University of Groningen Gestational diabetes mellitus: diagnosis and outcome … · 2017-11-07 · Chapter 7 122 ABSTRACT Aims/hypothesis: Detection and management of gestational

University of Groningen

Gestational diabetes mellitus: diagnosis and outcomeKoning, Saakje Hillie

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Citation for published version (APA):Koning, S. H. (2017). Gestational diabetes mellitus: diagnosis and outcome: Need for a revision of theDutch perspective?. Rijksuniversiteit Groningen.

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7 New diagnostic criteria for gestational diabetes mellitus and their impact on prevalence and pregnancy outcomes

Koning SH, van Zanden JJ, Hoogenberg K, Lutgers HL, Klomp AW, Korteweg FJ, van Loon AJ, Wolff enbuttel BHR, van den Berg PP

Submitted

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ABSTRACT

Aims/hypothesis: Detection and management of gestational diabetes mellitus (GDM) are crucial to reduce the risk of pregnancy-related complications for both mother and child. The World Health Organization (WHO) adopted stricter GDM diagnostic criteria in 2013 to improve pregnancy outcomes. However, the evidence for these criteria is limited. Therefore, these new criteria have not yet been endorsed in the Netherlands. The aim of this study was to determine the impact of these cri-teria on GDM prevalence and pregnancy outcomes.

Methods: Data on screening were available from 10,642 women who underwent a 75-g OGTT due to risk factors or signs suggestive of GDM. Women were treated if diagnosed with GDM according to the WHO-1999 criteria. Data on pregnancy outcomes were obtained from extensive chart reviews in 4,431 women and were compared between women with normal glucose tolerance (NGT) and women diag-nosed according to the WHO-1999 and WHO-2013 criteria, respectively.

Results: When we compared the two sets of GDM diagnostic criteria in terms of GDM prevalence, we found that applying the new WHO-2013 criteria would have resulted in a higher number of diagnoses than applying the WHO-1999 criteria (31% versus 22%) in this population of women at higher risk for GDM. Compared with NGT women, women classified as having GDM based only on the WHO-2013 fasting glucose (FG) cut-off were more likely to have been obese and hypertensive before pregnancy, and to have had higher rates of gestational hypertension, planned caesarean section and induction of labour. In addition, their neonates were more likely to have had an Apgar score <7 at 5 min and to have been admitted to the neonatology department. The numbers of large-for-gestational-age (LGA) neonates were not significantly different between the two groups. Women potentially missed due to higher 2-h glucose cut-off (2HG) of the WHO-2013 criteria had similar preg-nancy outcomes to NGT women. These women were treated for GDM, all with diet, and 20.5% additionally with insulin.

Conclusions/interpretation: Applying the WHO-2013 criteria will have a major im-pact on the prevalence of GDM. Using the FG cut-off levels of the WHO-2013 criteria identifies a group of women with an increased risk of adverse outcomes compared with NGT women. However, adopting the WHO-2013 criteria with a higher 2HG cut-off excluded women where GDM-treatment seems to be effective.

Impact of new diagnostic criteria for GDM on prevalence and outcomes

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7

BACKGROUND

Gestational diabetes mellitus (GDM) is a major health issue and is associated with an increased risk of pregnancy-related complications for both mother and child.1,2 International guidelines recommend active screening for GDM, since many of these risks can be reduced by detection and management of GDM.3,4 However, these guidelines lack uniformity in terms of their diagnostic cut-off values.

In 2010, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) proposed more stringent thresholds for diagnosing GDM, which were based on the results of the international prospective Hyperglycemia and Ad-verse Pregnancy Outcomes (HAPO) study.5,6 The HAPO study demonstrated a linear association between fasting and post-load maternal glucose levels and the risk of adverse pregnancy outcomes such as increased birth weight, primary caesarean de-livery and neonatal hypoglycaemia.6 The IADPSG diagnostic criteria (fasting plasma glucose (FG) level ≥5.1 mmol/l and/or 1-h plasma glucose level ≥10.0 mmol/l and/or 2-h plasma glucose level (2HG) ≥8.5 mmol/l) have now been adopted by many guideline committees and expert groups, including the World Health Organization (WHO) who published their new guideline in 2013.5,7

However, evidence that applying the stricter criteria for GDM improves preg-nancy outcomes is limited. There is still uncertainty about the optimal glucose thresholds to define GDM, and international consensus has not yet been reached.8,9 Applying the new criteria causes more women to be diagnosed with GDM and the resulting cost increases and medicalization of pregnancy are causes for concern for healthcare managers and caregivers.10,11 Better appraisal of the value of these new glucose thresholds requires studies into clinical outcomes and cost-effectiveness analyses. In the Netherlands, the new WHO-2013 criteria have not yet been en-dorsed. In their 2010 guideline “Diabetes and Pregnancy”, the Dutch Society of Ob-stetrics and Gynaecology recommends using the WHO-1999 criteria for diagnosing GDM (FG ≥7.0 mmol/l and/or 2HG ≥7.8 mmol/l).12,13 When compared with the new WHO-2013 criteria, these criteria use a much higher cut-off value for FG and a lower cut-off value for 2HG.

The consequences of adopting the WHO-2013 thresholds need to be evaluated in order to answer crucial questions: Do women who are additionally diagnosed with GDM using the WHO-2013 FG criteria (FG ≥5.1- ≤6.9 mmol/l) indeed have un-favourable pregnancy outcomes? And what are the pregnancy outcomes of those women who will be missed due to the higher 2HG cut-off of the WHO-2013 criteria (i.e. women with 2HG ≥7.8- ≤8.4 mmol/l)?

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The aim of this study was therefore to evaluate the possible impact on GDM prevalence and pregnancy outcomes of applying the new WHO-2013 criteria in-stead of the older WHO-1999 criteria.

METHODS

Study design and populationThis study is a retrospective evaluation of data on GDM screening (in women with risk factors for GDM), pregnancy management and pregnancy outcomes collected between January 2011 and September 2016 in the Groningen area by Certe, a regional primary- and secondary healthcare laboratory in the north of the Nether-lands, and by the University Medical Center Groningen (UMCG), a tertiary referral centre.

As previously described,14,15 pregnant women between 24 and 28 weeks of gesta-tion were referred either by their midwife (in primary care) or by their gynaecologist (in secondary/tertiary care) for a 75-gram oral glucose tolerance test (OGTT) if they had one or more risk factors for GDM according to the Dutch national guideline.13 These risk factors were having a pre-pregnancy body mass index (BMI) ≥30 kg/m2; having a first-degree relative with diabetes mellitus; having a previous neonate weighing ≥4500 gram at birth or a birth weight >95th percentile; having a history of GDM, intrauterine foetal death or polycystic ovary syndrome; and belonging to an ethnic risk group (South-Asian i.e. Hindu, African-Caribbean, Middle Eastern i.e. Moroccan and Egyptian). Universal testing is not recommended in the Dutch national guideline.

Women with previous GDM were screened using a 75-g OGTT between 16 and 18 weeks of gestation, and if these results were normal the OGTT was repeated between 24 and 28 weeks of gestation. An OGTT was also recommended for women with signs suggestive of GDM (e.g. foetal macrosomia or polyhydramnios). Women were treated if diagnosed with GDM according to the WHO-1999 criteria: FG ≥7.0 mmol/l and/or 2HG value ≥7.8 mmol/l.12 All women were referred to a dietician for dietary counselling and received instructions for self-monitoring of blood glucose values by a diabetes specialist nurse. If, after 1-2 weeks, repeated measurements indicated FG >5.3 mmol/l and/or one-hour postprandial plasma glucose levels >7.8 mmol/l, insulin therapy was started.15

The study was conducted in accordance with the guidelines of the Declaration of Helsinki and Good Clinical Practice, and approved by the Medical Ethical Review Committee of the UMCG.


