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Changes in plasma concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D during pregnancy: a Brazilian cohort

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Abstract

Purpose

To characterize the physiological changes in 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] throughout pregnancy.

Methods

Prospective cohort of 229 apparently healthy pregnant women followed at 5th–13th, 20th–26th, and 30th–36th gestational weeks. 25(OH)D and 1,25(OH)2D concentrations were measured by LC–MS/MS. Statistical analyses included longitudinal linear mixed-effects models adjusted for parity, season, education, self-reported skin color, and pre-pregnancy BMI. Vitamin D status was defined based on 25(OH)D concentrations according to the Endocrine Society Practice Guideline and Institute of Medicine (IOM) for adults.

Results

The prevalence of 25(OH)D <75 nmol/L was 70.4, 41.0, and 33.9%; the prevalence of 25(OH)D <50 nmol/L was 16.1, 11.2, and 10.2%; and the prevalence of 25(OH)D <30 nmol/L was 2, 0, and 0.6%, at the first, second, and third trimesters, respectively. Unadjusted analysis showed an increase in 25(OH)D (β = 0.869; 95% CI 0.723–1.014; P < 0.001) and 1,25(OH)2D (β = 3.878; 95% CI 3.136–4.620; P < 0.001) throughout pregnancy. Multiple adjusted analyses showed that women who started the study in winter (P < 0.001), spring (P < 0.001), or autumn (P = 0.028) presented a longitudinal increase in 25(OH)D concentrations, while women that started during summer did not. Increase of 1,25(OH)2D concentrations over time in women with insufficient vitamin D (50–75 nmol/L) at baseline was higher compared to women with sufficient vitamin D (≥75 nmol/L) (P = 0.006).

Conclusions

The prevalence of vitamin D inadequacy varied significantly according to the adopted criteria. There was a seasonal variation of 25(OH)D during pregnancy. The women with insufficient vitamin D status present greater longitudinal increases in the concentrations of 1,25(OH)2D in comparison to women with sufficiency.

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References

  1. Brito A, Cori H, Olivares M, Fernanda Mujica M, Cediel G, López de Romaña D (2013) Less than adequate vitamin D status and intake in Latin America and the Caribbean: a problem of unknown magnitude. Food Nutr Bull 34:52–64

    Article  Google Scholar 

  2. Palacios C, Gonzalez L (2014) Is vitamin D deficiency a major global public health problem? J Steroid Biochem Mol Biol 144 (Pt A):138–145. doi:10.1016/j.jsbmb.2013.11.003.

    Article  CAS  Google Scholar 

  3. Holick MF (2007) Vitamin D deficiency. N Engl J Med 357:266–281. doi:10.1056/NEJMra070553

    Article  CAS  Google Scholar 

  4. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM, Endocrine Society (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine society clinical practice guideline. J Clin Endocrinol Metab 96:1191–1130. doi:10.1210/jc.2011-0385

    Google Scholar 

  5. Kelishadi R, Sharifi-Ghazvini F, Poursafa P, Mehrabian F, Farajian S, Yousefy H, Movahedian M, Sharifi-Ghazvini S (2013) Determinants of hypovitaminosis D in pregnant women and their newborns in a sunny region. Int J Endocrinol 2013:460970. doi:10.1155/2013/460970

    Article  Google Scholar 

  6. Schneuer FJ, Roberts CL, Guilbert C, Simpson JM, Algert CS, Khambalia AZ, Tasevski V, Ashton AW, Morris JM, Nassar N (2014) Effects of maternal serum 25-hydroxyvitamin D concentrations in the first trimester on subsequent pregnancy outcomes in an Australian population. Am J Clin Nutr 99:287–295. doi:10.3945/ajcn.113.065672

