International Journal of Gynecology and Obstetrics 78 (2002) 69–77

Special communication
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO)
Study
HAPO Study Cooperative Research Group*
Northwestern University Feinberg School of Medicine, Chicago, IL, USA

Received 22 February 2002; received in revised form 9 April 2002; accepted 12 April 2002

Abstract

Objective: The objective of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study is to clarify
unanswered questions on associations of maternal glycemia, less severe than overt diabetes mellitus, with risks of
adverse pregnancy outcome. This report describes the background and design of the HAPO Study. Methods: HAPO
is a 5-year investigator-initiated prospective observational study that will recruit approximately 25 000 pregnant
women in 10 countries. HAPO utilizes a Central Laboratory for measurement of key metabolic variables, a Clinical
Coordinating Center, a Data Coordinating Center, and an independent Data Monitoring Committee. Glucose tolerance
is assessed by a 75 g 2-h OGTT at 24–32 weeks’ gestation. Results are unblinded to the woman and her caregivers
if: fasting plasma glucose )5.8 mmolyl, 2-h plasma glucose )11.1 mmolyl or any plasma glucose -2.5 mmolyl.
Random plasma glucose measurement is performed at 34–37 weeks or if symptoms suggest hyperglycemia; results
are unblinded for values G8.9 mmolyl. Sociodemographic and health history data are collected via questionnaire and
medical record abstraction. Maternal blood is obtained for measurement of serum C-peptide and hemoglobin A1c
(HbA1C), cord blood for serum C-peptide and plasma glucose, and a capillary specimen is taken between 1 and 2 h
following delivery for neonatal plasma glucose. Neonatal anthropometrics are obtained, and follow-up data are
collected at 4–6 weeks post-delivery. The primary outcomes to be assessed in relation to maternal glycemia are
cesarean delivery, increased fetal size (macrosomiayLGAyobesity), neonatal morbidity (hypoglycemia), and fetal
hyperinsulinism. 䊚 2002 International Federation of Gynecology and Obstetrics. Published by Elsevier Science
Ireland Ltd. All rights reserved.

Keywords: Gestational diabetes; Perinatal outcome; Hyperglycemia; Neonatal morbidities; Cesarean delivery

1. Introduction risk of adverse perinatal outcome. However, the

There is a consensus that during pregnancy overt
diabetes mellitus is associated with a significant
*Corresponding author: B.E. Metzger. Tel.: q1-312-503-
7979; fax: q1-312-503-1205.
E-mail address: bom@northwestern.edu (B.E. Metzger).
risk of adverse outcome associated with degrees
of maternal glucose intolerance less severe than
overt diabetes mellitus is controversial. The objec-
tive of the Hyperglycemia and Adverse Pregnancy
Outcome (HAPO) Study is to clarify this question
by studying a heterogeneous, multinational, mul-
ticultural, ethnically diverse cohort of 25 000

0020-7292/02/$ - see front matter 䊚 2002 International Federation of Gynecology and Obstetrics. Published by Elsevier Science
Ireland Ltd. All rights reserved.
PII: S 0 0 2 0 - 7 2 9 2 Ž 0 2 . 0 0 0 9 2 - 9
70 B.E. Metzger / International Journal of Gynecology and Obstetrics 78 (2002) 69–77
women in the third trimester of gestation with
medical caregivers ‘blinded’ to the status of glu-
cose tolerance (except when pre-defined criteria
are met). This will provide data on associations
between maternal glycemia and risk of specific
adverse outcomes that can be used to derive
internationally acceptable criteria for diagnosis and
classification of gestational diabetes mellitus.
This report describes the background and design
of the HAPO Study.
2. Background
Gestational diabetes mellitus (GDM), defined
as ‘glucose intolerance with onset or first recog-
nition during pregnancy’ w1,2x, is a common med-
ical diagnosis complicating gestation.
The criteria established by O’Sullivan and
Mahan w3x to define an abnormal 100 g oral
glucose tolerance test (OGTT) during pregnancy
were selected to identify women at risk for sub-
sequent diabetes mellitus. It has been observed
that, within a population, the prevalence of GDM
roughly parallels the overall prevalence of type 2
diabetes andyor impaired glucose tolerance in
women in the reproductive age range w4,5x. O’Sul-
livan w4,6x and others w7–12x have confirmed that
the diagnosis of GDM does indeed identify women
at high risk for diabetes outside of pregnancy. In
some women identified with GDM, glucose intol-
erance undoubtedly antedates pregnancy w13x; how
often this occurs is debatable. Thus, it is well
established that GDM, as presently defined and
diagnosed, identifies a condition related to diabetes
mellitus outside of pregnancy.