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GDM classificationBased on their OGTT results, women were retrospectively classified into the follow-ing diagnostic groups:

1. Normal glucose tolerance (FG <5.1 mmol/l and 2HG <7.8 mmol/l), denoted as “NGT”;

2. GDM according to both WHO-1999 and WHO-2013 criteria (FG ≥5.1 mmol/l and/or 2HG ≥7.8 mmol/l), denoted as “both criteria GDM”;

3. GDM according to WHO-2013 criteria (FG ≥5.1 mmol/l and/or 2HG ≥8.5 mmol/l), denoted as “WHO-2013”;

4. GDM according to WHO-1999 criteria (FG ≥7.0 mmol/l and/or 2HG ≥7.8 mmol/l), denoted as “WHO-1999”;

We also identified two groups of women classified as follows: 5. GDM according to WHO-2013 FG cut-off criterion, but not WHO-1999 criteria (FG ≥5.1-≤6.9 mmol/l and 2HG <7.8 mmol/l), denoted as “WHO-2013 only FG”; 6. GDM according to WHO-1999 2HG cut-off criterion, but not WHO-2013 criteria (FG <5.1 mmol/l and 2HG ≥7.8-≤8.4 mmol/l), denoted as “WHO-1999 only 2HG”.

It should be noted that women in the NGT group were screened with an OGTT because they had risk factors for GDM or signs suggestive of GDM (e.g. foetal macrosomia or polyhydramnios). Approximately 85% of the women were tested based on predefined risk factors for GDM. Since the women in the NGT group are not representative of all non-GDM pregnancies, neonatal outcomes regarding birth weight in the general obstetric population in the northern region of the Nether-lands (period 2011-2013) were obtained from the Dutch Perinatal Registry and the Municipal Health Service Groningen. The nature of this dataset unfortunately does not allow to exclude those screened for GDM.

OutcomesData on maternal characteristics and pregnancy outcomes were retrospectively collected from medical and obstetric records at midwives offices in primary care and at two hospitals, the UMCG and the Martini Hospital Groningen. All data were incorporated in an anonymised database. Maternal outcomes of interest were gestational hypertension, preeclampsia, induction of labour, and mode of delivery (spontaneous vaginal delivery, instrumental delivery, emergency caesarean section (CS), and planned CS). Gestational hypertension was defined as a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg, after 20 weeks of gestation in a previously normotensive woman. Preeclampsia was defined as

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gestational hypertension together with the presence of proteinuria (≥300 mg/24 hrs) and also included women who had eclampsia and HELLP syndrome.

Neonatal outcomes of interest were the following: stillbirth; gestational age at delivery; preterm delivery (delivery <37 weeks of gestation); birth weight; neonate born large for gestational age (LGA; birth weight >90th percentile corrected for gestational age, sex, parity, and ethnic background);16 neonate with macrosomia (birth weight >4000 gram); neonate born small for gestational age (SGA; birth weight <10th percentile corrected for gestational age, sex, parity, and ethnic back-ground);16 birth trauma (shoulder dystocia, fracture of humerus or clavicle, brachial plexus injury); Apgar score <7 at 5 min; hypoglycaemia (occurring >2 hrs after birth defined as a having a blood glucose level <2.6 mmol/l or requiring treatment with glucose infusion);13 hyperbilirubinaemia (defined as requiring treatment with pho-totherapy after birth); requirements for respiratory support (the need to intubate or apply continuous positive airway pressure); and admission to the neonatology department. The variables hypoglycaemia and hyperbilirubinaemia were only re-ported for the WHO-1999 group and WHO-1999 only 2HG, since only the women in these groups all delivered in secondary care.

Extrapolation models of data on birth weight and prevalence of LGA neonatesTreatment for GDM affects birth weight and the prevalence of LGA neonates. The positive effects of treatment are supported by previous studies that have shown that treating women who have mild GDM reduces birth weight by 100 to 140 grams.4,11 Based on our data, we developed extrapolation models to predict the influence of treatment (diet and/or additional insulin therapy) on birth weight and the likelihood of having an LGA neonate. We developed these extrapolation models for the follow-ing three GDM classification groups: WHO-1999 group, WHO-1999 only 2HG group and WHO-2013 only FG group. In our study, those women who were treated and responded well to dietary counseling were designated as the “diet-only” group, and those who remained significantly hyperglycaemic despite adequate diet and were therefore also prescribed insulin therapy were designated as the “insulin” group.

In Model 1, we hypothesized that neonates from mothers who had been treated for GDM and who had had more severe GDM (“WHO-1999” and “WHO-1999 only 2HG” groups) would have been an average of 100 grams heavier at birth in the diet-only group and 200 grams heavier in the insulin group if these women had not been treated. In Model 2, we applied a 200-gram birth weight difference in the diet-only group and a 400-gram difference in the insulin group if these women had not been treated. In Model 1, we also hypothesized that neonates from mothers who had not been treated for GDM and who had had milder GDM (“WHO-2013 only FG group”)


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7

would have had a 50 gram lower birth weight if the mother had been treated with diet only and a 100 gram lower birth weight if they had been treated with insulin. In Model 2, the hypothesized differences were 100 grams on diet only and 200 grams on insulin. The extrapolated birth weights were used to calculate the percentages of LGA neonates in each group. A schematic explanation about the categories and models are given in suppl. Table 1.

Since the women in the “WHO-1999” and “WHO-1999 only 2HG groups” were treated with diet-only and/or were treated with insulin, resulting in normalization of their glycaemic profiles, these two groups cannot be directly compared with the women in the NGT group, who were not offered treatment. Nevertheless, for these two groups we tried to estimate the birth weight and prevalence of LGA that would have resulted had the women not been treated.

Statistical analysesContinuous data are presented as mean ± standard deviation (SD) in case of normal distribution, or as median and interquartile range (IQR) in case of skewed distri-bution. Categorical data are presented as numbers and percentages. Differences between groups were tested using the Student’s unpaired t-test for continuous data, or the Mann-Whitney U Test in case of skewed distribution. For categorical data, a Chi-square test or Fisher’s exact test was used.

To examine the associations between the GDM classification and pregnancy outcomes, analyses were performed using logistic regression models in which the ORs and 95% CIs for each criteria group were calculated using the NGT group as reference group. Results are presented as unadjusted models and multivariable-adjusted models, with the multivariable-adjusted models adjusted for maternal age, pre-pregnancy BMI, ethnicity, parity, and maternal smoking during pregnancy. The model analysing the association between GDM classification and LGA was adjusted for maternal age, pre-pregnancy BMI, and maternal smoking during pregnancy. All P-values are two-tailed, and P-values <0.05 were considered statistically significant. All analyses were conducted with the use of the statistical package SPSS (version 23.0; Armonk, NY: IBM Corp).

RESULTS

Prevalence and maternal characteristicsOGTT data were collected from 10,642 pregnant women with GDM risk factors or signs suggestive of GDM. The prevalence of GDM in the total cohort was 22% (n=2,341) when the WHO-1999 criteria were applied and 31% (n=3,299) when the

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7

WHO-2013 criteria were applied. In total 61% of women classified on the WHO-2013 criteria were diagnosed solely on the FG, while only 1% of those classified with WHO-1999 criteria were diagnosed solely on the FG.

