Educational Materials

1. Associate Clinical Professor Dr Aisha Elbareg, MD, PhD
Senior Consultant Obstetrician& Gynecologist
Faculty of Medicine, MisrataUniversity, Libya
aishaelbareg@med.misuratau.edu.ly
Vitamin D in Pregnancy & Lactation is there any role?

2. Introduction: Vitamin D deficiency is considered a worldwide public
health problem (general population do not meet the dietary vitamin D
requirements as recommended by nutritional vitamin D guidelines). The
prevalence of vitamin D deficiency is particularly high during winter
 It is important for musculoskeletal health and, historically, is known to be
effective for the prevention and treatment of rickets and osteomalacia, and may
also reduce fractures and falls in the elderly ( Osteoporos . Int. 2011, 22, 2461–
2472, JAMA 2018, 319, 1552–1553).
 Exists in two main isoforms vitamin D3 (cholecalciferol): either derived from
ultraviolet-B (UV-B) induced production from its precursor 7-dehydrocholesterol
in the skin (Black skin is 90% less capable of vitamin D production, sunscreen
decreases production in the skin by 95–99%) or from intake of foods such as fatty
fish, cod liver oil or egg yolk, and vitamin D2 (ergocalciferol): is derived from
intake of fungal sources such as mushrooms and yeast (Physiol. Rev. 2016, 96,
365–408).
 About 80% of vitamin D supply is derived from endogenous production in the
skin whereas only about 20% of vitamin D supply is derived from oral intake.
 Vitamin D is converted to 25-hydroxyvitamin D (25(OH)D) by different 25-
hydroxylase enzymes in the liver.
 In the circulation, about 85 to 90% of 25(OH)D is bound to vitamin D-binding
protein (DBP), 10 to 15%to albumin and only less than 1% of serum 25(OH)D is
unbound (i.e., free) (Endocrinol. Metab. Clin. N. Am. 2017, 46, 901–918).

3.  Some tissues such as the kidneys, parathyroid glands and placenta are, able to
take up DBP-bound 25(OH)D by the megalin / cubilin complex.
 Hydroxylation step of 25(OH)D is required to produce 1,25-dihydroxyvitamin
D (1,25(OH)2D), the so-called active vitamin D hormone or calcitriol, that has
the highest affinity for the almost ubiquitously expressed vitamin D receptor.
 Serum 1,25(OH)2D is mainly derived from the 1-alpha-hydroxylase catalyzed
conversion of 25(OH)D to 1,25(OH)2D in the kidneys, but several extra-renal
tissues are also able to convert 25(OH)D to 1,25(OH)2D on a local/tissue level.
 Renal 1-alpha-hydroxylase activity is stimulated by parathyroid hormone and
inhibited by fibroblast-growth factor-23.
 1,25(OH)2D functions as a classic steroid hormone such as thyroid or sex
hormones.
 Degradation of vitamin D metabolites is initiated by 24-hydroxylation leading
to the formation of calcitroic acid (excreted in the bile and urine), after
several hydroxylation and oxidation steps.

4. General Requirements:
 It has been shown that an overall vitamin D intake (i.e., supplements plus diet)
of about 1000 IU per day is required to achieve a serum 25(OH)D
concentration of ≥50 nmol/L in 97.5% of the population (Nutrients 2017, 9, 469,
Nutrients 2018, 10, 533).It was further calculated that an intake of 400 IU is
required to achieve ≥ 25 nmol/L in 97.5% of the population. It is important to
note that general populations do not meet vitamin D requirements as, for
example, in Europe serum 25(OH)D concentrations <30 nmol/L and <50
nmol/L are detected in 13.0% and 40.4% of the population (Am. J. Clin. Nutr.
2016, 103, 1033–1044).

5. Vitamin D Metabolism

6. Vitamin D Metabolism

7. Vitamin D Metabolism

8. Vitamin D Metabolism during Pregnancy:
 Compared to non-pregnant women, there is a significant increase in
1,25(OH)2D concentrations, with a 2-fold increase in in the first trimester of
pregnancy and a further rise to a 2- to 3-fold increase during the course of
pregnancy and a rapid decline after delivery (Bone Res. 2017, 5, 17030), on the
other hand, some studies suggest that serum 25(OH)D might be lower in
pregnancy (J. Steroid Biochem. Mol. Biol. 2018, 181, 80–87).
 The kidney is the major production site of serum 1,25(OH)2D, apart from
proximal tubular cells, it might also be produced by activated immune cells
such as macrophages in the kidney. Others such as parathyroid hormone-
related peptide might also play a role in it’s regulation. The placenta is also
producing 1,25(OH)2D on a local/tissue level.
 Vitamin D-binding protein (DBP), with a peak of approximately 40–50%
higher serum concentrations compared to non-pregnant women at the
beginning of the third trimester and a decline at term (Front. Endocrinol.
(Lausanne) 2018, 9, 259). liver is usually the major production site, and
partially the result of the high turnover rate of trophoblast.
 Vitamin D concentrations in the umbilical cord are usually 60–89% of the
values in the mother’s blood, 25(OH)D crosses the placenta, 1,25(OH)2D does
not but is produced by the fetal kidneys.

