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Dr. Niranjan Chavan
MD, FCPS, DGO, DFP, MIOG, DICOG , FICOG
Professor and Unit Chief, L.T.M.M.C & L.T.M.G.H
Chairperson, FOGSI Oncology and TT Committee (2012-2014)
Treasurer, MOGS (2017- 2018)
Chair and Convener, FOGSI Cell- Violence against Doctors (2015-2016)
Chief Editor, AFG Times (2015-2017)
Editorial Board, European Journal of Gynecologic Oncology
Editor of FOGSI FOCUS, MOGS, AFG & IAGE Newsletters
Member, Managing Committee, IAGE (2013-2017)
Member , Oncology Committee, AOFOG (2013 -2015)
Recipient of 6 National & International Awards
Author of 15 Research Papers and 19 Scientific Chapters
Course Co-Ordinator, of 11 batches, of MUHS recognized Certificate Course of
Basic Infertility Management Including Endoscopy (BIMIE) at LTMGH
• Vitamin D is a Secosteriod (steroid with a
• The most important compounds in this group
are vitamin D3 (cholecalciferol) and vitamin
• Vitamin D2 and D3 are collectively called
• It is a pro hormone with its active form
• Vitamin D3 is three times more effective
and has a longer half life than vitamin D2.*
• Calcifediol or 25(OH)D serum levels are
measured to determine Vitamin D status.
* Logan VF, Gray AR, Peddie MC, Harper MJ, Houghton LA. Long-term vitamin D3 supplementation is more
effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D status over the winter months. Br J Nutr. 2013
Mar 28;109(6):1082-8. doi: 10.1017/S0007114512002851. Epub 2012 Jul 11.
Name Chemical Composition Structure
Mixture of molecular compounds
of ergocalciferol with lumisterol, 1:1
Vitamin D2 Ergocalciferol (made from ergosterol)
Cholecalciferol (made from 7-
dehydrocholesterol in the skin).
Vitamin D4 22-dihydroergocalciferol
Vitamin D5 Sitocalciferol (made from 7-dehydrositosterol)
• In 1922, Elmer McCollum discovered and named
Vitamin D ( D as it was the 4th vitamin to be
• In 1925, it was established that sunlight exposure
produces D3 from 7-dehydrocholesterol.
• Adolf Windaus, received the Nobel Prize in
Chemistry in 1928 for his work on the constitution
of sterols and their connection with vitamin D.
SOURCE OF VITAMNIN D
• Vitamin D subcutaneously
produced in humans from 7-
exposure to ultraviolet light B
• Fish-liver oils
• Fatty fish
• Egg yolks
• Vitamin D is absorbed with other dietary fats in
the small intestine.
• The main pathway of vitamin D uptake is
incorporation into chylomicrons that reach the
systemic circulation via the lymphatics.
• The products of vitamin D metabolism are
excreted through the bile into the faeces, and very
little is eliminated through the urine.
• Whether it is made in the skin or ingested,
cholecalciferol is hydroxylated in the liver at position
25 to form 25-hydroxycholecalciferol (calcifediol or
• This reaction is catalysed by vitamin D 25-
hydroxylase, the product of the CYP2R1 human gene,
and expressed by hepatocytes.
• Calcifediol is released into the plasma, where it is
bound to an α-globulin carrier protein named
the vitamin D-binding protein.
• Calcifediol is transported to the proximal tubules of
the kidneys, where it is hydroxylated at the 1-α
position to form calcitriol (1,25-
• It is catalysed by the enzyme 25-hydroxyvitamin
D3 1-alpha-hydroxylase, which is the product of
the CYP27B1 human gene.
• The activity of CYP27B1 is increased by parathyroid
hormone, and also by low calcium or phosphate.
WHAT IS THE OPTIMUM VITAMIN D LEVEL?
• Institute of Medicine defined adequate vitamin D status
as having serum 25-hydroxyvitamin D concentrations
greater than 50 nmol/L (or 20 ng/mL) in both the
general population and pregnant women.*
• Some studies have proposed that concentrations around
80 nmol/L (32 ng/mL) are optimal since they suppress
PTH levels and lead to the greatest calcium
*Food, Nutrition Board. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington DC:
National Academy Press, 2010.
