergic outcomes in the offspring. Somewhat conflicting findings imply that there might be critical time windows of exposure to adequate vitamin D levels during pregnancy. More research is needed in order to fully understand the contribution of maternal vitamin D status during pregnancy to the progress of immune-mediated diseases. ß 2011 Elsevier Inc.

I. Introduction Fetal nutrition and its impact on childhood immune responses is a highly active field of research. Heightened susceptibility to immunological disorders may originate in early life, with long-lasting structural or functional changes to the developing organs or organ systems (Burlingham, 2009). Nutrients act as cofactors and activators for the developing immune system (Cunningham-Rundles et al., 2009), and early education of the immune system seems to already begin in utero (e.g., Calder et al., 2006). Pregnancy is a time when maternal nutrition may play an important role in the development of the fetus. Today, the appreciation of the immunological properties of vitamin D has been extended to understand its role in the development of several childhood diseases as a result of in utero vitamin D exposure. Consequently, it has been suggested that maternal vitamin D status during pregnancy may play a possible etiological role in the development of several immunological disorders in the offspring during childhood (Lucas et al., 2008; Zittermann and Gummert, 2010). However, at the same time, there is no consensus on either the optimal level of vitamin D intake during pregnancy, or levels that might be unsafe (Hollis and Wagner, 2004; Kovacs, 2008; Prentice, 2008; Specker, 2004; Vieth, 2006). The present overview starts by briefly describing vitamin D metabolism and functions, which is followed by a discussion on maternal vitamin D status, dietary guidelines, and assessment methods during pregnancy. Finally, we present the current evidence on the possible etiological role of maternal vitamin D intake/status in the development of several immunemediated diseases in the offspring. Considering the extensive work that has been carried out in the area of skeletal outcomes, we now focus solely on nonskeletal outcomes in the offspring. A PubMed search was conducted in February, 2010, using the following search terms: vitamin D, pregnancy, immune system, asthma, allergy, autoimmune diseases, cancer, and infection.

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We included all original studies (published in English), in which the explanatory variable was either the intake and/or a biomarker of vitamin D or exposure to sunlight during pregnancy, and the response variable was one of the following: asthma, allergic rhinitis, atopic eczema, allergic sensitization, autoimmune disease, cancer, or infectious disease. The summary of the studies that were included can be found in Table 10.1. In the introduction to the basics of vitamin D, in order to avoid a potentially excessive reference list, we refer to the comprehensive reviews, wherever it is possible.

II. Vitamin D A. Forms and sources of vitamin D Globally, the most important source of vitamin D is sunlight UVB radiation. However, season, latitude, time of day, time spent outdoors, ageing, use of sunscreen, skin pigmentation, and clothing influence the amount of vitamin D produced in the skin (Holick, 2004). Although serum-25hydroxy vitamin D (S-25-OHD) concentration, a surrogate for vitamin D status, increases with increasing latitude (Kuchuk et al., 2009), factors related to affluence such as dietary supplement use or holidays in sunny resorts may confound this. The human diet contains two predominant forms of vitamin D, namely D2 and D3. Vitamin D2 originates from the algae, ergosterol, while vitamin D3 is derived from 7-dehydrocholesterol, a precursor of cholesterol. Biologically, D2 and D3 are not equivalent (Houghton and Vieth, 2006). D2 is metabolized faster in the body than D3. Furthermore, the effects of D2 on calcium metabolism are not as well studied. However, many supplements still contain D2, probably due to its better availability.

B. Vitamin D metabolism Vitamin D from skin or diet accumulates in the liver within a few hours. In the liver, vitamin D undergoes hydroxylation to 25-hydroxy vitamin D (25-OHD) which is rapidly released into circulation bound to its specific carrier, vitamin D binding protein, (DBP; Fig. 10.1). S-25-OHD is the most abundant vitamin D form in the body and a novel indicator of both cumulative exposure to sunlight and dietary vitamin D intake, making it a reliable marker of the overall vitamin D status. 25-OHD has also been found to be associated with chronic disease risk. Its half-life varies from 1 to 2 months (Vieth, 1999). A single assessment of 25-OHD is hardly enough to describe the lifelong variation in vitamin D status. However, S-25-OHD is still a prehormone requiring further hydroxylation to become the potent steroid hormone calcitriol. Calcitriol (1,25 (OH)2D) produced in the kidneys regulates calcium metabolism, whereas

Table 10.1

Summary of evidence of the role of maternal vitamin D during pregnancy on immune-mediated outcomes in the offspring

Study and country

Design

Asthma and allergic outcomes Nwaru et al. Prospective cohort (2010), Finland study with 5-year follow-up Erkkola et al. (2009), Finland

