Article Type: 3 Original Article - Australia, Japan, SE Asia

Accepted Article
Supplementation of Vitamin D in pregnancy and its correlation with feto-maternal
outcome.

Aanchal Sablok1, Aruna Batra1, Karishma Thariani1, Achla Batra1, Rekha Bharti1, Abha Rani
Aggarwal2, B C Kabi3, Harish Chellani4
1
Department of Obstetrics and Gynaecology, Vardhman Mahavir Medical College and
Safdarjung Hospital, New Delhi, India.
2
National Institute of Medical Statistics, All India Institute of Medical Sciences, New Delhi,
India.
3
Department of Biochemistry, Vardhman Mahavir Medical College and Safdarjung Hospital,
New Delhi, India.
4
Department of Paediatrics, Vardhman Mahavir Medical College and Safdarjung Hospital, New
Delhi, India.

Abbreviated title: Vitamin D deficiency in pregnancy and its effect on feto-maternal outcome.

Key-terms: Vitamin D; deficiency; supplementation; maternal outcomes.

Corresponding author:

Dr Aanchal Sablok
Senior Resident,
Department of Obstetrics and Gynaecology, Vardhman Mahavir Medical College and Safdarjung
Hospital, New Delhi. 110029
India.
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/cen.12751
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 Phone: +91 9873070927
Accepted Article
Email: aanchalsablok54@gmail.com

Disclosure statement: All the authors have nothing to disclose.

Abstract
Context: Vitamin D deficiency widely prevalent throughout the world. Pregnant women,
neonates and infants form most vulnerable groups for vitamin D deficiency. Objective: 1) To
find prevalence of vitamin D deficiency in pregnant women. 2) To evaluate effect of
supplementation with cholecalciferol in improving vitamin D levels in pregnant women and
evaluate its correlation with feto-maternal outcome. Design: Randomized control trial from years
2010-2012. Setting: Tertiary care centre, Delhi, India. Participants: 180 pregnant women.
Study population divided randomly into 2 groups; Group A: non-intervention (60 women) and
Group B: intervention (120 women). Intervention: The intervention group received
supplementation of vitamin D in dosages depending upon 25(OH)-D levels. Main Outcome
measures: Risk of maternal complications like Pre-term labour; pre-eclampsia and gestational
diabetes associated with Vitamin D deficiency and risk of Low birth weight and poor APGAR
score in infants of mothers with Vitamin D deficiency. Results: Adjusted serum 25(OH)-D
concentration was lower in group A as compared to group B (mean 46.11 74.21 nmol/L vs 80
51.53 nmol/L). 44% patients in group A and 20.3% patients in group B developed Pre-term
labour/Pre-eclampsia/Gestational Diabetes. New-borns of mothers in group A had lower cord
blood levels of 25(OH)-D levels as compared to group B ( mean 43.11 81.32 nmol/L vs 56.8
47.52 nmol/L). They also had lower birth weight of mean 2.4 0.38 kg as compared to group B
2.6 0.33 kg. Conclusions: Vitamin D supplementation reduces risk of maternal comorbidities
and helps improve neonatal outcomes.

Introduction

Vitamin D is a steroid with a hormone like activity that regulates the functions of over 200 genes and is

essential for growth and development of the body. Vitamin D deficiency is widely prevalent throughout

the world [1].

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 Pregnant women, neonates and infants form the most vulnerable groups for vitamin D deficiency.
Accepted Article
Research has suggested that vitamin D deficiency may put pregnant women at greater risk for

preeclampsia [2], preterm labour/ preterm birth, gestational diabetes, and infections [3], besides poor

weight gain and myopathy [4]. Women with serum 25(OH)-D levels >100 nmol/L (40ng/mL) in the 3rd

trimester are associated with a 47% reduction in preterm births [3].

The clinical significance of vitamin D supplementation as a part of routine antenatal care is yet to be

determined and further research in different populations is recommended [5].

Supplementation studies conducted with recommended daily allowance of 400 IU have not shown any

improvement in vitamin D status of pregnant women. Higher doses given either as a daily dose of 800 IU

or bolus dose of 200 000 IU given as a single dose or 2/3 divided doses given once a month has shown

significant improvement. However, even in these studies, adequate levels were achieved in only 30% of

the participants [6, 7]. In another randomized controlled trial, women with a singleton pregnancy at 1216

weeks gestation received 400, 2000 or 4000 IU vitamin D3/day until delivery, with 68% females

achieved 25(OH)-D Level 80 nmol/L at delivery with 4000IU vitamin D3/day compared to 43% females

who achieved 25(OH)-D Level 80 nmol/L at delivery with 400IU vitamin D3/day of supplementation

[8].

