1. 임신 중 vitamin D 의 보충 : 과연 필요한 것인가 ? 조 금 준 조 금 준 조 금 준 조 금 준 고려대학교 구로병원 산부인과

2. Contents

3. Contents Physiology and Action of vitamin D Definition of Vitamin D deficiency Vitamin D deficiency and Adverse pregnancy outcomes Vitamin D and Placenta Vitamin D deficiency screening in pregnancy Vitamin D supplementation in pregnancy

4. Physiology of Vitamin D 25(OH)D 1,25(OH) 2 D 1,24,25(OH) 3 D 24,25(OH) 2 D CYP27B1 (1 α-hydroxylase) CYP24A1 (24 -hydroxylase) CYP24A1 (Major circulating metabolite) (bioactive metabolite) (inactive metabolite) 7-dehydrocholesterolD Kidneys Liver Skin Holick MF. N Engl J Med. 2007;357:266-81.

5. Kidneys Bone Parathyroid hormone Calcium Resorption Calcium Absorption 1,25(OH) 2 D Preosteoclast Osteoblast ca 2+ and HPO 4 2- calcification Blood calcium and phosphorus ↑ 1,25(OH) 2 D ca 2+ and HPO 4 2- Actions of Vitamin D: classical Holick MF. N Engl J Med. 2007;357:266-81.

6. Parathyroid glands Innate immunity Immunomodulation Kidneys Pancreas 1-OHase 1,25(OH) 2 D Decreased parathyroid hormone VDR-RXR 1-OHase Decreased renin Increased insulin 1,25(OH) 2 D Breast, colon, prostate, etc. Enhance p21 and p27 Inhibits angiogenesis Induces apoptosis VDR-RXR 1-OHase 1,25(OH) 2 D 24-OHase Calcitroic acid Increased VDR Increased 1-OHase 25(OH)D Blood25(OH)D>30ng/ml Activated T lymphocyte Activated B lymphocyte Cytokine regulation Immunoglobulin synthesis Increased cathelicidin VDR-RXR 1,25(OH) 2 D macrophage/ monocyte Parathyroid hormone regulation Blood pressure regulation Blood sugar control Actions of Vitamin D: non-classical Holick MF. N Engl J Med. 2007;357:266-81.

7. Definition of Vitamin D deficiency ACOG, 2011: deficiency as 25(OH)D levels < 32 ng/mL (80 nmol/L) The endocrine society, 2011: deficiency as 25(OH)D levels < 20 ng/mL (50 nmol/L) and insufficiency as a 25(OH)D of 21–29 ng/ml (52.5–72.5 nmol/L).  Emerging evidence that too much of these nutrients may be harmful. As a result, the minimum concentration of 25(OH) D in serum recommended for good bone health was reduced from 30 to 20 ng/ml. ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 495 Endocrine Society. J Clin Endocrinol Metab 2011;96:1911–1930. Steer PJ. Lancet 2013;381:2143–5.

8. Identifying Vitamin D deficiency Lack of agreement among researchers in three areas: - Whether 25(OH)D levels are most accurate makers of deficiency - What level of 25(OH)D should be considered optimal in pregnant women - Which test of vitamin D deficiency is the most accurate Urrutia RP, et al. Curr Opin Obstet Gynecol. 2012;24:57-64.

9. Figure. Prevalence of low vitamin D status in adults worldwide Prevalence of low vitamin D status in adults worldwide

10. Rihwa Choi, et al. Nutrients 2015;7:3427-3448. Prevalence of Vitamin D deficiency in Korean pregnant women

11. Vitamin D and Pregnancy (1) Kovacs CS. et al. Endo Rev 1997;18:832-72. The early rise of 1,25(OH) 2 D during pregnancy Calcium requirements ↑ for mineralization of the fetal skeleton later in pregnancy