Prospective cohort study with 5-year follow-up

Miyake et al. (2009), Japan

Prospective cohort study

Gale et al. (2008), United Kingdom

Prospective cohort study

Camargo et al. (2007), United States Devereux et al. (2007), United Kingdom

Prospective cohort study with 3-year follow-up Prospective cohort study with 5-year follow-up

Autoimmune diseases Salzer et al. (2010), Case-control study Sweden

Number of subjects

Assessment of vitamin D

Main findings

Validated food frequency Increasing maternal intake of vitamin D from foods decreased the risk of IgEquestionnaire (FFQ) based sensitization to food allergens during the eighth month of pregnancy 1669 mother–child pairs Validated FFQ during the Increasing maternal intake of total vitamin D, and vitamin D from foods eighth month of was inversely associated with asthma pregnancy and allergic rhinitis 763 mother–child pairs A diet history questionnaire Maternal daily intake of
4.309 mg of vitamin D was associated with reduced risk of wheeze and eczema High maternal concentration of 25440 mother–child pairs Serum 25-OHD during 28–42 weeks gestation OHD was positively associated with at 9 months and 178 atopic eczema at 9 months and at 9 years asthma at 9 years 1194 mother–child pairs Validated FFQ during the High maternal intake of vitamin D from foods and supplements was inversely third trimester of associated with wheeze pregnancy 1212 mother–child pairs Validated FFQ during the High maternal intake of vitamin D 32-week of pregnancy decreased the risk of ever wheeze, wheeze in the previous year, and persistent wheeze 931 mother–child pairs

9361 multiple sclerosis (MS) cases and 12,116,853 controls

More cases of MS were born during the Sunlight exposure: each month of June than other months, month of birth separately indicating that decreased exposure to compared with birth sunlight during pregnancy in the during the other 11 winter months maybe a possible months explanation

Fewer of those born during the month of November were diagnosed with multiple sclerosis, which may be a result of increased exposure to sunlight in the summer months Prospective cohort 8694 mother–child pairs FFQ assessing supplemental Maternal supplemental vitamin D Brekke and intake was associated with decreased vitamin D during study at year 1 and 7766 at Ludvigsson risk of diabetes-related pregnancy year 2.5 (2007), Sweden autoimmunity at year 1 but not at year 2.5 Prospective cohort 233 mother–child pairs Validated FFQ during the Maternal intake of vitamin D from Fronczak et al. foods but not from supplements study third trimester of (2003), decreased the risk of appearance of pregnancy United States islet diabetes-related autoimmunity Maternal intake of cod liver oil was Stene et al. (2000), Population-based 85 T1D cases and 1070 Mailed questionnaire to associated with lower risk of type 1 Norway case-control study controls assess the use of cod liver diabetes oil and supplements during pregnancy Infectious diseases Mean serum 25-OHD concentrations Karatekin et al. Hospital-based case- 25 cases of acute lower Serum 25-OHD were lower in cases and their mothers (2009), Turkey control study respiratory infection than in the control group, indicating (ALRI) and 15 that newborns with subclinical controls vitamin D deficiency may have increased risk of ALRI High maternal concentration of serum 440 mother–child pairs Serum 25-OHD during Gale et al. (2008), Prospective cohort 28–42 weeks gestation 25-OHD was associated with study (at 9 months) and 178 United pneumonia and diarrhea at 9 months (at 9 years) Kingdom 1194 mother–child pairs Validated FFQ during the No association was found between Prospective cohort Camargo et al. maternal intake of vitamin D and third trimester of study with 3-year (2007), respiratory infections in the offspring pregnancy follow-up United States

Fernandes de Abreu et al. (2009), France

Descriptive study

583 trios; patient and both parents

Medical files and DNA samples

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Skin Liver

7-Dehydrocholesterol

CYP27A1

Solar UVB radiation

25(OH)VD3 PreVD3

Diet 25(OH)VD3 (Blood)

Vitamin D2/D3

Kidneys CYP27B1

VD3

1,25(OH)VD3

Immune cells 24-OHase Calcitroic acid

VD3 CYP27A1 25(OH)VD3

CYP27B1

CYP27B1

1,25(OH)2VD3 (Blood)

1,25(OH)2VD3 VDR/RXR VDR/RXR T/B Cells 24-OHase (CYP24A1)