**Dawson-Hughes B. Serum 25-hydroxyvitamin D and functional outcomes in the elderly. American Journal of Clinical
FACTORS AFFECTING VITAMIN D STATUS
Vitamin D status is affected by factors that regulate its production in
the skin and by factors affecting its absorption or metabolism.
• Skin pigmentation
• Dressing codes
• Sunscreen use
• Air pollution
• Diet with less fatty acids
• Bariatric surgery
• Malabsorption syndromes
• Celiac disease
• Chronic pancreatitis
• Cystic fibrosis
• Reduced magnesium levels
MAGNITUDE OF D3 DEFICIENCY DURING
• A recent review included 17 studies in pregnant and lactating women
found that Vitamin D deficiency is prevalent in
• 33% US
• 24% Canadian
• 60% India
• 35% UK
• 45% Pakistan
Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem?. Journal of Steroid
Biochemistry and Molecular Biology2014;144(Pt A):138-45.
VITAMIN D METABOLISM IN PREGNANCY
• By 12 weeks of gestation, 1,25(OH)2D levels are more than twice that of a
nonpregnant adult and continue to rise two- to threefold from the
nonpregnant baseline rising to over 700 pmol/l .
• There is an increase in Vitamin D Binding Protein (VDBP) and Free
• Calcitonin rises during pregnancy and stimulates renal 1-α-hydroxylase
gene expression independent of calcium levels & also protects by opposing
Møller UK, Streym S, Mosekilde L, Heickendorff L, Flyvbjerg A. Frystyk J, et al. Changes in calcitropic hormones,
bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study.
Osteoporosis International 2013;24(4):1307-20.
VITAMIN D METABOLISM IN PREGNANCY
• This is dependent on available 25-
dihydroxyvitamin D levels but independent
on calcium metabolism, which is a unique
feature of pregnancy that allows such high
levels of 1,25-dihydroxy vitamin D.
• So an increased dietary intake is required to
maintain the increase serum levels.
• Calcium metabolism uncoupled from
Wagner CL, Taylor SN, Johnson DD, Hollis BW. The role of vitamin D in pregnancy and lactation: emerging
concepts. Women’s health (London, England). 2012;8(3):323-340. doi:10.2217/whe.12.17.
VITAMIN D METABOLISM IN PREGNANCY
• The human endometrial decidua makes 1,25(OH)
2D and 24,25(OH) 2D and the placenta synthesizes
only 24,25(OH) 2D.
• 1,25(OH) 2D aids implantation and maintains
normal pregnancy, supports foetal growth and
limits production of proinflammatory cytokines.
• 24,25(OH) 2D accumulates in bone and may be
involved in ossification of the foetal skeleton.
Shin JS, Choi MY, Longtine MS, Nelson DM. Vitamin D effects on pregnancy and the placenta. Placenta. 2010;31:1027–34
• The 2012 recommendation from UK Chief Medical
Officers and NICE guidelines state that all pregnant
and breastfeeding women should take 10 micrograms of
vitamin D supplements daily.
• 1 micrograms is 40 IU.
• Three categories of vitamin D supplementation are
recommended are : General, High risk (subtypes high
risk for pre eclampsia & high rick for VDD) and
Chief Medical Officers for the United Kingdom. Vitamin D - advice on supplements for at risk groups. Cardiff, Belfast,
Edinburgh, London: Welsh Government, Department of Health, Social Services and Public Safety, The Scottish
Government, Department of Health; 2012
SCREENING OF VITAMIN D DEFICIENCY
• Routine screening of Vitamin D levels are not
• Even screening in all high risks (like on the basis
of skin colour or coverage, obesity, risk of pre-
eclampsia, or gastroenterological conditions
limiting fat absorption) is not cost effective.