9. Vitamin D Metabolismduring Pregnancy:
 The compound 1,25(OH)2D as the active form of vitamin D has non-genomic
and genomic effects through its action on vitamin D receptor (J. Steroid
Biochem. Mol. Biol. 2018, 180, 41–50). The non-genomic effects occur quickly
and include the activation of ion channels with the change of electrical state of
the cell and protein kinase activation, on the other hand, the genomic effects
which include the modulation of gene expression take more time.
 The abnormalities of the action of vitamin D receptor could manifest in signs
and symptoms of vitamin D deficiency, During pregnancy, this may present as
gestational diabetes, preeclampsia, preterm birth or miscarriage in early stages
of pregnancy.
 The prevalence of vitamin D deficiency is particularly high during winter, 67%
of pregnant women had serum 25(OH)D concentrations below 25 nmol/L in this
season (Arch. Gynecol. Obstet. 2017, 296, 43–51).
 Supplements: Capsules of vitamin D2 (ergocalciferol) contain 50,000 IU per
capsule. liquid form contains 8000 IU/mL of vitamin D2. Vitamin D3 in
products containing 400 IU, 800 IU, 1000 IU and 2000 IU also are available
 Food: fish oil:(400–1000 IU/spoon of oil), caught salmon (600–1000 IU/100 g),
sardines (300 IU/100 g), tuna in a tin can (230 IU/100 g), egg yolk (20–50 IU/1
egg yolk), cow milk (0.4–1.2 IU/100 mL), and cheese(7–28 IU/100 g)
(Endokrynol. Pol. 2013, 64, 319–327)

10.  Some vitamin D supplementation guidelines recommend for pregnant women
and women planning pregnancy a daily vitamin D intake of 1500–2000 IU in
order to obtain and maintain 25(OH)D concentrations as high as 75 nmol/L,
while others found that 1200 IU of vitamin D per day was required to ensure
that cord serum 25(OH)D concentrations were above 30 nmol/L in 95%, and
above 25 nmol/L in 99% of the infants, however, a supplemental vitamin D
intake of a dose: 800 to 1000 IU per day would be necessary to ensure a
sufficient vitamin D supply: (to achieve serum25(OH)D target concentrations
as recommended by vitamin D guidelines).

11.  women who received 4000 IU daily vitamin D supplementation during
pregnancy had an average concentration of 111.0 nmol/L 25(OH)D at the time
of birth. In this group, the incidence of several pregnancy complications was
the lowest (Calcif. Tissue Int. 2013, 92, 128–139).

13. Vitamin D and obstetric complications:
1-Vitamin D and Gestational Diabetes(GDM):
 Pregnancy is a diabetogenic state due to changes in the insulin sensitivity and beta
cell function in previously healthy women. Vitamin D has an effect on beta cell
function, insulin sensitivity and inflammatory markers both directly and
indirectly (Curr Diabetes Rev. 2012;8:42–7).
 Based on the existing literature it is probable that vitamin D deficiency could be
one of the cofactors that increase the risk of gestational diabetes. Several meta-
analyses of observational studies indicated an 18–80% increased risk of
gestational diabetes in women with vitamin D deficiency (Diabetes Care 2014, 37,
1837–1844, Arch. Gynecol. Obstet. 2016, 293, 959–966, Front. Endocrinol. 2018, 9,
7).
 A study in Saudi pregnant Women revealed a significantly higher risk of
development of GDM among pregnant women having deficient vitamin D status
(BMC Pregnancy and Childbirth (2018) 18:86).
 But a recent study( Diabetes Ther (2018) 9:2081–2090), demonstrated that
parathyroid hormone (PTH) was associated with decreased insulin sensitivity,
beta cell dysfunction and dysglycemia in pregnancy. In contrast, the vitamin D
level in pregnancy is not associated with GDM, insulin sensitivity and beta cell
function!! The PTH level may emerge as an underlying independent risk factor
relevant to the interpretation of the links between 25OHD and GDM.

14. Vitamin D andGestational Diabetes(GDM):
 In a most recent study (J Steroid Biochem Mol Biol. 2019 Feb;186:117-121),
it has been found that avoiding maternal vitamin D deficiency in early
pregnancy is associated with lower blood glucose in early pregnancy and
throughout pregnancy. Higher 25OHD in late pregnancy was associated
with higher odds of Large for gestational age at birth.