The characteristics of the women in the different GDM classification groups are presented in Table 1. Characteristics and pregnancy outcomes were collected for 4,431 women who had singleton pregnancies. The fasting and two-hour post-load values of these 4,431 women were similar to the values obtained for the other 6,211 complete 75-gram OGTTs. Treatment for GDM was only given to women diagnosed according to the WHO-1999 criteria (FG ≥7.0 and/or 2HG ≥7.8 mmol/l), since a WHO-2013-based GDM classification was only assigned retrospectively to GDM-negative women diagnosed using WHO-1999 criteria. Compared with women in the NGT group, women classified as having GDM (using the WHO-2013 criteria, WHO-1999 criteria or both) were older, had a higher pre-pregnancy BMI, and were more likely to be multiparous and to have chronic hypertension.

A total of 667 women were retrospectively classified as having GDM based only on the FG cut-off of the WHO-2013 criteria (≥5.1-≤6.9 mmol/l). Compared with women in the NGT group, women in this group were older, had a higher pre-pregnancy BMI (29.1 [IQR 24.8-33.5] vs. 25.2 [IQR 22.0-30.4] kg/m2, p <0.001), were more likely to be obese (46.1% vs. 28.1%, p <0.001), to have smoked during pregnancy (13.2% vs. 10.5%, p=0.05) and to have chronic hypertension (3.3% vs. 1.2%, p <0.001).

A total of 234 women were retrospectively classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria (≥7.8-≤8.4 mmol/l). These women were all treated for GDM, 79.5% with diet-only and 20.5% with additional insulin therapy. Compared with women in the NGT, women in this group were older, had a slightly higher pre-pregnancy BMI (26.4 [IQR 23.3-30.4] vs. 25.2 [IQR 22.0-30.4] kg/m2, p=0.01), were more likely to be overweight (33.9% vs. 23.0%, p <0.001) and had higher rates of chronic hypertension (3.0% vs. 1.2%, p <0.001).

Pregnancy outcomesMaternal and neonatal outcomes according to the different GDM classification groups are given in Table 2 and Table 3. Compared with women in the NGT group, women classified as having GDM (using the WHO-2013 criteria, WHO-1999 criteria or both) were more likely to develop gestational hypertension or preeclampsia and to have had a planned CS delivery or induced labour.

Compared with women in the NGT group, women classified as having GDM based only on the FG cut-off of the WHO-2013 criteria were more likely to have gestational hypertension (7.8% vs. 4.9%, OR 1.65;CI 1.19-2.30), to have a planned CS (10.3% vs. 6.5%, OR 1.64;CI 1.23-2.20) and induced labour (34.8% vs. 28.0%, p <0.001). After multivariable adjustment, there were no significant differences for

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129

7

TAB

LE 1

. M

ater

nal c

hara

cter

istic

s ac

cord

ing

to th

e G

DM

cla

ssifi

catio

n gr

oups

.

Crit

eria

(m

mol

/l)

NG

TBo

th c

rite

ria

GD

MW

HO

-201

3W

HO

-199

9W

HO

-201

3 on

ly

FGW

HO

-199

9 on

ly

2HG

FG <

5.1

and

2HG

<7.

8FG

≥5.

1 or

2HG

≥7.

8FG

≥5.

1 an

d/or

2HG

≥8.

5FG

≥7.

0 an

d/or

2HG

≥7.

8FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4

Char

acte

rist

ics

N

N44

3128

5115

8013

4691

366

723

4

Trea

ted

for G

DM

, n (%

)

Die

t

Addi

tiona

l ins

ulin

ther

apy

0 052

4 (3

3.2)

389

(24.

6)33

8 (2

5.1)

341

(25.

3)52

4 (5

7.4)

389

(42.

6)0 0

186

(79.

5)48

(20.

5)

Age

(yea

rs)

4431

30.7

± 4

.931

.9 ±

5.1

***

32.0

± 5

.2**

*32

.1 ±

5.1

***

31.6

± 5

.2**

*31

.6 ±

4.5

**

Pre-

preg

nanc

y BM

I (kg

/m2 )

4196

25.2

[22.

0-30

.4]

28.3

[24.

4-32

.5]**

*28

.7 [2

4.5-

32.9

]***

27.7

[24.

1-31

.8]**

*29

.1 [2

4.8-

33.5

]***

26.4

[23.

3-30

.4]**

Pre-

preg

nanc

y BM

I, n

(%)

<2

5 kg

/m2

25

-30

kg/m

2

≥3

0 kg

/m2

4196

1311

(48.

8)61

8 (2

3.0)

755

(28.

1)

***

452

(29.

9)

443

(29.

3)61

7 (4

0.8)

***

366

(28.

5)

365

(28.

4)55

1 (4

2.9)

***

285

(32.

0)

276

(30.

9)33

1 (3

7.1)

***

167

(26.

9)

167

(26.

9)28

6 (4

6.1)

***

86 (3

7.4)

78 (3

3.9)

66 (2

8.7)

Ethn

icity

, n (%

)

Cauc

asia

n

Asi

an

Afr

ican

-Am

eric

an

Med

iterr

anea

n

Oth

er

4431

2211

(77.

6)16

0 (5

.6)

150

(5.3

)20

7 (7

.3)

123

(4.3

)

1238

(78.

4)86

(5.4

)85

(5.4

)11

5 (7

.3)

56 (3

.5)

1060

(78.

8)62

(4.6

)78

(5.8

)95

(7.1

)51

(3.8

)

*

719

(78.

8)

65 (7

.1)

37 (4

.1)

68 (7

.4)

24 (2

.6)

*

519

(77.

8)

21 (3

.1)

48 (7

.2)

47 (7

.0)

32 (4

.8)

*

178

(76.

1)

24 (1

0.3)

7 (3

.0)

20 (8

.5)

5 (2

.1)

Nul

lipar

ous,

n (%

)44

3112

81 (4

4.9)

623

(39.

4)**

*52

3 (3

8.9)

***

373

(40.

9)*

250

(37.

5)**

*10

0 (4

2.7)

Chro

nic

hype

rten

sion

, n (%

)44

2734

(1.2

)59

(3.7

)***

52 (3

.9)**

*37

(4.1

)***

22 (3

.3)**

*7

(3.0

)*

Smok

ing

durin

g pr

egna

ncy,

n (%

)43

8129

6 (1

0.5)

188

(12.

0)16

5 (1

2.4)

101

(11.

1)87

(13.

2)*

23 (9

.8)

Abbr

evia

tions

: BM

I, bo

dy m

ass

inde

x; F

G, f

astin

g gl

ucos

e le

vel;

GD

M, g

esta

tiona

l dia

bete

s m

ellit

us; N

GT;

nor

mal

glu

cose

tole

ranc

e; W

HO

, Wor

ld H

ealth

Org

aniz

atio

n; 2

HG

, 2-

hour

glu

cose

leve

l. D

ata

are

expr

esse

d as

mea

n ±

SD, m

edia

n [IQ

R] o

r pro

port

ion

of n

(%).

P-va

lues

wer

e ba

sed

on S

tude

nt’s

unpa

ired

t-te

st (n

on-s

kew

ed c

ontin

uous

var

iabl

es),

Man

n-W

hitn

ey U

test

(ske

wed

con

tinuo

us v

aria

bles

), or

Chi

-squ

are

test

/Fis

her’s

exa

ct te

st.

* P<0.

05, **

P<0.

01, **

* P<0.

001

com

pare

d w

ith N

GT

grou

p.

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130


131

7

gestational hypertension (adjusted OR 1.38; CI 0.96-197) and planned CS (adjusted OR 1.36; CI 0.98-1.88) between this group and the NGT group.

Women with GDM classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria were more likely to have induced labour (62.8% vs. 28.0%, p <0.001) compared with women in the NGT group. There were no significant differ-ences in gestational hypertension, preeclampsia and mode of delivery between this group and the NGT group.