From an obstetrical perspective, the significance
of GDM is related to the frequency and severity
of risk for adverse pregnancy outcome, rather than
the risk for future diabetes mellitus in the mother.
In the past, undiagnosed GDM was associated with
an increased risk of perinatal mortality w3,6,14–
16x. However, many recent reports fail to demon-
strate an increase in perinatal mortality in GDM
w17x. This could reflect effective therapeutic inter-
vention. However, the background perinatal mor-
tality rate in contemporary obstetrical practice is
very low, making it extremely difficult to use as
an endpoint for outcome in pregnancy complicated
by glucose intolerance.
Excessive fetal growth is the most commonly
reported potentially adverse outcome of gestational
diabetic pregnancy and there have been numerous
attempts to relate its prevalence to level of mater-
nal glycemia. Pettitt et al. w15x reported a direct
association between glucose levels and macrosom-
ia (birthweight above the 90th percentile) in their
study of Pima Indian women. Others w18,19x have
reported a continuous relationship between increas-
ing maternal glycemia below levels diagnostic of
GDM and prevalence of macrosomia. This has led
to the suggestion that modified criteria for the
diagnosis of GDM may have to be developed by
consensus w18x. Other studies in populations out-
side of North America and Europe report evidence
for perinatal morbidity in cases with mild hyper-
glycemia below the usual criteria for GDM
w17,20–22x.
As expected, macrosomia has been associated
with increases in other adverse outcomes such as
cesarean delivery. However, many perinatal out-
comes are also influenced by the judgment and
expectations of the obstetrician. In a recent study
w23x, obstetricians with knowledge of the presence
of GDM in their patients were over 50% more
likely to perform cesarean delivery regardless of
birthweight, while obstetricians blinded to the
presence of mild GDM were more selective, with
increased cesarean delivery rates being related
primarily to macrosomia. This finding underscores
the critical importance of blinding in studies such
as HAPO.
The excessive fetal growth seen in GDM is
mediated by fetal hyperinsulinemia, brought about
by an excess of glucose or nutrients traversing or
secreted by the placenta w24,25x, and potentially
modified by genetic factors. In addition, fetal
hyperinsulinism in infants of diabetic and GDM
mothers may influence, or predict the development
of childhood obesity by the age of 7–8 years w26x
and adult obesity as well w27x. Finally, it could be
predicted from animal studies that exposure to
hyperglycemia in utero might lead to diabetes in
the offspring when they mature. Pettitt’s studies
on the offspring of Pima women with even mild
impairment of glucose tolerance during pregnancy
 B.E. Metzger / International Journal of Gynecology and Obstetrics 78 (2002) 69–77
show a direct relationship with subsequent devel-
opment of hyperglycemia and GDM when the
females grow up w28x, and Silverman et al. w29x
have recently reported a high prevalence of
impaired glucose tolerance in adolescent offspring
of diabetic mothers (including GDM) that is
strongly correlated with the presence of fetal
hyperinsulinism.
The evidence cited above suggests a continuum
of effects of maternal hyperglycemia on the off-
spring. However, in the past decade, there has
been more controversy than consensus regarding
risks of adverse pregnancy outcome associated
with GDM. The lack of uniformity in the approach
to ascertainment and diagnosis internationally has
been a major barrier w2,30x. Some have attributed
the observed risks cited above to confounding
characteristics such as obesity, advanced maternal
age of subjects with GDM or other medical com-
plications, rather than the glucose intolerance that
is present w31x. Bias of the caregiver toward the
expectation of adverse outcomes may actually
increase the likelihood of morbidity w32x. Balanced
against this skeptical view, others believe that the
criteria currently used are too restrained and that
even lesser degrees of hyperglycemia increase the
risk of an adverse perinatal outcome w33–35x. A
major confounder is the fact that studies that
incorporate any type of intervention are of limited,
if any, value as indicators of an association
between outcome and the severity of hyperglyce-
mia that was present at the time of diagnosis of
GDM. This emphasizes that caregivers must
remain blinded to level of glycemia in any study
designed to provide data that can be used to modify
existing diagnostic criteria. As a result of the
controversy, conflicting advice is being given, on
the one hand, to adopt approaches for screening
and diagnosis that substantially increase the num-
ber of women who are identified as having the
condition w33–35x and, on the other hand, to stop
all systematic efforts to identify the condition
unless more data become available to link signifi-
cant morbidities to specific degrees of glucose
intolerance w31,36x.