Bile

DC, macrophages Calcitroic acid

Figure 10.1 Overview of vitamin D metabolism. Vitamin D3 (VD3) is acquired in the diet or synthesized in the skin and hydroxylated in the liver to 25(OH)VD3, the main circulating form. 25(OH)VD3 is then hydroxylated in the kidneys by the cytochrome P450 protein CYP27B1 to become 1,25(OH)2VD3, the physiologically most active metabolite, which then reaches the blood where it has multiple systemic effects. Cells of the immune system, including macrophages, dendritic cells (DCs), T and B cells express the enzymes CYP27A1 and/or CYP27B1, and therefore can also hydroxylate 25(OH)VD3 to 1,25(OH)2VD3. 1,25(OH)2VD3 acts on immune cells in an autocrine or paracrine manner by binding to the vitamin D receptor (VDR). 24-hydroxylase (CYP24A1) catabolizes 1,25(OH)2VD3 to its inactive metabolite, calcitroic acid, which is excreted in the bile. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Immunology (Mora et al., 2008), copyright 2008.

the extrarenal production of calcitriol occurring in at least 10 tissues explains its other biological functions (Norman et al., 2007). Target organs presenting vitamin D receptor (VDR) have been identified in 37 tissues (Norman et al., 2007). Membrane-bound VDR induces rapid signaling such as opening an ion channel or activating enzymes, while nuclear receptor regulates gene

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expression. Since the VDRs are targeted mainly to calcitriol, circulating 25-OHD bound to DBP needs to form a complex with specific cell membrane proteins when entering the cell. After cytosolic 1-hydroxylation, it is able to manage genomic actions. Rapid actions cross talk with genomic actions delicately modifies the functions in cells (Norman et al., 2004). Parathyroid glands monitor serum calcium and phosphate concentrations. Parathyroid hormone (PTH), estrogens, growth hormones, and prolactin work together to enhance the production of calcitriol in the kidney (Norman et al., 2007). The production of calcitriol is tightly regulated by various negative feedback systems. Calcitriol also activates an alternative pathway by producing 24,25(OH)2D in the kidney. 24,25(OH)2D is related to a different set of biological functions than calcitriol (Norman, 2008), and it is more susceptible excreted to urine as a calcitronic acid (Zhou et al., 2010).

C. Functions in the body The main function of vitamin D is to maintain serum calcium and phosphorus concentrations within the normal range by enhancing calcium absorption from the intestine. If dietary calcium intake is insufficient to meet the body’s calcium requirements, calcitriol working together with PTH mobilizes calcium from the bone by activating bone remodeling. Conversely, when the calcium balance in the body becomes positive, vitamin D allows calcium accretion in the bone. In addition, vitamin D directly stimulates osteoblastogenesis (Zhou et al., 2010). The importance of vitamin D for skeletal development has long been recognized. In infancy and childhood, severe vitamin D deficiency results in poor skeletal growth and has been linked to rickets whereas osteomalacia and myopathy are consequences of deficiency in adulthood. There is convincing evidence that vitamin D decreases falls and fracture in the elderly (BischoffFerrari et al., 2009a,c). Based on animal data and limited human data, fetuses are thought to be protected from adverse skeletal effects of maternal vitamin D deficiency during pregnancy (Kovacs, 2008). Maternal and fetal adaptations seem to provide the necessary calcium relatively independently of the maternal vitamin D status. However, recent results have been contradictory, and suggest that maternal vitamin D status does affect bone mineral accrual and bone size in the fetus during the intrauterine period (Viljakainen et al., 2010). Beyond the impact on the skeletal development, vitamin D has also been associated with various physiologic systems, for example, in the brain, the pancreas, the heart and cardiovascular system, the immune system, and the development of cancer (Norman et al., 2007). Poor vitamin D status during pregnancy has been associated with increased risk of preeclampsia, gestational diabetes, and preterm birth (Bodnar and Simhan, 2010; Lapillonne, 2010). Mounting data link vitamin D deficiency to increased risk of many common chronic diseases (Lucas et al., 2008; Zittermann and Gummert, 2010). However, the exact mechanisms of vitamin D in each disease are not yet fully elucidated.

