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)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.
5. Kidneys
Bone
Parathyroid
hormone
Calcium Resorption Calcium Absorption
1,25(OH)2D
Preosteoclast
Osteoblast
ca2+ and HPO4
2-
calcification
Blood calcium and phosphorus ↑
1,25(OH)2D
ca2+ and HPO4
2-
Actions of Vitamin D: 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)2D 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) 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
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
22. 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.
23. 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.
24. 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.
25. Fig. Placental expression of VDR, CYP24A1, CYP27B1
Normal pregnancy
GDM
Normal pregnancy
GDMGDM
Normal pregnancy
CYP27B1VDRCYP24A1
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)2D 1,24,25(OH)3D
24,25(OH)2D
CYP27B1
CYP24A1↑
CYP24A1↑
Fig. Placenta from GDM
Vitamin D deficiency and GDM
28. 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 &
Coustan
Deficiency:
<20ng/ml
30wks No
Maghbooli et al.
(2007)
Iran
Carpenter &
Coustan
Deficiency:
<25nmol/l
24-28wks Yes
Soheilykhah et al.
(2010)
Iran
Carpenter &
Coustan
Deficiency:
<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
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. Vitamin D supplementation in pregnancy
RCOG. Scientific Impact Paper No. 43 : Vitamin D in Pregnancy. 2014.
Supplementation
Vitamin D
Daily units Combined with
400a N/A
800b Calcium
1000c N/A
Treatment
Cholecalciferol 2800 20,000 IU a week
Ergocalciferol 2800d 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
41. 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
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
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.
control CKD
Placental expression and production of CYP24A1↑
low level of vitamin D observed in GDM
CYP24A1 and Disease
Editor's Notes
Measuring vitamin D deficiency in pregnant women is complicated by a lack --------
임상에서 측정해 보시면 거의 대부분 vitamin D deficiency가 있는 것을
그러면 vitamin d deficiency와 임신 중 다양한 adverse pregnancy outcomes과의 연관성에 대해서 살펴보도록 하겠습니다
하지만 한 개의 연구 결과만을 가지고 관계를 단정짓기는 한계가 있을 것 같습니다.
먼저 GDM과의 연관성에 대한 연구를 살펴보시면
산모 입장에서 가장 관심이 있는 것 중 하나는
Vitamin D deficiency가 있으면 임신 중 다양한 질환이 발생한다고 말할 수 있을까
Vitamin D level과 임신 중 여러 질환과의 연관성을 이해하는데는 중요한 부분
즉 vitamin D deficiency와 GDM과의 연관성에 있어서 placenta가 중요하다는 것을 알 수 있다.
연관성 사이에는 placenta가 있기 때문에 정확한 관계를
즉 VITAMIN D 부족이 질환의 원인인지 아니면 질환 때문에 VITAMIN D부족이 발생하였는지 알 수 없다.
임신 중 그 연관성에는 태반이 중요한 역할을 할 수 있게다는 것이다.
태반의 역할을 포함하여 vitamin D deficiency와 임신 중 다양한 질환과의 연관성을 분석하는데 있어 태반의 역할을 고려하여 분석해야 할 것이다
따라서 단순히 vitamin D를 주면 다양한 adverse pregnancy 를 줄일 수 있다고 생각하기 어렵다.
실제 …. 도 이런 이유이다.
AI, Adequate intake; EAR, estimated average requirement; UL, tolerable upper intake level.
a Mother’s requiremen t, 4,000–6,000 IU/d (mother’s intake for infant’s requirement if infant is not receiving 400 IU/d).
Recommended dietary allowances (RDA) of the IOM
Particular care should be taken over high-risk women.
The recommendations are based on the classical actions of vitamin D, although many of the nonclassical
actions of vitamin D may be beneficial.
For the majority of women who are deficient in vitamin D, treatment for 4–6 weeks, either
with cholecalciferol 20 000 iu a week or ergocalciferol 10 000 iu twice a week, followed by standard
supplementation, is appropriate
Particular care should be taken over high-risk women.
The recommendations are based on the classical actions of vitamin D, although many of the nonclassical
actions of vitamin D may be beneficial.
어떤 목적을 가지고 줄 것인가? 결국 환자에게 검사를 하고 supplementation을 recommendation하고
De-Regil LM et al. Cochrane Database Syst Rev. (2012) We included six trials assessing a total of 1023 women
De-Regil LM eIn this updated review we included 15 trials assessing a total of 2833 women, excluded 27 trials, and 23 trials are still ongoing or unpublished. t al. Cochrane Database Syst Rev. (2016)
68. Steer PJ. Is vitamin D supplementation in pregnancy advisable? Lancet 2013;381:2143–5.
48. Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH. Association of maternal
vitamin D status during pregnancy with bone-mineral content in offspring: a prospective
cohort study. Lancet 2013;381:2176–83.
68. Steer PJ. Is vitamin D supplementation in pregnancy advisable? Lancet 2013;381:2143–5.
48. Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH. Association of maternal
vitamin D status during pregnancy with bone-mineral content in offspring: a prospective
cohort study. Lancet 2013;381:2176–83.
Particular care should be taken over high-risk women.
The recommendations are based on the classical actions of vitamin D, although many of the nonclassical
actions of vitamin D may be beneficial.