In pregnancies complicated by overt diabetes
mellitus, maternal hyperglycemia is accompanied
by a constellation of morbidities designated ‘dia-
71
betic fetopathy’ w37x and is associated with an
increased risk of perinatal loss. HAPO will test for
a specific association between less severe hyper-
glycemia and some adverse pregnancy outcomes
that are associated with diabetic fetopathy. Because
the background perinatal mortality rates in the
large majority of study sites are very low, HAPO
will focus on the morbidities that are most strongly
associated with maternal metabolic disturbances of
diabetes mellitus.
Primary outcomes therefore are: cesarean deliv-
ery; increased fetal size (macrosomiayLGAyobe-
sity); neonatal morbidity (hypoglycemia); and
fetal hyperinsulinism. Secondary outcomes are:
polycythemia; hyperbilirubinemia; respiratory dis-
tress; and birth injury (shoulder dystocia).
3. Study organization
The project as a whole is organized into four
tightly linked component parts: clinical study sites
(field centers) in 10 countries; a Central Labora-
tory; a Clinical Coordinating Center; and a Data
Coordinating Center. HAPO also includes an inde-
pendent Data Monitoring Committee. The conduct
of the study as a whole is overseen by a Steering
Committee.
Fasting and 2-h OGTT samples and random
plasma glucose samples are analyzed in ‘HAPO’
certified local field center laboratories so that when
the results indicate the need for unblinding, the
information is available on a timely basis. To
assure minimal analytical variability in the analysis
of study outcomes, aliquots of the fasting and 2-h
OGTT samples are also analyzed in the Central
Laboratory, and these values will be used in the
final analyses.
The Central Laboratory is responsible for rean-
alysis of the fasting and 2-h OGTT specimens for
plasma glucose (see above) and for assaying all
laboratory specimens not analyzed locally at the
field center. The Central Laboratory also shares
responsibility for monitoring quality control of
field center glucose analyses both prior to and
during field work (fasting and 2-h OGTT).
4. Study design
HAPO is a basic epidemiologic investigation to
clarify unanswered questions on relations of vari-
72 B.E. Metzger / International Journal of Gynecology and Obstetrics 78 (2002) 69–77
ous levels of glucose intolerance during pregnancy
to risk of adverse outcomes. Glucose tolerance is
being tested in a cohort of approximately 25 000
women in the late second and early third trimester
of gestation with medical caregivers ‘blinded’ to
the status of glucose tolerance (except when
exceeding pre-defined thresholds). This is being
accomplished by the use of a rigidly defined,
common protocol in all field centers. Each field
center is to enroll 1500 or, in the four US centers,
1750 participants.
Pregnant women are recruited early in gestation.
Those who give their informed consent to partici-
pate provide historical and antenatal data and
undergo metabolic evaluation (75 g OGTT and
measurement of HbA1C and serum C-peptide) as
close to 28 weeks’ gestation as feasible (maximal
range 24–32 weeks’ gestation). Women who
would ordinarily undergo early glucose testing in
field centers that perform a risk assessment for
GDM in early pregnancy and do early blood
glucose testing on those considered to be at high
risk are also being recruited for early testing
according to HAPO protocol and procedures.
Participants not identified as having hypergly-
cemia in excess of the pre-defined limits have the
standard obstetrical and neonatal care that is rou-
tinely provided in their community. None of the
participating field centers routinely delivers wom-
en at a fixed gestational age earlier than 41 weeks
or uses arbitrary maternal age criteria for cesarean
delivery. Cord blood is collected at delivery for
assessment of fetal b-cell function; neonatal gly-
cemia is determined between 1 and 2 h of life;
neonatal anthropometrics, including weight, length,
head circumference, and flank, triceps, and sub-
scapular skinfolds, are obtained within 72 h; and
data on delivery and neonatal outcomes are
recorded.
