Evaluating the therapeutic approach in pregnancies complicated by borderline glucose intolerance: a randomized clinical trial.
ABSTRACT Most studies relating minor gestational metabolic alterations to macrosomia refer to glucose intolerance classified on the basis of the National Diabetes Data Group or previous World Health Organization diagnostic thresholds. Our aim was to evaluate the consequences of very mild forms of gestational glucose intolerance, defined by an elevated 50-g glucose challenge test followed by a normal oral glucose tolerance test, using the more restrictive Carpenter and Coustan's criteria (Borderline Gestational Glucose Intolerance, BGGI).
Three hundred BGGI women were randomly assigned to: Group A (standard management), Group B (dietary treatment and regular monitoring). A control group (C) was also considered. Newborns were classified as macrosomic, large (LGA), or small for gestational age (SGA).
The three groups were similar in age, body mass index and parity. Therapy in Group B significantly improved fasting (from 4.68 +/- 0.45 to 4.28 +/- 0.45 mmol/l) and 2-h postprandial glycaemia (from 6.01 +/- 0.57 to 5.13 +/- 0.68 mmol/l). Fasting glycaemia at delivery was significantly lower in B (4.20 +/- 0.38 mmol/l) than in A (4.84 +/- 0.45 mmol/l), and was also lower than in C (4.31 +/- 0.39 mmol/l). Significantly fewer LGA babies were born to Group B (6.0%) than Group A (14.0%) and Group C (9.1%). No difference was found in the SGA rate. The neonatal Ponderal Index was higher (P = 0.030) in group A (2.73 +/- 0.35) than in C (2.64 +/- 0.30) and B (2.64 +/- 0.24).
Even very mild alterations in glucose tolerance can result in excessive or disharmonious fetal growth, which may be prevented by simple, non-invasive therapeutic measures.
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ABSTRACT: Nutrition plays a fundamental role in fetal growth and birth outcomes.American Journal of Clinical Nutrition 11/2014; 100(5):1298-321. · 6.50 Impact Factor
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ABSTRACT: The definition of optimal glycemic control in pregnancies affected by diabetes remains enigmatic. Diabetes phenotypes are heterogeneous. Moreover, fetal macrosomia insidiously occurs even with excellent glycemic control. Current blood glucose (BG) targets (FBG ≤95, 1-h post-prandial <140, 2 h <120 mg/dL) have improved perinatal outcomes, but arguably they have not normalized. The conventional management approach has been to replicate a pattern of glycemia in normal pregnancy. Although these patterns are lower than previously appreciated, a randomized controlled trial (RCT) has never compared current vs. lower glucose targets powered on maternal/fetal outcomes. This paper provides historical context to the current targets by reviewing evidence supporting their evolution. Using lower targets (FBG <90, 1 h <122, 2 h <110, mean BG ≤95 mg/dL) may help normalize outcomes, but phenotypic differences (type 1 vs. type 2 vs. gestational diabetes) might require different glycemic goals. There remains a critical need for well-designed RCTs to confirm optimal glycemic control that minimizes both small for and large for gestational age across pregnancies affected by diabetes.Current Diabetes Reports 01/2015; 15(1):565. · 3.38 Impact Factor
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ABSTRACT: Gestational diabetes (GD), which has a prevalence of 9%, is associated with high maternal and perinatal morbidity. Early diagnosis and treatment of maternal hyperglycemia reduce the risk of macrosomia and the associated intrapartum complications. Risk factors for GD can be identified in the first trimester from maternal history (age, obesity, previous macrosomia or GD, family history of diabetes), biochemical markers (adiponectin, sex hormone-binding globuline and others), and biophysical markers (arteriography, visceral adiposity). Risk factors for macrosomia include obesity and diabetes in the maternal history, pregnancy associated plasma protein-A and free β subunit of human chorionic gonadotropin as biochemical markers, and nuchal translucency and uterine artery Doppler as biophysical markers. Prediction models combining maternal history, biochemical and biophysical markers can achieve a detection rate of 65% and 35% for GD and macrosomia, respectively, with a false positive rate of 10%.Progresos de Obstetricia y Ginecología 09/2014;
© 2005 Diabetes UK.
