Post on 18-Jan-2017
임신 중 vitamin D 의 보충 : 과연 필요한 것인가 ?
조 금 준
고려대학교 구로병원 산부인과
Contents
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
Physiology of Vitamin D
25(OH)D
1,25(OH)2D 1,24,25(OH)3D
24,25(OH)2D
CYP27B1(1α-hydroxylase) CYP24A1
(24-hydroxylase)
CYP24A1
(Major circulating metabolite)
(bioactive metabolite) (inactive metabolite)
7-dehydrocholesterolD
Kidneys
Liver
Skin
mRNA TRANSLATION
PROTEIN FUNCTION
Holick MF. N Engl J Med. 2007;357:266-81.
Kidneys
Bone
Parathyroid hor-mone
Calcium Resorption Calcium Absorption
1,25(OH)2D
Preosteoclast Osteoblast
ca2+ and HPO42-
calcification
Blood calcium and phosphorus ↑
1,25(OH)2D
ca2+ and HPO42-
Actions of Vitamin D: classical
Holick MF. N Engl J Med. 2007;357:266-81.
Parathyroid glands
Innate immunity
Immunomodulation
KidneysPancreas1-OHase
1,25(OH)2D
Decreased parathyroid hor-
mone
VDR-RXR1-OHase
Decreased renin
Increased insulin
1,25(OH)2D
Breast, colon, prostate, etc.
Enhance p21 and p27Inhibits angiogenesisInduces apoptosis
VDR-RXR
1-OHase
1,25(OH)2D
24-OHase
Calcitroic acid
Increased VDRIncreased 1-OHase
25(OH)D
Blood25(OH)D
>30ng/ml
Activated T lymphocyte
Activated B lymphocyte
Cytokine regulation
Immunoglobulin syn-thesis
Increased catheli-cidin
VDR-RXR
1,25(OH)2D
macrophage/monocyte
Parathyroid hormone regulation
Blood pressure regulation
Blood sugar con-trol
Actions of Vitamin D: non-classical
Holick MF. N Engl J Med. 2007;357:266-81.
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 harm-ful. 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.
Identifying Vitamin D deficiency
Lack of agreement among researchers in three areas: - Whether 25(OH)D levels are most accurate makers of defi-
ciency - What level of 25(OH)D should be considered optimal in preg-
nant women - Which test of vitamin D deficiency is the most accurate
Urrutia RP, et al. Curr Opin Obstet Gynecol. 2012;24:57-64.
Figure. Prevalence of low vitamin D status in adults worldwide
Prevalence of low vitamin D status in adults worldwide
Rihwa Choi, et al. Nutrients 2015;7:3427-3448.
Prevalence of Vitamin D deficiency in Korean pregnant women
Vitamin D and Pregnancy (1)
Kovacs CS . et al. Endo Rev 1997;18:832-72.
The early rise of 1,25(OH)2D during pregnancy Calcium requirements ↑ for mineralization of the fetal skeleton
later in pregnancy
Lower birth weights and a higher risk of SGA in women with defi-cient 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.
Authors Cohort (n) GDM (n) Prevalence 25(OH)D deficiency
Significant difference in 25(OH)D between GDM vs NGT
Zhang et al. (2008) 171 57 19.8% Yes
Clifton-Bligh et al.(2008) 244 81 48% Yes
Farrant et al.(2009) 559 39 66% No
Maghbooli et al. (2007) 579 52 70.6% Yes
Soheilykhah et al. (2010) 165 54 78.4% Yes
Makgoba et al. (2011) 348 90 58.8% No
Baker et al. (2011) 180 60 7.2% No
Table. Summary of the observational studies
Vitamin D deficiency and GDM
Vitamin D deficiency and GDM
Fariba Aghajafari, et al. BMJ 2013;346:f1169
Vitamin D deficiency and GDM
Fariba Aghajafari, et al. BMJ 2013;346:f1169
Vitamin D deficiency and Preeclampsia
Fariba Aghajafari, et al. BMJ 2013;346:f1169
Vitamin D deficiency and Preeclampsia
Fariba Aghajafari, et al. BMJ 2013;346:f1169
Vitamin D deficiency and SGA
Fariba Aghajafari, et al. BMJ 2013;346:f1169
Vitamin D deficiency and SGA
Fariba Aghajafari, et al. BMJ 2013;346:f1169
Vitamin D deficiency and neonatal bone
Debbie A Lawlor, et al. Lancet 2013; 381: 2176–83
The mothers with measure-ments 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
MotherPlacenta Fetus
Decidua(maternal)
trophoblast(fetal)
25(OH)D
1,25(OH)2D1,25(OH)2D 1,25(OH)2D
AntimicrobialAnti-inflammatory
Fetal skeletal development
Maternal calcium homeostasis
1,25(OH)2D
25(OH)D 25(OH)D
Vitamin D and Placenta
CYP27B1
CYP24A1
VDR VDR
CYP27B1
Placenta contributing 20-50% of the circulating vitamin D in preg-nancy Editorial. J Clin Endocrionol Metab 2007;92:3402-3.
34.52
11.65 27.5
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.