Neonates from mothers classified as having GDM (using the WHO-2013 criteria, WHO-1999 criteria or both) had a lower birth weight, a lower gestational age at delivery and were less likely to have macrosomia compared with those from moth-ers in the NGT group. However, the likelihood of these neonates being born LGA did not differ significantly from that of neonates in the NGT group. The likelihood of these neonates being born SGA was lower than that of neonates in the NGT group. Moreover, neonates from mothers classified as having GDM (using the WHO-2013 criteria, WHO-1999 criteria or both) were more likely to have been admitted to the neonatology department compared to those from mothers in the NGT group.

Compared with neonates from mothers in the NGT group, neonates from moth-ers classified as having GDM based only on the FG cut-off of the WHO-2013 criteria had no differences in terms of birth weight (3580 g vs. 3544 g), nor in their likeli-hood of having foetal macrosomia (22.2% vs. 20.9%, adjusted OR 1.07;CI 0.85-1.34) or being born LGA (21.0% vs. 18.0%, adjusted OR 1.22;CI 0.97-1.53). However, these neonates were more likely to have had an Apgar score <7 after 5 min (4.4% vs. 2.6%, P=0.015) and to have been admitted to the neonatology department (15.0% vs. 11.0%, p=0.004). None of the other neonatal outcomes showed significant differ-ences between these two groups.

Compared with neonates from mothers in the NGT group, neonates from moth-ers classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria had a lower birth weight (3437 g vs. 3544 g, p=0.01) and were less likely to have foetal macrosomia (12.8% vs. 20.9%, adjusted OR 0.57; CI 0.38-0.85). The likelihood of these neonates being born LGA was not significantly different from that in the NGT group (15.4% vs. 18.0%, adjusted OR 0.86; CI 0.59-1.24). However, 20.5% of the women in this group were treated with insulin therapy. None of the other neonatal outcomes showed significant differences between these two groups.

When we compared the percentage of LGA neonates in our data with those found in the general obstetric population in the north of the Netherlands (11%), we found that all GDM classification groups as well as the NGT group had a higher percentage of LGA neonates.

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131

7

TAB

LE 2

. Pr

egna

ncy

outc

omes

acc

ordi

ng to

the

GD

M c

lass

ifica

tion

grou

ps.

Gen

eral

ob

stet

ric

popu

lati

on

in th

e no

rth

of th

e N

ethe

rlan

dsCr

iter

ia

(mm

ol/l)

NG

TBo

th c

rite

ria

GD

MW

HO

-201

3W

HO

-199

9W

HO

-201

3 on

ly

FGW

HO

-199

9 on

ly

2HG

FG <

5.1

and

2HG

<7.

8FG

≥5.

1 or

2HG

≥7.

8FG

≥5.

1 an

d/or

2HG

≥8.

5FG

≥7.

0 an

d/or

2HG

≥7.

8FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4

Preg

nanc

y ou

tcom

esN

N29

,562

4431

2851

1580

1346

913

667

234

Trea

ted

for G

DM

, n0

913

679

913

023

4

Mat

erna

l

Ges

tatio

nal h

yper

tens

ion,

n (%

)44

2713

9 (4

.9)

114

(7.2

)**98

(7.3

)**62

(6.8

)*52

(7.8

)**16

(6.9

)

Pree

clam

psia

, n (%

)44

2741

(1.4

)40

(2.5

)**35

(2.6

)**28

(3.1

)**12

(1.8

)5

(2.1

)

Indu

ctio

n of

labo

ur, n

(%)

4405

793

(28.

0)81

7 (5

1.9)

***

670

(50.

0)**

*58

7 (6

4.3)

***

230

(34.

8)**

147

(62.

8)**

*

Mod

e of

del

iver

y, n

(%)

Va

gina

l

Emer

genc

y CS

Pl

anne

d CS

In

stru

men

tal

4410

2051

(72.

3)32

7 (1

1.5)

185

(6.5

)27

2 (9

.6)

1069

(67.

9)**

205

(13.

0)17

1 (1

0.9)

***

130

(8.3

)

904

(67.

4)**

177

(13.

2)15

0 (1

1.2)

***

110

(8.2

)

618

(67.

7)**

116

(12.

7)10

3 (1

1.3)

***

76 (8

.3)

451

(68.

1)*

89 (1

3.4)

68 (1

0.3)

**

54 (8

.2)

165

(70.

5)28

(12.

0)21

(9.0

)20

(8.5

)

Ges

tatio

nal a

ge a

t del

iver

y (w

ks)

4431

39.7

[38.

7-40

.6]

38.6

[38.

0-39

.9]**

*38

.7 [3

8.0-

39.9

]***

38.3

[38.

0-39

.0]**

*39

.6 [3

8.3-

40.4

]***

38.6

[38.

1-39

.4]**

*

Neo

nata

l

Larg

e fo

r ges

tatio

nal a

ge, n

(%)

3246

(11.

0)44

3051

4 (1

8.0)

307

(19.

4)27

1 (2

0.1)

167

(18.

3)14

0 (2

1.0)

36 (1

5.4)

Mac

roso

mia

, n (%

)42

75 (1

4.5)

4431

595

(20.

9)25

6 (1

6.2)

***

226

(16.

8)**

108

(11.

8)**

*14

8 (2

2.2)

30 (1

2.8)

**

Smal

l for

ges

tatio

nal a

ge, n

(%)

2364

(8.0

)44

3019

5 (6

.8)

74 (4

.7)*

69 (5

.1)*

36 (3

.9)**

38 (5

.7)

5 (2

.1)**

Birt

h w

eigh

t (g)

4431

3544

± 5

7934

71 ±

578

***

3477

± 5

90**

3391

± 5

50**

*35

80 ±

596

3437

± 4

98**

Birt

h tr

aum

a, n

(%)

4420

64 (2

.3)

47 (3

.0)

43 (3

.2)

27 (3

.0)

20 (3

.0)

4 (1

.7)

Hyp

ogly

caem

ia, n

(%)a

4418

NA

NA

NA

38 (4

.2)**

*N

A4

(1.7

)

Hyp

erbi

lirub

inae

mia

, n (%

)a44

18N

AN

AN

A24

(2.6

)**N

A5

(2.1

)

Still

birt

h, n

(%)

4431

10 (0

.4)

6 (0

.4)

6 (0

.4)

2 (0

.2)

4 (0

.6)

0

Chapter 7

132


133

7

TAB

LE 2

. Pr

egna

ncy

outc

omes

acc

ordi

ng to

the

GD

M c

lass

ifica

tion

grou

ps. (

cont

inue

d)

Gen

eral

ob

stet

ric

popu

lati

on

in th

e no

rth

of th

e N

ethe

rlan

dsCr

iter

ia

(mm

ol/l)

NG

TBo

th c

rite

ria

GD

MW

HO

-201

3W

HO

-199

9W

HO

-201

3 on

ly

FGW

HO

-199

9 on

ly

2HG

FG <

5.1

and

2HG

<7.

8FG

≥5.

1 or

2HG

≥7.

8FG

≥5.

1 an

d/or

2HG

≥8.

5FG

≥7.

0 an

d/or

2HG

≥7.

8FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4

Pret

erm

del

iver

y, n

(%)

4431

146

(5.1

)10

3 (6

.5)

92 (6

.8)*

57 (6

.2)

46 (6

.9)

11 (4

.7)

Resp

irato

ry s

uppo

rt, n

(%)

4418

116

(4.1

)61

(3.9

)51

(3.8

)34

(3.7

)27

(4.1

)10

(4.3

)

Apg

ar s

core

<7

at 5

min

, n (%

)44

1474

(2.6

)59

(3.7

)*57

(4.3

)**30

(3.3

)29

(4.4

)*2

(0.9

)

Adm

issi

on to

neo

nato

logy

, n (%

)44

2331

5 (1

1.1)

230

(14.