    Article  CAS  Google Scholar 

  7. Pratumvinit B, Wongkrajang P, Wataganara T, Hanyongyuth S, Nimmannit A, Chatsiricharoenkul S, Manonukul K, Reesukumal K (2015) Maternal vitamin D status and its related factors in pregnant women in Bangkok, Thailand. PLoS One 10:e0131126. doi:10.1371/journal.pone.0131126

    Article  Google Scholar 

  8. Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM (2013) Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ 346:f1169

    Article  Google Scholar 

  9. Dantas EM, Pereira FV, Queiroz JW, Dantas DL, Monteiro GR, Duggal P, Azevedo MdeF, Jeronimo SM, Araújo AC (2013) Preeclampsia is associated with increased maternal body weight in a northeastern Brazilian population. BMC Pregnancy Childbirth 13:159. doi:10.1186/1471-2393-13-159

    Article  Google Scholar 

  10. Tedesco RP, Passini R, Cecatti JG, Camargo RS, Pacagnella RC, Sousa MH (2013) Estimation of preterm birth rate, associated factors and maternal morbidity from a demographic and health survey in Brazil. Matern Child Health J 17:1638–1647. doi:10.1007/s10995-012-1177-6

    Article  Google Scholar 

  11. Mendes CQ, Cacella BC, Mandetta MA, Balieiro MM (2015) Low birth weight in a municipality in the southeast region of Brazil. Rev Bras Enferm 68:1169–1175. doi:10.1590/0034-7167.2015680624i

    Article  Google Scholar 

  12. Trujillo J, Vigo A, Duncan BB, Falavigna M, Wendland EM, Campos MA, Schmidt MI (2015) Impact of the International Association of Diabetes and Pregnancy Study Groups criteria for gestational diabetes. Diabetes Res Clin Pract 108:288–295. doi:10.1016/j.diabres.2015.02.007

    Article  Google Scholar 

  13. Zhang R, Naughton DP (2010) Vitamin D in health and disease: current perspectives. Nutr J 9:65. doi:10.1186/1475-2891-9-65

    Article  CAS  Google Scholar 

  14. Institute of Medicine (2011) Dietary reference intakes for calcium and vitamin D. The National Academies Press, Washington. doi:10.17226/13050

    Google Scholar 

  15. Dror DK, Allen LH (2010) Vitamin D inadequacy in pregnancy: biology, outcomes, and interventions. Nutr Rev 68:465–477. doi:10.1111/j.1753-4887.2010.00306.x

    Article  Google Scholar 

  16. Jorde R, Sneve M, Emaus N, Figenschau Y, Grimnes G (2010) Cross-sectional and longitudinal relation between serum 25-hydroxyvitamin D and body mass index: the Tromsø study. Eur J Nutr 49:401–407. doi:10.1007/s00394-010-0098-7

    Article  CAS  Google Scholar 

  17. Jääskeläinen T, Knekt P, Marniemi J, Sares-Jäske L, Männistö S, Heliövaara M, Järvinen R (2013) Vitamin D status is associated with sociodemographic factors, lifestyle and metabolic health. Eur J Nutr 52:513–525. doi:10.1007/s00394-012-0354-0

    Article  Google Scholar 

  18. Lips P, van Schoor NM, de Jongh RT (2014) Diet, sun, and lifestyle as determinants of vitamin D status. Ann N Y Acad Sci 1317:92–98. doi:10.1111/nyas.12443

    Article  CAS  Google Scholar 

  19. Brannon PM, Picciano MF (2011) Vitamin D in pregnancy and lactation in humans. Annu Rev Nutr 31:89–115. doi:10.1146/annurev.nutr.012809.104807

    Article  CAS  Google Scholar 

  20. Papapetrou PD (2010) The interrelationship of serum 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D in pregnancy at term: a meta-analysis. Hormones (Athens) 9:136–144

    Article  Google Scholar 

  21. Zhang JY, Lucey AJ, Horgan R, Kenny LC, Kiely M (2014) Impact of pregnancy on vitamin D status: a longitudinal study. Br J Nutr 112:1081–1087. doi:10.1017/S0007114514001883