• Measurement of vitamin D levels is
recommended only in a hypocalcaemic or
Vitamin D in pregnancy, scientific impact paper no. 43, July 2014, Royal college of obstetricians and gynaecologists
• Vitamin D deficiency during pregnancy is associated with the non-
classical actions of this hormone.
• VDD is associated with
Insulin resistance & gestational diabetes mellitus
An increased risk for caesarean section delivery
Impaired neonatal immunity
In a meta analysis of 8 studies published in 2013, it was found that
Maternal vitamin D deficiency in pregnancy (25(OH)D < 50 nmol/L (20
ng/mL)) has been associated with an increased risk of pre-eclampsia.
• In another metanalysis of 3357 papers published in 2013 in BMJ , it
was found that low levels of Vitamin D is significantly associated with
new onset hypertension and proteinuria in pregnancy.
• There is an abnormal expression of 1α-hydroxylase
in preeclamptic pregnancies, revealing a potential
role for 1,25(OH) 2D3 as a regulator of
• There is decreased levels of IGF-I in pre
• In vitro, IGF-1 increases 1,25(OH) 2D production
by primary human syncytiotrophoblasts from
placentas from normal pregnancies but not from
• Thus, VDD CAUSES ABNORMAL
• Vitamin D is a potent endocrine suppressor role in renin
biosynthesis for the regulation of the renin-angiotensin
• VDD has been suggested to cause excess activity in Th-1
type cytokines and to decrease immunological tolerance for
implantation and to trigger preeclampsia.
• Vitamin D has angiogenetic properties . Thus, VDD is
associated with narrowing of spiral arteries leading to pre
Bakacak M, Serin S, Ercan O, et al. Comparison of Vitamin D levels in cases with preeclampsia, eclampsia and
healthy pregnant women. International Journal of Clinical and Experimental Medicine. 2015;8(9):16280-16286.
• Women at high risk of pre-eclampsia are
advised to take at least 800 units a day
combined with calcium.
Vitamin D in pregnancy, scientific impact paper no. 43, July 2014,
Royal college of obstetricians and gynaecologists
• In this case-control study, 54 women with diagnosed GDM and 39
women with IGT (1 abnormal oral glucose tolerance test) were
compared with 111 non-GDM control women in whom GDM were
excluded by glucose challenge test.
• Maternal serum 25-hydroxy vitamin D(3) concentration in GDM and
IGT groups at 24-28 weeks of gestation were significantly lower than
• Farrant et al studied 559 pregnant women in India and found no
association between second trimester 25(OH)D levels and GDM.
• Vitamin D has a direct effect on pancreatic beta cells and
increases transcription of insulin.
• It has regulation of extracellular calcium concentration
and flux through the beta cell, thus increasing insulin
• It also regulates the function of calbindin, and acts as a
modulator of depolarization-stimulated insulin
release via regulation of intracellular calcium.
Shahgheibi S, Farhadifar F, Pouya B. The effect of vitamin D supplementation on gestational diabetes in high-risk
women: Results from a randomized placebo-controlled trial. Journal of Research in Medical Sciences : The Official
Journal of Isfahan University of Medical Sciences. 2016;21:2. doi:10.4103/1735-1995.175148.
• 1,25(OH)2D appears to stimulate the expression of insulin
• It enhances insulin sensitivity by activating peroxisome
proliferator-activated receptor delta (PPAR-δ).
• It increases intracellular Ca concentration, which is required
for insulin mediated functions.
• VDD also leads to an increase in the levels of parathyroid
hormone (PTH), which has been associated with insulin
MITRI J, PITTAS AG. Vitamin D and diabetes. Endocrinology and metabolism clinics of North America. 2014;43(1):205-232.
• Vitamin D supplementations are not recommended for either
treatment or prevention of GDM.
• Rudnicki and Mølsted-Pedersen studied Vitamin D supplementation
and glucose levels in 1997, they found that only IV (not oral) vitamin
D administration lowered serum glucose levels compared to baseline,
from 5.6 to 4.8 mmol/L (P<0.01).
