Acta Diabetologica

https://doi.org/10.1007/s00592-018-1146-7

REVIEW ARTICLE

The post-HAPO situation with gestational diabetes: the bright

and dark sides
Annunziata Lapolla1 · Boyd E. Metzger2

Received: 9 November 2017 / Accepted: 15 April 2018

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Abstract
Aim  In 2010, in light of the data coming from the HAPO study, the International Association of Diabetes and Pregnancy
Study Groups (IADPSG) proposed a new detection strategy and diagnostic criteria for gestational diabetes based on a one-
step approach with a 75 g OGTT. This review analyzes and discusses the bright and dark sides of their application.
Methods  The assessment of these recommendations by the international organizations involved in the care of gestational
diabetes and a series of observational, retrospective and prospective studies that have been published since 2010 regarding
the use of the IADPSG recommendations have been evaluated.
Results  The different international associations involved in the care of pregnancy and of pregnancy complicated by diabetes
have not taken an univocal position some of which have accepted them, while others have criticized them. Then, the actual
application of the approach recommended by the IADPSG for detecting and diagnosing GDM varies, even at centers that
reportedly accept the new diagnostic criteria.
Conclusion  So the challenge lies in making every effort to achieve a global standardization of the strategies for detecting,
diagnosing and treating GDM.

Keywords  Gestational diabetes · Diagnostic criteria · Maternal outcome · Fetal outcome

Introduction criteria were based on predicting diabetes risks in the mother

Since the 1960s, when it was recognized that gestational
diabetes mellitus (GDM), a carbohydrate intolerance first
diagnosed during pregnancy [1], is associated with adverse
maternal and fetal outcomes [2–4], various strategies have
been proposed and adopted to deal with this condition
around the world, starting with O’Sullivan [5]. Diagnostic
criteria have either derived from the O’Sullivan studies, or
been the same as those used in non-pregnant individuals.
The value of the methods for detecting and treating GDM
has been intensely debated, however, because the diagnostic
Managed by Massimo Federici.
* Annunziata Lapolla
annunziata.lapolla@unipd.it
1
Diabetology and Dietetics Unit, Department of Medicine,
Padova University, Padova, Italy
2
Division of Endocrinology, Metabolism and Molecular
Medicine, Department of Medicine, Northwestern University
Feinberg School of Medicine, Chicago, USA
rather than the outcome of the pregnancy, and the effective-
ness of treating GDM had not been demonstrated. A number
of studies had showed that the glucose levels with an impact
on pregnancy outcome are lower than those adopted [6–10].
The HAPO study
The Hyperglycemia and Adverse Pregnancy Outcome
(HAPO) Study was designed to examine the associations
between maternal glycemia and multiple pregnancy out-
comes [11]. It was a prospective observational multina-
tional blinded study that enrolled 25,505 non-diabetic preg-
nant women at 15 centers in 9 countries. All women with
a fasting plasma glucose (FPG) level < 5.8 mmol/l, and a
2-h level < 11.1 mmol/l on a 75 g oral glucose tolerance
test (OGTT) performed at 24–32 weeks of gestation were
included. The study demonstrated continuous linear associa-
tions between fasting, 1- and 2-h OGTT glucose levels and
the four primary outcomes considered (birth weight greater
than 90th centile, cord blood C-peptide concentration greater

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 Acta Diabetologica

than 90th centile, primary Cesarean section, clinical neo-
natal hypoglycemia). Positive associations were also found
between maternal glycemia and the secondary outcomes
investigated (fetal adiposity greater than 90th centile, pre-
term delivery, preeclampsia, shoulder dystocia and/or birth
injury, admission to a neonatal intensive care unit [NICU],
and hyperbilirubinemia).
The IADPSG recommendations
To convert the findings of the HAPO study into practical
guidelines, the International Association of Diabetes in
Pregnancy Study Groups (IADPSG) conducted a 2-day
workshop that carefully examined the results of the HAPO
study, and other studies consistent with the HAPO results
[7, 12–14]. A consensus panel was then formed and, after
additional analyses on the HAPO study data, at another face-
to-face meeting it developed the recommendations for the
diagnosis of GDM shown in Fig. 1 [15]. In a time frame
that was concurrent with the HAPO study, two randomized