    Article  CAS  Google Scholar 

  22. Lee DH, Ryu HM, Han YJ, Lee SW, Park SY, Yim CH, Kim SH, Yoon HK (2015) Effects of Serum 25-hydroxy-vitamin D and Fetal Bone Growth during Pregnancy. J Bone Metab 22:127–133. doi:10.11005/jbm.2015.22.3.127

    Article  Google Scholar 

  23. Maeda SS, Borba VZC, Camargo MBR, Silva DMW, Borges JLC, Bandeira F, Lazaretti-Castro MSS et al (2014) Recommendations of the Brazilian Society of Endocrinology and Metabology (SBEM) for the diagnosis and treatment of hypovitaminosis D. Arq Bras Endocrinol Metab 58:411–33. doi:10.1590/0004-2730000003388.

    Article  Google Scholar 

  24. Joergensen C, Gall MA, Schmedes A, Tarnow L, Parving HH, Rossing P (2010) Vitamin D levels and mortality in type 2 diabetes. Diabetes Care 33:2238–2243. doi:10.2337/dc10-0582

    Article  Google Scholar 

  25. El-Khoury JM, Wang S (2012) Stability of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in human serum. Clin Biochem 45:707–708. doi:10.1016/j.clinbiochem.2012.03.016

    Article  CAS  Google Scholar 

  26. Sichieri R, Everhart JE (1998) Validity of a Brazilian food frequency questionnaire against dietary recalls and estimated energy intake. Nutr Res 18:1649–1659. doi:10.1016/s0271-5317(98)00151-1

    Article  CAS  Google Scholar 

  27. Brazilian Institute of Geography and Statistics. National Household Budget Survey. Nutritional composition table of food consumed in Brazil (2011). http://www.ibge.gov.br/home/estatistica/populacao/condicaodevida/pof/2008_2009_composicao_nutricional/. Accessed 18 Oct 2015

  28. Singer JD, Willet JB (2003) Applied longitudinal data analysis: modeling changes and event occurrence. Oxford University Press, New York

    Book  Google Scholar 

  29. Fox J (2003) Effect displays in R for generalised linear models. J Stat Softw 8(15):1–27

    Article  Google Scholar 

  30. StataCorp (2011) Stata statistical software: release 12. StataCorp LP, College Station (TX)

    Google Scholar 

  31. Choi R, Kim S, Yoo H, Cho YY, Kim SW, Chung JH, Oh SY, Lee SY (2015) High prevalence of vitamin D deficiency in pregnant Korean women: the first trimester and the winter season as risk factors for vitamin D deficiency. Nutrients 7:3427–3448. doi:10.3390/nu7053427

    Article  CAS  Google Scholar 

  32. Pérez-López FR, Fernández-Alonso AM, Ferrando-Marco P, González-Salmerón MD, Dionis-Sánchez EC, Fiol-Ruiz G, Chedraui P (2011) First trimester serum 25-hydroxyvitamin D status and factors related to lower levels in gravids living in the Spanish Mediterranean coast. Reprod Sci 18:730–736. doi:10.1177/1933719110396720.

    Article  Google Scholar 

  33. Dror DK, King JC, Durand DJ, Allen LH (2011) Association of modifiable and nonmodifiable factors with vitamin D status in pregnant women and neonates in Oakland, CA. J Am Diet Assoc 111:111–116. doi:10.1016/j.jada.2010.10.002

    Article  CAS  Google Scholar 

  34. Saraf R, Morton SM, Camargo CA, Grant CC (2015) Global summary of maternal and newborn vitamin D status–a systematic review. Matern Child Nutr doi:10.1111/mcn.12210

    Google Scholar 

  35. Kiely ME, Zhang JY, Kinsella M, Khashan AS, Kenny LC (2016) Vitamin D status is associated with uteroplacental dysfunction indicated by pre-eclampsia and small-for-gestational-age birth in a large prospective pregnancy cohort in Ireland with low vitamin D status. Am J Clin Nutr 104(2):354–361. doi:10.3945/ajcn.116.130419