The present study was undertaken to determine the status of vitamin D in pregnancy and evaluate the

effect of supplementation on matero-fetal outcomes in north-Indian population.

Materials and methods:

The study was conducted in the Department of Obstetrics and Gynaecology along with the Department of

Biochemistry and Neonatal division of Paediatrics in Safdarjung hospital, New Delhi, India.

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 A sample size of 180 was calculated taking 15% as the margin of error and 95% confidence limit.
Accepted Article
Primigravidae with singleton pregnancy at 14-20 weeks, willing to comply to the study protocol were

included in the study whereas pregnant women with pre-existing osteomalacia, known

hyperparathyroidism, renal, liver dysfunction, tuberculosis, sarcoidosis and women not willing to comply

to the study protocol were excluded from the study.

Randomization was done using computer generated random number tables, into two groups: Group A

(n=60) formed the non-intervention group who did not receive any supplementation of vitamin D whereas

Group B (n=120) formed the supplementation group who received vitamin D supplementation in dosages

depending upon the level of serum 25(OH)-D levels estimated at entry into the study.

At the initial visit a detailed history including symptoms of vitamin D deficiency (generalized body ache,

muscular weakness), menstrual history and obstetrical history was taken. Dietary history was taken in

detail based on one week recall method. Diet software (Dietsoft Vr. 1.1.7) was used to calculate the daily

intake of calorie, protein and calcium intake. Vitamin D intake was calculated approximately based on

vitamin D content in different food products. Serum vitamin D levels using sandwich ELISA and serum

calcium, phosphorus and serum ALP levels were estimated in group B at the initial visit.

Vitamin D status was classified as sufficient: > 50nmol/L, insufficient: 25-50nmol/L and deficient:

<25nmol/L. Depending on the serum vitamin D levels women in group B having sufficient levels of

vitamin D received only one dose of 60 000 IU cholecalciferol at 20 weeks, women having insufficient

levels received two doses of 120 000 IU at 20 weeks and 24 weeks and women having deficient levels

received four doses of 120 000 IU cholecalciferol at 20, 24, 28 and 32 weeks.

At the time of delivery, both the groups underwent clinical evaluations and including record of period of

gestation and a complete anthropometric assessment of the neonate. Serum vitamin D, calcium,

phosphorus and serum ALP levels were estimated again in group B and also in group A for the first time.

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 Biochemical analysis
Accepted Article
5ml of fresh maternal/cord blood was collected in vacutainers and were immediately transported to the

laboratory on ice where centrifugation was done within one hour. If analysis was done within 24 hours of

collection, serum was stored at 2-8 C, otherwise the serum was stored at -20C until analysed. Repeated

freeze thaw cycles were avoided.

Statistical analysis

Statistical analysis was done using SPSS statistical package (version 17; SPSS). Normally distributed

continuous variables were expressed as means and standard deviations, and non parametric variables as

medians and IQR. Proportions were compared using the chi square test. P values were expressed without

a bonferroni correction. Spearmans test was used for correlations. Two- tailed significance at p< 0.05

was considered significant. To find the odds ratio, regression analysis was done. In running data, simple

regression was used and in categorical data, logistic regression was applied.

Observations and results

Three patients in group A and twelve patients in group B were lost to follow up. Thus the maternal and

cord blood data at delivery was available for 57 patients in group A and 108 patients in group B, and the

data was analysed in 165 patients.

Age was found to have no effect on vitamin D levels in the body (p>0.05). A strong association was

found with religion, more muslims were found to have vitamin D deficiency as compared to hindus (75%

vs 45.2%).

A very strong association was seen between BMI 25 and vitamin D deficiency (p=0.000). OR 4.6, 95%

CI (90.4-225.7).

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 Strongest association was found between vitamin D levels and sun exposure. Sufficient levels of vitamin
Accepted Article
D were seen in 93.3% patients who had > 4hrs of sun exposure every day as compared to 1.85% in those

with < 1hr of daily sun exposure (p= 0.00). Sun exposure was thus found to have a protective effect

against vitamin D deficiency, OR 0.05, 95% CI (0.019-0.128).

