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Hyperglycemia and Adverse Pregnancy Outcomes The HAPO Study Cooperative Research Group*

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Abstract BACKGROUND: It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. METHODS: A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. RESULTS: For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker. CONCLUSIONS: Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels.
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n engl j med 358;19 www.nejm.org may 8, 2008
1991
The new england
journal of medicine
established in 1812
may 8, 2008
vol. 358 no. 19
Hyperglycemia and Adverse Pregnancy Outcomes
The HAPO Study Cooperative Research Group*
A B S T R AC T
The members of the Writing Group (Boyd
E. Metzger, M.D., Lynn P. Lowe, Ph.D.,
Alan R. Dyer, Ph.D., Northwestern Uni-
versity Feinberg School of Medicine, Chi-
cago; Elisabeth R. Trimble, M.D., Queen’s
University Belfast, Belfast, Northern Ire -
land; Udom Chaovarindr, M.D., Rajavithi
Hospital, Bangkok, Thailand; Donald R.
Coustan, M.D., Women and Infants’ Hos-
pital of Rhode Island–Brown University
Medical School, Providence, RI; David R.
Hadden, M.D., David R. McCance, M.D.,
Royal Jubilee Maternity Hospital, Belfast,
Northern Ireland; Moshe Hod, M.D.,
Helen Schneider Hospital for Women,
Rabin Medical Center–Sackler Faculty of
Medicine, Tel-Aviv University, Petah-
Tiqva, Israel; Harold David McIntyre, M.B.,
B.S., Jeremy J.N. Oats, M.D., Mater Mi-
sericordiae Mothers’ Hospital– University
of Queensland, Brisbane, Australia; Bengt
Persson, M.D., Ph.D., Karolinska Institute,
Stockholm, Sweden; Michael S. Rogers,
M.D., Prince of Wales Hospital–Chinese
University of Hong Kong, Hong Kong;
and David A. Sacks, M.D., Kaiser Foun-
dation Hospital, Bellflower, CA) of the
Hyperglycemia and Adverse Pregnancy
Outcome (HAPO) Study Cooperative Re-
search Group assume responsibility for the
overall content and integrity of the article.
Address reprint requests to Dr. Metzger
at the Northwestern University Feinberg
School of Medicine, Endocrinology, 645
N. Michigan Ave., Suite 530-22, Chicago,
IL 60611, or at bem@northwestern.edu.
*Members of the Hyperglycemia and Ad-
verse Pregnancy Outcome (HAPO) Study
Cooperative Research Group are listed in
the Appendix.
N Engl J Med 2008;358:1991-2002.
Copyright © 2008 Massachusetts Medical Society.
BACKGR OUND
It is controversial whether maternal hyperglycemia less severe than that in diabetes
mellitus is associated with increased risks of adverse pregnancy outcomes.
METHO DS
A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g
oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded
if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or
less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per
liter) or less. Primary outcomes were birth weight above the 90th percentile for ges-
tational age, primary cesarean delivery, clinically diagnosed neonatal hypoglyce-
mia, and cord-blood serum C-peptide level above the 90th percentile. Secondary
outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth
injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia.
RESU LTS
For the 23,316 participants with blinded data, we calculated adjusted odds ratios for
adverse pregnancy outcomes associated with an increase in the fasting plasma glu-
cose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour
plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an in-
crease in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol
per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38
(95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44),
respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55
(95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesar-
ean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12);
and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and
1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Sig-
nificant associations were also observed for secondary outcomes, although these
tended to be weaker.
CONCL USIONS
Our results indicate strong, continuous associations of maternal glucose levels below
those diagnostic of diabetes with increased birth weight and increased cord-blood se-
rum C-peptide levels.
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T h e
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n engl j med 358;19 www.nejm.org may 8, 2008
1992
G
estational diabetes mellitus, de-
fined as “glucose intolerance with onset
or f irst recognition during pregnancy,
1,2
has been the subject of considerable controversy.
Criteria for the diagnosis were initially established
more than 40 years ago
3
and, with minor modi-
fications, remain in use today. These criteria are
not designed to identify pregnant women who are
at increased risk for adverse perinatal outcomes
but rather women who are at high risk for the de-
velopment of diabetes after pregnancy,
3,4
or they
are the criteria used for the general population.
5
Overt diabetes mellitus during pregnancy is
associated with signif icantly increased risks of
adverse perinatal outcomes. Whereas some data
suggest that current diagnostic criteria for ges-
tational diabetes mellitus
1
are too restrictive and
that lesser degrees of hyperglycemia also increase
risk,
6-11
risks associated with hyperglycemia that
is less severe than that diagnostic of overt diabetes
mellitus are uncertain for a number of reasons.
First, there are no uniform international standards
for the ascertainment and diagnosis of gesta-
tional diabetes mellitus.
2
In addition, the extent
to which adverse outcomes associated with gesta-
tional diabetes mellitus may be explained by con-
founders (including obesity, advanced maternal
age, or associated medical complications) is un-
clear.
12-14
Caregiver bias (i.e., an expectation of
adverse outcomes due to gestational diabetes mel-
litus) may increase the likelihood of disorders or
problems due to increased intervention.
15
We conducted the Hyperglycemia and Adverse
Pregnancy Outcome (HAPO) study to clarify the
risks of adverse outcomes associated with various
degrees of maternal glucose intolerance less se-
vere than that in overt diabetes mellitus.
M e t h o d s
The protocol was approved by the institutional re-
view board at each field center. All participants
gave written informed consent. An external data
and safety monitoring committee provided over-
sight. The study methods have been published pre-
viously.
16,17
A brief overview is presented here.
Part icipant s
All pregnant women at a given center were eligi-
ble to participate unless they had one or more of
the following exclusion criteria
16
: age younger than
18 years, a plan to undergo delivery at another hos-
pital, an uncertain date of last menstrual period
and no ultrasonographic estimation between 6 and
24 weeks of gestational age, inability to complete
the oral glucose-tolerance test within 32 weeks
of gestation, multiple pregnancy, conception by
means of gonadotropin ovulation induction or in
vitro fertilization, glucose testing before recruit-
ment or a diagnosis of diabetes during the cur-
rent pregnancy, diagnosis of diabetes before the
current pregnancy and requiring treatment with
medication, participation in another study that
could interfere with the HAPO study, infection
with the human immunodeficiency virus or hep-
atitis B or C virus, previous participation in the
HAPO study, or inability to converse in the lan-
guages used on center forms without the aid of an
interpreter. If glucose measurements were made
outside the setting of the HAPO study after ini-
tial enrollment, participation was terminated. Age
and education level were recorded for women who
declined to participate.
Gestational age and expected date of delivery
were determined from the date of the last men-
strual period, if the date was certain. If the date
was uncertain, the expected date of delivery was
estimated by means of ultrasonography performed
between 6 and 24 weeks of gestation. The final
expected date of delivery was also determined with
the use of ultrasonography if the gestational age
estimated on the basis of the date of the last men-
strual period differed by more than 5 days from
that based on ultrasonography performed between
6 and 13 weeks of gestation or by more than 10
days from that based on ultrasonography per-
formed between 14 and 24 weeks of gestation.
Ora l Gluco se-To leran ce Tes t
Participants underwent a standard oral glucose-
tolerance test, with the use of a 75-g dose of glu-
cose, between 24 and 32 weeks of gestation (tar-
get time of testing, 28 weeks). Height, weight, and
blood pressure were measured at the test visit. Data
concerning smoking and alcohol use, history of
diabetes and hypertension among first-degree fam-
ily members, and demographic characteristics were
collected by means of standardized questionnaires.
Race or ethnic group was self-reported by partici-
pants. A blood specimen was collected between
34 and 37 weeks of gestation for evaluation of the
random plasma glucose level, as a safety measure
to identify cases with hyperglycemia above a pre-
defined threshold.
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Hy pergl ycem ia a nd A dver se Pre gnanc y O ut come s
n engl j med 358;19 www.nejm.org may 8, 2008
1993
Gluco se Analys is
For purposes of clinical decision making, plasma
glucose levels were measured at center laborato-
ries by means of enzymatic methods, with exten-
sive quality control, as previously described.
17
To
avoid the confounding effects of analytic variation
among centers, aliquots of all oral glucose-toler-
ance test specimens were analyzed at the central
laboratory of the HAPO study, and the results were
used in the analyses reported here.