The usefulness of an active therapeutic approach to overt
gestational diabetes mellitus (GDM) has recently found wide-
spread and authoritative approval [1–4], in an attempt to limit
Metaboliche, Ospedale Niguarda Ca’Granda, Piazza Ospedale Maggiore 3,
20162 Milano, Italy. E-mail: email@example.com
: Dr Matteo Bonomo, Centro di Diabetologia e Malattie
somia refer to glucose intolerance classified on the basis of the National Diabetes
Data Group or previous World Health Organization diagnostic thresholds. Our
aim was to evaluate the consequences of very mild forms of gestational glucose
intolerance, defined by an elevated 50-g glucose challenge test followed by a
normal oral glucose tolerance test, using the more restrictive Carpenter and
Coustan’s criteria (Borderline Gestational Glucose Intolerance, BGGI).
Most studies relating minor gestational metabolic alterations to macro-
(standard management), Group B (dietary treatment and regular monitoring).
A control group (C) was also considered. Newborns were classified as macro-
somic, large (LGA), or small for gestational age (SGA).
Three hundred BGGI women were randomly assigned to: Group A
Therapy in Group B significantly improved fasting (from 4.68
0.45 mmol/l) and 2-h postprandial glycaemia (from 6.01
mmol/l). Fasting glycaemia at delivery was significantly lower in B (4.20
mmol/l) than in A (4.84
0.45 mmol/l), and was also lower than in C (4.31
0.39 mmol/l). Significantly fewer LGA babies were born to Group B (6.0%)
than Group A (14.0%) and Group C (9.1%). No difference was found in the
SGA rate. The neonatal Ponderal Index was higher (
0.35) than in C (2.64
0.30) and B (2.64
The three groups were similar in age, body mass index and parity.
0.45 to 4.28
0.57 to 5.13
0.030) in group A
sive or disharmonious fetal growth, which may be prevented by simple, non-
invasive therapeutic measures.
Even very mild alterations in glucose tolerance can result in exces-
Diabet. Med. 22, 1536–1541 (2005)
Ponderal Index, macrosomia, pregnancy outcome
gestational glucose intolerance, gestational diabetes, neonatal
mass index; GCT, glucose challenge test; GDM, gestational diabetes mellitus;
LGA, large for gestational age; NDDG, National Diabetes Data Group; OGTT,
oral glucose tolerance test; SGA, small for gestational age
BGGI, borderline gestational glucose intolerance; BMI, body
Blackwell Publishing, Ltd. Oxford, UKDMEDiabetic Medicine 0742-3071 Blackwell Publishing, 200522Original Article Original article
Therapeutic approach in borderline gestational glucose intolerance M. Bonomo et al.
Evaluating the therapeutic approach in pregnancies
complicated by borderline glucose intolerance: a
randomized clinical trial
M. Bonomo, D. Corica*, E. Mion, D. Gonçalves, G. Motta†, R. Merati*, A. Ragusa*
and A. Morabito‡
Diabetes Unit, *Department of Obstetrics and
Gynaecology and †Department of Neonatology,
Interdisciplinary Diabetes and Pregnancy Centre,
Niguarda Ca'Granda Hospital, and ‡Department of
Statistics, S. Paolo Hospital, University of Milano,
Accepted 14 December 2004
© 2005 Diabetes UK.
obstetric and perinatal complications [5,6]. The same is not
true, however, for minor degrees of glucose intolerance in
pregnancy, characterized by a borderline glucose-intolerant
state, intermediate between normal and GDM.
The definition of this nosological category continues to be
hindered by the persistent lack of uniformity in the criteria
used to classify glucose tolerance in pregnancy. Many data [7–
13] refer to diagnostic procedures based on National Diabetes
Data Group (NDDG) criteria for a 100-g oral glucose toler-
ance test (OGTT) . Others, however, using a 75-g OGTT,
in line with previous  and current World Health Organiza-
tion (WHO) criteria , or a 100-g OGTT according to the
Amankwah criteria , also focused on women with blood
glucose values exceeding normal limits, but without reaching
the diagnostic threshold for GDM [18–20 ]. In spite of this
diagnostic heterogeneity, in many reports these clinical situa-
tions have a higher rate of adverse obstetric and perinatal
Only a few reports [13,22–27] deal with minor degrees of
glucose intolerance classified according to the more selective
Carpenter and Coustan’s criteria , where the metabolic
abnormalities are even milder. Little is known about the effect
of therapeutic interventions on the perinatal outcome of
pregnancies in women with minor alterations in blood glucose
levels. At the moment, most are left untreated and are reas-
sured after a test which does not reach diagnostic cut-offs. This
approach would need to be re-assessed if a more active approach
to treatment proves useful in reducing perinatal morbidity.