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D. Immunological functions Vitamin D plays a very important role in the homeostasis of the immune system (Fig. 10.1). The widespread presence of VDR in the immune system and the expression of the enzymes responsible for the synthesis of the active calcitriol regulated by specific immune signals suggest a paracrine immunomodulatory role for calcitriol (Baeke et al., 2008). Vitamin D has been suggested to modulate innate immunity; epithelial cells, macrophages, monocytes, and granulocytes are able to produce antimicrobial peptides, such as cathelidicin and defencin (Liu et al., 2006). The synthesis of antimicrobial peptides is vitamin D dependent and cells contain 1-a-hydroxylase to activate their production locally. Antimicrobial peptides are responsible for rapid defense against pathogens in epithelial tissues such as the epidermis, mucosa, bladder, and lungs. Infectious pathogens activating toll-like receptors are killed by antimicrobial peptides and oxygen reactants. Vitamin D is shown to decrease chemokine and interferon release in virus-infected epithelial cells, while not affecting viral replication (Hansdottir et al., 2010; Jeffery et al., 2009). This explains the lower inflammatory response and decreased disease severity in humans with superior vitamin D status (Laaksi et al., 2006; McNally et al., 2009; Yamshchikov et al., 2009). Perinatal exposure to vitamin D acts as an immunoregulatory hormone on the maturation of the immune system by interfering with cytokine production of monocytes and lymphocytes, including those involved in the development of IgE-mediated allergy (Pichler et al., 2002). Vitamin D selectively suppresses Th1, but not Th2 or CD8þ cell activity (Mora et al., 2008). However, in cord blood (naı¨ve) T cells, calcitriol appears to inhibit both Th-1 and Th-2 differentiation (Pichler et al., 2002). The contradictory findings on the role of vitamin D in allergies may be explained by the fact that the effects of vitamin D might differ between naive T cells and the more mature cells. Furthermore, the timing of exposure of the cells to vitamin D (i.e., prenatal vs. postnatal) seems to be of importance. It is also possible that lower vitamin D intakes have different consequences than relatively high-dose supplementation, an excess of potentially toxic vitamin D possibly causing totally opposite effects. However, the role of vitamin D in fetal and early postnatal immunity is not well understood and merits further investigation.

E. Methods for assessing S-25-OHD Currently, there are six methods to assess S-25-OHD concentration in humans. Care must be taken when comparing study results in the literature as these are produced by different methods that vary in their specificity for 25-OHD3 and 25-OHD2. In addition, the available commercial kits have changed over time as their antibodies have been developed and assays recalibrated (Carter, 2009; Looker et al., 2008), which complicates the comparison even further.

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High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS/MS) are direct methods for detecting 25-OHD and have greater accuracy than immunoassays. However, these higher-technology methods are demanding and require skilful and experienced analysts. Since we are still lacking a reference measurement procedure for 25-OHD, most of the direct measurements are in-house methods with different protocols (Carter et al., 2010). The bottom line in 25-OHD measurements is still adhering to the vitamin D quality assessment scheme and comparing one’s own method with others to ensure that the level of results is maintained. The most commonly used methods are DiaSorin radioimmunoassay and Immunodiagnostic Systems (IDS) enzyme immunoassay. As discussed by Binkley et al. (2009), the use of different methods has let the debate on thresholds for vitamin D status to continue for decades.

III. Vitamin D Status During Pregnancy The S-25-OHD concentrations of pregnant women are similar to that of nonpregnant women in that they fluctuate according to season and are affected by dietary intake. While the S-25-OHD status of pregnant women is either inferior or similar to nonpregnant women, the concentration of calcitriol is elevated (Kovacs, 2008; Lucas et al., 2008). This illustrates efficient vitamin D metabolism, and is possibly due to the increased requirement. 25-OHD crosses the placenta and similar 25-OHD concentrations are observed both in mothers and their newborn (Greer, 2008; Nicolaidou et al., 2006). Circulating concentrations of calcitriol double or triple from early to late pregnancy, and have been shown to be higher in pregnant compared to nonpregnant women (Kovacs, 2008). No studies have yet addressed whether the ideal concentration of 25-OHD during pregnancy should differ from the concentration considered sufficient for nonpregnant women. Currently, S-25-OHD below 50 nmol/l is considered deficient, between 50 and 80 nmol/l insufficient, and above 80 nmol/l sufficient (Bischoff-Ferrari et al., 2009b; Lips et al., 2009). The only way to achieve a 25-OHD concentration of above 80 nmol/l without vitamin D supplementation is to spend time in the sun (Vieth, 2006). Relatively few countries have nationally representative data on either the vitamin D status of their population or the risk of vitamin D deficiency, as estimated by S-25-OHD concentration (Prentice, 2008). However, vitamin D deficiency during pregnancy is a common problem worldwide (Holmes et al., 2009; Nicolaidou et al., 2006; Sahu et al. 2009; Viljakainen et al. 2010). There has been increasing recognition of a high prevalence of severe vitamin D deficiency (<25 nmol/l; 10 ng/ml), especially among pregnant women from ethnic minority groups in Northern Europe, Australasia, and the United States, suggesting a high risk of vitamin D deficiency diseases (Prentice, 2008).