Unblind ing of Data
Fasting and 2-hour specimens from the oral glu-
cose-tolerance tests and the blood specimen taken
for determination of the random plasma glucose
level were analyzed at center laboratories. The data
were unblinded if the 2-hour plasma glucose lev-
el was diagnostic of diabetes (i.e., >200 mg per
deciliter [11.1 mmol per liter]) or, for ethical and
safety reasons, if the fasting plasma glucose level
exceeded 105 mg per deciliter (5.8 mmol per liter),
the random plasma glucose level was 160 mg per
deciliter (8.9 mmol per liter) or more, or any plas-
ma glucose level was less than 45 mg per deciliter
(2.5 mmol per liter). Otherwise, women, caregiv-
ers, and the staff of the HAPO study (except for
laboratory personnel) remained unaware of the
glucose values. Only women whose data were
blinded and who did not undergo any additional
glucose testing outside the HAPO study were in-
cluded in our analyses.
Cord -B lood P lasm a Gluco se and S erum
C-Pe ptid e Leve ls
Cord-blood specimens were collected at delivery
for the measurement of serum C-peptide and plas-
ma glucose levels. The specimens were analyzed
at the central laboratory with the use of an im-
munoassay (AutoDELFIA, PerkinElmer) for serum
C peptide and a chemical analyzer (Vitros 750,
Ortho-Clinical Diagnostics) for plasma glucose.
17
Because approximately 15% of cord-blood samples
have detectable hemolysis after serum or plasma
is separated out, because hemolysis is known to
increase insulin degradation but not to affect
C-peptide level,
17
and because C peptide and in-
sulin are secreted in equimolar levels, we used
cord-blood serum C-peptide level rather than in-
sulin level as our index of fetal β-cell function.
Prenatal Care , Del ivery, and Neonatal C are
Prenatal care, timing of delivery, and neonatal care
were determined by means of the standard prac-
tice at each center. No center arbitrarily induced
delivery before full term or routinely performed
cesarean delivery at a specified maternal or ges-
tational age. Medical records were abstracted to
obtain data regarding the prenatal course, labor
and delivery, the postpartum course, and the new-
born course.
Outc omes
Primary and Secondary Outcomes
The four primary outcomes were birth weight
above the 90th percentile for gestational age, pri-
mary cesarean delivery, clinical neonatal hypogly-
cemia, and cord-blood serum C-peptide level above
the 90th percentile (fetal hyperinsulinemia). Sec-
ondary outcomes were premature delivery (before
37 weeks of gestation), shoulder dystocia or birth
injury, need for intensive neonatal care, hyperbili-
rubinemia, and preeclampsia.
Possible Severe Adverse Outcomes
Additional data were abstracted at centers when-
ever a possible severe adverse event (e.g., death,
shoulder dystocia, birth injury, and major malfor-
mation) was identified. Data were reviewed by the
members of an outcome review committee, who
were unaware of the mother’s glycemic status, to
confirm whether the event was present. Perinatal
deaths were classified according to the Australian
and New Zealand Antecedent Classification of
Perinatal Mortality guidelines,
18
and major mal-
formations were classified according to codes of
the International Classification of Diseases, Tenth Revi-
sion.
19
The HAPO data and safety monitoring com-
mittee reviewed data regarding adverse outcomes
and deaths after having been made aware of the
results of the oral glucose-tolerance test and the
random plasma glucose levels.
Statis tic al Analys is
Mean and standard deviation are reported for con-
tinuous variables, and number and percentage are
reported for categorical variables. Pearson product-
moment correlations were used to assess associ-
ations among glucose measures. For associations
of glycemia with primary outcomes, as prespec-
ified in the HAPO study protocol, each glucose
measurement was considered as both a categori-
cal and a continuous variable in multiple logistic-
regression analyses. For secondary outcomes, only
results for continuous variables are presented. For
categorical analyses, each measure of glycemia
was divided into seven categories, such that the
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1994
1- and 2-hour plasma glucose measures reflected
data for approximately the same number of wom-
en in each category as did the fasting plasma
glucose measure. Categories for the fasting plas-
ma glucose level were originally prespecified in
the HAPO study protocol as 100 mg per deciliter
(5.6 mmol per liter) or more, 95 to 99 (5.3 to 5.5),
90 to 94 (5.0 to 5.2), 85 to 89 (4.8 to 4.9), and less
than 85. Subsequently, the category of less than
85 mg per deciliter was further subdivided into
less than 75 mg per deciliter (4.2 mmol per liter),
75 to 79 (4.2 to 4.4), and 80 to 84 (4.5 to 4.7). The
highest and second-highest categories for each
glucose measure, accounting for 1% and 3% of
participants, respectively, were specifically chosen
to allow for assessment of whether there were
threshold effects.
For continuous-variable analyses, odds ratios
were calculated for a 1-SD increase in fasting,
1-hour, and 2-hour plasma glucose levels. As pre-
specified, to assess whether the log of the odds of
each outcome was linearly related to glucose level,
we added squared terms for glucose level for each
adverse pregnancy outcome to assess whether
there were significant quadratic associations. For
each outcome, two logistic models were fit.
Table 1. Characteristics of the Study Participants and Their Newborns and Frequency of Outcomes.*
Characteristic or Outcome
No. of Participants
(%) Mean ±SD
Range of Means
among Centers
Maternal characteristics
Age (yr) 23,316 (100) 29.2±5.8 25.4–33.6
Body-mass index 23,316 (100) 27.7±5.1 24.4–29.9
Mean arterial pressure (mm Hg) 23,316 (100) 80.9±8.3 75.9–84.1
Plasma glucose (mg/dl)
Fasting 23,316 (100) 80.9±6.9 78.2–83.7
1 hr 23,316 (100) 134.1±30.9 119.5–148.2
2 hr 23,316 (100) 111.0±23.5 99.6–120.9
Length of gestation at time of OGTT (wk) 23,316 (100) 27.8±1.8 25.9–29.5
Any prenatal smoking — % 1,581 (6.8) 0.2–23.7
Any prenatal alcohol use — % 1,612 (6.9) 0.1–26.5
Family history of diabetes — % 5,282 (22.7) 12.1–37.7
Parity (delivery ≥20 wk) at enrollment 12,233 (52.5) 34.8–68.9
Prenatal urinary tract infection — % 1,655 (7.1) 0.4–22.5
Hospitalization before delivery — % 3,271 (14.0) 2.3–33.2
Newborn characteristics
Gestational age at delivery (wk) 23,316 (100) 39.4±1.7 38.7–39.9
Birth weight (g) 23,217 (99.6) 3292±529 3109–3526
Cord-blood serum C peptide (μg/liter) 19,885 (85.3) 1.0±0.6 0.9–1.2
Cord-blood plasma glucose (mg/dl) 19,859 (85.2) 81.5±19.6 74.2–90.4
Male sex — % 12,003 (51.5) 49.3–54.0
Obstetrical outcomes
Cesarean delivery — %
Primary 3,731 (16.0) 8.6–23.5
Repeat 1,792 (7.7) 3.3–11.8
Hypertension — %†
Chronic hypertension 582 (2.5) 0.5–9.4
Gestational hypertension 1,370 (5.9) 0.7–17.7
Preeclampsia 1,116 (4.8) 1.4–11.4
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1995
Model I included adjustment for center or the
variables used in estimating the 90th percentile
for birth weight for gestational age (infant’s sex,
race or ethnic group, center, and parity). Model II
included adjustment for multiple potential pre-
specified confounders, including age, body-mass
index (BMI), smoking status, alcohol use, pres-
ence or absence of a family history of diabetes,
gestational age at the oral glucose-tolerance test,
sex of the infant, parity (0, 1, or ≥2, except for
primary cesarean deliveries), mean arterial pres-
sure and presence or absence of hospitalization
before delivery (except for preeclampsia), and pres-
ence or absence of a family history of hyperten-
sion and maternal urinary tract infection (for
analysis of preeclampsia only). Height was also
included as a potential confounder, on the basis
of post hoc findings of an association with birth
weight greater than the 90th percentile, and two
prespecified confounders (maternal urinary tract
infection and previous prenatal death) were exclud-
ed from primary and secondary outcome analy-
ses when neither was found to be related to any
primary outcome or to affect primary outcome–
glucose associations. Squared terms for age, BMI,
and mean arterial pressure were prescreened for
possible inclusion in model II adjustment when
only the center had been included (i.e., models
without glucose or other covariates); these terms
were included in model II when significant. Only
Table 1. (Continued.)