Langer  and Berkus  reported positive results with diet
and insulin treatment in women with one abnormal OGTT
value, but they only considered the NDDG, not the Carpenter
and Coustan’s criteria, for diagnostic classification.
In a previous study we found that the high prevalence of
macrosomia in untreated pregnancies with minor degrees of
glucose intolerance could be reduced by an appropriate diet,
with regular metabolic monitoring throughout pregnancy
. The aim of the present randomized trial was to confirm
such a positive effect on pregnancy outcome when an active
therapeutic approach was adopted in a larger group of women
with the mildest level of gestational glycometabolic alteration
[borderline gestational glucose intolerance (BGGI) consisting
of an altered glucose challenge test (GCT) followed by a normal
100-g OGTT, according to Carpenter and Coustan], followed
prospectively during pregnancy.
Patients and methods
Study subjects were recruited through a screening procedure at
the Diabetic and Pregnancy Centre of Niguarda Ca’Granda
Hospital in Milan, Italy, from 1997 to 2002. The rate of deliveries
at our hospital at that time was approximately 1800/year. In the
study period 4117 pregnant women were screened for carbohydrate
intolerance. Only women of caucasian origin were considered.
For those with standard risk factors for the disorder (listed in
Table 1), as defined in 1996 by the Italian Society of Diabetology
, the screening was done at booking. Women with a normal
screening test were re-tested from weeks 24–28, at which time
all those without risk factors were also tested.
The screening procedure consisted of a 50-g GCT, with a 1-h
blood glucose cut-off set at 7.8 mmol/l. Women with a positive
screening test underwent a confirmatory 100-g OGTT within
7 days, evaluated using Carpenter and Coustan’s criteria. The
complete diagnostic path was repeated at week 30–34 in women
with a positive GCT but without a diagnostic OGTT.
Classification and subjects
We considered all women with an elevated GCT (plasma glucose
60 min after challenge
7.8 mmol/l), followed by a normal
OGTT, as having BGGI. Women with a normal GCT were clas-
sified as having normal glucose tolerance and excluded from
the study, apart from those enrolled as control subjects (Group
C). Women with only one abnormal value at the OGTT, and
women fulfilling Carpenter and Coustan’s diagnostic criteria for
GDM were also excluded. The control group comprised body
mass index (BMI)- and age-matched, randomly selected pregnant
women, with normal screening test results.
After diagnosis, women with BGGI were stratified according
to age (< 25, 25–35, 35 years) and BMI (< 19.8, 19.8–26, 26
), then randomly assigned to one of two study groups:
(no treatment): women were reassured after testing,
and were given no special care, diet, or pharmacological treatment.
(treatment): women were immediately given dietary
advice providing 24–30 kcal/kg per day, based on prepregnancy
body weight; caloric intake was divided into three meals and
two or three snacks, and distributed as 50–55% carbohydrate,
25–30% protein, 20–25% fat. They then entered an out-patient
management protocol, which involved visits every 2 weeks, when
the main clinical parameters (weight, blood pressure) were
recorded, discussion of dietary habits with evaluation of
therapeutic compliance, and measurement of fasting and 2-h
postprandial blood glucose, of HbA
and fructosamine. Blood
Table 1 Major risk factors for gestational diabetes mellitus
• Previous gestational diabetes
• Diabetes in first-degree relatives
• Obesity (BMI ≥ 28 kg/m2 before pregnancy)
• Age > 35 years
• Previous large infant (≥ 4000 g or ≥ 90th weight centile)
• Previous stillbirth
Related to the current pregnancy
• Maternal weight gain > 1200 g in the 1st trimester,
or > 400 g/week in the 2nd and 3rd trimesters
• Recurrent glycosuria
• Excessive and/or disharmonious fetal growth
BMI, body mass index. The risk factors were defined according to the
scoring system suggested by the Italian Society of Diabetology at the
time of the beginning of the study .