• Ongoing RCTs of vitamin D supplementation in pregnancy all are
targeted at treatment of GDM and none is testing prevention of
Rudnicki PM, Mølsted-Pedersen L. Effect of 1,25-dihydroxycholecalciferol on glucose metabolism in gestational diabetes
mellitus. Diabetologia. 1997 Jan;40(1):40-4.
• Its was cross-sectional, descriptive analytical study, involving 112
neonates in Iraq – Tehran.
• Mean maternal vitamin D (vit D) level was 31.46 nmol/L in the study.
• Vitamin D levels were significantly lower in mothers of LBW.
• Adequate nutritional vitamin D status during
pregnancy is important for foetal skeletal development,
tooth enamel formation and perhaps general foetal
growth and development.
• Approximately 25-30 g of calcium are transferred to
the foetal skeleton by the end of pregnancy, this
requires high levels of D3.
• Mannion et al., in 2006 found that with every additional
40 IU of maternal vitamin D intake, there was an
associated 11-g increase in birth weight .
Mannion C, Gray-Donald K, Koski K. Milk restriction and low maternal vitamin D intake during pregnancy
are associated with decreased birth weight. CMAJ. 2006;174(9):1273–1277.
• Maternal circulating 25-OHD deficiency <50 nmol/L is associated with
• Vitamin D supplementation suggested that 25-OHD serum concentration
> 100 nmol/L (vs <50 nmol/L) could significantly reduce the risk of PTB.
Zhou SS, Tao YH, Huang K, Zhu BB, Tao FB. Vitamin D and risk of preterm birth: Up-to-date meta-analysis of
randomized controlled trials and observational studies. J Obstet Gynaecol Res. 2017 Feb;43(2):247-256. doi:
10.1111/jog.13239. Review. Erratum in: J Obstet Gynaecol Res. 2017 Apr;43(4):783.
• Protective effect is due to immunomodulator effects
• Vitamin D might protect against PTB by reducing
infection and inflammation.
• Inhibits inflammatory factors, such as tumour
necrosis factor-α and interleukin & promotes anti-
inflammatory cytokine and cathelicidin.
• Improves placental function, and reduces oxidative
Chesney RW. Vitamin D and The Magic Mountain: The anti-infectious role of the vitamin. J Pediatr 2010; 56: 698–
• Low cord blood 25(OH)D concentrations have been associated with
respiratory syncytial virus bronchiolitis and respiratory infections.
• Low levels of neonatal vitamin D have been linked to childhood asthma.
• Cord blood samples deficient in vitamin D had less effect on adult monocyte
cathelicidin gene expression compared with vitamin D replete cord blood
• Maternal vitamin D supplementation is
associated increased gene expression of
tolerogenic immunoglobulin such as
immunoglobulin-like transcripts 3 and 4 (ILT3
• Cord blood 25(OH)D is correlated with
mononuclear cell release of IFN-γ and hence Th1
• Vit. D Up-regulates the production of the
antimicrobial peptides by macrophages and
Chi A, Wildfire J, McLoughlin R, Wood RA, Bloomberg GR, Kattan M, et al. Umbilical cord plasma 25-
hydroxyvitamin D concentration and immune function at birth: the Urban Environment and Childhood Asthma
study. Clin Exp Allergy 2011;41:842–50.
• The risk was four-fold higher in women with serum 25(OH) D levels
below 37.5 nmol/L (15ng/mL) in women undergoing LSCS.*
• Vitamin D deficiency results in proximal muscle weakness and decreased
lower extremity muscle function perhaps contributing to the risk for
• Vitamin D deficiency is also associated with bacterial vaginosis in
*Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM. Association between
maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and
meta-analysis of observational studies. BMJ 2013;346:f1169.
**Hensel KJ, Randis TM, Gelber SE, Ratner AJ. Pregnancy-specific association of vitamin D
deficiency and bacterial vaginosis. Am J Obstet Gynecol 2011;204:41.e1–9.
TREATMENT OF VDD IN PREGNANCY
• Treatment : either with cholecalciferol
20 000 IU a week or ergocalciferol 10 000 IU
twice a week.