Characteristic or Outcome
No. of Participants
(%) Mean ±SD
Range of Means
among Centers
Newborn outcomes
Birth weight >90th percentile — %‡ 2,221 (9.5) 9.0–9.9
Clinical neonatal hypoglycemia — %§ 480 (2.1) 0.3–6.4
Cord-blood serum C peptide >90th percentile — %¶ 1,671 (8.4) 5.9–15.1
Premature delivery (before 37 wk) — % 1,608 (6.9) 3.9–9.1
Shoulder dystocia or birth injury 311 (1.3) 0.1–3.4
Intensive neonatal care — %‖ 1,855 (8.0) 3.0–28.8
Hyperbilirubinemia — %** 1,930 (8.3) 3.0–25.4
* The body-mass index (the weight in kilograms divided by the square of the height in meters), mean arterial pressure,
and glucose levels were obtained at the oral glucose-tolerance test (OGTT). To convert the values for glucose to milli-
moles per liter, multiply by 0.05551. For additional characteristics of the participants, see Table A in the Supplemen-
tary Appendix.
Chronic hypertension was defined as hypertension that was present before 20 weeks of gestation and that did not
progress to preeclampsia. Hypertension disorders occurring during pregnancy after 20 weeks of gestation were cate-
gorized according to the International Society for the Study of Hypertension guidelines.
20
Preeclampsia was defined
as systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more on two or more
occasions a minimum of 6 hours apart and proteinuria of 1+ or more on a dipstick test or a protein level in the urine
of 300 mg or more for a 24-hour period. If the criteria for elevated blood pressure were met but those for proteinuria
were not, the hypertension was classified as gestational hypertension.
For birth weight above the 90th percentile, the 90th percentiles for gestational age (30 to 44 weeks only) were deter-
mined with the use of quantile regression analyses for each of eight groups of newborns based on infant’s sex and
race or ethnic group (white or other, black, Hispanic, or Asian), with adjustment for gestational age, field center, and
parity (0, 1, or ≥2). A newborn was considered to have a birth weight above the 90th percentile if the birth weight was
greater than the estimated 90th percentile for the infant’s sex, gestational age, race or ethnic group, field center, and
maternal parity. Otherwise, the newborn was considered to have a birth weight at or under the 90th percentile. Birth
weights were available for 23,217 newborns.
§ Clinical neonatal hypoglycemia was defined as being present if there was a notation of neonatal hypoglycemia in the
medical record and there were symptoms or treatment with a glucose infusion or a local laboratory report of a glu-
cose value of 30.6 mg per deciliter (1.7 mmol per liter) or less in the first 24 hours after birth or 45.0 mg per deciliter
(2.5 mmol per liter) or less after the first 24 hours.
21
A cord-blood serum C-peptide level above the 90th percentile was defined on the basis of the 19,885 newborns for
whom data were available.
Intensive neonatal care was defined by admission to any type of unit for care more intensive than normal newborn
care and lasting more than 24 hours or by death of the baby or transfer to another hospital. Data were excluded for
admissions that were only for possible sepsis or sepsis, observation, or feeding problems.
** Hyperbilirubinemia was defined by treatment with phototherapy after birth, at least one laboratory report of a biliru-
bin level of 20 mg per deciliter (342 μmol per liter) or more, or readmission for hyperbilirubinemia.
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1996
the fully adjusted model results are presented in
this report. (Results for all models are given in
Tables B through F in the Supplementary Ap-
pendix, available with the full text of this article
at www.nejm.org.)
In post hoc analyses, we tested for interactions
of each glucose measure with center in models I
and II (except with regard to the outcomes of
clinical neonatal hypoglycemia and shoulder dys-
tocia or birth injury, owing to small numbers in
some centers [a total of 42 tests]). We also tested
for interactions of each glucose measure with BMI,
age, height, and mean arterial pressure in model
II (105 tests). P values less than 0.001 were con-
sidered to indicate statistical significance for
squared terms for glucose, age, BMI, and mean
arterial pressure and interaction terms for all out-
comes, except neonatal hypoglycemia and shoul-
der dystocia or birth injury, for which P values less
than 0.05 were considered to indicate statistical
signif icance, owing to the smaller numbers of
babies with these outcomes.
All analyses were conducted in SAS version 9.1
or Stata 10.0. All reported P values are two-sided
and were not adjusted for multiple testing.
R e s u lt s
Part icipant s
Among 53,295 eligible women (from 15 centers in
nine countries; see the Appendix), 28,562 (53.6%)
agreed to participate in this blinded study, between
July 2000 and April 2006. Among the women who
agreed to participate and those who refused to par-
ticipate, the mean age and years of education were
29.0 and 12.9 years and 28.5 and 12.5 years, re-
spectively. A total of 25,505 women completed an
oral glucose-tolerance test: 746 (2.9%) were exclud-
ed because their data were unblinded, 1412 (5.5%)
were excluded primarily because they had under-
gone glucose testing or delivery outside the con-
text of the HAPO study, and 31 (0.1%) were ex-
cluded owing to missing key data or an implausible
gestational age (>44 weeks); data from the remain-
ing 23,316 were available for analyses. Of these
23,316 patients, 48.3% were self-reported to be
white, 11.6% to be black, 8.5% to be Hispanic,
29.0% to be Asian or Oriental,” and 2.6% to be
of other races or ethnic groups.
Characteristics of the mothers and newborns
and pregnancy outcomes are summarized in
Ta-
ble 1
. The mean age of participants was 29.2 years,
and the mean fasting, 1-hour, and 2-hour plasma
glucose levels were 80.9 mg per deciliter (4.5 mmol
per liter), 134.1 mg per deciliter (7.4 mmol per li-
ter), and 111.0 mg per deciliter (6.2 mmol per li-
ter), respectively. Correlations among these three
glucose measures were as follows: 0.38 for the
fasting plasma glucose level and the 1-hour plas-
ma glucose level, 0.30 for the fasting plasma glu-
cose level and the 2-hour plasma glucose level,
and 0.68 for the 1-hour plasma glucose level and
the 2-hour plasma glucose level (P<0.001 for all
three comparisons). There were 2 maternal deaths
(1 due to pulmonary embolism, the other due to
respirator y failure secondary to pneumonia), 14
cases of eclampsia, 321 cases of major malforma-
tion of the newborn, and 130 perinatal deaths (89
fetal and 41 neonatal or infant) (incidence, 5.6 per
1000) among the 23,316 deliveries.
Glycemia a nd Pregnan cy Ou tcomes
Categorical Analyses
The frequency of each primary outcome across the
seven glucose categories is shown in
Figure 1
. With
increasing maternal glucose levels, the frequency
of each primary outcome increased, although less
so for clinical neonatal hypoglycemia than for the
other outcomes. For example, for the fasting plas-
ma glucose level, frequencies in the lowest and
highest categories, respectively, were 5.3% and
26.3% for birth weight above the 90th percentile,
13.3% and 27.9% for primary cesarean section,
2.1% and 4.6% for clinical neonatal hypoglycemia,
and 3.7% and 32.4% for C-peptide level above the
90th percentile.
Table 2
shows the associations of maternal
glucose as a categorical variable with each primary
outcome, including odds ratios and 95% confi-
dence intervals for each category, as compared
with the lowest category, with adjustment for con-
founders. There were strong associations with
birth weight above the 90th percentile that in-
creased across the increasing glycemia categories.
Differences in mean birth weight between the low-
est and highest categories of the fasting, 1-hour,
and 2-hour plasma glucose levels were 242 to
305 g when birth weight was modeled as a con-
tinuous variable, with adjustment for multiple
confounders (data not shown). The odds ratio for
primary cesarean section increased across catego-
ries of maternal glycemia and was 1.86 in the
highest category of 1-hour plasma glucose; the
odds ratio in the highest category of 2-hour plasma
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1997
glucose did not differ significantly from 1.00. The
adjusted odds ratios for clinical neonatal hypogly-
cemia were substantially attenuated, and none of
the odds ratios for the highest glucose categories
were significantly different from 1.00. After ad-
justment for confounders, there was a strong as-
sociation between cord-blood serum C-peptide
level above the 90th percentile and maternal glyce-
mia, with the association increasing with increas-
ing glycemia category; the odds ratio was 7.65
(95% confidence interval [CI], 5.17 to 11.32) for the
highest category of the fasting plasma glucose.