Women were defined ‘at risk’ in presence of at least one major risk factor.
© 2005 Diabetes UK.
Therapeutic approach in borderline gestational glucose intolerance •
M. Bonomo et al.
glucose targets were < 5 mmol/l fasting, and < 6.7 mmol/l 2-h
postprandial. Urine was tested every morning at home for
Stratification by age and BMI was used to avoid imbalances
in randomization, which was done using tables of random
A total of 25 BGGI women refused to participate in the
study, before randomization. Baseline characteristics of these
women were similar to those of the recruited subjects. Recruit-
ment was continued until the required number of women was
reached. After randomization, 21 women had to be replaced
either because they had left care (six women, all in Group B) or
GDM had been diagnosed at the week 30–34 re-evaluation
(nine in Group B, six in Group A).
The study population finally included 300 subjects (150 Group
A, 150 Group B): only singleton pregnancies were considered.
Group C (control,
= 150) was established by selecting for
every pair of women enrolled in Groups A and B the first
screened woman with normal GCT at screening, falling into the
same stratification category for age and BMI.
The study was not blinded: all women, and the attending
physicians, were informed of the results of the GCT and OGTT.
All subjects gave written, informed consent to participation
in the study. The study protocol was approved by the Ethical
Committee of the ‘Niguarda Ca’Granda’ Hospital.
Obstetric, fetal and neonatal assessment
Gestational age was assigned on the basis of menstrual history,
corrected, if necessary, by pregnancy ultrasound scan before
20 weeks of gestation.
The following data were recorded for all newborn infants:
gestational week at delivery, sex, birth weight, birth length,
5-min Apgar score.
The following parameters were considered as adverse out-
comes of pregnancy:
• For the mother: rate of Caesarean sections.
• For the newborn: rates of macrosomia, large (LGA) and small
for gestational age (SGA), hypoglycaemia, hyperbilirubinaemia,
polycythaemia, 5-min Apgar score < 7, admission to neonatal
intensive cure unit (NICU).
Infants were considered macrosomic when their birth weight
4000 g, and LGA or SGA when it was
centile, respectively, on the basis of sex-specific growth standards
developed for the Northern Italian population .
All neonates were monitored for hypoglycaemia: the first
measurement was taken immediately at birth, then hourly for
the next 3 h. Hypoglycaemia was diagnosed if any of two
consecutive blood glucose values was < 1.7 mmol/l. Neonatal
hyperbilirubinaemia was diagnosed as plasma values
mol/l. Polycythaemia was defined as haematocrit > 60%. The
neonatal ponderal index was also calculated (g
Venous plasma glucose was measured by the glucose oxidase
method (Modular instrument; Roche-Hitachi, Roche Laboratory
Systems, Mannheim, Germany): CV 0.9% within-run, 1.8%
Glycated haemoglobin HbA
high-performance liquid chromatography with a VARIANT II
instrument (Bio-Rad Laboratories GmbH, München, Germany),
expressed as a percentage of the total Hb (normal range
4.1–6.1% outside pregnancy; CV 0.89% within-run, 1.66%
Serum fructosamine was assayed by a colorimetric method with
nitroblue tetrazolium (Modular instrument; Roche-Hitachi, Roche
Laboratory Systems): normal range 170–285
within-run, 2.9% between-run.
was measured by automated
mol/l; CV 0.9%
Data are expressed as means
checked for normality of distribution of all variables and if
necessary a suitable transformation was adopted.
The sample size was calculated to provide 0.8 power (
= 0.05 significance level to detect a 11% difference in LGA
newborn infants between the treated and non-treated groups, on
the basis of an earlier study at our Centre, where, in the subgroup
presenting a degree of glucose intolerance comparable to that
considered in the present study, we recorded 8.3% and 19.4%
LGA babies, respectively, in treated and non-treated women .