4.1. Standardization of methods and quality control
procedures
Uniformity of study methods and clinical and
laboratory procedures are essential to the success
of the HAPO Study. The geographic distribution
of the participating field centers assures ethnicy
racial and socioeconomic diversity of the study
population and worldwide applicability of the find-
ings; however, it introduces a number of challenges
to obtaining the maximal possible uniformity of
methods and procedures. These include language
barriers, cultural differences and variability of
clinical conditions and analytical methods.
Steps taken in HAPO to assure standardized
procedures include: a common Protocol and Man-
ual of Operations; regional training of field center
personnel; measurement of key metabolic variables
(plasma glucose, serum C-peptide, HbA1C) in a
Central Laboratory; shipment of blood specimens
to the Central Laboratory under specified condi-
tions for preservation; use of glucose test samples
from the Wales External Quality Assessment
Scheme (WEQAS) to assure standardization of
glucose measurements among field centers and
between the Central Laboratory and field centers;
use of standard equipment and supplies; and com-
mon centrally prepared data collection forms, with
translation and back-translation of questionnaires
administered to participants, where English is not
the primary language.
Additional quality control procedures include: a
‘dry run’ of all procedures before the start of actual
data collection, with sufficient time for central
review and any needed correction prior to start of
field work; use of blind duplicate samples from a
random 5% of participants to assess technical error
of both the Central Laboratory and local field
center laboratories; entry locally of all data forms,
except forms reporting adverse events, using a
Data Entry System developed by the Data Coor-
dinating Center, with appropriate range, logic, and
consistency checks, and with a 5% random sample
of all forms re-entered; re-abstraction and re-entry
of data based on medical records of a 5% random
sample of all participants; and site visits during
the ‘dry run’.
4.2. Recruitment and enrollment
All pregnant women less than 31 weeks of
gestation at a given field center are eligible for
enrollment, except where specific exclusion criteria
are present. Medical records are reviewed to deter-
mine initial eligibility. Potential participants are
contacted, the HAPO Study explained, and agree-
 B.E. Metzger / International Journal of Gynecology and Obstetrics 78 (2002) 69–77
ment for participation requested. Participants are
scheduled to have an OGTT at a prenatal visit as
close to 28 weeks of gestation as possible and
always within 24–32 weeks. At that visit, the
OGTT is obtained, standardized questionnaires are
administered to ascertain prenatal data, and height,
weight, and blood pressure are measured and
urinalysis performed. For women who decline to
participate, or who do not meet inclusion criteria,
age, education level attained, and the reason for
exclusion are recorded.
4.3. Criteria for exclusion
1. Age -18 years.
2. Planning to deliver at another hospital or
location.
3. Date of last menstrual period not certain and
no ultrasound estimation from 6–24 weeks of
gestational age available.
4. Unable to complete OGTT within 32 weeks of
gestation.
5. Known multiple pregnancy.
6. Became pregnant with assistance of advanced
reproductive technology such as in-vitro fertil-
ization or superovulation with gonadotropins.
7. Any unblinded blood glucose testing andyor
diagnosis of GDM during this pregnancy prior
to enrollment in this protocol.
8. Previous diagnosis of diabetes requiring treat-
ment with medication outside of pregnancy.
9. Currently receiving treatment with oral gluco-
corticoids, thiazide diuretics, b-blockers, ACE
inhibitors, oral b-mimetics, dilantin, or antire-
troviral agents.
10. Participation in another study which may inter-
fere with HAPO.
11. Known to be HIV positive or to have Hepatitis
B (or be B surface antigen positive) or C.
12. Participation in HAPO during a previous
pregnancy.
13. Inability to converse in language(s) used in
field center forms without the aid of an
interpreter.
4.4. Interpretation of the OGTT
OGTT results obtained at field centers are
revealed to the clinician responsible for the care
73
of the pregnant woman only if the fasting plasma
glucose level exceeds 5.8 mmolyl or the 2-h post-
load level exceeds 11.1 mmolyl. (Sacks et al. w18x
found no increased rate of perinatal death, and no
relation between glucose tolerance and perinatal
deaths in individuals with values below these
thresholds.) Because participants with a low value
(-2.5 mmolyl) require further evaluation, they
are also unblinded. Although women with unblind-
ed glucose values are not part of the formal study
(the main analyses), all HAPO Study data, includ-
ing outcome variables and neonatal assessment,
are still collected.