Continuous Analyses
Results for analyses of glucose level as a continu-
ous variable, with model II adjustment for both
primary and secondary outcomes, are shown in
Table 3
. Among the primary outcomes, odds ra-
tios for an increase in the glucose level by 1 SD
were highest for birth weight greater than the 90th
percentile (range, 1.38 to 1.46) and cord-blood
serum C-peptide level above the 90th percentile
(range, 1.37 to 1.55). For primary cesarean sec-
tion and clinical neonatal hypoglycemia, the as-
sociations were weaker and the associations of
33p9
30
Frequency (%)
20
25
15
10
5
0
2 3 4 5 71 6
Glucose Category
CClinical Neonatal Hypoglycemia
ABirth Weight >90th Percentile
35
30
Frequency (%)
20
25
15
10
5
0
2 3 4 5 71 6
Glucose Category
BPrimary Cesarean Section
5
Frequency (%)
3
4
2
1
0
2 3 4 5 71 6
Glucose Category
35
30
Frequency (%)
20
25
15
10
5
0
2 3 4 5 71 6
Glucose Category
DCord-Blood Serum C Peptide >90th Percentile
AUTHOR:
FIGURE:
JOB:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st
2nd
3rd
Metzger
1 of 1
05-08-08
ARTIST: ts
35819 ISSUE:
Fasting glucose 1-Hr glucose 2-Hr glucose
Figure 1. Frequency of Primary Outcomes across the Glucose Categories.
Glucose categories are defined as follows: fasting plasma glucose level — category 1, less than 75 mg per deciliter
(4.2 mmol per liter); category 2, 75 to 79 mg per deciliter (4.2 to 4.4 mmol per liter); category 3, 80 to 84 mg per
deciliter (4.5 to 4.7 mmol per liter); category 4, 85 to 89 mg per deciliter (4.8 to 4.9 mmol per liter); category 5, 90 to
94 mg per deciliter (5.0 to 5.2 mmol per liter); category 6, 95 to 99 mg per deciliter (5.3 to 5.5 mmol per liter); and
category 7, 100 mg per deciliter (5.6 mmol per liter) or more; 1-hour plasma glucose level — category 1, 105 mg per
deciliter (5.8 mmol per liter) or less; category 2, 106 to 132 mg per deciliter (5.9 to 7.3 mmol per liter); category 3,
133 to 155 mg per deciliter (7.4 to 8.6 mmol per liter); category 4, 156 to 171 mg per deciliter (8.7 to 9.5 mmol per
liter); category 5, 172 to 193 mg per deciliter (9.6 to 10.7 mmol per liter); category 6, 194 to 211 mg per deciliter
(10.8 to 11.7 mmol per liter); and category 7, 212 mg per deciliter (11.8 mmol per liter) or more; and 2-hr plasma
glucose level — categor y 1, 90 mg per deciliter (5.0 mmol per liter) or less; category 2, 91 to 108 mg per deciliter
(5.1 to 6.0 mmol per liter); category 3, 109 to 125 mg per deciliter (6.1 to 6.9 mmol per liter); category 4, 126 to 139 mg
per deciliter (7.0 to 7.7 mmol per liter); category 5, 140 to 157 mg per deciliter (7.8 to 8.7 mmol per liter); category 6,
158 to 177 mg per deciliter (8.8 to 9.8 mmol per liter); and category 7, 178 mg per deciliter (9.9 mmol per liter) or more.
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1998
clinical neonatal hypoglycemia with the fasting
plasma glucose level and the 2-hour plasma glu-
cose level were not significant.
Twelve of the 15 analyses of secondary out-
comes showed significant positive associations
with maternal glycemia, after adjustment for con-
founders (
Table 3
). The strongest associations were
found for preeclampsia, for which the odds ratio
for each 1-SD increase in each glucose measure
ranged from 1.21 to 1.28; corresponding odds ra-
tios for shoulder dystocia or birth injury were ap-
proximately 1.20. Premature delivery, intensive
neonatal care, and hyperbilirubinemia were sig-
nificantly related to the 1-hour and 2-hour plasma
glucose levels but not to the fasting plasma glu-
cose level.
The only significant quadratic (nonlinear) as-
sociation found in these analyses was for the fast-
ing plasma glucose level with clinical neonatal
hypoglycemia (P = 0.01). Among the 147 tests for
interactions, 7 were significant: the fasting plas-
ma glucose level with field center, in relation to
primary cesarean delivery, in both models I and II
(P<0.001); age with the fasting, 1-hour, and 2-hour
plasma glucose levels, with regard to clinical neo-
natal hypoglycemia (P = 0.05, P = 0.03, and P = 0.001,
respectively); BMI and 1-hour plasma glucose level,
for clinical neonatal hypoglycemia (P<0.001); and
mean arterial pressure with fasting plasma glu-
cose level, for premature delivery (P<0.001).
We also examined associations of glucose mea-
sures with birth weight below the 10th percentile
for gestational age, using the same methods to
estimate the 10th percentiles as were used to es-
Table 2. Adjusted Odds Ratios for Associations between Maternal Glucose as a Categorical Variable and Primary Outcomes.*
Glucose
Category† Plasma Glucose Level
Fasting At 1 Hr At 2 Hr
total no.
(no. with outcome)
odds ratio
(95% CI)
total no.
(no. with outcome)
odds ratio
(95% CI)
total no.
(no. with outcome)
odds ratio
(95% CI)
Birth weight >90th percentile
1 4035 (213) 1.00 4177 (268) 1.00 4264 (297) 1.00
2 7501 (572) 1.37 (1.16–1.62) 7524 (584) 1.21 (1.04–1.41) 7422 (587) 1.11 (0.96–1.30)
3 6168 (622) 1.72 (1.46–2.03) 6003 (593) 1.65 (1.41–1.93) 5865 (580) 1.51 (1.30–1.75)
4 2741 (323) 1.95 (1.62–2.35) 2768 (352) 2.27 (1.91–2.71) 3024 (396) 2.15 (1.82–2.54)
5 1883 (310) 2.73 (2.25–3.31) 1858 (264) 2.66 (2.19–3.21) 1720 (210) 2.10 (1.73–2.56)
6 672 (124) 3.00 (2.34–3.86) 645 (111) 3.50 (2.72–4.50) 690 (101) 2.68 (2.08–3.45)
7 217 (57) 5.01 (3.54–7.09) 242 (49) 4.49 (3.16–6.39) 232 (50) 4.46 (3.15–6.33)
Primary cesarean section‡
1 3721 (495) 1.00 3826 (458) 1.00 3903 (535) 1.00
2 6806 (1151) 1.19 (1.06–1.34) 6792 (1113) 1.21 (1.07–1.36) 6664 (1032) 0.97 (0.86–1.09)
3 5483 (1014) 1.21 (1.07–1.37) 5311 (1032) 1.26 (1.11–1.42) 5201 (1017) 1.11 (0.99–1.26)
4 2378 (506) 1.33 (1.15–1.54) 2425 (522) 1.31 (1.13–1.52) 2650 (583) 1.15 (1.00–1.32)
5 1601 (380) 1.44 (1.23–1.69) 1623 (407) 1.48 (1.26–1.74) 1506 (350) 1.17 (0.99–1.37)
6 560 (134) 1.39 (1.11–1.75) 547 (132) 1.30 (1.04–1.64) 615 (162) 1.32 (1.08–1.63)
7 183 (51) 1.60 (1.12–2.27) 208 (67) 1.86 (1.35–2.57) 193 (52) 1.28 (0.91–1.81)
Clinical neonatal hypoglycemia
1 4043 (83) 1.00 4183 (72) 1.00 4266 (78) 1.00
2 7503 (144) 0.91 (0.69–1.21) 7523 (153) 1.12 (0.84–1.49) 7421 (134) 0.87 (0.66–1.17)
3 6164 (122) 0.92 (0.68–1.23) 6003 (131) 1.24 (0.92–1.68) 5868 (117) 0.96 (0.71–1.30)
4 2744 (59) 1.00 (0.70–1.43) 2772 (54) 1.11 (0.77–1.62) 3027 (80) 1.23 (0.88–1.71)
5 1884 (48) 1.19 (0.81–1.75) 1860 (45) 1.48 (0.99–2.22) 1720 (44) 1.13 (0.76–1.68)
6 672 (14) 1.01 (0.55–1.84) 643 (20) 2.17 (1.28–3.69) 693 (21) 1.36 (0.81–2.28)
7 217 (10) 1.98 (0.97–4.05) 243 (5) 1.29 (0.51–3.31) 232 (6) 1.12 (0.47–2.67)
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1999
timate the 90th percentiles (
Table 1
). In the con-
tinuous-variable models, odds ratios for each 1-SD
increase in glucose measures ranged from 0.77 to
0.80, with no evidence of nonlinear associations
(data not shown) and little difference from the
results from unadjusted models.
