Maternal serum 25-hydroxyvitamin D levels at11+0–13+6 weeks in pregnant women withdiabetes mellitus and in those with macrosomicneonatesMD Savvidou,a,b R Akolekar,b RBB Samaha,b AP Masconi,b,c KH Nicolaides,b,c

a Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster Hospital, London UK b Harris

Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK c Department of Fetal Medicine, University College

Hospital, London, UK

Correspondence: Dr MD Savvidou, Department of Maternal Fetal Medicine, Imperial College School of Medicine, Chelsea and Westminster

Hospital, 369 Fulham Road, London SW10 9NH, UK. Email msavvidou@dsla.ndo.co.uk

Accepted 8 March 2011.

Objective To investigate whether maternal serum levels of

25-hydroxyvitamin D [25(OH)D] in the first trimester are altered

in pregnant women with pre-existing type 2 diabetes, women who

subsequently develop gestational diabetes mellitus (GDM) and

women who deliver large for gestational age (LGA) neonates

compared with normoglycaemic pregnant women who deliver an

appropriate for gestational age (AGA) neonate.

Design Case–control study.

Setting Antenatal clinic.

Population Singleton pregnancies at 11+0–13+6 weeks, including

50 women with type 2 diabetes, 100 women who subsequently

developed GDM, 50 nondiabetic women who subsequently

delivered LGA neonates and 1000 nondiabetic controls who

delivered AGA neonates.

Methods Maternal serum total 25(OH)D levels were measured in

the four groups of pregnancies. Multiple regression analysis in the

controls was used to identify factors among maternal

characteristics with a significant contribution to the levels of

serum 25(OH)D, so that the values in all cases were expressed as

a multiple of the median (MoM) in the controls.

Main outcome measures Comparison of MoM 25(OH)D in the

four groups.

Results In controls, significant independent contributions to the

serum level of 25(OH)D were provided by maternal age, body

mass index, smoking status, racial origin and season of

sampling. The median and interquartile range (IQR) of serum

25(OH)D in the type 2 diabetes group (1.01; IQR, 0.68–1.47

MoM), GDM group (0.93; IQR, 0.67–1.23 MoM) and LGA

group (0.97; IQR, 0.67–1.25 MoM) were not significantly

different from those in the controls (0.99; IQR, 0.71–1.33 MoM)

(overall P = 0.643).

Conclusions The first-trimester maternal serum level of 25(OH)D

is not altered in women with type 2 diabetes, those who develop

GDM or those who deliver LGA neonates.

Keywords Gestational diabetes mellitus, large for gestational age

neonates, pregnancy, type 2 diabetes, vitamin D.

Please cite this paper as: Savvidou M, Akolekar R, Samaha R, Masconi A, Nicolaides K. Maternal serum 25-hydroxyvitamin D levels at 11+0–13+6 weeks in

pregnant women with diabetes mellitus and in those with macrosomic neonates. BJOG 2011;118:951–955.

Introduction

Vitamin D, which plays a central role in calcium homeosta-

sis, is implicated in the pathogenesis of cardiovascular

disease, cancer and diabetes mellitus.1–6 Deficiency in

25-hydroxyvitamin D [25(OH)D] predisposes to the devel-

opment of both type 1 and 2 diabetes.4,5,7 Pancreatic b-cells

express the vitamin D receptor, and allelic variations in the

genes involved in vitamin D metabolism and its receptor

are associated with glucose (in)tolerance.8 There is contra-

dictory evidence on the association of vitamin D deficiency

with gestational diabetes mellitus (GDM), with some stud-

ies reporting that, in affected pregnancies, maternal serum

or plasma levels of 25(OH)D are decreased,9,10 and others

reporting that there is no significant difference from

normoglycaemic controls.11,12 A case–control study reported

that the median maternal plasma 25(OH)D concentration

at an average of 16 weeks of gestation was significantly

ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG 951

DOI: 10.1111/j.1471-0528.2011.02982.x

www.bjog.orgMaternal medicine

lower in 57 pregnant women who subsequently developed

GDM compared with 114 who did not develop GDM.13

In a study of 90 pregnant women who developed GDM,

maternal serum 25(OH)D concentration at 11–13 weeks of

gestation was not significantly different from that of con-

trols.14 No studies have assessed the maternal 25(OH)D

levels in women who deliver large for gestational age

(LGA) neonates. There are several techniques for the quan-

tification of 25(OH)D, including radioimmunoassay,

chemiluminescent assays, high-performance liquid chroma-

tography and, more recently, liquid chromatography-mass

spectrometry/mass spectrometry, which is thought to pro-

vide the most accurate results, but is expensive to per-

form.15

The aim of this study was to investigate further possible dif-

ferences in maternal serum levels of 25(OH)D at 11+0–13+6

weeks of gestation in pregnant women with pre-existing

type 2 diabetes mellitus, those who subsequently develop

GDM and those who deliver a LGA neonate compared

with nondiabetic pregnant women who deliver an appro-

priate for gestational age (AGA) neonate.