Paired and unpaired Student’s
and Scheffe’s test were used to assess differences in means
between groups. Categorical data were evaluated by the
with Yates correction. The Kruskal–Wallis test was used for
comparison of medians. The SAS (SAS Institute, Cary, NC,
USA) statistical package was used for all analyses. Statistical
significance was set at
, medians, or percentages. We
-test, or analysis of variance
Clinical characteristics and baseline levels
Table 2 summarizes baseline maternal characteristics and the
main metabolic parameters at diagnosis for the 300 BGGI
women in the study, and the 150 control subjects (Group C).
BMI and age were almost identical in all three groups. There
were no significant differences in parity, and fasting plasma
glucose was similar in Groups A and B.
The post-challenge blood glucose in all women with BGGI
0.89 mmol/l, significantly higher (
in control subjects (Group C) (6.44
result was no different in Groups A (8.41
0.91 mmol/l). The GCT
0.94 mmol/l) and
Metabolic control after diagnosis
The effect on metabolic control of the therapeutic intervention
in Group B, evaluated by comparison of the values at diagnosis
and mean values calculated from diagnosis to delivery, is
reported in Table 3. There was a highly significant improve-
ment in both fasting and 2-h postprandial plasma glucose, while
and fructosamine remained unchanged.
The comparison with non-treated Group A BGGI patients
and with normal Group C women had to be limited to fasting
© 2005 Diabetes UK.
plasma glucose, the only glycometabolic index available for
both groups. Therapeutic intervention resulted in a decrease of
fasting blood glucose in Group B (from 4.68
diagnosis to 4.18
0.38 mmol/l at term,
values at delivery were significantly lower than in Group A
0.45 mmol/l), and also lower than in control subjects
(Group C) (4.31
< 0.01), so that
0.45 mmol/l at
Maternal weight gain
Maternal weight gain was similar in all three groups, with
no difference between Group A (12.6
4.3 kg), and between the two BGGI group and control
subjects (Group C) (13.6
3.9 kg) and Group B
The frequency of Caesarean sections was similar in the two
BGGI groups (28.0% in Group A, 29.0% in Group B), and
slightly lower (24.0%) in the control group. As shown in Table 4,
the rate of macrosomia was lower in Group B than in A, but the
difference did not reach statistical significance. The percentage
of LGA neonates was significantly lower in Group B than A, and
also lower than in Group C (though not significantly). No dif-
ferences were found for SGA neonates, with only a slightly higher
frequency in Group B than A and C. In the untreated Group A the
mean neonatal ponderal index was higher than in Groups B and
0.05). The frequency of other neonatal morbidities and of
admission to the NICU was very low, similar in all three groups.
BGGI ABGGI BControl C
Fasting plasma glucose (mmol/l)
30.7 ± 5.1
23.0 ± 4.5
4.77 ± 0.52
31.1 ± 4.7
23.1 ± 4.4
4.68 ± 0.45
31.1 ± 4.4
23.0 ± 4.1
4.56 ± 0.40
BGGI, borderline gestational glucose intolerance (A = untreated; B = treated); BMI, body mass index.
A suitable transformation (reciprocal square) was adopted to obtain a Gaussian distribution of BMI.
*Comparing only the two BGGI groups.
Table 2 Clinical characteristics and baseline
glycaemic parameters at diagnosis in the two
study groups and controls (Group C)
Fasting plasma glucose (mmol/l)
2-h postprandial plasma glucose (mmol/l)
4.68 ± 0.45
6.00 ± 0.57
4.9 ± 0.5
209 ± 29
4.28 ± 0.45
5.13 ± 0.68
5.0 ± 0.4
212 ± 31
The ‘during treatment’ value is the mean of results recorded every 2 weeks from diagnosis to delivery.