    Article  CAS  Google Scholar 

  36. Haggarty P, Campbell DM, Knox S, Horgan GW, Hoad G, Boulton E, McNeill G, Wallace AM (2013) Vitamin D in pregnancy at high latitude in Scotland. Br J Nutr 109(5):898–905. doi:10.1017/S0007114512002255

    Article  CAS  Google Scholar 

  37. Diogenes ME, Bezerra FF, Rezende EP, Donangelo CM (2015) Calcium plus vitamin D supplementation during the third trimester of pregnancy in adolescents accustomed to low calcium diets does not affect infant bone mass at early lactation in a randomized controlled trial. J Nutr 145:1515–1523. doi:10.3945/jn.114.208140

    Article  CAS  Google Scholar 

  38. Engelsen O, Brustad M, Aksnes L, Lund E (2005) Daily duration of vitamin D synthesis in human skin with relation to latitude, total ozone, altitude, ground cover, aerosols and cloud thickness. Photochem Photobiol 81(6):1287–1290

    Article  CAS  Google Scholar 

  39. Marques R, Dos Santos ES (2012) Inhalabel particulate matter network monitoring, law and health hazards. Hygeia 8:115–28.

    Google Scholar 

  40. World Health Organization (2006). Air quality guidelines for particulate matter, ozone, nitrogen dioxide and sulfur dioxide: Global update. World Health Organization, Geneva. http://www.euro.who.int/__data/assets/pdf_file/0005/78638/E90038.pdf?ua=1. Accessed 18 Oct 2015

  41. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL (2011) Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res 26:2341–2357. doi:10.1002/jbmr.463

    Article  CAS  Google Scholar 

  42. Charatcharoenwitthaya N, Nanthakomon T, Somprasit C, Chanthasenanont A, Chailurkit LO, Pattaraarchachai J, Ongphiphadhanakul B (2013) Maternal vitamin D status, its associated factors and the course of pregnancy in Thai women. Clin Endocrinol (Oxf) 78:126–133. doi:10.1111/j.1365-2265.2012.04470.x.

    Article  CAS  Google Scholar 

  43. Blumfield ML, Hure AJ, Macdonald-Wicks L, Smith R, Collins CE (2013) A systematic review and meta-analysis of micronutrient intakes during pregnancy in developed countries. Nutr Rev 71(2):118–132. doi:10.1111/nure.12003

    Article  Google Scholar 

  44. Brasil (2013). Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção Básica. Programa Nacional de Suplementação de Ferro: manual de condutas gerais / Ministério da Saúde. Secretaria de Atenção à Saúde. Departamento de Atenção Básica. Brasília: Ministério da Saúde 24 p. il

  45. Brazilian Institute of Geography and Statistics (2010) Census: general characteristics of the population, religion and people with disabilities. http://biblioteca.ibge.gov.br/visualizacao/periodicos/94/cd_2010_religiao_deficiencia.pdf. Accessed 03 Aug 2015

  46. Pereira-Santos M, Costa PR, Assis AM, Santos CA, Santos DB (2015) Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obes Rev 16:341–349. doi:10.1111/obr.12239

    Article  CAS  Google Scholar 

  47. Novakovic B, Sibson M, Ng HK, Manuelpillai U, Rakyan V, Down T, Beck S, Fournier T, Evain-Brion D, Dimitriadis E, Craig JM, Morley R, Saffery R (2009) Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface. J Biol Chem 284:14838–14848. doi:10.1074/jbc.M809542200

    Article  CAS  Google Scholar 

  48. Barrett H, McElduff A (2010) Vitamin D and pregnancy: an old problem revisited. Best Pract Res Clin Endocrinol Metab 24:527–539. doi:10.1016/j.beem.2010.05.010