Fig. 1  IADPSG recommenda-
tions for the diagnosis of GDM. First Visit
GDM Gestational diabetes,
HbA1c glycated hemoglobin,
FPG fasting plasma glucose,
OGTT​oral glucose tolerance
test, IADPSG International Measure FPG, HbA1c, or random plasma glucose on all or only high-risk women
Association of Diabetes and
Pregnancy Study Groups
FPG ≥7.0 mmol/l (126 mg/dl) FPG ≥5.1 mmol/l (92 mg/dl) FPG < 5.1 mmol/l (92 mg/dl)
HbA1c ≥ 6.5% (DCCT/UKPDS standardized) ≤7.0 mmol/l (126 mg/dl)
Random plasma glucose ≥ 11.1 mmol/l (200 mg/dl)
+ confirmaon

Overt diabetes GDM OGTT 75 g

24-28 g.w.

24-28 g.w.
2-h 75-g OGTT
(aer overnight fast on all women not previously found to have overt diabetes or
GDM during tesng earlier in this pregnancy)

FPG ≥7.0 mmol/l (126 mg/dl) FPG ≥ 5.1 mmol/l (92 mg/dl)
1-h plasma glucose ≥ 10.0 mmol/l (180 mg/dl)
2-h plasma glucose ≥ 8.5 mmol/l (153 mg/dl)

Overt diabetes GDM

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Acta Diabetologica
control trials comparing standard obstetric care with active
treatment for women with “mild GDM” were published [12,
13]. In the trial conducted by Landon et al. (the NHCHD-
MFMU trial), pregnant women found positive on the glucose
challenge test (GCT), and with an OGTT test result with
two or three abnormal plasma glucose levels, but a fasting
plasma glucose < 95 mg/dl were enrolled [13]. In the study
reported by Crowther et al. (ACHOIS), participants were
pregnant women with a positive glucose challenge test result
and plasma glucose on OGTT < 140 mg/dl under fasting
conditions, and between 140 and 198 mg/dl at 2 h after a
75 g glucose load [12]. The results of these trials show that
the women treated with a controlled diet, plus insulin if the
treatment goals were not achieved, had better maternal and
fetal outcomes in terms of a lower frequency of LGA babies,
shoulder dystocia, gestational hypertension or preeclamp-
sia than the women given standard prenatal care. Although
patient selection for these trials differed from that of the
HAPO study (i.e., with a two-step instead of a one-step
diagnosis of GDM), the overlap in the characteristics of the
women taking part in the three studies justified considering
the results of the two trials as complementary to the HAPO
study findings [15].
In principle, the recommendations emerging from the
HAPO findings should have solved the long-standing con-
troversies regarding the diagnosis and treatment of GDM,
but this is not the case. Instead, a lengthy debate on the pos-
sible pros and cons of applying the recommendations has
ensued [16–20].
A key strength of the IADPSG criteria lies in having used
the HAPO and other data to derive thresholds of maternal
glycemia associated with adverse neonatal outcomes in a
large, blinded cohort prospectively tested with a 75 g OGTT.
As for its potential weaknesses, the rise in the number of
pregnant women with GDM as a consequence of using the
new criteria means that more women are treated with medi-
cal and obstetrical interventions, with a consequent increase
in the medicalization of pregnancy, and in the related health
care costs [16–19].
Looking on the bright side
Clinical studies
The frequency of GDM when the IADPSG criteria are used