4.5. Random plasma glucose
To reduce the unlikely possibility that undiagno-
sed diabetes may evolve in late gestation, a ran-
domly timed venous plasma glucose is also
measured at the field center on one other occasion
at 34–37 weeks of gestation. If the level equals or
exceeds 8.9 mmolyl or is less than 2.5 mmolyl,
the result is revealed to the clinician and the
patient withdrawn from the primary study. In both
instances, all HAPO Study data are still collected.
The value of 8.9 mmolyl was arbitrarily settled
upon, and was selected to insure the absence of
severe hyperglycemia, not to detect additional
persons with GDM or those at higher risk of a
fetus with macrosomia. Similarly, the value of 2.5
mmolyl was arbitrarily settled upon, and was
selected to insure that women with potential hypo-
glycemia receive evaluation.
4.6. General obstetric care
Following the OGTT, routine pregnancy care
such as frequency of visits and indications for fetal
monitoring or ultrasound are conducted as per
usual practice at a given field center. Frequency
of visits and indications for and use of fetal
monitoring and ultrasound are recorded. Fetal kick
counts are made by participants from 28 weeks’
gestation on a daily basis. If fewer than 10 kicks
are recorded in a 2-h period, or if she ever feels
no movements for a 12-h period, she is asked to
notify her obstetrical caregivers.
74 B.E. Metzger / International Journal of Gynecology and Obstetrics 78 (2002) 69–77
4.7. Symptoms suggestive of hyperglycemia or
hypoglycemia
If a participant complains of symptoms sugges-
tive of significant hyperglycemia (e.g. polyuria or
polydipsia) or hypoglycemia, the responsible cli-
nician may order a random plasma glucose meas-
urement by the field center laboratory. The result
is revealed to the clinician only if it equals or
exceeds 8.9 mmolyl or if it is below 2.5 mmolyl.
In this case, the woman is also removed from the
primary study, again with all HAPO Study data
still collected. It is anticipated that such additional
blood glucose testing will be very uncommon.
4.8. Timing of delivery and course of labor
Determination of the timing of delivery in the
event of obstetric complications is according to
standard practice for the individual field center.
General practices and cesarean delivery rates are
similar across field centers. If labor is induced, the
intravenous fluid for oxytocic infusion is to be a
non-glucose containing fluid. Caregivers are being
instructed not to use glucose-containing solutions
during labor or delivery. However, if the length of
labor exceeds 8 h, at the discretion of the respon-
sible physician, a solution containing no more than
5% dextrose may be administered at a rate not to
exceed 125 mlyh, while the laboring mother is
fasting, in order to satisfy caloric requirements and
avoid ketosis.
4.9. Neonatal care
After delivery, customary neonatal care is car-
ried out at each field center with limited exceptions
related to the study protocol. First feeding is
offered routinely 2 h after birth following the
collection of blood for plasma glucose determina-
tion. Mothers who wish to put their babies to the
breast or offer a bottle early after delivery are
permitted to do so. In a pilot study, we found no
difference in plasma glucose concentration among
babies receiving no feeding or offered the breast
or bottle during the first hour after delivery w38x.
Caregivers are asked not to give additional oral or
parenteral glucose prior to the time the neonatal
glucose specimen is obtained, if possible.
Analysis of neonatal plasma glucose collected
1–2 h after delivery is performed at the Central
Laboratory and results are not provided to caregiv-
ers. To confirm that neonatal plasma glucose con-
centration does not tend to decline progressively
in healthy newborns, rather than showing an early
post-delivery nadir, a second sample is drawn at 4
h after birth in 5% of the babies, randomly selected
and identified pre-delivery.
Additional measurements of plasma glucose
may be performed for clinical indications at the
discretion of the attending physician, if signs or
symptoms suggest sustained or later development
of hypoglycemia. Such additional measurements
are performed without blinding in the local field
center laboratory using a glucose enzymatic meth-
od. Information concerning symptoms of hypogly-
cemia, values of neonatal glucose measurements
performed for clinical indications, and treatment
are abstracted. The need for other assessments,
e.g. bilirubin, status of respiratory function, are
determined by clinical indications. All data regard-
ing the assessments of potential neonatal morbid-
ities are collected from the medical records of the
neonates. Data on morbidities occurring after dis-
charge from hospital are collected at 4–6 weeks’
post-partum (by telephone or mail questionnaire
and from subsequent review of medical records as
needed).