12. Lower birth weights and a higher risk of SGA in women with deficient vitamin D level An inverse association with having a cesarean section and BV and vitamin D level Association with lower vitamin D level and GDM Lower vitamin D level in preeclampsia compared with normal pregnancy Vitamin D and Pregnancy (2) Leffelaar ER. et al. Br J Nutr 2010;104:108-17. Merewood A, et al. J Clin Endocrinol Metab 2009;94:940-5. Dunlop AL. et al. Infect Dis Obstet Gynecol. 2011;2011:216217 Baker AM. et al. J Clin Endocrinol Metab 2010;95:5105-9. Clifton-Bligh RJ. et al. Diabet Med 2008;25:678–84.

13. Authors Cohort (n) GDM (n) Prevalence 25(OH)D deficiency Significant difference in 25(OH)D between GDM vs NGT Zhang et al. (2008) 1715719.8%Yes Clifton-Bligh et al. (2008) 2448148%Yes Farrant et al. (2009) 5593966%No Maghbooli et al. (2007) 5795270.6%Yes Soheilykhah et al. (2010) 1655478.4%Yes Makgoba et al. (2011) 3489058.8%No Baker et al. (2011) 180607.2%No Table. Summary of the observational studies Vitamin D deficiency and GDM

14. Fariba Aghajafari, et al. BMJ 2013;346:f1169

15. Vitamin D deficiency and GDM Fariba Aghajafari, et al. BMJ 2013;346:f1169

16. Vitamin D deficiency and Preeclampsia Fariba Aghajafari, et al. BMJ 2013;346:f1169

17. Vitamin D deficiency and Preeclampsia Fariba Aghajafari, et al. BMJ 2013;346:f1169

18. Vitamin D deficiency and SGA Fariba Aghajafari, et al. BMJ 2013;346:f1169

19. Vitamin D deficiency and SGA Fariba Aghajafari, et al. BMJ 2013;346:f1169

20. Vitamin D deficiency and neonatal bone Debbie A Lawlor, et al. Lancet 2013; 381: 2176–83 The mothers with measurements of 25(OH)D concentration in pregnancy and the offspring undergone DEXA at age 9–10 years No relevant association between maternal vitamin D status in pregnancy and off spring BMC in late childhood

21. Mother PlacentaFetus Decidua(maternal)trophoblast(fetal) 25(OH)D 1,25(OH) 2 D AntimicrobialAnti-inflammatory Fetal skeletal development Maternal calcium homeostasis 1,25(OH) 2 D 25(OH)D Vitamin D and Placenta CYP27B1 CYP24A1 VDRVDR CYP27B1 contributing 20-50% of the circulating vitamin D in pregnancy Placenta contributing 20-50% of the circulating vitamin D in pregnancy Editorial. J Clin Endocrionol Metab 2007;92:3402-3.

22. 34.52 11.65 27.5 27.5 85.0 85.0 Figure. The mean level of 25(OH)D and prevalence of vitamin D deficiency ** * p-value<0.05 Vitamin D deficiency and GDM Cho et al. Am J Obsetet Gynecol 2013;209: 560.e1–560.e8.

23. Table. Logistic regression analysis of GDM OR95% CI Age0.870.68-1.11 BMI1.301.02-1.64 Parity0.460.10-2.11 Birth weight14.351.03-199.48 Winter season at delivery0.820.12-5.48 Gender-male0.630.10-3.76 Total calcium level1.370.16-11.94 Vitamin D deficiency 45.744.95-422.26 * All variables in table are adjusted in model. Vitamin D deficiency and GDM Cho et al. Am J Obsetet Gynecol 2013;209: 560.e1–560.e8.

24. VDRCYP27B1CYP24A1 Fig. Placental protein expression * NormalGDMNormalGDMNormalGDM * p-value<0.05 Vitamin D deficiency and GDM Cho et al. Am J Obsetet Gynecol 2013;209: 560.e1–560.e8.