has been analyzed in several retrospective and prospective
studies [21–28]: calculated at the various centers participat-
ing in the HAPO study it ranged from 9 to 26% [21].
A large Spanish cohort study assessed 1750 pregnant
women using the two-step approach (Carpenter and Cous-
tan criteria, CC), and 1526 pregnant women using the
one-step (IADPSG) criteria. The results showed that the
latter one-step approach generated a higher frequency of
GDM than the two-step method (35 vs 10.6%), but was
associated with a lower rate of adverse pregnancy out-
comes (gestational hypertension—14.6%, p < 0.021; pre-
maturity—0.9%, p < 0.039; Cesarean section—23.9%,
p  <  0.002; SGA—6.5%, p  <  0.042; LGA—20%,
p < 0.004; and admission to neonatal intensive care unit
-24.4%, p < 0.001) [22]. Using the IADPSG criteria did
not change the proportion of women needing insulin ther-
apy to achieve good metabolic control. These data thus
confirm the benefits of adopting the IADPSG criteria,
in terms of maternal and fetal outcomes, in a setting of
“standard care”, with no overtreatment of patients. The
frequency of GDM in the Spanish study was high using
both the CC and the IADPSG criteria; however, it is hard
to say whether its findings can be generalized to other
populations.
In a retrospective study, Lapolla et al. [23] examined the
clinical characteristics and pregnancy outcomes of 3953
pregnant women classified as normal using the CC crite-
ria (which require two abnormal values for a diagnosis of
GDM), and reclassified according to the IADPSG criteria
(in which the diagnosis is based on one abnormal value).
Using IADPSG criteria, 2138 of these women were diag-
nosed with GDM, including 112 (2.8%) considered normal
according to the CC criteria. In these newly identified GDM
women, the plasma glucose levels on OGTT, the number of
Cesarean sections, and the newborn’s ponderal indexes were
significantly higher than in normal pregnancy (p < 0.001).
In other words, the IADPSG criteria are able to identify
women hitherto considered as having a normal pregnancy
but showing the clinical characteristics and pregnancy out-
comes resembling those of women with GDM.
Other studies also found a higher frequency of GDM
when the IADPSG criteria were used instead of the CC cri-
teria: some of them reported a higher risk of adverse mater-
nal and fetal outcomes in the women classified as GDM
according to the IADPSG criteria [24], while others found
no differences [28].
A well-conducted retrospective study compared the accu-
racy of different GDM screening procedures and diagnos-
tic criteria (NICE, ADA, Irish, IADPSG) in the pregnant
women taking part in the ATLANTIC DIP program. The
results showed that using the IADPSG criteria enabled more
cases of GDM to be diagnosed (prevalence 12.4%). When
the NICE, Irish and ADA guidelines were applied, 20, 16
and 5% of the cases of GDM identified by the IADPSG cri-
teria would have been overlooked because the women con-
cerned had no risk factors These women, nonetheless, had
more adverse pregnancy outcomes than the women with a
normal glucose tolerance. These findings provide a strong
argument in favor of adopting the IADPSG detection strat-
egy and diagnostic criteria [29].
13