EFFECT OF SUPPLEMENATION

Improvement in 25(OH)-D levels in group B

All the patients in group B having baseline 25(OH)-D level < 25nmol/L showed an increase in 25(OH)-D

levels after supplementation. These women had received a total of 480000 IU of vitamin D3. The median

levels being 65nmol/L post supplementation compared to 38nmol/L pre-supplementation and 24 nmol/L

in group A. Table 1.

Cord blood 25(OH)-D levels in group A and group B.

It was found that 64.9.% of the babies in group A whose mothers were not supplemented with vitamin D

had cord blood levels of 25(OH)-D levels of < 25nmol/L, and only 14% had 25(OH)-D levels

>50nmol/L. On the other hand, only 27% of the babies in group B whose mothers were supplemented

with vitamin D had cord blood levels of 25(OH)-D <25 nmol/L and 46.2% of the babies had 25(OH)-D

level >50 nmol/L. This difference in the two groups was statistically significant, p= 0.000. Table 2.

Pregnancy complications in group A and group B

In group A, 21.1% of the patients had Pre-term labour (PTL); whereas in group B, only 8.3% had PTL,

p= 0.02. Similarly, 21.1% in group A had hypertensive complications during pregnancy, whereas 11.1%

of the patients in group B had such complications. However, this difference was not statistically

significant (p=0.08).

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 The occurrence of gestational diabetes (GDM) was very low in both the groups and the difference was not
Accepted Article
statistically significant. Table 3.

NEONATAL OUTCOME

Neonatal birth-weights in group A and group B

There was a significant difference in the mean birth weight of babies in the supplemented group (Group

B) as compared to that in the non-supplemented group (Group A), p = 0.01. The mean birth weight of

babies in Group B was 2.4 0.31 and in Group A the mean birth weight was 2.6 0.41 kg. Table 4.

Apgar score of babies in group A and group B at 5 min.

Apgar level <7 was seen in 13% of mothers having vitamin D deficiency compared to 1.1% in those who

were vitamin D sufficient at delivery (p = 0.000).

Discussion

Prevalence of vitamin D deficiency

As shown in fig. 1, the prevalence of hypovitaminosis D (serum 25(OH)-D <50 nmol/L) in the present

study population was almost 77.5% (128/165). A global report showed widespread prevalence of

hypovitaminosis D in almost every region of the world studied. The 25(OH)-D levels below 75 nmol/L

were common in most populations, but the levels below 25nmol/L were most commonly seen in

population at risk that includes most of the South-Asian countries. [1]

Maternal 25(OH)-D levels and religion and ethnicity

In the present study vitamin D status was found to be affected by religion with a higher prevalence of

vitamin D deficiency was in muslims (75%) vs. hindus (45.2%), p = 0.006. Higher prevalence of vitamin

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 D deficiency has also been reported in pregnant muslim population in tropical countries, in whom the
Accepted Article
practice of purdah might have played an important role. [9-13]

Ethnic variations among people living in same geographical area may be related to skin pigmentation [14-

17]. Melanin acts as a filter for ultraviolet rays hence reducing the production of vitamin D by the skin.

Maternal 25(OH)-D levels and duration of sun exposure

There was a highly significant association between the duration of sun exposure and vitamin D levels.

Odds ratio for women with sun exposure < 1 hr/day was 0.50, CI (0.19-0.128). A study done in London

also found a positive correlation between duration of sun exposure and prediction of 25(OH)-D [6].

The vitamin D levels were lower in studies in western countries which are far away from equator [18-20].

The importance of UV rays was further shown by seasonal variation in the concentration of vitamin D

between summer and winter, with higher levels of vitamin D during the summer compared with the

winter months [21, 22].

Maternal 25(OH)-D levels and BMI

Association between BMI 25 and low 25(OH)-D levels was highly significant, p = 0.000, odds ratio

being 4.6, 95% CI (90.37 225.74). Present study has results comparable to several studies conducted

during pregnancy [23-27] which demonstrated that circulating 25(OH)-D concentrations were lower in

obese than lean individuals. Vitamin D metabolism is affected in obese individuals, as it is deposited in

body fat stores, making it less bioavailable [28].