6)**

206

(15.

3)**

*13

0 (1

4.2)

*10

0 (1

5.0)

**24

(10.

3)

Abbr

evia

tions

: CS,

cae

sare

an se

ctio

n; F

G, f

astin

g gl

ucos

e; G

DM

, ges

tatio

nal d

iabe

tes m

ellit

us; N

GT,

nor

mal

glu

cose

tole

ranc

e; W

HO

, Wor

ld H

ealth

Org

aniz

atio

n; 2

HG

, 2-h

glu

-co

se.

Dat

a ar

e ex

pres

sed

as m

ean

± SD

, med

ian

[IQR]

or p

ropo

rtio

n of

n (%

). P-

valu

es w

ere

base

d on

Stu

dent

’s un

paire

d t-

test

(non

-ske

wed

con

tinuo

us v

aria

bles

), M

ann-

Whi

tney

U

test

(ske

wed

cont

inuo

us v

aria

bles

), or

Chi

-squ

are

test

/Fis

her’s

exa

ct te

st. * P<

0.05

, **P<

0.01

, *** P<

0.00

1 co

mpa

red

with

NG

T gr

oup.

a D

ata

wer

e co

llect

ed in

prim

ary

care

(mid

wiv

es) a

nd se

cond

ary

care

(hos

pita

l). In

prim

ary

care

neo

nata

l hyp

ogly

caem

ia a

nd h

yper

bilir

ubin

aem

ia w

ere

not r

epor

ted

and

mea

-su

red

in a

ll pr

egna

ncie

s. Th

eref

ore

we

only

repo

rted

the

perc

enta

ge fo

r the

WH

O-1

999

grou

p, a

ll th

ese

wom

en d

eliv

ered

in se

cond

ary

care

.

Chapter 7

132


133

7

TAB

LE 3

. O

dss

ratio

’s fo

r pre

gnan

cy o

utco

mes

acc

ordi

ng to

the

GD

M c

lass

ifica

tion

grou

ps.

Crit

eria

(m

mol

/l)

NG

TBo

th c

rite

ria

GD

MW

HO

-201

3W

HO

-199

9W

HO

-201

3 on

ly

FGW

HO

-199

9 on

ly

2HG

FG <

5.1

and

2HG

<7.

8FG

≥5.

1 or

2HG

≥7.

8FG

≥5.

1 an

d/or

2HG

≥8.

5FG

≥7.

0 an

d/or

2HG

≥7.

8FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4

Preg

nanc

y ou

tcom

es

N28

5115

8013

4691

366

723

4

Trea

ted

for G

DM

, n0

913

679

913

023

4

Larg

e fo

r ges

tatio

nal a

ge N

o. o

f cas

es, n

(%)

Una

djus

ted

OR

Mul

tivar

iabl

e-ad

just

ed O

R a

514

(18.

0)1.

00 (R

ef)

1.00

(Ref

)

307

(19.

4)1.

10 (0

.94-

1.28

)1.

10 (0

.93-

1.30

)

271

(20.

1)1.

15 (0

.97-

1.35

)1.

14 (0

.96-

1.36

)

167

(18.

3)1.

02 (0

.84-

1.23

)1.

02 (0

.83-

1.25

)

140

(21.

0)1.

21 (0

.98-

1.49

)1.

22 (0

.97-

1.53

)

36 (1

5.4)

0.83

(0.5

7-1.

19)

0.86

(0.5

9-1.

24)

Mac

roso

mia

N

o. o

f cas

es, n

(%)

Una

djus

ted

OR

Mul

tivar

iabl

e-ad

just

ed O

R

595

(20.

9)1.

00 (R

ef)

1.00

(Ref

)

256

(16.

2)0.

73 (0

.62-

0.86

)***

0.71

(0.6

0-0.

85)**

*

226

(16.

8)0.

77 (0

.65-

0.91

)**

0.73

(0.6

1-0.

88)**

108

(11.

8)0.

51 (0

.41-

0.63

)***

0.50

(0.4

0-0.

63)**

*

148

(22.

2)1.

08 (0

.88-

1.33

) 1.

07 (0

.85-

1.34

)

30 (1

2.8)

0.56

(0.3

8-0.

83)**

0.57

(0.3

8-0.

85)**

Ges

tatio

nal h

yper

tens

ion

No.

of c

ases

, n (%

) U

nadj

uste

d O

R M

ultiv

aria

ble-

adju

sted

OR

139

(4.9

)1.

00 (R

ef)

1.00

(Ref

)

114

(7.2

)1.

52 (1

.18-

1.96

)**

1.35

(1.0

3-1.

77)*

98 (7

.3)

1.53

(1.1

7-2.

00)**

1.33

(1.0

0-1.

77)*

62 (6

.8)

1.42

(1.0

5-1.

94)*

1.29

(0.9

4-1.

79)

52 (7

.8)

1.65

(1.1

9-2.

30)**

1.38

(0.9

6-1.

97)

16 (6

.9)

1.44

(0.8

4-2.

46)

1.40

(0.8

1-2.

42)

Pree

clam

psia

No.

of c

ases

, n (%

) U

nadj

uste

d O

R M

ultiv

aria

ble-

adju

sted

OR

41 (1

.4)

1.00

(Ref

)1.

00 (R

ef)

40 (2

.5)

1.78

(1.1

5-2.

77)*

1.80

(1.1

2-2.

88)*

35 (2

.6)

1.83

(1.1

6-2.

89)**

1.82

(1.1

2-2.

97)*

28 (3

.1)

2.17

(1.3

3-3.

53)**

2.20

(1.3

1-3.

68)**

12 (1

.8)

1.26

(0.6

6-2.

41)

1.20

(0.6

0-2.

38)

5 (2

.1)

1.50

(0.5

9-3.

84)

1.59

(0.6

1-4.

12)

Plan

ned

CS N

o. o

f cas

es, n

(%)

Una

djus

ted

OR

Mul

tivar

iabl

e-ad

just

ed O

R

185

(6.5

)1.

00 (R

ef)

1.00

(Ref

)

171

(10.

9)1.

75 (1

.40-

2.17

)***

1.47

(1.1

6-1.

86)**

150

(11.

2)1.

80 (1

.44-

2.26

)***

1.52

(1.1

9-1.

94)**

103

(11.

3)1.

82 (1

.41-

2.35

)***

1.51

(1.1

5-1.

98)**

68 (1

0.3)

1.64

(1.2

3-2.

20)**

1.36

(0.9

8-1.

88)

21 (9

.0)

1.41

(0.8

8-2.

27)

1.32

(0.8

2-2.

16)

Abbr

evia

tions

: CS,

cae

sare

an se

ctio

n; F

G, f

astin

g gl

ucos

e; G

DM

, ges

tatio

nal d

iabe

tes m

ellit

us; N

GT,

nor

mal

glu

cose

tole

ranc

e; W

HO

, Wor

ld H

ealth

Org

aniz

atio

n; 2

HG

, 2-h

glu

-co

se.

OR,

95%

confi

denc

e in

terv

als,

and

P-va

lues

wer

e de

rived

from

logi

stic

regr

essi

on m

odel

s.* P<0.

05, **

P<0.

01, **

* P<0.

001c

ompa

red

with

NG

T gr

oup

(refe

renc

e po

pula

tion)

.M

ultiv

aria

ble

adju

stm

ent i

nclu

ded

mat

erna

l age

, pre

-ges

tatio

nal b

ody

mas

s ind

ex, e

thni

city

, par

ity a

nd m

ater

nal s

mok

ing.

a La

rge

for g

esta

tiona

l age

was

adj

uste

d fo

r mat

erna

l age

, pre

-ges

tatio

nal b

ody

mas

s ind

ex a

nd m

ater

nal s

mok

ing.