25. Fig. Placental expression of VDR, CYP24A1, CYP27B1 Normal pregnancy GDM GDM GDM CYP27B1VDRCYP24A1 Vitamin D deficiency and GDM

26. 25(OH)D level CYP27B1 r=-0.45, p<0.01 VDRCYP24A1 r=-0.13, p=0.32 r=0.06, p=0.65 Fig. Correlation between Placental expression and serum level Vitamin D deficiency and GDM

27. 25(OH)D level↓ and vitamin D deficiency↑ in GDM compared with normal pregnancy The placental expression of CYP24A1↑  serum 25(OH) D level↓ The placental expression of CYP24A1↑ in GDM 25(OH)D 1,25(OH) 2 D 1,24,25(OH) 3 D 24,25(OH) 2 D CYP27B1 CYP24A1↑ CYP24A1↑ Fig. Placenta from GDM Vitamin D deficiency and GDM

28. AuthorsLocation GDM criteria Determinant Determined at Significant difference Zhang et al. (2008) USADA Deficiency: <20ng/ml 16wksYes Clifton-Bligh et al. (2008) AustraliaADPS Deficiency: <25nmol/l 28.7 wksYes Farrant et al. (2009) India Carpenter & Coustan Deficiency: <20ng/ml 30wksNo Maghbooli et al. (2007) Iran Carpenter & Coustan Deficiency: <25nmol/l 24-28wksYes Soheilykhah et al. (2010) Iran Carpenter & Coustan Deficiency: <20ng/ml 24-28wksYes Makgoba et al. (2011) UKWHO Deficiency: <25nmol/l 12wksNo Baker et al. (2011) USNDDG Deficiency: <20ng/ml 13wksNo Table. Summary of the observational studies Vitamin D and GDM

30. Consequence of Dz process TNF-α  insulin signaling and glucose uptake↓  DM and insulin resistance Serum & placental TNF-α↑ in GDM TNF-α  2-to 5-fold increase in CYP24A1 in placenta TNF-α↑ in GDM  CYP24A1↑ in placenta  vitamin D deficiency Chen HL, et al. Am J Pathol 1991;139:327–335. Winkler G, et al. Diabetes Res Clin Pract 2002;56:93-9. Díaz L, et al. J Reprod Immunol. 2009;81(1):17-24. Specific receptors for vitamin D in pancreatic β cells A role of vitamin D in the secretion of insulin Vitamin D deficiency  DM and insulin resistance Placental CYP24A1↑  vitamin D deficiency  GDM Causal of GDM Kadowaki S, et al. J Clin Invest 1984; 73: 759–66. Scragg R, et al. Diabetes Res Clin Pract 1995; 27: 181–8. Roth J, et al. Endocrinology 1982;110: 2216–8. Vitamin D and GDM

31. Significant public health efforts to ensure that all pregnant women achieve 25(OH)D intakes of 400IU/day Little positive impact on prevalence of vitamin D deficiency Increased placental activity of CYP24A1 accounting for the resistance to vitamin D therapy in pregnancy Inadequate vitamin D supplementation doses in pregnancy Hollis BW, et al. Am J Clin Nutr 2004;79:717–726. Placental CYP24A1 and GDM

32. Screening for vitamin D deficiency in pregnancy No data to support routine screening for vitamin D deficiency in pregnancy in terms of health benefits or cost effectiveness. Reasonable to measure 25(OH)D in groups of people at high risk for vitamin D deficiency and in whom a prompt response to optimization of vitamin D status could be expected Endocrine Society. J Clin Endocrinol Metab 2011;96:1911–1930.