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IV. Dietary Guidelines and Maternal Vitamin D Intake A. Dietary guidelines during pregnancy Vitamin D requirements during pregnancy must be met through dietary intake, dietary supplements, and sun exposure (Hollis and Wagner, 2004; Kovacs, 2008; Specker, 2004). Internationally, the recommendations for vitamin D intake during pregnancy vary widely, as much as 10-fold (Lucas et al., 2008). The appropriate dose of vitamin D during pregnancy is still unknown, although it is thought to be higher than the current dietary reference intake of 200–400 IU/day (5–10 mg/day). The scientific basis for this recommendation is not well defined, and the recommended dose has been criticized as having little or no effect in women (Hollis and Wagner, 2004; Vieth, 1999). Several studies have indicated that doses exceeding 25 mg (1000 IU) vitamin D/day are required during pregnancy to achieve a robust normal concentration of circulating 25-OHD (Hollis and Wagner, 2004; Vieth, 1999). Studies reviewed by Vieth (1999) support the belief that totalbody sun exposure can easily provide the equivalent of 250 mg (10,000 IU) vitamin D/day, suggesting that this is a physiologic limit. Vitamin D is potentially toxic though the exact amount of vitamin D required to induce toxicity is unknown in humans. However, intake of >25 mg (1000 IU)/day has not been recommended. There is no evidence of adverse effects on S-25-OHD concentrations, which do not exceed 140 nmol/l; to exceed this level is thought to require a total vitamin supply of 250 mg (10,000 IU; Vieth, 1999). In comparison to the toxic amounts in animal models, millions of units of vitamin D would have to be ingested to achieve the similar toxicity in humans. Dosing recommendations for mothers during pregnancy should be aimed at preventing any health problems in neonates and infants, and a vitamin D dose sufficient for the mother during pregnancy should produce normal cord blood 25-OHD concentrations at birth (Kovacs, 2008). It could also be argued whether the same dietary recommendations apply to such a heterogeneous group as pregnant women in general. Additional recommendations, specially focused on some subgroups of pregnant women, could be beneficial.

B. Maternal vitamin D intake from food and supplements Vitamin D intake from diet varies from one country to another depending on dietary habits, the use of dietary supplements, and the extent to which the national food supply is fortified with vitamin D. Naturally, vitamin D is found only in a limited number of foods such as fish, egg yolk, and some wild mushrooms (Holick, 1994). In many countries, specific foods, namely

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margarine, breakfast cereals, and milk products, are fortified with vitamin D. A considerable leap in vitamin D intake from food sources in pregnant women has been illustrated as a consequence of food fortification with vitamin D (Prasad et al., 2010). Populations at risk of vitamin D deficiency are those for which, for environmental, cultural, or medical reasons, exposure to sunlight is poor and the dietary intake of vitamin D is low. Studies in developed countries have indicated that vitamin D is one of the most critical nutrients in terms of deficiencies during pregnancy (Holmes et al., 2009; Nicolaidou et al., 2006; Prasad et al., 2010; Sahu et al., 2009). Studies conducted in Europe during the past two decades have shown that the prevalence of low vitamin D status is higher in the countries of the Mediterranean and Central Europe than in Scandinavia and other northern regions reflecting the higher vitamin D intakes in Northern European countries coupled with differences in skin exposure to UVB sunlight (Prentice, 2008). Accordingly, differences are due to different skin types; the response to solar exposure in fair skin is more efficient than in dark skin (Clemens et al., 1982). Intake of vitamin D from dietary supplements is of particular importance in countries located furthest north, thus vitamin D supplementation in winter months (between October and March) is recommended during pregnancy (Nordic Nutrition Recommendations, 2004). However, it appears that less than half of the pregnant women adhere to these recommendations (Arkkola et al., 2006). The use of dietary supplements is influenced by socio-demographic factors: those belonging to older age groups, having longer education, and normal weight before pregnancy favoring more frequent supplement use (Arkkola et al., 2006). Few intervention studies during pregnancy have successfully improved vitamin D status of both the mothers and their newborn (Brooke et al., 1980; Mallet et al., 1986). However, women who report taking multivitamin supplements during pregnancy might have higher vitamin D status, but may still remain vitamin D insufficient (Bodnar et al., 2007; Holmes et al., 2009).