Chapter 7

134

Extrapolation of data on birth weight and prevalence of LGA neonatesFigure 1 and suppl. Table 2 illustrate the two models in which we predicted the possible influence of diet-only or diet plus insulin therapy on birth weight and prevalence of LGA neonates. In the WHO-1999 group, 57.4% of the women were treated with diet-only and 42.6% with additional insulin. In the group of women classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria, 79.5% of the women were treated with diet-only and 20.5% with additional insulin. Women classified as having GDM based only on the FG cut-off of the WHO-2013 criteria were not treated for GDM.

Both models predicted that non-treatment would significantly increase the percentage of LGA neonates in the WHO-1999 group. Model 1 predicted an increase from 19.5% to 27.9% for those women in the diet-only group, and from 16.7% to 29.6% for those in the insulin group. Model 2 predicted an increase from 19.5% to 35.7% in the diet-only group and from 16.7% to 48.3% in the insulin. For the group of women classified as having GDM based exclusively on the 2HG cut-off of the WHO-1999 criteria, non-treatment was also estimated to result in an increase in the percentage of LGA neonates. Overall, withholding treatment would double the percentage of LGA neonates. Moreover, Model 1 and Model 2 both estimated that for women with GDM based only on the FG cut-off of the WHO-2013, treatment would reduce the percentage of LGA neonates.

FIGURE 1. Prevalence of LGA-neonates and the estimated changes in LGA prevalence according to non-treatment and treatment.Abbreviations: WHO, World Health Organization; 2HG, 2-hour glucose level; FG fasting glucose level; LGA, large for gestational age. Data are expressed as proportion (%). Detailed explanation of the categories and models are given in Supplemental Table 1.


135

7

DISCUSSION

This large retrospective cohort study to evaluate the possible impact on GDM prevalence and pregnancy outcomes of applying the new WHO-2013 criteria dem-onstrates that GDM prevalence would increase from 22% to 31%, relative to the WHO-1999 criteria. We also show that applying these new criteria indeed identifies a new group of women (FG ≥5.1-≤6.9 mmol/l) who have unfavourable character-istics and more adverse pregnancy outcomes when compared either with women otherwise found to be normal glucose tolerance upon screening or with the general obstetric population. Our results show that women potentially missed due to the higher 2HG cut-off (2HG ≥7.8-≤8.4 mmol/l) of the WHO-2013 criteria have similar pregnancy outcomes to NGT women. Our results also indicate that neonates from mothers who are screened for GDM but are found to have normal glucose tolerance (NGT group) are more likely to be born large for gestational age or with macrosomia than those born to mothers in the general obstetric population in our region.

Strengths and limitationsA major strength of our study is the relatively large cohort of laboratory results of 75-gram OGTTs and the extensive and detailed information regarding pregnancy outcomes in a subset of 4,431 women with singleton pregnancies. All women with GDM were treated according to a detailed protocol in two large hospitals.14,15 Ma-ternal and pregnancy outcome data were collected manually from patient’s charts at their midwifes offices. This study also has limitations that should be noted. First, since universal screening for GDM is not currently recommended in the Nether-lands, only women with one or more risk factors for GDM or signs suggestive of GDM such as macrosomia were screened. The prevalence of GDM found in our study is therefore not a reflection of the general obstetric population, and repre-sents a selected group of women at higher risk of GDM. Universal testing is now recommended in several countries around the world. However, controversy in the literature on the best method of screening (universal or risk-based) remains.8 Sec-ondly, the WHO-2013 criteria also recommend that GDM diagnosis should include a one-hour plasma glucose level of ≥10.0 mmol/l following a 75-g OGTT. Since we did not have data for one-hour glucose levels, the prevalence of GDM reported here may be an underestimation. Thirdly, all women diagnosed according the WHO-1999 criteria were offered GDM treatment. Fourthly, we have compared outcomes with those in the general population in the north of the Netherlands between 2011 and 2013. Unfortunately data after 2013 have not yet been made available from public datasets. Also, this dataset does not indicate which women were tested with an OGTT. Finally, the models that we constructed to try and estimate the birth weight

Chapter 7

136

that would have resulted if women classified as having GDM based on the WHO-1999 criteria had not been treated cannot predict other pregnancy and neonatal outcomes. It therefore remains unclear whether these women could safely have been left untreated.

Prevalence and maternal characteristicsSeveral authors have expressed concerns about the adoption of the WHO-2013 cri-teria, as this will significantly increase the prevalence of GDM, and impose a higher burden on healthcare provided by obstetricians.10,11 Numerous studies have shown that implementing the new WHO-2013 criteria will result in a 2-3 fold increase in the prevalence of GDM.9,11,17 The increase from 22% to 31% observed in our cohort of women at higher risk of GDM was mainly the result of an increase in the number of women who would be diagnosed on the basis of an elevated FG level (between 5.1 and 7.0 mmol/l). Despite this net increase, at the same time a number of women would not be diagnosed due to the higher 2HG cut-off of the WHO-2013 criteria.

Our study clearly demonstrated that the lower FG cut-off of the WHO-2013 criteria (FG ≥5.1-≤6.9 mmol/l) identifies a group of women who are more likely than NGT women to be obese (BMI >30 kg/m2) and hypertensive. Moreover, the women classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria (2HG ≥7.8-8.4) were also more likely than NGT women to be overweight (BMI >25 kg/m2). It is known that impaired FG (IFG; FG ≥5.6-≤6.9 mmol/l) and/or impaired glucose tolerance (IGT; 2HG ≥7.8-≤11.0 mmol/l) are both predictors for the future development of type 2 diabetes mellitus (T2DM).18 IFG and IGT are associated with an unfavourable metabolic profile, including obesity and hypertension. Both groups successfully identify a group of high-risk women with an adverse metabolic profile.

Pregnancy outcomesAlthough uncertainty remains regarding the optimal glucose threshold used to de-fine GDM, hyperglycaemia during pregnancy is clearly associated with an increased risk of adverse pregnancy outcomes.6 Indeed, women in this study classified as hav-ing GDM by any criteria had higher rates of adverse maternal outcomes, including hypertensive disorders during pregnancy, planned CS and induced labour when compared with NGT women. Moreover, the neonates of mothers classified as having GDM by any criteria were likely to have been admitted to the neonatology department.

Concerns have been raised about the so-called medicalization of pregnancy should the new –more stringent – WHO-2013 criteria be used.10 Based on the WHO-1999 criteria currently applied in the Netherlands, these women are not diagnosed as having GDM and are therefore not treated with diet and/or insulin. However, our


137

7

findings suggest that despite not being diagnosed as having GDM, these women already have higher intervention rates. We demonstrated that, when compared with NGT women, the women classified as having GDM based only on the FG cut-off of the WHO-2013 criteria (≥5.1-≤6.9 mmol/l) had higher rates of gestational hypertension, planned CS and induced labour, and their neonates were more likely to have an Apgar score <7 at 5 min and to be admitted to the neonatology depart-ment compared with NGT women. These findings are consistent with those of other studies that found that women reclassified as having GDM based on the WHO-2013 criteria are at increased risk of adverse pregnancy outcomes, including gestational hypertension, caesarean section, neonatal intensive care admission, and LGA neo-nates.19-22

In terms of the likelihood of having an LGA neonate, we found no significant differences between the women classified as having GDM based on the FG cut-off of the WHO-2013 criteria and women in the NGT group. However, the percentage of women in this group having an LGA neonate was much higher than for the general obstetric population in the north of the Netherlands (21% versus 11%). Based on these findings, it seems that women classified with GDM based only on the FG cut-off of the WHO-2013 criteria should not be left untreated. The results of our model estimates indicate that treating these women with diet and/or insulin will reduce the percentage of LGA neonates by 2% to 8%. This prediction is supported by the results of a study by Landon et al., which suggests that early treatment in women with mild GDM reduces the percentage of women giving birth to LGA neonates by 7%.4

Our study has also shown that implementing the new WHO-2013 criteria with a higher 2HG cut-off may exclude a group of women who now benefit from treat-ment. The women classified as having GDM based only on the 2HG cut-off of the WHO-1999 criteria (≥7.8-≤8.4 mmol/l) had pregnancy outcomes similar to those of women in the NGT group. A notable finding was that they had the lowest rate of LGA neonates of all other diagnostic groups. The only obstetric parameter which differed with the NGT group was the rate of induced labour, but it has to be borne in mind that induction of labour at 38/39 weeks of gestation is more likely to be recommended in women being treated for GDM, especially those receiving insulin therapy.