On the other hand, when Donovan et al. [30] compared
the one-step (IADPSG) and the two-step (Carpenter and
Coustan) approach in 178,527 pregnancies in Alberta (Can-
ada), they favored the use of the latter (CC) criteria because
a negative 50 g test was associated with a low risk of adverse
pregnancy outcomes in their sample. They found a gradual
increase in this risk, however, when the 50 g test was posi-
tive; therefore, they suggested that further well-designed
research be conducted to establish the best approach for the
diagnosis of GDM.
Sacks et al. [31] compared the adverse pregnancy out-
comes among untreated women who met the IADPSG
criteria using two different thresholds, i.e., GDM-1 (FPG
92–94 mg/dl; 180–190 mg/dl at 1 h; 153–161 mg/dl at 2 h)
or GDM-2 (one result ≥ FPG 95 mg/dl; 191 mg/dl at 1 h;
162 mg/dl at 2 h). They found that women classified as
GDM 2 showed only some adverse fetal outcomes, such as
a high birth weight and LGA babies. It would, therefore, be
important to ascertain whether these women would benefit
from less intensive treatment. These findings may not be
generally applicable, however, because the cohort had a very
high rate of obesity, was predominantly Mexican American,
and a large proportion of the GDM group had OGTT fasting
glucose values ≥ 95, 191 at 1 h, and 162 mg/dl at 2 h.
A secondary analysis recently conducted on a subset of
HAPO study participants produced some important findings
[32]. The analysis was run on the North American HAPO
study centers, including 6,159 of the original 23,316 blinded
participants, 81% of them with a normal OGTT, 4.2% with
GDM according to the Carpenter and Coustan criteria, and
14.3% with GDM based on the IADPSG criteria. Cases
meeting only the IADPSG criteria showed adjusted odds
ratios (95% CI) of 1.87 (1.50–1.3) for high birth weight,
2.00 (1.54–2.58) for high cord C-peptide concentrations,
1.73 (1.35–2.23) for newborn with a percentage of fat higher
than the 90th centile, 1.31 (1.07–1.60) for Cesarean delivery,
and 1.73 (1.32–2.27) for preeclampsia, when compared with
women without GDM. This evidence of the higher frequency
of adverse outcomes in the women diagnosed with GDM
according to the IADPSG criteria underscore the importance
of designing clinical studies to assess the effects of treating
these women to contain the negative pregnancy outcomes.
Costs and benefits
As emphasized above, a very important point raised in sev-
eral publications on the new IADPSG recommendations
concerns its real cost-effectiveness [33, 34]. Mission et al.
used a decision analytic model to compare routine screening
with the 2-h OGTT versus the 1-h glucose challenge test.
The probabilities, costs and benefits were drawn from data
in the literature. The results of the study show that the 2-h
OGTT was more expensive, but more cost-effective, at US$
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Acta Diabetologica
61,503 per quality-adjusted year of life. In a one-way sensi-
tivity analysis, the IADPSG criteria remained cost-effective
even if an additional 2.0% or more women were diagnosed
and treated for GDM [33].
In a large cohort of Spanish women, Duran et al. then
showed that, even though using the IADPSG criteria to diag-
nose GDM resulted in a higher frequency of detection of
this condition, this approach is still cost-effective. In fact,
treating these women was able to reduce the adverse mater-
nal and fetal outcomes, with a consequent saving of Euro
14,358.06 for every 100 women assessed with the IADPSG
instead of the Carpenter and Coustan criteria [22]. The cost
saving was mainly due to the reduction of the numbers of
Cesarean sections and of newborn admitted to a NICU. This
compensated for the increase in the costs due to more out-
patient visits and more diabetes test strips. Therefore, using
the IADPSG criteria could save money.
Wermer et al. used a decision analysis model to compare
different strategies for diagnosing GDM, showing that the
IADPSG recommendations are only cost-effective if the
diagnosis of GDM is accompanied by post-delivery care
capable of reducing the incidence of diabetes mellitus [34].
This study is in line with the findings of Marseille et al. [35],
who applied the Gestational Diabetes Formulas for Cost-
Effectiveness (GeDiForCE) model, and showed that inter-
vention for GDM is cost-effective when long-term effects
are taken into account.
The dark side
Frequency of GDM
When the frequency of GDM was assessed by the single
centers participating in the HAPO study, there were marked
differences from one center to another, ranging from 9.3 to
25.5%. This was due to differences concerning the women’s
race, BMI, age, and family history of diabetes [21]. In an
Australian study, Moses reported an increase in the preva-
lence of GDM from 9.6 to 13.0% after adopting the IADPSG
criteria [36]. More recently, Agarwal et al. [37] examined
the differences between eight sets of international expert
panel diagnostic criteria for GDM and the IADPSG criteria,
finding that its prevalence varied from 9.2 to 45.3%. Switch-
ing from the previous criteria to the IADPSG approach
increased the prevalence of GDM by 1.5–4.9 times. Several
studies consequently examined the feasibility of using dif-
ferent risk stratifications as a fetal macrosomia management
risk score based on BMI and fasting plasma glucose [38],
and a composite risk model, associating FPG with maternal
age and BMI [39].
Then a number of alternative measures have been pro-
posed for diagnosing GDM [40–43].
Acta Diabetologica
Among these, fasting plasma glucose was found to work