15. 2-VITAMIND & Gestational Hypertension and Preeclampsia:
 Gestational hypertension and preeclampsia usually defined according to the
criteria of the International Society for the Study of Hypertension in Pregnancy.
Women without pre-existing hypertension are classified as having gestational
hypertension if they have a systolic blood pressure ≥140 mm Hg and/or diastolic
blood pressure ≥90 mm Hg on at least two occasions first occurring after 20
gestational weeks. Pre-eclampsia is defined as gestational hypertension in
combination with proteinuria (≥0.3 g/d).
 Studies in humans have demonstrated an association between vitamin D
insufficiency and endothelial dysfunction, implying that vitamin D has a role in
regulating the conductance and resistance of blood vessels (Journal of the
American College of Cardiology. 2011; 58(2):186–92). This provides a mechanism
by which vitamin D insufficiency could be associated with PET.
 However, many observational studies reporting conflicting results, some
demonstrating an inverse association between maternal vitamin D status and the
risk of pre-eclampsia (Epidemiology (Cambridge, Mass). 2014; 25(2):207–14,
BJOG : an international journal of obstetrics and gynaecology. 2012; 119(7):832–9),
and others no association (Journal of human hypertension. 2013; 27(2):115–8,
Annals of epidemiology. 2014; 24(5):399–403.e1).
 A recent systematic review and meta-analysis, published in the BMJ in 2017,
showed that vitamin D had no significant influence on the risk of GHT or pre-
eclampsia (BMJ (Clinical research ed). 2017; 359:j5237).

16. VDAART preeclampsia CONSORT diagram

17. VITAMIND & Gestational Hypertension and Preeclampsia:
 In contrast, a systemic review and meta-analysis of vitamin D deficiency and
pregnancy outcomes, showed a significant association between pre-eclampsia
and 25(OH)D insufficiency compared with the comparison group (BMJ.
2013; 346:f1169).
 Another study published in the Journal of Clinical Investigation, Nov 2016:
Vitamin D supplementation initiated in weeks 10–18 of pregnancy did not
reduce preeclampsia incidence, however, vitamin D levels of 30 ng/ml or higher
at trial entry and in late pregnancy were associated with a lower risk of
preeclampsia.
 Latest study published in the 2018 : (Vitamin D and risk of pregnancy related
hypertensive disorders: mendelian randomisation study); Found no strong
evidence to support a causal effect of 25-hydroxyvitamin D levels on
gestational hypertension or pre-eclampsia (BMJ 2018;361:k2167).

18. 3-Caesarean Delivery:
 It has been suggested that vitamin D deficiency may reduce pelvic muscle
strength and control (Nutrients. 2012; 4(4):319–30). However, again, findings
are inconsistent. Several studies which assessed 25(OH)D in early pregnancy
(at the time of GDM screening) or at delivery, reported an increased risk of
Caesarean delivery in 25(OH)D deficient women (official journal of the
American College of Endocrinology and the American Association of Clinical
Endocrinologists. 2012; 18(5):676–84), whilst other studies measuring
25(OH)D in the first trimester demonstrated no increased risk (European
journal of clinical nutrition. 2014, International journal of gynaecology and
obstetrics, 2012; 116(1):6–9).
 A meta analyses of 16 trials found no overall evidence to support the use of
vitamin D supplementation to reduce rates of Caesarean section (BMJ
(Clinical research ed). 2017; 359:j5237).

19. 4-Preterm Delivery:
 Several observational studies found no association between preterm labour and maternal
vitamin D levels (Int. J. Gynaecol. Obstet. 2012, 116, 6–9, Asia.
Pac. J. Clin. Nutr. 2017, 26, 287–290). In contrast, one study showed that women with
vitamin D concentrations lower than 75 nmol/L delivered prematurely in 49.4% compared to
26.2% of preterm deliveries in women with vitamin D concentrations higher than 75 nmol/L
(Obstet. Gynecol. 2013, 122, 91–98), taking into consideration that the results of these studies
might not be applicable to general populations as some of them focused on specific
populations such as mothers with previous history of preterm birth, twin gestations, and
women with higher risk of preeclampsia.
• However, a meta-analysis of seven observational studies failed to prove an association
between maternal vitamin D levels and preterm birth (Health Technol. Assess. 2014, 18, 1–
190), but a limiting factor : not all studies were adjusted for confounders and the definition
of preterm labour was not consistent between the studies.
• A recent study on a general population and participants with different medical conditions,
socioeconomic status and different race groups (PLoS ONE 2017, 12, e0180483) reported a
62% lower risk of preterm labour in women with vitamin D concentrations higher than 40
ng/mL at the time of delivery compared to those with concentrations below 20 ng/mL .
• More randomized controlled trials needed before vitamin D supplementation
with the aim of reducing the risk of preterm birth can be recommended.