Although the HAPO study did not have the
statistical power to permit examination of perina-
tal death as a primary outcome, with only 130
deaths, unadjusted analyses showed no increase in
the risk of perinatal death with increasing glu-
cose levels. Unadjusted odds ratios for perinatal
death for each 1-SD increase in the fasting, 1-hour,
and 2-hour plasma glucose levels, respectively,
were 0.91 (95% CI, 0.76 to 1.08), 0.93 (95% CI, 0.78
to 1.11), and 0.99 (95% CI, 0.83 to 1.18), with no
evidence of nonlinear associations.
Di s c u s s io n
In 1952, Jorgen Pedersen
22
postulated that ma-
ternal hyperglycemia led to fetal hyperglycemia,
which evoked an exaggerated fetal response to in-
sulin. Since then, the Pedersen hypothesis has
formed the basis for understanding the pathophys-
iological consequences of diabetes during preg-
nancy. The objective of the HAPO study was to
clarify risks of adverse outcomes associated with
degrees of maternal glucose intolerance less se-
vere than overt diabetes mellitus. The data pre-
sented here show associations between increasing
levels of fasting, 1-hour, and 2-hour plasma glucose
obtained on oral glucose-tolerance testing and
birth weight above the 90th percentile and cord-
blood serum C-peptide level above the 90th per-
centile, with weaker associations between glucose
levels and primary cesarean delivery and clinical
neonatal hypoglycemia. We also found positive as-
sociations between increasing plasma glucose lev-
els and each of the f ive secondary outcomes ex-
amined: premature delivery, shoulder dystocia or
birth injury, intensive neonatal care, hyperbiliru-
binemia, and preeclampsia.
Associations between maternal glycemia and
Table 2. (Continued.)
Glucose
Category† Plasma Glucose Level
Fasting 1 Hr 2 Hr
total no.
(no. with outcome)
odds ratio
(95% CI)
total no.
(no. with outcome)
odds ratio
(95% CI)
total no.
(no. with outcome)
odds ratio
(95% CI)
Cord-blood serum C peptide >90th percentile
1 3546 (131) 1.00 3593 (176) 1.00 3599 (193) 1.00
2 6453 (378) 1.41 (1.15–1.74) 6372 (366) 1.07 (0.88–1.29) 6353 (401) 1.06 (0.88–1.27)
3 5255 (429) 1.75 (1.42–2.15) 5132 (458) 1.62 (1.34–1.95) 5039 (440) 1.44 (1.20–1.73)
4 2308 (266) 2.36 (1.88–2.97) 2424 (274) 1.95 (1.58–2.41) 2609 (286) 1.72 (1.40–2.11)
5 1592 (181) 3.62 (2.87–4.58) 1607 (251) 2.76 (2.21–3.43) 1495 (202) 2.21 (1.77–2.76)
6 561 (131) 4.46 (3.36–5.93) 549 (95) 2.91 (2.18–3.89) 596 (109) 2.86 (2.18–3.77)
7 170 (55) 7.65 (5.17–11.32) 208 (51) 4.65 (3.19–6.79) 194 (40) 3.48 (2.33–5.21)
* Associations were adjusted for the following variables: field center, age, body-mass index, height, smoking status, alcohol use, presence or
absence of family history of diabetes, gestational age at oral glucose-tolerance test, infant’s sex, presence or absence of hospitalization be-
fore delivery, mean arterial pressure (in all models), parity (0, 1, or ≥2; not included in the model for primary cesarean delivery), cord-blood
plasma glucose level (included in the model for cord-blood serum C-peptide level >90th percentile only). Additional details are shown in
Tables B, C, D, and E in the Supplementary Appendix.
† Glucose categories are defined as follows: fasting plasma glucose level — category 1, less than 75 mg per deciliter (4.2 mmol per liter); cat-
egory 2, 75 to 79 mg per deciliter (4.2 to 4.4 mmol per liter); category 3, 80 to 84 mg per deciliter (4.5 to 4.7 mmol per liter); category 4, 85
to 89 mg per deciliter (4.8 to 4.9 mmol per liter); category 5, 90 to 94 mg per deciliter (5.0 to 5.2 mmol per liter); category 6, 95 to 99 mg
per deciliter (5.3 to 5.5 mmol per liter); and category 7, 100 mg per deciliter (5.6 mmol per liter) or more; 1-hour plasma glucose level —
category 1, 105 mg per deciliter (5.8 mmol per liter) or less; category 2, 106 to 132 mg per deciliter (5.9 to 7.3 mmol per liter); category 3,
133 to 155 mg per deciliter (7.4 to 8.6 mmol per liter); category 4, 156 to 171 mg per deciliter (8.7 to 9.5 mmol per liter); category 5, 172 to
193 mg per deciliter (9.6 to 10.7 mmol per liter); category 6, 194 to 211 mg per deciliter (10.8 to 11.7 mmol per liter); and category 7, 212
mg per deciliter (11.8 mmol per liter) or more; and 2-hr plasma glucose level — category 1, 90 mg per deciliter (5.0 mmol per liter) or less;
category 2, 91 to 108 mg per deciliter (5.1 to 6.0 mmol per liter); category 3, 109 to 125 mg per deciliter (6.1 to 6.9 mmol per liter); category
4, 126 to 139 mg per deciliter (7.0 to 7.7 mmol per liter); category 5, 140 to 157 mg per deciliter (7.8 to 8.7 mmol per liter); category 6, 158
to 177 mg per deciliter (8.8 to 9.8 mmol per liter); and category 7, 178 mg per deciliter (9.9 mmol per liter) or more.
‡ Data for women who had had a previous cesarean section were excluded.
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2000
adverse outcomes generally remained significant
after adjustment for multiple potential confound-
ers 10 of 12 associations for primary outcomes
and 12 of 15 for secondary outcomes — and were
generally consistent across centers, except the as-
sociation for the fasting plasma glucose level and
primary cesarean delivery. Furthermore, findings
with respect to cord-blood serum C-peptide levels,
and hence fetal insulin levels, support Pedersen’s
proposed mechanism to explain the propensity
for excessive growth in fetuses of mothers with
hyperglycemia. When associations between ma-
ternal glucose level and birth weight were esti-
mated with the use of birth weight as a continu-
ous variable, the difference in mean birth weight
between the lowest and highest glucose categories
was in the range of 240 to 300 g, even after full
adjustment for potential confounders.
Two primary outcomes — birth weight above
the 90th percentile and cord-blood serum C-pep-
tide level above the 90th percentile though
strongly associated with maternal glycemia, could
be viewed as physiological consequences of ma-
ternal glycemia rather than as true disorders or
problems. However, the other two primary out-
comes (primary cesarean delivery and clinical
neonatal hypoglycemia) and the five secondary
outcomes reported (premature delivery, shoulder
dystocia or birth injury, intensive neonatal care,
hyperbilirubinemia, and preeclampsia) also showed
continuous linear associations with the 1-hour
plasma glucose level (seven analyses), the 2-hour
plasma glucose level (six analyses), and the fast-
ing plasma glucose level (three analyses). These are
well-recognized complications of pregnancies in
mothers with preexisting or gestational diabetes,
as currently defined.
Questions have been raised regarding the
benefits of treating “mild” gestational diabetes
mellitus.
13,23,24
However, one recently published
randomized clinical trial, the Australian Carbo-
hydrate Intolerance Study in Pregnant Women
(ACHOIS), found reduced perinatal morbidity and
mortality when standard contemporary treatment
of gestational diabetes mellitus was compared
with no intervention
25
; another study on treatment
of “mild” gestational diabetes mellitus is ongo-
ing.
26
Taken together, the current results and re-
sults of the ACHOIS trial
25
indicate that mater-
nal hyperglycemia less severe than that used to
define overt diabetes is related to clinically impor-
tant perinatal disorders or problems and that their
Table 3. Adjusted Odds Ratios for Associations between Maternal Glycemia as a Continuous Variable and Primary
and Secondary Perinatal Outcomes.*
Outcome Plasma Glucose Level
Fasting At 1 Hr At 2 Hr
odds ratio (95% CI)
Primary outcome
Birth weight >90th percentile 1.38 (1.32–1.44) 1.46 (1.39–1.53) 1.38 (1.32–1.44)
Primary cesarean section† 1.11 (1.06–1.15) 1.10 (1.06–1.15) 1.08 (1.03–1.12)
Clinical neonatal hypoglycemia 1.08 (0.98–1.19)‡ 1.13 (1.03–1.26) 1.10 (1.00–1.12)
Cord-blood serum C peptide >90th percentile 1.55 (1.47–1.64) 1.46 (1.38–1.54) 1.37 (1.30–1.44)
Secondary outcome
Premature delivery (before 37 wk) 1.05 (0.99–1.11) 1.18 (1.12–1.25) 1.16 (1.10–1.23)
Shoulder dystocia or birth injury 1.18 (1.04–1.33) 1.23 (1.09–1.38) 1.22 (1.09–1.37)
Intensive neonatal care 0.99 (0.94–1.05) 1.07 (1.02–1.13) 1.09 (1.03–1.14)
Hyperbilirubinemia 1.00 (0.95–1.05) 1.11 (1.05–1.17) 1.08 (1.02–1.13)
Preeclampsia 1.21 (1.13–1.29) 1.28 (1.20–1.37) 1.28 (1.20–1.37)
* Odds ratios were for an increase in the glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter] for the fasting plas-
ma glucose level, 30.9 mg per deciliter [1.7 mmol per liter] for the 1-hr plasma glucose level, and 23.5 mg per deciliter
[1.3 mmol per liter] for the 2-hr plasma glucose level). The model for preeclampsia did not include adjustment for hos-
pitalization or mean arterial pressure, and presence or absence of family history of hypertension or prenatal urinary tract
infection was included in the model for preeclampsia only. See Table 2
for other details about adjustments in each model.