All women classified as having GDM based on the WHO-1999 were actively treated with diet and/or insulin. These interventions normalized their glycaemic profile and the outcome findings for this group suggest that these interventions were indeed effective. Nevertheless, it is unclear whether these women can be safely left untreated after implementing the new WHO-2013 criteria. Indeed, our model estimates indicate that not treating these women with diet and/or insulin

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will increase the percentage of LGA neonates by 10% to 30%. These estimates are supported by a recent study by Farrar et al., who showed that even women with a two-hour post-load glucose level ≥7.5 mmol/l are at increased risk of adverse outcomes (i.e. birth weight >90th percentile, high infant adiposity, and caesarean section).23 These authors therefore recommend using a two-hour post-load glucose cut-off value even lower than that recommended by both WHO-1999 and WHO-2013 criteria.

A notable finding of our study is that the women in the NGT group who had undergone an OGTT for screening or diagnostic purposes and were subsequently found to be normal glucose tolerant – also had a rate of LGA neonates higher than that of the women receiving treatment after being diagnosed with GDM based on the 2HG cut-off of the WHO-1999 criteria (18.0% versus 15.4%). Although this finding was not statistically significant, it was a large difference compared with the incidence of LGA neonates in the general obstetric population (18% versus 11%). This coincidental finding shows that even women with a risk factor or signs sug-gestive of GDM and without a positive diagnosis of GDM are at increased risk of giving birth to an LGA neonate. This finding is agreement with a study by Meek et al., who demonstrated that women diagnosed and treated for GDM according to the National Institute for Health and Care Excellence (NICE) criteria in the United Kingdom had lower rates of LGA neonates than women negative for GDM according to both the NICE and IADPSG/WHO-2013 criteria.21 A possible explanation for this finding is that these women were screened too early in pregnancy and were there-fore not diagnosed with GDM at this screening test. Besides, studies have shown that the OGTT has a poor reproducibility, which means that some women who first test negative for GDM can test positive on a second test.24 We therefore agree with the suggestion made by Meek et al. that standard lifestyle interventions (including dietary advice) given to women with GDM might also benefit NGT women.

CONCLUSIONS

This large retrospective cohort study evaluated the possible impact on GDM preva-lence and pregnancy outcomes of applying the new WHO-2013 criteria, rather than the old WHO-1999 criteria. We demonstrated that the prevalence of GDM would increase markedly if the WHO-2013 criteria were implemented. Nevertheless, the FG cut-off of the WHO-2013 criteria (FG ≥5.1-≤6.9 mmol/l) identifies a group of women with an increased risk of pregnancy complications. We therefore recommend that to improve GDM outcomes the FG cut-off level in the Dutch national guideline needs to be adjusted. However, it is unclear from our data whether women with a 2HG level


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between 7.8 and 8.5 mmol/l can be safely left untreated. Recent studies suggest that a post-load 2HG cut-off level of 7.5 mmol/l may be more appropriate. Future studies should evaluate whether a stricter post-GTT threshold further improves pregnancy outcomes. Such studies should also address pregnancy outcomes in women who are screened but found to be normal glucose tolerant.

Acknowledgements

The authors wish to thank the endocrinologists, gynaecologists, diabetes specialist nurses, and dieti-cians of the University Medical Center and Martini Hospital Groningen. Special thanks are expressed to the participating midwife practices: De Verloskundigenpraktijk van Groningen, Verloskundigenpraktijk Hoogezand, Verloskundigenpraktijk La Vie, Verloskundigenpraktijk New Life, Verloskundige Stadsprak-tijk, Verloskundigenpraktijk ‘t Stroomdal, Verloskundigenpraktijk Veendam. We would also like to thank H. Hepkema-Geerligs (customer relations manager Laboratory of Clinical Chemistry, Certe) and the students S. Klöppner and J. van Amstel for their contribution to the data collection. Finally, we thank epidemiologist H. Groen, the Dutch Perinatal Registry and the Municipal Health Service Groningen for providing the data on the reference population in the northern region of the Netherlands.

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REFERENCES

1. Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: The consequences of not treating. Obstet Gynecol. 2005;192:989-97.

2. Yang X, Hsu-Hage B, Zhang H, Zhang C, Zhang Y, Zhang C. Women with impaired glucose tolerance during pregnancy have significantly poor pregnancy outcomes. Diabetes Care. 2002;25:1619-24.

3. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gesta-tional diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352:2477-86.

4. Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gesta-tional diabetes. N Engl J Med. 2009;361:1339-48.

5. International Association of Diabetes and Pregnancy Study Groups Consensus Panel, Metzger BE, Gabbe SG, et al. International Association of Diabetes and Pregnancy Study Groups recom-mendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676-82.

6. Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358:1991-2002.

7. World Health Organization (WHO). Diagnostic criteria and Classification of Hyperglycemia First Detected in Pregnancy. 2013. Available from: http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf, accessed 12 May 2017.

8. Benhalima K, Damm P, Van Assche A, et al. Screening for gestational diabetes in Europe: Where do we stand and how to move forward?: A scientific paper commissioned by the European board & college of obstetrics and gynaecology (EBCOG). Eur J Obstet Gynecol Reprod Biol. 2016;201:192-6.

9. Buckley B, Harreiter J, Damm P, et al. Gestational diabetes mellitus in Europe: Prevalence, current screening practice and barriers to screening. A review. Diabet Med. 2012;29:844-54.

10. Visser GHA, de Valk H,W. Is the evidence strong enough to change the diagnostic criteria for gestational diabetes now? Obstet Gynecol. 2013;208:260-4.

11. Cundy T, Ackermann E, Ryan EA. Gestational diabetes: New criteria may triple the prevalence but effect on outcomes is unclear. BMJ. 2014;11:348-g1567

12. World Health Organization (WHO). Definition and Classification of Diabetes mellitus and its Complications. Report of a WHO consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, WHO, 1999. Department of Noncommunicable Disease Surveillance.

13. The Dutch Society of Obstetrics and Gynaecology. Diabetes mellitus and Pregnancy. Clinical guideline version 2.0. 2010. Available from: http://www.nvog-documenten.nl/richtlijn/item/pagina.php?richtlijn_id=863, accessed 12 May 2017.

14. Koning SH, Hoogenberg K, Scheuneman KA, et al. Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus: A retrospective study. BMC Endocr Disord. 2016;16:52.

15. Koning SH, Scheuneman KA, Lutgers HL, et al. Risk stratification for healthcare planning in women with gestational diabetes mellitus. Neth J Med. 2016;74:262-9.

16. Visser GH, Eilers PH, Elferink-Stinkens PM, Merkus HM, Wit JM. New Dutch reference curves for birthweight by gestational age. Early Hum Dev. 2009;85:737-44.