Effects of supplementation

The universal recommended dietary intake for vitamin D during pregnancy is 400 IU/d. The studies on

supplementation with 800-1600 IU/day during the last trimester of pregnancy in women with 25(OH)-D

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 levels < 15 ng/ ml showed that vitamin D levels increased from 5.8 ng/ml to a mere 11 ng/ ml [ 29-31].
Accepted Article
Studies conducted in the past have reprted the effect of bolus vitamin supplementation to be similar as

compared to the daily supplementation [6,7]. A recent trial by Hollis et al has reported the beneficial

effect of daily supplementation with 2000IU and 4000IU on feto-maternal outcome during pregnancy,

with upto 68% women achieved a serum levels >80 nmol/L of 25(OH)-D at term of pregnancy with

4000IU/day supplementation compared to only 43% women achieving the serum levels >80 nmol/L of

25(OH)-D at term of pregnancy with 400IU vitamin D3/day [8].

Another study by Hollis et al has also demonstrated that rather than bolus interval dosage of vitamin D,

daily supplementation of vitamin D is more beneficial for overall effect and benefits of vitamin D, due to

its very small half-life in circulation. But, bolus interval dosage is still beneficial in pregnancy because

25(OH)-D has a long half-life and the human placenta possess a megalin-cubilin endocytotic system. This

system is the key in the delivery of 25(OH)-D to the 25-hydroxyvitamin D-1-- hydroxylase and

conversion to 25(OH)-D2. Also, 25(OH)-D can be actively transported across the placenta because of the

megalin-cubilin endocytotic system, attaining high levels of vitamin D in the fetus [32].

Keeping in mind the results of these studies and due to the non-availability of higher dose (4000IU) daily

preparations, the present study was planned to give supplementation according to the baseline levels viz.

25(OH)-D >50 nmol/L: one dose 60,000 IU at 20 weeks; 25-50 nmol/L: two doses 120,000 IU at 20 and

24wks; <25nmol/L: four doses 120,000 IU at 20, 24, 28, 32 wks.

In the present study, amongst the women who had very low baseline levels (<25 nmol/L), despite

receiving a total of 480,000IU starting at 20 weeks, only 52.8% achieved levels of >50nmol/L at

delivery. The women with baseline 25(OH)-D 25-50nmol/L and more than 50nml/L receiving a total of

240,000 IU & 60,000 IU respectively, achieved sufficiency at delivery in 85.1% and 89% in the

intervention group.

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 Cochrane review [5] also analysed that women who received vitamin D supplements had higher 25(OH)-
Accepted Article
D concentrations than those women who received no intervention or a placebo. The response to

supplementation, however, was highly heterogeneous.

Though there was a significant rise in vitamin D levels in the intervention group post supplementation,

none of the patient developed hypervitaminosis D [25(OH)-D>375 nmol/L][7].

Cord Blood (CB) 25(OH)-D Levels

Only 14% of the babies in group A had 25(OH)-D levels > 50 nmol/L, whereas, in group B, 46.2% of the

babies had 25 (OH)-D level > 50 nmol/L. Other studies conducted in the past have also reported [6, 20,

33] a rise in cord blood 25(OH)-D following maternal vitamin D supplementation. A positive correlation

was also found between maternal and cord blood 25(OH)-D levels (r= 0.915, p= 0.000).

PREGNANCY COMPLICATIONS

Pregnancy complication in the form of preterm labour (PTL), gestational hypertension (GHTN) /

preeclampsia (PE), or gestational diabetes mellitus (GDM) were seen in 25/57 (44%) women in Group A

compared to 22/108 (20.4%) women in the intervention group (group B).

In the present study a significant decrease in incidence of PTL/PTB was seen in the supplementation

group (p=0.02) (Fig. 2). In a study by Hollis et al [34] there were 20.7% PTL/PTB in the group receiving

400 IU/d of vitamin D, 19.7% PTL/PTB in the group receiving 2000 IU/day and 17.1%% of PTL/PTB in

the group receiving 4000 IU/day.

As seen in Fig. 2, 12/57 (21.1%) of patients in group A had GHTN/PE during pregnancy, compared to

11.1% (12/108) in group B (intervention). In a study by Hollis et al a significant decrease in the incidence

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 of GHTN/PE in the 4000 IU supplementation group was found as compared to 400 IU and 2000 IU
Accepted Article
groups. (p=0.05). [34].