Methods

Study populationThis was a case–control study drawn from a large prospec-

tive observational investigation of the early prediction of

pregnancy complications in women attending for their rou-

tine first hospital visit in pregnancy at King’s College Hos-

pital, London, UK, from March 2006 to June 2009. In this

visit, which is held at 11+0–13+6 weeks of gestation, we

record maternal characteristics and medical history and

perform combined screening for aneuploidies by measure-

ment of the fetal crown–rump length, nuchal translucency

thickness and maternal serum pregnancy-associated plasma

protein A and free b-human chorionic gonadotrophin.16,17

We stored serum and plasma at )80�C for subsequent bio-

chemical analysis from women who provided written

informed consent for participation in the study, which was

approved by King’s College Hospital ethics committee.

In this study, we measured maternal serum concentra-

tion of 25(OH)D2 and 25(OH)D3 in 1200 singleton preg-

nancies, including 50 with type 2 diabetes, 100 women who

subsequently developed GDM, 50 nondiabetic women who

subsequently delivered LGA neonates and 1000 nondiabetic

controls who delivered a phenotypically normal AGA neo-

nate at term. Cases were selected at random from our data-

base of stored samples. We then matched each case with

five controls who were examined on the same day.

Outcome measuresScreening for GDM in our hospital is based on a two-step

approach. In all women, random plasma glucose is mea-

sured at 24–28 weeks of gestation and, if the concentration

is more than 6.7 mmol/l, an oral glucose tolerance test

(OGTT) is carried out within the subsequent 2 weeks. The

diagnosis of GDM is made if the fasting plasma glucose

level is at least 6.1 mmol/l or the plasma glucose level

2 hours after the oral administration of 75 g glucose is

7.8 mmol/l or more.18 In women with normal random

blood sugar, an OGTT is performed if they have persistent

glucosuria, develop polyhydramnios or if the fetus becomes

macrosomic. Women with a diagnosis of GDM are given

dietary and exercise advise, and are encouraged to test cap-

illary blood glucose before and 1 hour after each meal.

If, during a period of 1–2 weeks, the pre-meal or 1-hour

post-meal blood glucose level is higher than 5.5 or

7 mmol/l, respectively, the women are treated with insulin.

The neonate was considered to be LGA if the birthweight

was above the 95th percentile for gestation at delivery,

using a reference range derived from our population.19

Neonates between the 5th and 95th percentiles were con-

sidered to be AGA.

Details of the maternal characteristics and the findings of

the 11+0–13+6-week assessment were recorded in our data-

base. Data on pregnancy outcome were obtained from the

maternity computerised records or the general medical

practitioners of the women, and were also recorded in our

database.

Sample analysisNone of the samples had been thawed and refrozen previ-

ously. Duplicate samples of 100 ll were used to analyse

25(OH)D2 and 25(OH)D3 by liquid chromatography-mass

spectrometry/mass spectrometry (Prominence HPLC sys-

tem, equipped with a Phenomenex Luna C8 3 · 50 mm

column and AB Sciex API-5000 ESI triple quadrupole;

Shimadzu Scientific Instruments, Columbia, OH, USA).

The analysis was performed using the MSMS Vitamin D

kit 3075-0010 (PerkinElmer, Inc., Turku, Finland). Individ-

ual runs were calibrated using National Institute of Stan-

dards and Technology (NIST) Standard Reference Material

(SRM) 2972. The average inter-assay coefficients of varia-

tion (CV) for 25(OH)D2 and 25(OH)D3 were 6.6% and

7.3%, respectively, and the intra-assay CVs were 6.3% and

6.5%, respectively. The total serum 25(OH)D concentration

was calculated by adding together the measured 25(OH)D2

and 25(OH)D3 concentrations.

Statistical analysisComparison between outcome groups was performed by

Mann–Whitney U-test with post hoc Bonferroni correction

for continuous variables, and v2 test or Fisher’s exact test

for categorical variables.

The distribution of 25(OH)D was made Gaussian by

square root transformation and the normality of distribution

Savvidou et al.

952 ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG

was assessed using histograms and probability plots.

In each case and control, the measured concentration of

total vitamin D was converted into a multiple of the med-

ian (MoM) in controls after adjusting for maternal age,

body mass index (BMI), smoking status, method of con-

ception, season of sampling and racial origin, as described

previously.20 Mann–Whitney U-test with post hoc Bonfer-

roni correction was used to compare median MoM values

of total 25(OH)D between the outcome groups. Nonpara-

metric correlation analysis was used to determine the sig-

nificance of association between total 25(OH)D and

birthweight percentile in the outcome groups.