4.10. Dataset sufficient for analytical purposes
It is our objective to complete every item of
data for each participant and her baby. However,
in practice, there may be some missing data for
reasons that are beyond the control of investigators.
The following ‘minimal’ data must be available
for a woman to be included in the analysis of
outcomes: completed enrollment forms and ques-
tionnaires; completion of and results available from
the OGTT; type of delivery; status of the baby at
delivery (aliveydead); birthweight; and the
absence of exclusionary criteria. In the absence of
this ‘minimal data set’, a woman is designated a
dropout. The enrollment target for each field center
is 1500 women (1750 in the four centers in the
 B.E. Metzger / International Journal of Gynecology and Obstetrics 78 (2002) 69–77
US) with a data set ‘sufficient for analytical
purposes’, i.e. exclusive of dropouts.
4.11. Power and sample size
The sample size of 25 000 was selected to
ensure that there would be sufficient numbers of
women throughout the range of fasting, 1-h, and
2-h plasma glucose values to provide adequate
power (0.80 or higher) for valid assessment of the
association between maternal glycemia and each
primary outcome. For example, it was estimated
that 25 000 women would yield 400 women with
a fasting plasma glucose between 5.6 and 5.8
mmolyl and 15 250 with values less than 4.7
mmolyl. These group sizes provide approximately
80% power to detect a relative risk of 1.8 for the
cesarean delivery rates for women in these two
glucose categories, if the cesarean delivery rate in
women with fasting plasma glucose values less
than 4.7 mmolyl is 7%, and the rate in the women
with the higher values is 12.6%.
4.12. Study timeline
The study was initiated April 1, 1999 and the
first 12 months were used to finalize the Protocol
and develop study procedures. The next 36–48
months are devoted to completion of regional
training, enrollment of study participants, and com-
pletion of all data collection. The final 12 months
will be used for statistical analysis of study data,
and for the preparation of reports for presentation
and publication. Translation of the results into
clinical practice will then follow. This translation
may be straightforward if the association between
maternal glycemia and an important perinatal out-
come(s) indicates a ‘threshold’. However, if the
relationships are continuous and linear, the deci-
sions about the points where ‘clinical significance’
is seen will have to be made by consensus. In that
case, many individuals and groups will undoubt-
edly need to take part in the dialogue that will be
needed to reach consensus.
5. Conclusions
The diversity of the HAPO Study’s population
samples, its high quality standardized methods of
75
data collection, including collection of data on
potential confounding variables, its use of a Cen-
tral Laboratory for measurement of key metabolic
variables with medical caregivers ‘blinded’ to stat-
us of glucose tolerance (except when exceeding
pre-defined thresholds), all give a high probability
of valid assessment of its hypothesis, and of
development of the criteria for diagnosis and
classification of GDM.
Acknowledgments
This study is funded by grants R01-HD34242
and R01-HD34243 from the National Institute of
Child Health and Human Development (NICHD)
and the National Institute of Diabetes, Digestive,
and Kidney Diseases (NIDDK), by the National
Center for Research Resources (NCRR) (M01-
RR00048, M01-RR00080) and by the American
Diabetes Association. Support has also been pro-
vided to local field centers by Diabetes UK
(RD00y0001994), KK Women’s and Children’s
Hospital, Mater Mother’s Hospital, Novo Nordisk,
and the Howard and Carol Bernick Family
Foundation.
Appendix A: HAPO Study Cooperative
Research Group
Field Centers: (North American Region): M. Contreras,
D.A. Sacks, W. Watson (Kaiser Foundation Hospital, Bellflow-
er, California); S.L. Dooley, M. Foderaro, C. Niznik, D.H.
Polk (Prentice Women’s Hospital of Northwestern Memorial
HospitalyNorthwestern University Feinberg School of Medi-
cine, Chicago, IL); J. Bjaloncik, P.M. Catalano, S. Fox, L.