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17. Agarwal MM. Gestational diabetes mellitus: An update on the current international diagnostic criteria. World J Diabetes. 2015;6:782-91.

18. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37 (Suppl. 1):S81-90.

19. Laafira A, White SW, Griffin CJ, Graham D. Impact of the new IADPSG gestational diabetes diagnos-tic criteria on pregnancy outcomes in western Australia. Aust N Z J Obstet Gynaecol. 2016;56:36-41.

20. Lapolla A, Dalfrà M, Ragazzi E, De Cata A, Fedele D. New international association of the diabetes and pregnancy study groups (IADPSG) recommendations for diagnosing gestational diabetes compared with former criteria: A retrospective study on pregnancy outcome. Diabet Med. 2011;28:1074-77.

21. Meek CL, Lewis HB, Patient C, Murphy HR, Simmons D. Diagnosis of gestational diabetes mellitus: Falling through the net. Diabetologia. 2015;58:2003-12.

22. O’Sullivan E, Avalos G, O’Reilly M, et al. Atlantic diabetes in pregnancy (DIP): The prevalence and outcomes of gestational diabetes mellitus using new diagnostic criteria. Diabetologia. 2011;54:1670-5.

23. Farrar D, Fairley L, Santorelli G, et al. Association between hyperglycaemia and adverse perinatal outcomes in South Asian and white British women: Analysis of data from the born in Bradford cohort. Lancet Diabetes Endocrinol. 2015;3:795-804.

24. Harlass FE, Brady K, Read JA. Reproducibility of the oral glucose tolerance test in pregnancy. Obstet Gynecol. 1991;164:564-8.

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SUPPLEMENTAL DATA

SUPPLEMENTAL TABLE 1. Explanation of the extrapolation models on birth weight and prevalence of LGA.

Criteria mmol/l

WHO-1999 WHO-1999 only 2HG WHO-2013 only FG

FG ≥7.0 and/or2HG ≥7.8

FG <5.1 and2HG ≥7.8-≤8.4

FG ≥5.1-≤6.9 and2HG <7.8

Treatment In the current national guideline women classified as having GDM according to the WHO-1999 criteria are treated for GDM with diet (“diet-only group“) or with diet + insulin when diet-only fails (“insulin group”).

In the current national guideline women classified as having GDM according the WHO-2013 only FG are not treated for GDM

This category indicated the birth weight and prevalence of LGA neonates observed in this group of women currently treated with diet-only or diet + insulin.

This category indicated the birth weight and prevalence of LGA neonates observed in this group of women currently not-treated.

Since these women were treated with diet-only and/or insulin these groups cannot be directly compared with women who were not offered treatment. Therefore, in model 1 and 2 we predicted the birth weight and prevalence of LGA neonates if their mothers had not been treated for GDM.

Since these women were not treated with diet-only and/or insulin this group cannot be directly compared with women who were offered treatment.Therefore, in model 1 and 2 we predicted the birth weight and prevalence of LGA neonates if their mothers had been treated for GDM.

Model 1a Hypothetical effect on birth weight: Hypothetical effect on birth weight:

Diet+ 100 gram

Diet + Insulin + 200 gram

Diet-50 gram

Diet + Insulin-100 gram

Model 2a Hypothetical effect on birth weight: Hypothetical effect on birth weight:

Diet+ 200 gram

Diet + Insulin+ 400 gram

Diet -100 gram

Diet + Insulin- 200 gram

Abbreviations: GDM, gestational diabetes mellitus; WHO, World Health Organization; 2HG, 2-hour glucose level; FG fasting glucose level; LGA, large for gestational age.

a The models were not corrected for a possible effect that a higher birth weight may lead to earlier start of deliv-ery. However, most of the women delivered between 38-39 weeks of gestation.


143

7

SUPP

LEM

ENTA

L TA

BLE

2.

Estim

ated

cha

nges

in b

irth

wei

ght a

nd L

GA

pre

vale

nce

acco

rdin

g to

non

-tre

atm

ent a

nd tr

eatm

ent.

Crit

eria

m

mol

/l

WH

O-1

999

WH

O-1

999

only

2H

GW

HO

-201

3 on

ly

FG

FG ≥

7.0

and/

or2H

G ≥

7.8

FG <

5.1

and

2HG

≥7.

8-≤8

.4FG

≥5.

1-≤6

.9 a

nd2H

G <

7.8

N91

323

466

7

N (%

)Tr

eatm

ent

Die

t52

4 (5

7.4)

Die

t + In

sulin

389

(42.

6)D

iet

186

(79.

5)D

iet +

Insu

lin48

(20.

5)no

t tre

ated

Birt

h w

eigh

t, gr

am34

38 ±

556

3328

± 5

3734

71 ±

524

3304

± 3

4935

80 ±

596

Larg

e fo

r ges

tatio

nal a

ge, n

(%)a

102

(19.

5)65

(16.

7)32

(17.

2)4

(8.3

)14

0 (2

1.0)

Ges

tatio

nal a

ge, w

ks38

.7 [3

8.1-

39.7

]38

.1 [3

8.0-

38.4

]38

.8 [3

8.1-

39.7

]38

.1 [3

8.0-

38.4

]39

.6 [3

8.3-

40.4

]

Mod

el 1

bN

o tr

eatm

ent

+ 10

0 gr

amN

o tr

eatm

ent

+ 20

0 gr

amN

o tr

eatm

ent

+ 10

0 gr

amN

o tr

eatm

ent

+ 20

0 gr

am T

reat

men

t die

t-5

0 gr

amTr

eatm

ent d

iet +

insu

lin- 1

00 g

ram

Birt

h w

eigh

t, gr

am35

38 ±

556

3528

± 5

3735

71 ±

524

3504

± 3

4935

30 ±

596

3480

± 5

96

Larg

e fo

r ges

tatio

nal a

ge, n

(%)a

146

(27.

9)11

5 (2

9.6)

51 (2

7.4)

9 (1

8.8)

127

(19.

0)11

5 (1

7.2)

Mod

el 2

bN

o tr

eatm

ent

+ 20

0 gr

amN

o tr

eatm

ent

+ 40

0 gr

amN

o tr

eatm

ent

+ 20

0 gr

amN

o tr

eatm

ent

+ 40

0 gr

am T

reat

men

t die

t-1

00 g

ram

Trea

tmen

t die

t + in

sulin

- 200

gra

m

Birt

h w

eigh

t, gr

am36

38 ±

556

3728

± 5

3736

71±

524

3704

± 3

4934

80 ±

596

3380

± 5

96

Larg

e fo

r ges

tatio

nal a

ge, n

(%)a

187

(35.

7)18

8 (4

8.3)

64 (3

4.4)

19 (3

9.6)

115

(17.

2)84

(12.

6)

Abbr

evia

tions

: WH

O, W

orld

Hea

lth O

rgan

izat

ion;

2H

G, 2

-hou

r glu

cose

leve

l; FG

fast

ing

gluc

ose

leve

l; LG

A, la

rge

for g

esta

tiona

l age

. D

ata

are

expr

esse

d as

mea

n ±

SD, m

edia

n [IQ

R] o

r pro

port

ion

of n

(%).

a Bi

rth

wei

ght >

90th

per

cent

ile, c

orre

cted

for g

esta

tiona

l age

, gen

der n

eona

te, p

arity

and

eth

nic

back

grou

nd.

b Det

aile

d ex

plan

atio

n of

the

cate

gorie

s and

mod

els a

re g

iven

in S

uppl

emen

tal T

able

1.

University of Groningen Gestational diabetes mellitus: diagnosis and outcome … · 2017-11-07 · Chapter 7 122 ABSTRACT Aims/hypothesis: Detection and management of gestational

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