Table 3 Metabolic control at diagnosis and
during treatment in Group B borderline
gestational glucose intolerance women
Table 4 Neonatal outcome in the two study groups and control subjects (Group C)
BGGI A BGGI BControl C
Gestational week (n)
Ponderal index (g × 100/cm3)
Admission to NICU (%)
39.6 ± 1.7
3436.6 ± 462
50.1 ± 2.0
9.5 ± 0.5
2.73 ± 0.35
39.4 ± 1.2
3365.0 ± 436
50.2 ± 1.7
9.7 ± 0.5
2.64 ± 0.24
39.5 ± 1.4
3342.7 ± 483
50.2 ± 2.2
9.7 ± 0.5
2.64 ± 0.30
BGGI, borderline gestational glucose intolerance (A = untreated; B = treated); LGA, large for gestational age; SGA, small for gestational age;
NICU, Neonatal Intensive Care Unit.
*BGGI A vs. B.
**BGGI A vs. B and controls (Group C).
© 2005 Diabetes UK.
Therapeutic approach in borderline gestational glucose intolerance •
M. Bonomo et al.
In the last decade, increasing attention has been given to altera-
tions of glucose metabolism in pregnancy, which do not fulfil
the diagnostic criteria for GDM. These ‘borderline’ situations
can alter with pregnancy outcome, with a range of possible
effects, mainly on fetal growth, not dissimilar from those in
overt GDM. Most studies, however, refer to nosographic
entities classified on the basis of the old NDDG [7–11] or
WHO  criteria, which are less restrictive than those ori-
ginally proposed by Carpenter and Coustan and now interna-
tionally adopted, according to the conclusions of the 4th
Chicago Workshop-Conference . Many situations formerly
defined as ‘minor alterations’ could now be re-classified as very
mild forms of GDM, applying the newer diagnostic criteria.
The few studies on pregnant women with only an abnormal
50-g GCT followed by a normal confirmatory OGTT have
given contrasting results [22–27]. Little is known, therefore,
about the utility of therapeutic intervention in BGGI, which
can be considered the mildest carbohydrate disturbance in
Our results suggest that even this bland metabolic disorder
may result in altered fetal growth. Although the percentage of
macrosomic and LGA newborn infants in the untreated BGGI
group was only slightly higher than in the control subjects with
completely normal glucose tolerance (Group C), the neonatal
ponderal index was significantly different, reflecting typical
asymmetric growth consequent to fetal hyperinsulinization in
diabetic pregnancies. This index was significantly higher in the
non-treated BGGI group than in the control group (Group C),
but almost normal in the treated BGGI group. The difference
is probably a consequence of a more physiological pattern of
fetal growth, resulting in near-normal anthropometric para-
meters at birth.
The prevalence of LGA newborn infants was also lower in
Group B than in A. This encouraging result was obtained by
means of a simple, non-invasive dietary recommendation,
leading to substantial improvement in maternal blood glucose
values. It is quite possible that the real effect of this interven-
tion was underestimated, as the women in Group A were aware
of being part of a study (not blinded). However, they were
never re-examined by the diabetes team after the initial dia-
gnostic procedure, receiving only standard obstetric care. They
are therefore unlikely to have made significant changes to their
A major role of other maternal risk factors in growth
alterations, as suggested by other authors , seems unlikely
in our study population, as the initial stratification meant that
the two BGGI groups and the control subjects (Group C) were
almost identical for maternal age, parity and prepregnancy
In conclusion, our findings support the theory that for car-
bohydrate homeostasis in pregnancy a dichotomous separation
between normality and GDM is no longer sustainable. Even very
slight alterations in glucose tolerance can result in excessive or
disharmonious fetal growth, similar to that observed in
women with frankly pathological metabolic disturbances.
These growth abnormalities have been shown to influence
negatively the offspring’s metabolic future ; our study sug-
gests the possibility of preventing or minimizing these conse-
quences by using simple therapeutic measures, without the risk
of excessive fetal growth restriction.
Our data are probably insufficient to justify a generalized
interventionist attitude towards the minimal degree of glucose
intolerance represented only by an altered GCT. If these find-
ing are confirmed, however, we feel that the non-interventionist
attitude usually adopted towards borderline carbohydrate
alterations in pregnancy might be worth reconsidering. This
would obviously call for much larger studies in several ethnic
As regards the mother’s outlook, we still do not have enough
evidence to label BGGI as a ‘prediabetic situation’. Further
investigations are needed to quantify the risk of developing
diabetes or other forms of carbohydrate intolerance in these
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