† Data for women who had had a previous cesarean section were excluded.
‡ The P value for the quadratic (nonlinear) association was 0.013.
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2001
effects can be reduced by means of treatment, al-
though a threshold for the need for treatment is
not established.
The individual measures from the oral glucose-
tolerance tests were not highly correlated, and no
single measure was clearly superior in predicting
the primary outcomes. When adjusted for poten-
tial confounders, relative increases in each glucose
measure were similarly predictive of birth weight
above the 90th percentile. When the glucose mea-
sures were analyzed as continuous variables, each
was a signif icant predictor of primary cesarean
delivery, with 1-SD increases in glucose level be-
ing associated with an increase of 8 to 11% in the
odds of delivery by cesarean section. Clinical neo-
natal hypoglycemia was infrequent (overall inci-
dence, 2.1%), and when adjusted for confounders,
only the 1-hour plasma glucose level remained a
signif icant predictor of this outcome. All three
measures of plasma glucose were highly predictive
of cord-blood serum C-peptide values, with the
fasting plasma glucose level being the strongest
predictor.
Our study had some limitations. The nutritional
status and gestational weight gain of the partici-
pants could affect fetal growth and other perinatal
outcomes; we do not have data on these variables.
Some confounders, such as previous gestational
diabetes mellitus, maternal BMI, or previous mac-
rosomia, may have inf luenced clinical decisions
such as the choice of route of delivery. Because of
the observational design of our study, we cannot
conclude that maternal glycemia is causally related
to the adverse outcomes observed; however, such a
relationship is plausible. Although the rate of par-
ticipation in this blinded study was 54%, we be-
lieve this is unlikely to materially affect our es-
timates of associations. Differences in age and
education level were small between those who
agreed to participate and those who did not.
The broad inclusion criteria, the large number
and the geographic distribution of centers in-
volved, and the similarity across centers in the as-
sociations we found between maternal glycemia
and outcomes provide support that our results can
be generalized to develop outcome-based criteria
for classifying glucose metabolism in pregnancy
that can be applied worldwide. Lack of clear
thresholds for risk and the fact that the four pri-
mary outcomes are not necessarily of equal clini-
cal importance make direct translation of our re-
sults into clinical practice challenging. However,
our findings of significant associations between
adverse outcomes and higher levels of maternal
glucose within what is currently considered a non-
diabetic range indicate the need to reconsider cur-
rent criteria for diagnosing and treating hyper-
glycemia during pregnancy.
Supported by grants from the Eunice Kennedy Shriver Na-
tional Institute of Child Health and Human Development and
the National Institute of Diabetes and Digestive and Kidney
Diseases (R01-HD34242 and R01-HD34243); the National Center
for Research Resources (M01-RR00048 and M01-RR00080); and
the American Diabetes Association; and g rants to local field
centers from Diabetes UK (R D04/0002756), Kaiser Permanente
Medical Center, KK Women’s and Children’s Hospital, Mater
Mother’s Hospital, Novo Nordisk, the Myre Sim Fund of the
Royal College of Physicians of Edinburgh, and the Howard and
Carol Bernick Family Foundation.
Dr. Metzger reports receiving an educational grant from Novo
Nordisk; Dr. Hadden, an honorarium from Novo Nordisk; Dr.
McCance, an honorarium from Takeda; and Dr. Persson, hono-
raria from Novo Nordisk. No other potential conflict of interest
relevant to this article was reported.
APPENDIX
The members of the HAPO Study Cooperative Research Group were as follows: North American Field Centers — Kaiser Foundation Hospi-
tal, Bellflower, CA: M. Contreras, D.A. Sacks, W. Watson (deceased); Prentice Women’s Hospital of Northwestern Memorial Hospital–Northwestern
University Feinberg School of Medicine, Chicago: S.L. Dooley, M. Foderaro, C. Niznik; MetroHealth Medical Center–Case Western Reserve University,
Cleveland: J. Bjaloncik, P.M. Catalano, L. Dierker, S. Fox, L. Gullion, C. Johnson, C.A. Lindsay, H. Makovos, F. Saker; Women and Infants’
Hospital of Rhode Island–Brown University Medical School, Providence: M.W. Carpenter, J. Hunt, M.H. Somers; Sunnybrook and Women’s College
Health Sciences Centre–University of Toronto, Toronto: K.S. Amankwah, P.C. Chan, B. Gherson, E. Herer, B. Kapur, A. Kenshole, G. Lawrence,
K. Matheson, L. Mayes, K. McLean, H. Owen; European–Caribbean Field Centers — Queen Elizabeth Hospital–School of Clinical Medicine and
Research, University of the West Indies, Barbados: C. Cave, G. Fenty, E. Gibson, A. Hennis, G. McIntyre, Y.E. Rotchell, C. Spooner, H.A.R.
Thomas; Royal Jubilee Maternity Hospital, Belfast, Northern Ireland: J. Gluck, D.R. Hadden, H. Halliday, J. Irwin, O. Kearney, J. McAnee, D.R.
McCance, M. Mousavi, A.I. Traub; St. Mary’s Hospital–Manchester University, Manchester, United Kingdom: J.K. Cruickshank, N. Derbyshire, J.
Dry, A.C. Holt, F. Khan, C. Lambert, M. Maresh, F. Prichard, C. Townson; University Hospital–University Medical Center Utrecht, Utrecht, the
Netherlands: T.W. van Haeften, A.M.R. van de Hengel, G.H.A. Visser, A. Zwart; Middle EasternAsian Field Centers — Rajavithi Hospital,
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Rogers, K.W. Wong; John Hunter Hospital, Newcastle, Australia: M. Edgar, W. Giles, A. Gill, R. Glover, J. Lowe, F. Mackenzie, K. Siech, J.
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American Diabetes Association. Clini-
cal practice recommendat ions 2001: ges-
tationa l diabetes mellitus. Diabetes Care
2001;24:Suppl 1:S77-S79.
Metzger BE, Coustan DR. Summary
and recommendations of the Fourt h In-
ternational Workshop-Conference on Ges-
tationa l Diabetes Mellitus. Diabetes Care
1998;21:Suppl 2:B161-B167.
O’Sullivan JB, Mahan C. Criteria for
oral glucose tolerance test in pregnancy.
Diabetes 1964;13:278-85.
Metzger BE, Buchanan TA, Coustan
DR, et al. Summary and recommenda-
tions of the Fifth International Work-
shop-Conference on Gestational Diabetes
Mellitus. Diabetes Care 2007;30:Suppl 2:
S251-S260. [Erratum, Diabetes Care 2007;
30:3154.]
WHO Expert Committee on Diabetes
Mellitus: second report. World Health Or-
gan Tech Rep Ser 1980;646:1-80.
Jensen DM, Damm P, Sorensen B, et
al. Clinical impact of mild carbohydrate
intolerance in pregnancy: a study of 2904
nondiabetic Danish women with risk fac-
tors for gestational diabetes. Am J Obstet
Gynecol 2001;185:413-9.
Yang X, Hsu-Hage B, Zhang H, Zhang
C, Zhang Y, Zhang C. Women with im-
paired glucose tolerance during pregnan-
cy have significantly poor pregnancy out-
comes. Diabetes Care 2002;25:1619-24.
Vambergue A, Nuttens MC, Verier-
Mine O, Dognin C, Cappoen JP, Fontaine
P. Is mild gestational hyperglycemia as-
sociated with maternal and neonatal com-
plications? The Diagest Study. Diabet Med
2000;17:203-8.