C. Dietary assessment during pregnancy Pregnant women are more conscious about their diet, and their food choices are more strongly driven by safety concerns, when compared to nonpregnant women (Verbeke and De Bourdeaudhuij, 2007). Differences in food choice mainly relate to the claimed avoidance of specific foods (Verbeke and De Bourdeaudhuij, 2007), and more frequent use of dietary supplements during pregnancy (Arkkola et al., 2006). The result of measurements of dietary intake and status of pregnant women is influenced by the timing of the assessment. Appetite fluctuations, nausea, vomiting, and heartburn are the most common symptoms experienced in pregnancy, and they may influence results of long-term diet reports ( Jewell and Young,

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2003; Richter, 2003; Wirfa¨lt, 1998). Diet during pregnancy is recalled with similar accuracy or perhaps slightly lower accuracy than adult diet in general (Bunin et al., 2001). In most of the studies that are reviewed in the present chapter (Table 10.1), the dietary information was collected retrospectively by a food frequency questionnaire (FFQ). The FFQ is often considered as the primary dietary assessment method in nutritional epidemiology (Willett, 1998). Although FFQs are not considered appropriate for estimating actual nutrient intakes, they can be used for categorizing individuals accurately according to relative intake, and for identifying subjects at the extremes of intakes. The FFQ method typically leads to overestimation of nutrient intake (Erkkola et al., 2001). However, overestimation does not necessarily produce problems in epidemiological studies if the ranking of the persons according to their dietary intake is valid (Willett, 1998). Since the mothers fill in the FFQs retrospectively, the influence of the current diet is a possible source of bias (Bunin et al., 2001). However, changes in food intake during pregnancy tend to be relatively small and, hence, difficult to detect by using this rather imprecise dietary assessment method (King, 2000). Getting the maximum insight into the relationship between nutrient intake and disease risk requires examining the intake from both foods and supplements. Pregnancy seems to act as an additional motivator for taking dietary supplements, thus their use is widespread among pregnant women (e.g., Arkkola et al., 2006). Therefore, ranking subjects according to nutrient intake exclusively from diet could lead to serious misclassification. Inclusion of dietary supplement intake is of particular importance in northern countries where vitamin D supplementation is recommended during pregnancy. However, with the continuous renewal of dietary supplements available in the market, maintaining a valid database is challenging and requires frequent updating

V. Maternal Vitamin D During Pregnancy and Disease Outcomes in the Offspring A. Allergic diseases and asthma Although the immunological processes related to the development of allergic diseases and asthma are not very clearly understood (Michail, 2009), current evidence suggests that the process may be the result of an induced shift in the balance between the Th1 and Th2 cytokines that favors Th2 dominance (Kay, 2001). The activities of vitamin D are believed to support the above proposition (Litonjua and Weiss, 2007). However, it has also been suggested that vitamin D may play a dual effect by both enhancing, whilst at the same time suppressing, Th2 allergy-associated responses

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(Litonjua, 2009). These suggested contradictory effects are, however, believed to be due to the timing and chronicity of vitamin D administration (Ginde et al., 2009; Litonjua, 2009). So far, the only empirical evidence linking maternal vitamin D status or intake to allergic diseases and asthma in the offspring has come from some recent observational epidemiological studies. The most recent one is a prospective Finnish birth cohort study, in which maternal intake of vitamin D from foods (assessed by means of a validated FFQ) during pregnancy, was inversely associated with IgE-based sensitization to food allergens in 931 children followed for 5 years (Nwaru et al., 2010). In a different subject series of the same Finnish cohort (n ¼ 1669), increasing maternal intake of total vitamin D from foods during pregnancy was inversely associated with asthma, allergic rhinitis, but not with atopic eczema in 5-year-old children (Erkkola et al., 2009). High maternal intake of vitamin D from foods assessed by means of a dietary history questionnaire during pregnancy has been associated with a reduced risk of wheeze and eczema in Japanese infants aged 16–24 months (Miyake et al., 2009). Similar observations have been reported in two earlier prospective cohort studies from the U.S. (Camargo et al., 2007) and UK (Devereux et al., 2007). In the American study, which was FFQ based, high maternal vitamin D intake from foods and supplements was inversely associated with wheeze but not with eczema in 3-yearold children, while the UK study reported a decreased risk of wheezing but not atopic sensitization in children aged 5 years. Contrary to the findings from the above-mentioned studies, which may be limited by the questionnaire-based assessment of maternal vitamin D status, another UK study with a 9-year follow-up reported an association between high maternal concentration of vitamin D (25-OHD) during pregnancy and increased risk of atopic eczema at the age of 9 months, and asthma at age of 9 years (Gale et al., 2008). However, this study was subject to a number of shortcomings, including substantial loss to follow-up, especially at 9 years of age, as well as the lack of adjustment for potential confounders. Overall, at present, the observational evidence linking low maternal vitamin D status during pregnancy with increase in the risk of allergies and asthma in the offspring seems stronger. The next step to elucidate this hypothesis would be a clinical trial, and at the moment, one ongoing prenatal vitamin D supplementation is reported in the U.S. (Litonjua, 2009).