better than C-reactive protein concentrations, insulin lev-
els, or insulin sensitivity indices, [42], and better than lipid
profile [43]. However, bearing in mind that most studies are
performed on small numbers of patients, show a preselec-
tion bias, and analyze specific populations, it is difficult to
see FPG as a “gold standard” for diagnosing GDM. The
idea advanced by Agarwal et  al. [44] is intriguing, if it
proves useful in different populations: these authors sug-
gest using different FPG levels “to rule in and rule out”
the need for an OGTT to diagnose GDM. At 24–28 g.w., a
FPG ≥ 5.1 mmol/l indicates that no OGTT is required, while
a FPG of 4.5–5.0 mmol/l warrants an OGTT; and if the FPG
is ≤ 4.4 mmol/l, no OGTT is required because there is little
risk of the woman concerned developing GDM.
Early pregnancy testing
A crucial issue arising from the IADPSG recommendation
regards testing in early pregnancy to diagnose diabetes mel-
litus. The question is how to classify FPG values in the range
of 5.1–6.9 mmol/l, extrapolated from the cutoff values used
to diagnose GDM in later pregnancy in the HAPO study.
The issue arises because there is a physiological drop in
FPG early in normal pregnancy. In this context, while some
studies evidenced that fasting plasma glucose early in preg-
nancy is able to diagnose GDM [45, 46], others show that
this value can predict future development of GDM [47, 48],
and few others found that FPG was unable to diagnose GDM
at the first prenatal visit due to its limited specificity [49].
In short, robust evidence in favor of this approach is lacking
for the time being.
Barriers to diagnosing GDM with the IADPSG criteria
A survey administered to diabetologists, gynecologists and
other health care personnel working on GDM in 173 coun-
tries around the world to obtain data on the prevalence of
GDM and on GDM screening and management practices has
shown that the countries adopted different diagnostic crite-
ria, that the practices often diverged from the guidelines,
and the diversity of the strategies implemented to diagnose
GDM in the various countries makes it difficult to establish
the real frequency of this condition, and consequently the
real burden of the disease [50].
Considering Europe as a whole, the situation is even more
discouraging; as shown by a survey conducted in 2011 [51],
as part of the Vitamin D and Lifestyle Intervention for Ges-
tational Diabetes Mellitus (DALI) research program, the
reported prevalence of GDM was 2–4%, and it was lower in
Northern Europe and higher in the South and Mediterranean
area. There was no consensus regarding the test methods
to use or the glycemic thresholds to consider as diagnostic
of GDM. The lack of evidence of any real utility of diag-
nosing GDM was the main reason why clinicians showed
little interest in making an effort to improve the diagnosis
of GDM.
These results fit well with the wide variability in the
methods used to diagnose GDM in Europe. France, Ireland,
parts of Belgium, and Italy screen with the 75 g OGTT and
adopt IADPSG criteria [14, 52], but only in selected women
with GDM risk factors. Much the same applies in Germany,
but only for women with a positive GCT result. Other coun-
tries, such as the Netherlands, adopt the WHO diagnostic
criteria [53], a part of Belgium uses the ACOG criteria [54,
55], Spain uses the ADA criteria [56], and the UK uses the
NICE [57].
In this context, it is to underline that in a recent retrospec-
tive study conducted on 23,270 pregnant women in Tuscany
(Italy), which examined compliance with national guidelines
on GDM, it emerged that 80% of the women were screened,
including 40% who were at low risk, i.e., women who do not
need to be screened according to the Italian guidelines. But
the GDM rate was 7% among these women not normally eli-
gible for screening, suggesting the need for universal screen-
ing to capture all cases of GDM [58].
In a very important study, Nielsen et al. [59] used a mixed
method exploratory study (literature search, questionnaires,
interviews) to see whether GDM projects supported by the
World Diabetes Foundation (WDF) in developing countries
are used. A huge difference was found in the diagnostic
criteria used, in terms of the type of screening (selective
vs. universal), the types of test and the cutoff values used.
Numerous problems with the screening procedures were
identified, such as difficulties with screening the pregnant
women within the recommended time, problems with con-
ducting the test in fasting conditions, poor compliance with
repetitions of the test, poor tolerance of the sugar load due to
nausea, lack of equipment at the primary care level, limited
awareness of the importance of risk factors in determining
the occurrence of GDM (obesity, family history of diabe-
tes, and so on). The important take-home message emerging
from this study is that, given the very high rate of GDM in
developing countries, and their limited resources, simple,
clear, feasible, and universally applicable recommendations
on the diagnosis of GDM are urgently needed that can be
adopted in different point of care settings. These findings are
also confirmed by a recent report from Agarwal et al. [60].
Position of the international associations
Certainly, one of the problems with the implementation
of the IADPSG criteria concerns the fact that the different
international associations involved in the care of pregnancy,
and of pregnancy complicated by diabetes, have not taken an
unequivocal position as it is clearly shown in Table 1.
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 Acta Diabetologica