Langer O, Brustman L, Anyaegbunam
A, Mazze R. The significance of one ab-
normal glucose tolerance test value on
adverse outcome in pregnancy. Am J Ob-
stet Gynecol 1987;157:758-63.
1.
2.
3.
4.
5.
6.
7.
8.
9.
Sacks DA, Greenspoon JS, Abu-Fadil
S, Henr y HM, Wolde-Tsadik G, Yao JFF.
Toward universal criteria for gestational
diabetes: the 75-gram glucose tolerance
test in pregnancy. Am J Obstet Gynecol
1995;172:607-14.
Sermer M, Naylor CD, Gare DJ, et al.
Impact of increasing carbohydrate intoler-
ance on maternal-fetal outcomes in 3637
women without gestational diabetes. Am J
Obstet Gynecol 1995;173:146-56.
Jarrett R J. Reflections on gestational
diabetes mellitus. Lancet 1981;2:1220-1.
Hunter DJS, Keirse MJNC. Gestational
diabetes. In: Chalmers I, Enkin M, Kierse
M, eds. Effective care in pregnancy and
childbirt h. Oxford, England: Oxford Uni-
versity Press, 1989:403-10.
Spellacy WN, Miller S, Winegar A, Pe-
terson PQ. Macrosomia: maternal charac-
teristics and infant complications. Obstet
Gynecol 1985;66:158-61.
Coustan DR. Management of gesta-
tional diabetes: a self-fulfilling prophecy?
JAMA 1996;275:1199-200.
HAPO Study Cooperative Research
Group. The Hyperglycemia and Adverse
Pregnancy Outcome (HAPO) Study. Int J
Gynecol Obstet 2002;78:69-77.
HAPO Study Cooperative Research
Group, Nesbitt GS, Smye M, Sheridan B,
Lappin TR, Trimble ER. Integration of lo-
cal and cent ral laborator y functions i n a
worldwide multicent re study: experience
from the Hyperglycemia and Adverse
Pregnancy Outcome (HAPO) Study. Clin
Trials 2006;3:397-407.
Chan A, King JF, Flenady V, Haslam R,
Tudehope D. Classif ication of perinatal
deaths: development of the Australian
and New Zealand classifications. J Paedi-
atr Child Health 2004;40:340-7.
International statistical classification
of diseases and related health problems,
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
10th revision: ICD-10. Geneva: World
Health Organi zation, 1992.
Brown MA, Lindheimer MD, de Swiet
M, Van Assche A, Moutquin JM. The clas-
sification and diagnosis of the hyperten-
sive disorders of pregnancy: statement
from the International Society for the
Study of Hy pertension i n P regnancy
(ISSHP). Hy pertens Preg nancy 2001;20:
ix-xiv.
Alkalay AL, Sarnat HB, Flores-Sarnat
L, Elashoff JD, Farber SJ, Simmons CF.
Population meta-analysis of low plasma
glucose thresholds in full-term normal
newborns. Am J Perinatol 2006;23:115-
9.
Pedersen J. Diabetes and pregnancy:
blood sugar of newborn infants. (Ph.D.
thesis. Copenhagen: Danish Science Press,
1952:230.)
Brody SC, Harris RH, Whitener BL, et
al. Screening for gestational diabetes: sys-
tematic evidence review. Rock ville, MD:
Agency for Healthcare Research and Qual-
ity, 2003.
Tuffnell DJ, West J, Walkinshaw SA.
Treatments for gestational diabetes and
impaired glucose tolerance in pregnancy.
Cochra ne Database Syst Rev 20 03;3:
CD003395.
Crowther CA, Hiller JE, Moss JR, et al.
Effect of treatment of gestational diabetes
on pregnancy outcomes. N Engl J Med
2005;352:2477-86.
Landon MB, Thom E, Spong CY, et al.
The Nationa l Instit ute of Child Health
and Human Development Maternal-Fetal
Medicine Unit Network randomized clini-
cal trial in progress: standard therapy
versus no therapy for mild gestat ional
diabetes. Diabetes Care 2007;30:Suppl 2:
S194-S199.
Copyright © 2008 Massachusetts Medical Society.
20.
21.
22.
23.
24.
25.
26.
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... It is linked to serious short-and long-term morbidities for both the mother and the fetus (fetal morbidities include spontaneous abortion, preterm birth, malformations, altered fetal growth, unexplained fetal demise, respiratory distress syndrome, hydraminous, hypoglycemia and hypocalcaemia, hyperbilirubinemia, polycythemia, cardiomyopathy, and long-term cognitive development delay; and maternal morbidities includes Preeclampsia, Diabetic Nephropathy, Diabetic Retinopathy, Diabetic Neuropathy, Diabetic Ketoacidosis and infections [12][13][14][15][16][17][18][19][20][21][22][23]. ...
Article
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Background In Ethiopia, gestational diabetes mellitus (GDM) is a significant public health issue and a risk to maternal and child health. Understanding the prevalence and factors of GDM in Ethiopia may also help determine the best interventions. Therefore, we tried to review gestational diabetes and its factors in Ethiopia.AQ: Please check and confirm the edit made to the article title.yes i have checked and confirm Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) instrument was used to conduct the review. In order to report on the prevalence and contributing factors of gestational diabetes mellitus, the following databases were used: Google Scholar, PubMed, EMBASE, Scopus, Web of Sciences, and Grey literature. Pilo-tests were conducted using a standardized data gathering form in research using a random sample. All statistical analyses were performed using STATA version 16 software for Windows and the random-effects meta-analysis method. The results are presented using texts, tables, and forest plots, along with measure of effect and a 95% confidence interval.Affiliations: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author Given name: [Fentahun Yenealem], Last name [Beyene], Given name: [Bekalu Getnet], Last name [Kassa], Given name: [Gedefaye Nibret], Last name [Mihretie], Given name: [Alemu Degu], Last name [Ayele].yes checked and corrected AQ: Is this word Pilo-tests spelled correctly throughout the article?Thank you the correction Affiliations: Please check and confirm whether the city name is correctly identified for the affiliation 2.yes checked and corrected Results Out of 1755 records, 10 studies with 6525 participants that fully satisfy the inclusion criteria were included for the meta-analysis. The pooled prevalence of gestational diabetes mellitus in Ethiopia was 12.04% [95% CI (8.17%, 15.90%)]. Inadequate dietary diversity, high body mass index, having a family history of DM, history of having macrosomic neonate, low physical activity, and previous history of GDM were statistically significant.AQ: Please note that the sentence Inadequate dietary diversity, high body mass index… is repeated under the below heading Conclusion.yes checked and corrected Conclusion The pooled prevalence of gestational diabetes mellitus is high in Ethiopia. Inadequate dietary diversity, high body mass index, having a family history of DM, history of having macrosomic neonate, low physical activity and previous history of GDM were statically significant variables. Emphasize on early screening, prenatal care and all women having risk factors and trying to get pregnant should get screens for diabetes to improve the maternal and child health at large.AQ: Please check the clarity of the sentence Emphasize on early screening, prenatal…it is clear and easly understand the readers
Article
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Internationally accepted diagnostic criteria recommendations for gestational diabetes (GDM) in 2010 resulted in a rise in global prevalence of GDM. Our aim was to describe the trends in GDM before and after Icelandic guideline changes in 2012 and the trends in pregestational diabetes (PGDM). The study included all singleton births (N = 101 093) in Iceland during 1997–2020. Modified Poisson regression models were used to estimate prevalence ratios (PRs) with 95% confidence intervals (CIs) for risk of GDM overall and by maternal age group, as well as overall risk of PGDM, according to time period of birth. The overall prevalence of GDM by time period of birth ranged from 0.6% (N = 101) in 1997–2000 to 16.2% (N = 2720) in 2017–2020, and the prevalence of PGDM ranged from 0.4% (N = 57) in 1997–2000 to 0.7% (N = 120) in 2017–2020. The overall relative GDM prevalence rate difference before and after 2012 was 380%, and the largest difference was found among women aged <25 years at 473%. Risk of GDM increased in 2017–2020 (PR 14.21, CI 11.45, 17.64) compared to 1997–2000 and was highest among women aged >34 years with PR 19.46 (CI 12.36, 30.63) in 2017–2020. Prevalence rates of GDM and PGDM increased during the study period. An accelerated rate of increase in GDM was found after 2012, overall, and among all maternal age groups. Women aged >34 years had the greatest risk of GDM throughout all time periods, while women aged <25 years appear to have a higher relative rate difference after 2012.
