임신부와 Vitamin d

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


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


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


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



Vitamin D deficiency and Preeclampsia


Vitamin D deficiency and Preeclampsia


Vitamin D deficiency and SGA


Vitamin D deficiency and SGA


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


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.



VDR CYP27B1CYP24A1

Fig. Placental protein expression

*

Normal GDM Normal GDM Normal GDM

* p-value<0.05



Fig. Placental expression of VDR, CYP24A1, CYP27B1

Normal pregnancy

GDM

Normal pregnancy

GDMGDM

Normal pregnancy

CYP27B1VDRCYP24A1


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


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


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


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


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.


Fertil Steril 2015;103:1278–88.


Vitamin D levels

Preeclampsia

GDM

Fertil Steril 2015;103:1278–88.


SGA

LBW

Preterm birth

Fertil Steril 2015;103:1278–88.


C/S

Birth length

Birth weight



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.


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.


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

Health & Medicine

임신부와 Vitamin d