Table 1  International recommendations for the diagnosis of GDM

Recommendation Approach Timing Fasting PG mg/dl 1-h PG mg/dl 2-h PG mg/dl 3-h PG mg/dl
(mmol/l) (mmol/l) (mmol/l) (mmol/l)

ADA-1 [55] One step: OGTT 24–28 g.w ≥ 92 (5.1) ≥ 180 (10.0) ≥ 153 (8.5) n/a
75 g
ADA-2 [55] Two steps: GCT 24–28 g.w > 95 (5.3) or > 105 > 180 (10.0) or > 155 (8.6) or > 145 > 140 (7.8) or > 145
50 g + OGTT (5.8)a > 190 (10.6)a (8.1)a (8.1)a
100 g
NICE [57] One step: OGTT 24–28 g.wb ≥ 100 (5.6) n/a ≥ 140 (7.8) n/a
75 g
WHO [54] One step: OGTT 24–28 g.w ≥ 92 (5.1) ≥ 180 (10.0) ≥ 153 (8.5) n/a
75 g
ACOG [55] Two steps: GCT 24–28 g.w > 95 (5.3) > 180 (10.0) > 155 (8.6) > 140 (7.8)
50 g + OGTT
100 g

PG plasma glucose, OGTT​oral glucose tolerance test, GCT​glucose challenge test, GDM gestational diabetes
a
 OGTT 100 g interpreted according to Carpenter and Coustan criteria or by MDDG
b
 OGTT should be done as soon as possible if the pregnant woman has a history of GDM, and repeated at 24–28 g.w

In this “variegated world”, taking into consideration the
increasing frequency of diabetes and obesity worldwide,
and the close link between hyperglycemia and adverse
pregnancy outcomes, and the risk of metabolic and car-
diac disease later in life for women with GDM and their
offspring, the Federation of Gynecologists and Obstetrics
(FIGO) has prepared a document entitled: “Initiative on
Gestational Diabetes Mellitus (GDM): a pragmatic guide
for diagnosis, management and care” [61]. The importance
of this document stems from the fact that its pragmatic
approach is adaptable to different settings and levels of
resources, even in low-income countries. Figure 2 shows
how the various options for GDM diagnosis are simplified.

Fig. 2  The Federation of Gynecologists and Obstetrics (FIGO) proposal for the diagnosis of GDM. FPG fasting plasma glucose, RBG random
plasma glucose, Hba1c glycated hemoglobin, OGTT​oral glucose tolerance test

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Acta Diabetologica
Conclusions
The results of the HAPO study and two randomized clini-
cal trials on GDM treatment vs. usual obstetric care have
answered long-standing controversies regarding the value
of detecting and treating GDM. The strong independent
associations between maternal glucose levels identified on
OGTT at a mean 28 weeks of gestation and adverse preg-
nancy outcomes provided the bulk of the evidence used by
the IADPSG to recommend new criteria for the diagnosis
of GDM, which have been adopted by many organizations,
including the WHO, but have not been universally accepted.
The actual application of the approach recommended by the
IADPSG for detecting and diagnosing GDM varies, even at
centers that reportedly accept the new diagnostic criteria. So,
moving forward, the challenge lies in making every effort to
achieve a global standardization of the strategies for detect-
ing, diagnosing and treating GDM.
Compliance with ethical standards  17. Ryan EA (2011) Diagnosis of gestational diabetes. Diabetologia
Conflict of interest  The authors declare no conflict of interest.
Ethical approval  This article does not contain any studies with human
participants performed by any of the authors.
Informed consent  For this type of study formal consent is not required.
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