VITAMIN D AND NEONATAL OUTCOME

The relation of fetal 25(OH)-D to neonatal outcome was studied by comparing cord blood levels in

supplemented and control group and also correlating the levels to certain neonatal parameters. The

parameters studied were birth weight, APGAR score (A.S) at 5 minutes and signs of calcium deficiency

in neonates.

In supplemented group (Group B), 8% of the babies were Small for Gestational Age (SGA) as compared

to non-supplemented group (Group A) in which 19.2% of the babies were SGA ( p = 0). The mean birth

weight of the babies in Group A was lower than Group B i.e 2.4 0.31 kg Vs 2.6 kg 0.41 kg, p=0.04

and a strong correlation was noted between BBW and maternal vitamin D status.

A significant improvement in birth weight of infants born to vitamin D supplemented mothers has been

seen in some studies [6, 35-37] and not seen in others [20, 33].

A positive correlation was found between maternal vitamin D status and A.S of babies (r= 0.325, p=

0.000). Similar improvement in APGAR scores was seen in babies born to females who received 4000IU

Vitamin D3/day supplementation during pregnancy by Hossain et al [38].

None of the babies in either group had any signs of calcium deficiency including craniotabes and

hypocalcemic neonatal seizures.

Conclusions and recommendations

1. Vitamin D deficiency is highly prevalent throughout the world. All women need to be given

supplemental vitamin D during pregnancy, as there is inadequate sun-exposure as well as dietary

intake of vitamin D in the majority.

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 2. Supplementation can be given easily, using a cost-effective high-dose preparation to ensure
Accepted Article compliance.

3. A single dose of 60,000 IU cholecalciferol (at 20 weeks gestation) does not appear to be adequate

to achieve maternal serum 25(OH)-D level of > 50 nmol/L at delivery in majority of the women.

Two doses of 120,000 IU each at 20 and 24 weeks may be sufficient for women who have an

adequate sun-exposure, normal BMI and adequate nutritional intake.

4. Pregnant women with risk factors for vitamin D deficiency such as an inadequate sun exposure,

high BMI and poor nutritional intake can be safely given a total of 480,000 IU divided in four

doses of 120,000 IU each at 20, 24, 28, and 32 weeks of gestation.

5. High dose vitamin D supplementation therapy in pregnancy can help in reducing the incidence of

gestational hypertension/preeclampsia, preterm labor/births; and have a beneficial effect on the

neonates.

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Table 1: Improvement in 25(OH)-D levels in group B

Baseline 25(OH)-D Total Amt Change in Post Treatment 25(OH)-D levels

Levels (nmol/L) of Vit. D
25(OH)-D levels
Received
(I.U) or no <25nmol/L 25- >50nmol/L
change 50nmol/L

< 25 (n= 53) 480 000 53 0 6 19 28

25-50 (n=27) 240 000 24 3 1 3 23

> 50 (n= 28) 60 000 12 16 2 1 25

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 Table 2: Cord Blood 25(OH)-D Levels in group A and group B
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Neonatal GROUP A GROUP B

25(OH)-D Levels (Non-Intervention) (Intervention)

(nmol/L)
n=57 n=108

No. % No. %

<25 37 64.9 30 27.7

25-50 12 21.1 28 25.9

>50 08 14.0 50 46.2

Chi square test, p value= 0.000

Table 3: Pregnancy complications in group A and B

GROUP A GROUP B

(Non-Intervention) (Intervention)

n=57 n=108
Pregnancy complications

No. % No. %

PTL 12 21.1 09 8.3

GHTN / PE 12 21.1 12 11.1

GDM 01 1.8 01 0.9

Nil 32 56.1 86 79.6

PTL - p = 0.02, Gestational Hypertension/Pre-eclampsia (GHTN/PE) - p = 0.08, Gestational Diabetes

(GDM) p = 0.90

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 Table 4: Neonatal Birth Weights in group A and group B
Accepted Article
GROUP A GROUP B

Neonatal (Non-Intervention) (Intervention)

Birth Weight n=57 n=108

No. % No. %

SGA 11 19.2 9 8

AGA 46 80.8 99 92

Mean (kg) 2.4 0.31 2.6 0.41

Median (kg) 2.4 (1.6 - 3) 2.6 (1.6 - 3.6)

(Range)

Chi square test, p value = 0.04

SGA: Small for gestational age.
AGA: Appropriate for gestational age.

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Accepted Article

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.