The statistical software package spss 16.0 (SPSS Inc.,

Chicago, IL, USA) was used for data analyses.

Results

The maternal characteristics of each of the outcome groups

are compared in Table 1. In comparison with the controls,

in the type 2 diabetes and GDM groups, the median mater-

nal age, BMI and neonatal birthweight percentile were

higher and, in the LGA group, more women were parous

and had a higher median maternal age and BMI. In addi-

tion, in the type 2 diabetes group, more women were

parous and of African racial origin.

The median and interquartile range (IQR) of serum

25(OH)D in the type 2 diabetes group (1.01; IQR, 0.68–1.47

MoM), GDM group (0.93; IQR, 0.67–1.23 MoM) and LGA

group (0.97; IQR, 0.67–1.25 MoM) were not significantly

different from those of the controls (0.99; IQR, 0.71–1.33

MoM) (overall P = 0.643). This was the case when serum

25(OH)D2 and 25(OH)D3 were considered separately (data

not given but available on request). Within the GDM group,

there was no significant difference in the median 25(OH)D

MoM between those treated with diet (n = 73; median, 0.93;

IQR, 0.64–1.23 MoM) and those treated with insulin (n =

24) or metformin (n = 3) (median, 0.95; IQR, 0.73–1.30

MoM; P = 0.622). Similarly, there was no significant differ-

ence between groups with regard to the proportion of

women with serum 25(OH)D below 30 ng/ml, which is gen-

erally accepted to be the cut-off for the diagnosis of vitamin

D insufficiency (controls, 796 of 1000; type 2 diabetes, 42 of

50; GDM, 84 of 100; LGA, 40 of 50; P = 0.620).21

There was no significant association between total

25(OH)D MoM and birthweight percentile in any of the

groups (controls, P = 0.086; type 2 diabetes, P = 0.991;

GDM, P = 0.712; LGA, P = 0.877).

Discussion

The findings of this study indicate that, in the first trimes-

ter of pregnancy, maternal serum 25(OH)D levels are not

altered in women who have type 2 diabetes, in nondiabetic

women who deliver LGA neonates and in those who

Table 1. Maternal and pregnancy characteristics in the outcome groups

Maternal characteristic Controls

(n = 1000)

Type 2 diabetes

(n = 50)

Gestational

diabetes mellitus

(n = 100)

Large for

gestational

age

(n = 50)

Maternal age in years, median (interquartile range, IQR) 31.5 (27.2–35.4) 35.4 (31.0–39.5)* 33.9 (31.4–37.2)* 34.0 (31.3–37.9)*

Maternal body mass index in kg/m2, median (IQR) 24.2 (21.9–27.5) 30.5 (26.3–37.6)* 28.6 (24.2–34.1)* 27.7 (24.5–31.3)*

Crown–rump length in mm, median (IQR) 63.3 (58.0–68.5) 65.3 (58.3–68.9) 62.3 (58.0–68.0) 66.5 (59.6–72.8)

Gestation at sampling (weeks), median (IQR) 12.4 (12.1–12.9) 12.4 (12.3–13.0) 12.5 (12.1–12.7) 12.6 (12.3–13.0)

Racial origin

Caucasian, n (%) 580 (58.0) 15 (30.0) 64 (64.0) 30 (60.0)

African, n (%) 325 (32.5) 33 (66.0)* 25 (25.0) 14 (28.0)

Asian, n (%) 95 (9.5) 2 (4.0) 11 (11.0) 6 (12.0)

Parity

Nulliparous, n (%) 481 (48.1) 10 (20.0) 41 (41.0) 10 (20.0)

Parous, n (%) 519 (51.9) 40 (80.0)* 59 (59.0) 40 (80.0)*

Cigarette smoker, n (%) 73 (7.3) 3 (6.0) 6 (6.0) 3 (6.0)

Conception

Spontaneous, n (%) 980 (98.0) 47 (94.0) 97 (97.0) 48 (96.0)

Assisted, n (%) 20 (2.0) 3 (6.0) 3 (3.0) 2 (4.0)

Birthweight percentile, median (IQR) 50.0 (29.5–68.7) 66.5 (37.9–90.3)* 54.9 (32.3–78.8)* 99.1 (98.7–99.7)*

Comparisons between outcome groups (v2 test and Fisher’s exact test for categorical variables and Mann–Whitney U-test with post hoc

Bonferroni correction for continuous variables).

*Adjusted significance level P < 0.0167.

Maternal serum vitamin D levels in early pregnancy

ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG 953

subsequently develop GDM, irrespective of whether their

diabetes is controlled by diet alone or in combination with

pharmacological intervention.