    Article  CAS  Google Scholar 

  49. Saito A, Iino N, Takeda T, Gejyo F (2007) Role of megalin, a proximal tubular endocytic receptor, in calcium and phosphate homeostasis. Ther Apher Dial 11(Suppl 1):S23–S26. doi:10.1111/j.1744-9987.2007.00514.x

    Article  CAS  Google Scholar 

  50. Shahbazi M, Jeddi-Tehrani M, Zareie M, Salek-Moghaddam A, Akhondi MM, Bahmanpoor M, Sadeghi MR, Zarnani AH (2011) Expression profiling of vitamin D receptor in placenta, decidua and ovary of pregnant mice. Placenta 32:657–664. doi:10.1016/j.placenta.2011.06.013

    Article  CAS  Google Scholar 

  51. Lundqvist A, Sandström H, Stenlund H, Johansson I, Hultdin J (2016) Vitamin D status during pregnancy: A longitudinal study in Swedish women from early pregnancy to seven months postpartum. PLoS One 11(3):e0150385. doi:10.1371/journal.pone.0150385

    Article  Google Scholar 

  52. Fernández-Alonso AM, Dionis-Sánchez EC, Chedraui P, González-Salmerón MD, Pérez-López FR, Group SVDaWsHR (2012) First-trimester maternal serum 25-hydroxyvitamin D3 status and pregnancy outcome. Int J Gynaecol Obstet 116:6–9. doi:10.1016/j.ijgo.2011.07.029

    Article  Google Scholar 

  53. Jones KS, Assar S, Vanderschueren D, Bouillon R, Prentice A, Schoenmakers I (2015) Predictors of 25(OH)D half-life and plasma 25(OH)D concentration in The Gambia and the UK. Osteoporos Int 26:1137–1146. doi:10.1007/s00198-014-2905-0

    Article  CAS  Google Scholar 

  54. Jones KS, Assar S, Prentice A, Schoenmakers I (2016) Vitamin D expenditure is not altered in pregnancy and lactation despite changes in vitamin D metabolite concentrations. Sci Rep 6:26795. doi:10.1038/srep26795

    Article  CAS  Google Scholar 

  55. Lips P (2007) Relative value of 25(OH)D and 1,25(OH)2D measurements. J Bone Miner Res 22:1668–1671. doi:10.1359/jbmr.070716.

    Article  CAS  Google Scholar 

  56. Spiro A, Buttriss JL (2014) Vitamin D: an overview of vitamin D status and intake in Europe. Nutr Bull 39:322–350. doi:10.1111/nbu.12108.

    Article  CAS  Google Scholar 

  57. Young BE, McNanley TJ, Cooper EM, McIntyre AW, Witter F, Harris ZL, O’Brien KO (2012) Vitamin D insufficiency is prevalent and vitamin D is inversely associated with parathyroid hormone and calcitriol in pregnant adolescents. J Bone Miner Res 27:177–186

    Article  CAS  Google Scholar 

  58. Jones G (2007) Expanding role for vitamin D in chronic kidney disease: importance of blood 25-OH-D levels and extra-renal 1alpha-hydroxylase in the classical and nonclassical actions of 1alpha, 25-dihydroxyvitamin D(3). Semin Dial 20:316–324. doi:10.1111/j.1525-139X.2007.00302.x

    Article  Google Scholar 

  59. Holick MF, Chen TC (2008) Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 87:1080S–6S

    Article  Google Scholar 

  60. Palaniswamy S, Williams D, Järvelin MR, Sebert S (2015) Vitamin D and the Promotion of Long-Term Metabolic Health from a Programming Perspective. Nutr Metab Insights 8(Suppl 1):11–21. doi:10.4137/NMI.S29526