Gullion, C. Johnson, C.A. Lindsay, H. Makovos, F. Saker
(MetroHealth Medical CenteryCase Western Reserve Univer-
sity, Cleveland, OH); M.W. Carpenter, M.H. Somers (Women
and Infants Hospital of Rhode IslandyBrown University Med-
ical School, Providence, Rhode Island); K.S. Amankwah, P.C.
Chan, B. Kapur, A. Kenshole, G. Lawrence, K. Matheson, L.
Mayes, H. Owen (Sunnybrook and Women’s College Health
Sciences CenteryUniversity of Toronto, Toronto, Ontario);
(European Region): P. Basdeo, C. Cave, G. Fenty, E. Gibson,
A. Hennis, Y.E. Rotchell, C. Spooner, H.A.R. Thomas (Queen
Elizabeth HospitalySchool of Clinical Medicine and Research,
University of the West Indies, Barbados); J. Fox, D.R. Hadden,
76 B.E. Metzger / International Journal of Gynecology and Obstetrics 78 (2002) 69–77
H. Halliday, J. Irwin, O. Kearney, D.R. McCance, M. Smye,
A.I. Traub (Royal Jubilee Maternity Hospital, Belfast,
Northern Ireland); J.K. Cruickshank, J. Dry, A.C. Holt, F.
Khan, C. Lambert, M. Maresh, F. Prichard (St. Mary’s Hos-
pitalyManchester University, Manchester, UK); T.W. van Haef-
ten, A.M.R. van de Hengel, G.H.A. Visser, A. Zwart
(University HospitalyUniversity Medical Center Utrecht,
Utrecht, Netherlands) (not participating in Phase 2); (Middle
EasternyAsian Region): U. Chaovarindr, U. Chotigeat, C.
Deerochanawong, I. Panyasiri, P. Sanguanpong (Rajavithi Hos-
pital, Bangkok, Thailand); D. Amichay, A. Golan, K. Marks,
M. Mazor, J. Ronen, A. Wiznitzer (Soroka Medical Centery
Ben-Gurion University, Beersheba, Israel); R. Chen, A. Fak-
torovich, D. Harel, N. Hoter, J. Pardo (Rabin Medical
Center-Beilinson CampusySackler Faculty of Medicine, Tel-
Aviv University, Petah-Tiqva, Israel); (Austral-Asian Region):
F. Bowling, D. Cowley, H.G. Liley, H.D. McIntyre, B. Morri-
son, D. Tudehope (Mater Misericordiae Mothers’ Hospitaly
University of Queensland, Brisbane, Australia); S.L. Kong,
C.Y. Li, K.F. Ng, P.C. Ng, M.S. Rogers (Prince of Wales
HospitalyChinese University of Hong Kong, Hong Kong); J.
Beverly, M. Edgar, W. Giles, A. Gill, J. Lowe, J. Verma (John
Hunter Hospital, Newcastle, Australia); A. Koh, E. Tan, C.C.
Teo, V. Rajadurai, H.Y. Wee, G.S.H. Yeo (KK Women’s and
Children’s Hospital, Singapore).
Regional Centers: D. Coustan, B. Haydon (Providence); A.
Alexander, D.R. Hadden (Belfast); O. Attias-Raved, M. Hod
(Petah-Tiqva), J.J.N. Oats, A.F. Parry (Brisbane).
Clinical Coordinating Center: A.S. Frank, L.P. Lowe, B.E.
Metzger, A. Thomas (Northwestern University Feinberg
School of Medicine, Chicago).
Data Coordinating Center: T. Case, P. Cholod, A.R. Dyer,
L. Engelman, M. Xiao (Northwestern University Feinberg
School of Medicine, Chicago).
Central Laboratory: C.I. Burgess, T.R.J. Lappin, G.S. Nes-
bitt, B. Sheridan, E.R. Trimble (Queen’s University of Belfast,
Belfast).
Steering Committee: D. Coustan (Providence), A.R. Dyer
(Chicago), D.R. Hadden (Belfast), M. Hod (Petah-Tiqva),
B.E. Metzger (Chicago), L.P. Lowe, ex officio (Chicago),
J.J.N. Oats (Brisbane), B. Persson (Stockholm), E.R. Trimble
(Belfast).
Data Monitoring Committee: G.R. Cutter, S.G. Gabbe, J.W.
Hare, L.E. Wagenknecht.
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