B. Autoimmune diseases The processes that initiate the development of autoimmune diseases are not yet clearly understood (Chaudhuri, 2005; Harris, 2005; Knip et al., 2010; Zipitis and Akobeng, 2008). Here we discuss the two most common autoimmune diseases in children—type 1 diabetes and multiple sclerosis.

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Type 1 diabetes is generally considered to be a chronic, immune-mediated disease with a subclinical prodrome during which b cell autoimmunity develops into a clinical manifestation at a variable rate in genetically susceptible individuals (Knip et al., 2010). Accumulated evidence supports a critical role for environmental factors in the disease development, and prospective birth cohort studies have shown that the first signs of b cell autoimmunity may be initiated during the first year of life. The etiology of multiple sclerosis is still strongly debated (Behan et al., 2002), although there is evidence suggesting that it may be related to geographic location and seasonality (Chaudhuri, 2005). In this regard, some studies have proposed that sunlight exposure and seasonal fluctuation in vitamin D concentration may be associated with multiple sclerosis (Chaudhuri, 2005). Vitamin D deficiency has been shown to be associated with an increased risk of Th1-mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes, suggesting that vitamin D deficiency leads to a decreased suppression of pathologic Th1-polarized immune responses (Baeke et al., 2008). The preventive role of vitamin D against the incidence of type 1 diabetes has been indicated in animal models in which active vitamin D has modified T-cell differentiation, dendritic cell action, and induced cytokine secretion, resulting in a shift of balance to regulatory T cells (Mathieu and Badenhoop, 2005). In a recent large Swedish registry-based case-control study, the relationship between birth season and multiple sclerosis incidence was examined by comparing each month of birth separately to birth during the other 11 months of the year. More multiple sclerosis subjects were born during June compared to those born during the other months. The authors concluded that their findings support the previous suggestions of an association between multiple sclerosis and season of birth. However, a more likely explanation for these findings may be the decreased exposure to sunlight during the winter period, which leads to low vitamin D concentration during pregnancy for births taking place after winter (Salzer et al., 2010). Fernandes de Abreu et al. (2009) investigated whether it was the season of birth, or VDR polymorphisms or the combination of a high risk month of birth and VDR polymorphisms that is associated with multiple sclerosis. Medical files and DNA samples from 583 French multiple sclerosis patients and both of their parents were used. They reported a decrease in the number of children born during November with multiple sclerosis with no association observed between the VDR polymorphisms and multiple sclerosis. The study concluded that high levels of vitamin D during the third trimester of pregnancy (i.e., during the summer month for births occurring during winter) could be a protective factor for multiple sclerosis. The results from the above studies favor the suggested immunosuppressive effects of ultraviolent radiation, which has been shown by the latitudinal variations in the occurrence of multiple sclerosis (McMichael and Hall, 1997). However,

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this proposal has also been debated, and it has been advocated that actual routine supplementation of vitamin D during pregnancy may be favorable in preventing multiple sclerosis in the offspring, both from the public health perspective and in economic terms (Chaudhuri, 2005). A Norwegian case-control study that evaluated the effect of cod liver oil and multivitamin supplementation during pregnancy on type 1 diabetes in the offspring associated maternal consumption of cod liver oil with a lower risk of type 1 diabetes (Stene et al., 2000). Multivitamin supplementation during pregnancy, however, was not associated with the risk of type 1 diabetes. Since cod liver oil is rich both in vitamin D and omega-3 fatty acids, the authors concluded that the protective effect of maternal cod liver oil intake may be due to either vitamin D or omega-3 fatty acids, or a combination of both. A study from the U.S. (Fronczak et al., 2003) and another from Sweden (Brekke and Ludvigsson, 2007) prospectively examined the effects of maternal vitamin D intake during pregnancy on the appearance of diabetes-related autoimmunity in the offspring. The U.S. study followed the subjects for 4 years and observed a decreased risk of islet autoimmunity with maternal intake of vitamin D from food but not from supplements. Conversely, the Swedish study observed a decreased risk of diabetes-related autoimmunity in the children at the age of 1 year with maternal vitamin D intake from supplements. In addition to these ambiguous findings, the use of islet autoimmunity as an endpoint in the above studies makes it more difficult to draw a valid conclusion on the effect of maternal pregnancy vitamin D on type 1 diabetes in the offspring. Some previous studies have reported a similar protective effect of intake of vitamin D supplements during infancy and later type 1 diabetes (Hyppo¨nen et al., 2001; The EURODIAB Substudy 2 Study Group, 1999). However, no significant differences were observed between the circulating vitamin D concentrations of pregnant women from Russian Karelia and Finland, the former having a low incidence and the latter an extremely high incidence of type 1 diabetes (Viskari et al., 2006). This finding speaks against a critical role of vitamin D deficiency in the development of b cell autoimmunity and type 1 diabetes.