Table. Logistic regression analysis of GDM
OR 95% CI
Age 0.87 0.68-1.11
BMI 1.30 1.02-1.64
Parity 0.46 0.10-2.11
Birth weight 14.35 1.03-199.48
Winter season at delivery 0.82 0.12-5.48
Gender-male 0.63 0.10-3.76
Total calcium level 1.37 0.16-11.94
Vitamin D deficiency 45.74 4.95-422.26
* 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.
VDR CYP27B1CYP24A1
Fig. Placental protein expression
*
Normal GDM Normal GDM Normal GDM
* p-value<0.05
Vitamin D deficiency and GDM
Cho et al. Am J Obsetet Gynecol 2013;209: 560.e1–560.e8.
Fig. Placental expression of VDR, CYP24A1, CYP27B1
Normal pregnancy
GDM
Normal pregnancy
GDMGDM
Normal pregnancy
CYP27B1VDRCYP24A1
Vitamin D deficiency and GDM
25(O
H)D
leve
l
CYP27B1
r=-0.45, p<0.01
VDR CYP24A1
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
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)2D 1,24,25(OH)3D
24,25(OH)2D
CYP27B1
CYP24A1↑
CYP24A1↑
Fig. Placenta from GDM
Vitamin D deficiency and GDM
Authors Location GDM criteria Determinant Determined at Significant difference
Zhang et al. (2008) US ADA Deficiency: <20ng/ml 16wks Yes
Clifton-Bligh et al.(2008) Australia ADPS Deficiency:
<25nmol/l 28.7 wks Yes
Farrant et al.(2009) India Carpenter &
CoustanDeficiency:
<20ng/ml 30wks No
Maghbooli et al. (2007) Iran Carpenter &
CoustanDeficiency:
<25nmol/l 24-28wks Yes
Soheilykhah et al. (2010) Iran Carpenter &
CoustanDeficiency:
<20ng/ml 24-28wks Yes
Makgoba et al. (2011) UK WHO Deficiency:
<25nmol/l 12wks No
Baker et al. (2011) US NDDG Deficiency: <20ng/ml 13wks No
Table. Summary of the observational studies
Vitamin D and GDM
Vitamin D and GDM
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
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 preg-
nancy
Inadequate vitamin D supplementation
doses in pregnancy
Hollis BW, et al. Am J Clin Nutr 2004;79:717–726.
Placental CYP24A1 and GDM
Screening for vitamin D deficiency in pregnancy
No data to support routine screening for vitamin D defi-ciency in pregnancy in terms of health benefits or cost effective-ness.
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 sta-tus could be expected
Endocrine Society. J Clin Endocrinol Metab 2011;96:1911–1930.
At this time, insufficient evidence to support a recommenda-tion 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 con-centration, 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
Endocrine Society. J Clin Endocrinol Metab 2011;96:1911–1930.
Vitamin D supplementation in pregnancy
Vitamin D supplementation in pregnancy
RCOG. Scientific Impact Paper No. 43 : Vitamin D in Pregnancy. 2014.
Supplementation
Vitamin D
Daily units Combined with400a N/A800b Calcium1000c N/A
Treatment Cholecalciferol 2800 20,000 IU a weekErgocalciferol 2800d 10,000 IU 2x weeklya Recommended for all pregnant womenb Recommended for women with high risk of preeclampsiac Recommended for women at high risk of vitamin D deficiencyd To be taken through and after the high-dose supplementation
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 de-ficiency have not been studied during pregnancy.
Recommendations concerning routine vitamin D supplemen-tation during pregnancy beyond that contained in a prenatal vi-tamin should await the completion of ongoing randomized clin-ical trials.
At this time, there is insufficient evidence to recommend vi-tamin D supplementation for the prevention of preterm birth or preeclampsia.
ACOG Committee. Obstet Gynecol 2011; 118:197–198.
Vitamin D supplementation in pregnancy
Fertil Steril 2015;103:1278–88.
Vitamin D supplementation in pregnancy
Vitamin D levels
Preeclampsia
GDM
Fertil Steril 2015;103:1278–88.
Vitamin D supplementation in pregnancy
SGA
LBW
Preterm birth
Fertil Steril 2015;103:1278–88.
Vitamin D supplementation in pregnancy
C/S
Birth length
Birth weight
Vitamin D supplementation in pregnancy
Vitamin D supplementation in pregnancy
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
Vitamin D supplementation during pregnancy Definition of vitamin D level in pregnancy ?? Vitamin D deficiency adverse pregnancy outcomes ?? Vitamin D supplementation adverse pregnancy out-
comes ??
Further rigorous randomized trials are required to evaluate the role of vitamin D supplementation in pregnancy.
Conclusion
Thank you for your attention
Poor vitamin D status the risk of rickets in offspring ↑ rec-ommendations for routine maternal supplementation
No association between maternal 25(OH)D concentration in any trimester and offspring bone-mineral content or other bone out-comes.
Vitamin D supplementation in pregnancy
Lawlor DA, et al. Lancet 2013;381:2176–83.
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 re-mained 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
A mechanism attenuating vi-tamin D-mediated growth inhi-bition in numerous human tu-morsAnderson MG. Cancer Chemother Pharmacol 2006;57:234–40.
A significant mechanism con-tributing to vitamin D defi-ciency and resistance to vita-min D therapy in CKDChristian FH. et al. Kidney International 2010;78:463-72.
control CKD
Placental expression and production of CYP24A1↑ low level of vitamin D observed in GDM
CYP24A1 and Disease