AJ, Wolff enbuttel BHR, van den Berg PP
Submitted
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.
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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)?
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 population
This 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 classification
Based 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.
Outcomes
Data 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
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 neonates
Treatment 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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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 analyses
Continuous 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-multivariable-adjusted models multivariable-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 characteristics
OGTT 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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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 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 outcomes
Maternal 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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TABLE 1.Maternal characteristics according to the GDM classification groups. Criteria (mmol/l)
NGTBoth criteria GDMWHO-2013WHO-1999WHO-2013 only FGWHO-1999 only 2HG FG <5.1 and 2HG <7.8FG ≥5.1 or 2HG ≥7.8FG ≥5.1 and/or 2HG ≥8.5FG ≥7.0 and/or 2HG ≥7.8FG ≥5.1-≤6.9 and 2HG <7.8FG <5.1 and 2HG ≥7.8-≤8.4 CharacteristicsN N4431285115801346913667234 Treated for GDM, n (%) Diet Additional insulin therapy0 0524 (33.2) 389 (24.6)338 (25.1) 341 (25.3)524 (57.4) 389 (42.6)0 0186 (79.5) 48 (20.5) Age (years)443130.7 ± 4.931.9 ± 5.1***32.0 ± 5.2***32.1 ± 5.1***31.6 ± 5.2***31.6 ± 4.5** Pre-pregnancy BMI (kg/m2)419625.2 [22.0-30.4]28.3 [24.4-32.5]***28.7 [24.5-32.9]***27.7 [24.1-31.8]***29.1 [24.8-33.5]***26.4 [23.3-30.4]** Pre-pregnancy BMI, n (%) <25 kg/m2 25-30 kg/m2 ≥30 kg/m2
4196 1311 (48.8) 618 (23.0) 755 (28.1)
*** 452 (29.9) 443 (29.3) 617 (40.8)
*** 366 (28.5) 365 (28.4) 551 (42.9)
*** 285 (32.0) 276 (30.9) 331 (37.1)
*** 167 (26.9) 167 (26.9) 286 (46.1)
*** 86 (37.4) 78 (33.9) 66 (28.7) Ethnicity, n (%) Caucasian Asian African-American Mediterranean Other
4431 2211 (77.6) 160 (5.6) 150 (5.3) 207 (7.3) 123 (4.3) 1238 (78.4) 86 (5.4) 85 (5.4) 115 (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 (10.3) 7 (3.0) 20 (8.5) 5 (2.1) Nulliparous, n (%)44311281 (44.9)623 (39.4)***523 (38.9)***373 (40.9)*250 (37.5)***100 (42.7) Chronic hypertension, n (%)442734 (1.2)59 (3.7)***52 (3.9)***37 (4.1)***22 (3.3)***7 (3.0)* Smoking during pregnancy, n (%)4381296 (10.5)188 (12.0)165 (12.4)101 (11.1)87 (13.2)*23 (9.8) Abbreviations: BMI, body mass index; FG, fasting glucose level; GDM, gestational diabetes mellitus; NGT; normal glucose tolerance; WHO, World Health Organization; 2HG, 2-hour glucose level. Data are expressed as mean ± SD, median [IQR] or proportion of n (%). P-values were based on Student’s unpaired t-test (non-skewed continuous variables), Mann-Whitney U test (skewed continuous variables), or Chi-square test/Fisher’s exact test. *P<0.05, **P<0.01, ***P<0.001 compared with NGT group.
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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
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