• Duration : 4 – 6 weeks
• Maintenance dose:1000 IU daily throughout
Vitamin D: screening and supplementation during pregnancy, committee opinion number 495, july 2011 (reaffirmed
2017), The American College of Obstetrician and Gynaecologists.
National Institute for Health and Clinical Excellence. Antenatal care. NICE clinical guideline
62. Manchester: NICE; 2008.
DRUG SAFETY DURING PREGNANCY
• US FDA pregnancy category: C
• US Recommended DA during pregnancy and lactation is
400IU and 600IU respectively.
• The daily upper safe limit for vitamin D has been set at
4000 IU by IOM and 10,000 IU by the Endocrine Society.
• Animal studies have shown foetal abnormalities associated
with hypervitaminosis D, similar to supravalvular aortic
National Institute for Health and Clinical Excellence. Antenatal care. NICE clinical guideline 62. Manchester:
• Vitamin D deficiency (VDD) during pregnancy is an unappreciated
• There is an increased requirement of vitamin D during pregnancy.
• Routine screening for general and even in all high risk pregnancies is
• Both RCOG and ACOG advocate routine 400 IU daily
supplementation of Vitamin D during pregnancy and lactation.
• Low vitamin D concentrations have been associated with a wide range
of adverse maternal and offspring health outcomes in observational
• Further research should focus on the potential benefits and optimal
dosing of vitamin D use in pregnancy.
• Logan VF, Gray AR, Peddie MC, Harper MJ, Houghton LA. Long-term vitamin D3
supplementation is more effective than vitamin D2 in maintaining serum 25-hydroxyvitamin D
status over the winter months. Br J Nutr. 2013 Mar 28;109(6):1082-8. doi:
10.1017/S0007114512002851. Epub 2012 Jul 11.
• Food, Nutrition Board. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin
D. Washington DC: National Academy Press, 2010.
• Dawson-Hughes B. Serum 25-hydroxyvitamin D and functional outcomes in the elderly. American
Journal of Clinical Nutrition2008;88(2):527S-540S.
• Palacios C, Gonzalez L. Is vitamin D deficiency a major global public health problem?. Journal of
Steroid Biochemistry and Molecular Biology2014;144(Pt A):138-45.
• Møller UK, Streym S, Mosekilde L, Heickendorff L, Flyvbjerg A. Frystyk J, et al. Changes in
calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and
postpartum: a controlled cohort study. Osteoporosis International 2013;24(4):1307-20.
• Shin JS, Choi MY, Longtine MS, Nelson DM. Vitamin D effects on pregnancy and the placenta.
• Wagner CL, Taylor SN, Johnson DD, Hollis BW. The role of vitamin D in pregnancy and lactation:
emerging concepts. Women’s health (London, England). 2012;8(3):323-340. doi:10.2217/whe.12.17.
• Chief Medical Officers for the United Kingdom. Vitamin D - advice on supplements for at risk
groups. Cardiff, Belfast, Edinburgh, London: Welsh Government, Department of Health, Social
Services and Public Safety, The Scottish Government, Department of Health; 2012
• Vitamin D in pregnancy, scientific impact paper no. 43, July 2014, Royal college of obstetricians
• Vitamin D: screening and supplementation during pregnancy, committee opinion number 495, July
2011 (reaffirmed 2017), The American College of Obstetrician and Gynaecologists.
• National Institute for Health and Clinical Excellence. Antenatal care. NICE clinical guideline 62.
Manchester: NICE; 2008.
• Mithal A, Kalra S. Vitamin D supplementation in pregnancy. Indian Journal of Endocrinology and
Metabolism. 2014;18(5):593-596. doi:10.4103/2230-8210.139204.
• Scholl TO, Chen X, Stein P. Maternal vitamin D status and delivery by
cesarean. Nutrients 2012;4(4):319-30.
• Tabesh M, Salehi-Abargouei A, Tabesh M, Esmaillzadeh A. Maternal vitamin D
status and risk of pre-eclampsia: a systematic review and meta-analysis. Journal of
Clinical Endocrinology and Metabolism2013;98(8):3165-73.