33. At this time, insufficient evidence to support a recommendation for screening all pregnant women For pregnant women with increased risk, measurement of 25(OH)D levels can be considered Measurement of vitamin D in women with a low calcium concentration, bone pain, gastrointestinal disease, alcohol abuse, a previous child with rickets and those receiving drugs which reduce vitamin D. RCOG. Scientific Impact Paper No. 43 : Vitamin D in Pregnancy. 2014. ACOG Committee on Obstetric Practice. ACOG Committee Opinion No. 495 Screening for vitamin D deficiency in pregnancy

34. Endocrine Society. J Clin Endocrinol Metab 2011;96:1911–1930. Vitamin D supplementation in pregnancy

35. RCOG. Scientific Impact Paper No. 43 : Vitamin D in Pregnancy. 2014. Supplementation Vitamin D Daily unitsCombined with 400 a N/A 800 b Calcium 1000 c N/A Treatment Cholecalciferol280020,000 IU a week Ergocalciferol2800 d 10,000 IU 2x weekly a Recommended for all pregnant women b Recommended for women with high risk of preeclampsia c Recommended for women at high risk of vitamin D deficiency d To be taken through and after the high-dose supplementation

36. When vitamin D deficiency is identified during pregnancy, 1,000–2,000 IU/day is safe. Higher dose regimens used for the treatment of vitamin D deficiency have not been studied during pregnancy. Recommendations concerning routine vitamin D supplementation during pregnancy beyond that contained in a prenatal vitamin should await the completion of ongoing randomized clinical trials. At this time, there is insufficient evidence to recommend vitamin D supplementation for the prevention of preterm birth or preeclampsia. ACOG Committee. Obstet Gynecol 2011; 118:197–198. Vitamin D supplementation in pregnancy

37. Fertil Steril 2015;103:1278–88. Vitamin D supplementation in pregnancy Vitamin D levels Preeclampsia GDM

38. Fertil Steril 2015;103:1278–88. Vitamin D supplementation in pregnancy SGA LBW Preterm birth

39. Fertil Steril 2015;103:1278–88. Vitamin D supplementation in pregnancy C/S Birth length Birth weight

40. Vitamin D supplementation in pregnancy

41. De-Regil LM et al. Cochrane Database Syst Rev. (2012) De-Regil LM et al. Cochrane Database Syst Rev. (2016) six trials assessing a total of 1023 women 15 trials assessing a total of 2833 women

42. Vitamin D supplementation during pregnancy  Definition of vitamin D level in pregnancy ??  Vitamin D deficiency  adverse pregnancy outcomes ??  Vitamin D supplementation  adverse pregnancy outcomes ?? Further rigorous randomized trials are required to evaluate the role of vitamin D supplementation in pregnancy.Conclusion

43. Thank you for your attention

44. Poor vitamin D status  the risk of rickets in offspring ↑  recommendations for routine maternal supplementation No association between maternal 25(OH)D concentration in any trimester and offspring bone-mineral content or other bone outcomes. Vitamin D supplementation in pregnancy Lawlor DA, et al. Lancet 2013;381:2176–83.

45. Success in raising 25-hydroxy vitamin D levels in pregnant women and neonates albeit with varying doses of 25-hydroxy vitamin D in RCTs of vitamin D supplementation Despite increases with supplementation, 25(OH)D levels remained low in most studies. 600 IU/day of 25-hydroxy vitamin D for pregnant women specifically to support bone metabolism and no more than 4000 IU/day to avoid hypercalcemia ACOG endorses these recommendations and proposes 1000– 2000 IU/day of 25(OH)D when deficiency is identified (<20 ng/ml) Institute of Medicine. Washington, DC: The National Academies Press; 2011. ACOG Committee. Obstet Gynecol 2011; 118:197–198. Roth DE. J Perinatol 2011; 31:449–459. Vitamin D supplementation in pregnancy

46. A mechanism attenuating vitamin D-mediated growth inhibition in numerous human tumors Anderson MG. Cancer Chemother Pharmacol 2006;57:234–40. A significant mechanism contributing to vitamin D deficiency and resistance to vitamin D therapy in CKD Christian FH. et al. Kidney International 2010;78:463-72. controlCKD Placental expression and production of CYP24A1↑  low level of vitamin D observed in GDM CYP24A1 and Disease