    Google Scholar 

  61. Litonjua AA, Carey VJ, Laranjo N, Harshfield BJ, McElrath TF, O’Connor GT, Sandel M, Iverson RE, Lee-Paritz A, Strunk RC, Bacharier LB, Macones GA, Zeiger RS, Schatz M, Hollis BW, Hornsby E, Hawrylowicz C, Wu AC, Weiss ST (2016) Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years: the VDAART randomized clinical trial. JAMA 315(4):362–370. doi:10.1001/jama.2015.18589

    Article  CAS  Google Scholar 

  62. Urrutia-Pereira M, Solé D (2015). Vitamin D deficiency in pregnancy and its impact on the fetus, the newborn and in childhood. Rev Paul Pediatr 33(1): 104–113. doi:10.1016/j.rpped.2014.05.004

    Article  Google Scholar 

  63. Weinert LS, Silveiro SP (2015) Maternal-fetal impact of vitamin D deficiency: a critical review. Matern Child Health J 19(1):94–101. doi:10.1007/s10995-014-1499-7

    Article  Google Scholar 

  64. Pet MA, Brouwer-Brolsma EM (2016) The impact of maternal vitamin D status on offspring brain development and function: a systematic review. Adv Nutr 7(4):665–678. doi:10.3945/an.115.010330

    Article  CAS  Google Scholar 

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Acknowledgements

The National Council for Scientific and Technological Development (CNPq) and the Carlos Chagas Filho Foundation for Research Support of Rio de Janeiro State (FAPERJ) supported this study. Gilberto Kac has a research productivity scholarship from CNPq.

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Correspondence to Gilberto Kac.

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The Research Ethics Committees of the Municipal Secretariat of Health and Civil Defense of the State of Rio de Janeiro (Protocol no: 0012.0.249.000-09) approved this study. Written consent from all participants was obtained freely and spontaneously, after all necessary clarifications were provided in accordance with principles of the Declaration of Helsinki.

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The authors declare that they have no conflict of interest.

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394_2017_1389_MOESM1_ESM.tif

Online Resource Fig. 1 Flowchart of the selection process of study final sample of pregnant woman followed at a public health center in Rio de Janeiro, Brazil, 2009-2012. a 25(OH)D, total number of observations (data)=565 and total number of groups (women=225). b 1,25(OH)2D, total number of observations=522, and total number of groups=214. All women with information for 1,25(OH)2D also present data from 25(OH)D concentrations. 25(OH)D=25-hydroxyvitamin D; 1,25(OH)2D=1,25-dihydroxyvitamin D. The group refers to the number of women with at least one data point in time and observations refer to the total number of data points in time for all women (TIF 191 KB)

394_2017_1389_MOESM2_ESM.tif

Online Resource Fig. 2 Correlation between 1,25(OH)2D and 25(OH)D concentrations during first (a), second (b), and third (c) trimesters in women followed at a public health center in Rio de Janeiro, Brazil, 2009-2012. a first trimester (n=178), b second trimester (n=177), c third trimester (n=167). 25(OH)D=25-hydroxyvitamin D; 1,25(OH)2D=1,25-dihydroxyvitamin D (TIF 3043 KB)

394_2017_1389_MOESM3_ESM.docx

Online Resource Table 1 Confounders estimates in the longitudinal model of plasma 25(OH)D and 1,25(OH)2D concentrations during pregnancy in women followed at a public health center in Rio de Janeiro, Brazil, 2009-2012. Longitudinal linear regression coefficient (β), 95% confidence interval (CI), and P were calculated using linear mixed effects; winter=June 21st to September 21st; spring=September 22nd to December 20th; summer=December 21st to March 19th; autumn=March 20th to June 20th; 25(OH)D=25-hydroxyvitamin D; 1,25(OH)2D=1,25-dihydroxyvitamin D; BMI=Body Mass Index (DOCX 19 KB)

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Figueiredo, A.C.C., Cocate, P.G., Adegboye, A.R.A. et al. Changes in plasma concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D during pregnancy: a Brazilian cohort. Eur J Nutr 57, 1059–1072 (2018). https://doi.org/10.1007/s00394-017-1389-z

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