Our findings of a lack of significant difference in mater-

nal vitamin D between pregnant women who develop

GDM and normoglycaemic controls are compatible with

those of two previous studies.11,12 Three other studies

reported an association between GDM and vitamin D defi-

ciency, but this apparent contradiction may be the conse-

quence of the small number of cases examined, the

gestational age at sampling (second or third trimester) and

the method used to measure vitamin D [(radio)immunoas-

say and enzyme-linked immunosorbent assay].9,10,13

The rationale for our study was based on the following:

first, evidence from investigations in nonpregnant women

which showed that serum 25(OH)D is decreased in type 2

diabetes mellitus and is inversely associated with plasma

glucose levels and abdominal obesity in those without dia-

betes;5,21–23 and, second, studies reporting decreased serum

25(OH)D in women with established GDM.9,10,13 In a pre-

vious study of pregnant women who developed GDM, we

reported that the maternal serum concentration of

25(OH)D at 11–13 weeks was not significantly different

from that in normal pregnancies.14 We wanted to investi-

gate this finding further by including women with pre-

existing diabetes and those with LGA neonates because, in

all three conditions, there may be a common pathophysio-

logical mechanism involving varying degrees of glucose

intolerance. About 20% of women with GDM develop type

2 diabetes within 10 years of the index pregnancy, com-

pared with 2% in those without GDM.25,26 Macrosomic

neonates of nondiabetic mothers have a similar metabolic

profile to the neonates of pregnant women affected by

GDM.27–29 In addition, in women with GDM, there is a

significant positive correlation between maternal glucose

levels and the incidence of macrosomia.30 Consequently, in

women with glucose challenge test results that do not fulfil

the current criteria for GDM, it is likely that there is an

association between neonatal macrosomia and a degree of

impaired maternal glucose tolerance.

The finding of our study that, in all three groups of

complicated pregnancies, the maternal serum level of

25(OH)D was not significantly different from controls sug-

gests that, in these conditions, at least at 11+0–13+6 weeks

of gestation, there is no evidence of an increased prevalence

of vitamin D insufficiency or deficiency. An alternative

explanation is that all three conditions are associated with

vitamin D insufficiency. We have certainly found that, in a

very high proportion of women with type 2 diabetes, GDM

and those delivering LGA neonates (84%, 84% and 80%,

respectively), the serum level of 25(OH)D is in the range

that, in nonpregnant women, is thought to be indicative of

vitamin D insufficiency or deficiency.21 Failure to demon-

strate such an insufficiency by comparison with controls

may be a mere consequence of the finding that a high pro-

portion of patients in the latter group were also insufficient

in vitamin D. Our findings are more applicable to Cauca-

sian or African women, and not to Asians, who represent

the minority of our population and are known to have a

higher incidence of glucose intolerance and vitamin D defi-

ciency.30,31 There are several reports suggesting that there

may be an epidemic of vitamin D deficiency in pregnancy,

and advocating the need for pharmacological intervention,

because this condition is thought to be associated with a

wide range of adverse pregnancy outcomes.33–35

In a previous study, we used the pragmatic approach of

examining the distribution of serum 25(OH)D values in a

diverse inner city population of singleton pregnancies with

normal outcome, and suggested that the cut-off for the

diagnosis of low levels should be about 10 ng/ml, which

corresponds to the 5th percentile.20 We suggested that, in

the absence of conclusive evidence that in pregnancies with

serum 25(OH)D below 30 ng/ml there is an increased risk

for specific pregnancy complications and adverse postnatal

outcome, it may be inappropriate to classify about 80% of

pregnancies with normal outcome as suffering from vita-

min D insufficiency in need of treatment with vitamin D

supplements.

Conclusion

In summary, we found that, at 11–13 weeks of gestation,

maternal serum levels of 25(OH)D in women with type 2

diabetes, in those who develop GDM and in nondiabetic

women who deliver LGA neonates are not significantly dif-

ferent from those in normal pregnancies delivering AGA

neonates at term.

Disclosure of interestNone.

Contribution to authorshipMDS is the main corresponding author, and she conceived

and designed the study. RA, RBBS and APM contributed

to the design and conduct of the study and the interpreta-

tion of the results. KHN is the main supervisor. All the

authors participated and contributed to the writing of the

manuscript.

Details of ethics approvalEthical approval was granted by the King’s College Hospital

Ethics Committee (02-03-033).

FundingThis study was supported by a grant from the Fetal Medi-

cine Foundation (United Kingdom Charity No. 1037116).

Savvidou et al.

954 ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG

The assays were performed by Dr Blas Cerda at Perkin-

Elmer Life & Analytical Sciences, Waltham, MA, USA.

AcknowledgementsThe assays were performed by Dr Blas Cerda at Perkin-

Elmer Life & Analytical Sciences, Waltham, MA, USA. j

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Maternal serum vitamin D levels in early pregnancy

ª 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology ª 2011 RCOG 955