20. Bodnar et al demonstrated (among a group of 3453 pregnant women) that there was a
51% lower risk of preterm birth for women with a vitamin D serum level of 38 ng/ml or
greater, compared to women with 8 ng/ml. Obstet Gynecol. 2015 Feb; 125(2): 439–447

21. PLOS ONE | https://doi.org/10.1371/journal.pone.0180483 July 24, 2017

22. 5-Bacterial Vaginosis:
 It has been found that vitamin D deficiency was associated with bacterial
vaginosis in black women but not in Caucasians (J. Nutr. 2009, 139, 1157–
1161).In another study involved 146 mixed ethnicity pregnant women among
whom 8.8% developed bacterial vaginosis, significantly lower concentrations
of vitamin D were observed in patients with bacterial vaginosis (Infect. Dis.
Obstet. Gynecol. 2011, 2011, 216217). A meta-analysis of three observational
studies reported an inverse association between maternal vitamin D and the
risk of bacterial vaginosis (Health Technol. Assess. 2014, 18, 1–190).
 But, two randomized trials have not shown any effect of vitamin D
supplementation on lowering the rates of bacterial vaginosis during pregnancy
(J. Steroid. Biochem. Mol. Biol. 2013, 136, 313–320).
 In conclusion: it is currently not justified to supplement vitamin D in
pregnancytolowertheratesof bacterial vaginosis.

23. Vitamin D and Lactation

24. Vitamin D and Lactation:
 Vitamin D content of breast milk is often expressed as antirachitic activity
(ARA). ARA of breast milk has to be 513 IU/L to provide the same vitamin D
supply for infants as a daily vitamin D supplement with 400 IU, that is usually
recommended for infants for the purpose of rickets prevention.
 Only minimal amounts of maternal serum 25(OH)D are transferred to human
breast milk, and vitamin D concentration in breast milk is only approximately
as high as 20% of the maternal serum vitamin D concentrations, therefore,
the vitamin D intake of the mother during lactation has to be much higher
compared to the intake during pregnancy and adequate vitamin D supply by
breast milk is possible but can only be achieved by relatively high doses of
maternal vitamin D supplementation, therefore, maternal vitamin D
supplementation alone with 6400 IU/day safely supplies breast milk with
adequate vitamin D to satisfy the requirement of her nursing infant and offers
an alternate strategy to direct infant supplementation.

26. Vitamin D and Lactation:
 In a study: (Vitamin D supplementation in pregnancy and lactation to promote
infant growth), published in (N Engl J Med. 2018 Aug 9), the conclusion was:
{in a population with widespread prenatal vitamin D deficiency and
fetal/infant growth restriction, maternal vitamin D supplementation from mid-
pregnancy until birth or 6 months postpartum does not influence fetal or infant
growth, and has no beneficial or harmful effects on numerous other birth and
infant outcomes}!!
 Effects of vitamin D supplementation of lactating women on clinical
outcomes in the infants are still not well investigated!!

27. Summery & Conclusions:
 Inadequate vitamin D intakes and vitamin D deficiency in pregnant and
lactating women are very common worldwide.
 The prevalence of vitamin D deficiency is particularly high during winter
season ( 67% of pregnant women had serum 25(OH)D concentrations below
25 nmol/L in this time of the year).
 It has been hypothesized that vitamin D might (in utero) modifies gene
expression without changes in the DNA code itself that may improve early
development and later health (Br. Med. Bull. 2018, 126, 57–77).
 Vitamin D intakes ranging from 400 to 800 IU of vitamin D per day in order
to reach serum 25(OH)D target concentrations of at least 25 to 50 nmol.
 During pregnancy a supplemental vitamin D intake of 1500–2000 IU per day
would be necessary to ensure a sufficient vitamin D supply (25(OH)D
concentrations as high as 75 nmol). The Institute of Medicine suggests that
toxic effects can occur above the threshold of 125nmol/L, and recommend
avoidance of intakes above 4000IU/day.
 In terms of obstetric outcomes, there is mixed and conflicting evidence on the
benefits of vitamin D supplementation in pregnancy.

28. Summery & Conclusions:
 There is some evidence to support a positive relationship between vitamin D
status and offspring birth weight and offspring bone mass, but conflicting
evidence still exists.
 Several randomised controlled trials failed to prove an association between
vitamin D supplementation and reduction of the risk of various pregnancy
complications, which could be due to the inadequate power or other limitations
of the studies, but it could also mean that the observed associations are in fact
not causative, despite all of these problems of interpretation, Vitamin D
supplementation might be of value in reducing the risk of pregnancy
complications such as gestational diabetes, preeclampsia, and preterm labour.
 High quality clinical studies and meta-analyses of high quality data are still
needed to throw further light on the subject.

29. Thank You