C. Infectious diseases The role of vitamin D in preventing infections has long been recognized (Martineau et al., 2007). For instance, from the 1930s until the introduction of anti-infective chemotherapy in the 1950s, vitamin D3, which was isolated from cod liver oil, was widely used for the treatment of tuberculosis (Martineau et al., 2007). It has been shown that vitamin D can help in enhancing innate immunity by stimulating the synthesis of an antimicrobial peptide cathelicidin in human skin cells (Schauber et al., 2008). Of recent, some epidemiological studies have demonstrated a protective role for

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vitamin D in respiratory tract infections (Ginde et al., 2009; Laaksi et al., 2007; Urashima et al., 2010). A recent case-control study showed that newborns with subclinical vitamin D deficiency, as a result of low maternal S-25-OHD concentrations during pregnancy, may be at increased risk of acute lower respiratory infection (Karatekin et al., 2009). However, in an earlier prospective cohort study, maternal intake of vitamin D during pregnancy was not associated with any respiratory infection in the offspring at 3 years of age (Camargo et al., 2007). Moreover, Gale et al. (2008) reported an increased risk of pneumonia and diarrhea at 9 months with high maternal concentrations of S-25-OHD during pregnancy, in another prospective cohort study. Since no consensus can be found in the above studies, the role of maternal vitamin D status during pregnancy in preventing infectious diseases in the offspring remains inconclusive; thus, more rigorous randomized controlled trials would be required to decipher the putative effect of vitamin D.

D. Cancer Recent evidence suggests that VDRs, which have been found on melanoma cell lines and tissues, are possibly associated with a decreased risk of cancers through vitamin D actions on cell proliferation, differentiation, cell death, and angiogenesis (Egan, 2009; Eisman et al., 1980). 1,25-hydroxy vitamin D has also been identified to promote cell survival and inhibit the invasion and metastasis of tumor cells (Osborne and Hutchinson, 2002). To our knowledge, no study has so far investigated the association between maternal vitamin D during pregnancy and cancers in the offspring. However, a recent Finnish population-based case-control study focusing on the association between maternal S-25-OHD levels measured during the first trimester of pregnancy and breast cancer and pregnancy-associated breast cancer, reported an association between vitamin D and an increased risk of pregnancy-associated breast cancer but not with breast cancer (Agborsangaya et al., 2010). Another case-control study derived from the same cohort reported a null association between S-25-OHD and the risk of ovarian cancer in the women (Toriola et al., 2010).

VI. Conclusions Vitamin D deficiency during pregnancy is prevalent in many parts of the world, a fact that goes hand in hand with the observed increase in the incidence of immune-mediated diseases in the offspring. Maternal vitamin D status during pregnancy is a key determinant of the vitamin D status of the infant. S-25-OHD concentration presents a useful marker of the risk of

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clinical deficiency, despite limitations caused by the lack of methodological standardization. There is general agreement that the appropriate dose of vitamin D during pregnancy is likely higher than the current dietary reference intake for the pregnant women with only modest UVB-exposure. If the advice to avoid UVB light is followed, the goal of raising 25-OHD concentrations can be achieved efficiently only by providing vitamin D through dietary supplementation. The observations from birth cohort studies indicate a beneficial association for higher maternal vitamin D intake during pregnancy against childhood asthma and allergic diseases in the offspring. However, some conflicting findings do suggest that the timing of exposure to lower or higher vitamin D levels is of importance. Further work is required to define the critical windows of exposure to adequate vitamin D levels during pregnancy. The effect of maternal vitamin D on type 1 diabetes, multiple sclerosis, and infectious diseases remains inconclusive. More research is required to confirm the contribution of maternal dietary factors to the development of immune-mediated diseases. We lack the knowledge on the mechanisms by which vitamin D influences fetal development. The complex relationship between maternal nutrition and birth outcomes emphasizes the need for consistent and thorough assessment of women’s diets throughout the duration of pregnancy. Researchers in this field are also faced with the methodological challenges of eliminating biases and adequately adjusting for potentially important confounding factors. More evidence is needed to better understand the net risks and benefits of maternal and early postnatal vitamin D status in relation to a range of immunologic and other diseases. There is a call for clinical trials and large birth cohorts where there are valid measures of maternal and fetal vitamin D intake and long-term health outcomes.

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