Article
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To investigate whether the increased risk of fetal abdominal obesity (FAO) is present in the older (≥ 35 years) and/or obese (≥ body mass index 25 kg/m²) women with normal glucose tolerance, we reviewed medical record of 6721 singleton pregnancy. At 24–28 gestational weeks (GW), fetal abdominal overgrowth was assessed by the fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference per actual GA by the last menstruation period, estimated GA of biparietal diameter or femur length, respectively. FAO was defined as FAOR ≥ 90th percentile. Compared to young and non-obese women, older women showed significantly higher FAORs irrespective of obesity and the prevalence of FAO in older and non-obese women was significantly higher (11.8% vs. 8.6%, p < 0.05). The odds ratio for large for gestational age at birth were 3.06(1.96–4.77, p < 0.005), 1.47(1.16–1.86, p < 0.005) and 2.82(1.64–4.84, p < 0.005) in young and obese, older and non-obese, and older and obese women, respectively. The odds ratio for primary cesarean delivery in older and non-obese women was 1.33 (1.18–1.51, p < 0.005). An increased risk of FAO at 24–28 GW and subsequent adverse perinatal outcomes have been observed in the older women with or without obesity, compared to younger and non-obese women, despite normal glucose tolerance.
Article
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Gestational diabetes mellitus (GDM) is a condition characterized by glucose intolerance, with hyperglycemia of varying severity with onset during pregnancy. An uncontrolled GDM can lead to an increased risk of morbidity in the fetus and newborn, and an increased risk of obesity or developing type 2 diabetes, hypertension or neurocognitive developmental impairment in adulthood. In this study, we used nuclear magnetic resonance (NMR) spectroscopy and gas chromatography–mass spectrometry (GS-MS) to analyze the urinary metabolomic profile of newborns of diabetic mothers (NDMs) with the aim of identifying biomarkers useful for the monitoring of NDMs and for early diagnosis of predisposition to develop related chronic diseases. A total of 26 newborns were recruited: 21 children of diabetic mothers, comprising 13 in diet therapy (NDM-diet) and 8 in insulin therapy (NDM-insulin), and 5 control children of non-diabetic mothers (CTR). Urine samples were collected at five time points: at birth (T1), on the third day of life (T2), one week (T3), one month (T4) and six months postpartum (T5). At T1, variations were observed in the levels of seven potential biomarkers (acetate, lactate, glycylproline/proline, isocitrate, N,N-dimethylglycine, N-acetylglucosamine and N-carbamoyl-aspartate) in NMD-insulin infants compared to NDM-diet and CTR infants. In particular, the altered metabolites were found to be involved in several metabolic pathways such as citrate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, amino sugar and nucleotide sugar metabolism, and pyruvate metabolism. In contrast, these changes were not visible at subsequent sampling times. The impact of early nutrition (maternal and formula milk) on the metabolomic profile was considered as a potential contributing factor to this finding.
Article
Objectives: To study the neurodevelopmental status of offsprings of mothers with gestational diabetes (OGDM) aged 3½ mo. Methods: This cross-sectional study was conducted at a tertiary hospital, New Delhi which included infants aged 3½ mo (+1 wk) who were either offsprings of women with gestational diabetes (cases) or infants of mothers without gestational diabetes mellitus presenting to tertiary care public hospital in India from January, 2018 through March, 2019, with enrollment of infants done between 10 April, 2018 and 30 March, 2019. Results: The development quotient (DQ) using Developmental Assessment Scales for Indian Infants (DASII) was calculated as Motor DQ, Mental DQ and a composite DQ. The mean motor DQ of the enrolled infants was 101.7 (12.02); it was significantly lower for OGDM than controls [101 (1.41) vs. 109.5 (10.6); P <0.001]. The mean mental DQ of the enrolled infants was 88.9 (12.0); it was significantly lower for OGDM than the control group [84 (9.89 vs. 88 (8.48); P = 0.03]. The total development quotient for the enrolled infants was 95.3 (11.3). The total development quotient for study group was significantly lower than the control group [92.5 (5.65) vs. 98.75 (9.54); P = 0.001]. Conclusions: The mean motor, mental total DQ of offsprings of mothers with GDM were significantly lower than those born to mothers without GDM. Hence follow up, early intervention should be considered for this high risk group.
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Resumen En la actualización del PAPPS de 2022 presentamos aquellas actividades preventivas específicas para la salud de la mujer, exceptuando las relacionadas con la prevención del cáncer (que se incluye en otro documento) y los aspectos relacionados con la morbilidad diferencial de género, aspecto este transversal para todos los grupos de trabajo. La anticoncepción es una actividad preventiva esencial, considerando básico el derecho a decidir tanto el número de hijos como el momento de tenerlos. Debemos informar sobre los posibles métodos anticonceptivos, garantizando en el seguimiento su seguridad, eficacia y efectividad (se incluyen tablas sobre cambio de un método a otro para preservar la protección anticonceptiva). Debemos informar sobre la anticoncepción de urgencia y proponerla en caso de relación sin protección. Todo ello se hará mediante cribado oportunista sin precisar cribado de trombofilia ni de dislipemia, y sí de hipertensión arterial. El embarazo constituye una vivencia vital importante y el médico de familia no debe permanecer ajeno. Debemos ser competentes tanto en la consulta preconcepcional (recomendando la toma de ácido fólico, evitando la exposición a riesgos laborales y medioambientales, realizando cribado de determinadas patologías y valorando la toma de fármacos no indicados durante el embarazo) como en el seguimiento de la gestación. Hagamos o no seguimiento del embarazo, no debemos desentendernos de su control aprovechando este periodo para promocionar estilos de vida saludables y participando de los procesos intercurrentes que puedan acontecer. La menopausia en general y la osteoporosis, en particular, ejemplifican la estrategia de medicalización de procesos vitales que se ha seguido desde diferentes instancias y organismos. En nuestra actualización abordamos la prevención y el tratamiento de aquellos síntomas secundarios a la deprivación estrogénica. Así mismo, planteamos la prevención de la osteoporosis, incluyendo la realización de densitometría en función del riesgo de fractura en los próximos 10 años, y por ello no se aconseja el cribado densitométrico en mujeres menores de 60 años. En la valoración del riesgo preconizamos la utilización de la herramienta frax o mejor, la calibración del riesgo de fractura de cadera con datos de prevalencia de la Comunidad de Madrid. La indicación del tratamiento la vinculamos con la Z-score (densidad mineral ósea comparada con mujeres de su misma edad), al ser una patología asociada al envejecimiento, y no en comparación con mujeres de 20 años de la T-score.
Article
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Objective The aim of the paper is to discuss how a pragmatic definition could change our conception of diagnosis, using gestational diabetes mellitus (GDM) as an example. Study design We review the diagnostic controversy that followed an observational study showing a linear relationship between maternal glycaemia and adverse pregnancy outcomes and the resolution proposed 15 years later by a recent pragmatic trial comparing two screening approaches (one- vs two-step) with different diagnostic thresholds. Results The pragmatic trial involved approximately 24,000 women. The one-step screening strategy using lower GDM thresholds diagnosed twice as many women with GDM, but pregnancy outcomes were not different. We examine how the pragmatic approach integrates research into practice and defines the meaning of a diagnosis according to patient outcomes. The approach is ethically and scientifically sound as compared to the previous methodology, where observational research separated from care gave a theoretical definition of GDM that may have misled medical practice for two decades. Conclusion Pragmatic research integrated into practice can revolutionize our conception of medical diagnosis in the best medical interest of patients.
Article
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There is apparent widespread acceptance of universal laboratory screening for GDM in the U.S., despite both the 2001 ACOG Technical Bulletin on Gestational Diabetes and the Fourth International Workshop-Conference on Gestational Diabetes failing to endorse this practice (4,18). The clinical dilemma of GDM was summarized during the Fourth International Workshop-Conference, which concluded that "although there is a general consensus that prevalence of GDM is increasing globally, there is considerable controversy about the clinical importance of GDM and the magnitude of its impact on mother and offspring" (14,18). Similarly, the Canadian Task Force on Periodic Health Examination stated that "further research is needed to establish the relative risk of neonatal and perinatal illness in relation to various degrees of sub-diabetic elevations in maternal blood glucose levels. The quality of available evidence cannot support a recommendation to include universal screening for gestational diabetes" (15). Instead, this panel suggested that a decision to proceed with screening for this diagnosis must be made on other nonspecific grounds. This vague recommendation was accompanied by an admission that the Task Force recognized that a proportion of women with various degrees of carbohydrate intolerance during pregnancy will have adverse outcomes and might benefit from screening. In 2003, the U.S. Preventative Services Task Force acknowledged that no well-conducted randomized controlled trial existed that provided direct evidence for the health benefits of screening for GDM (2). Whereas insulin therapy may decrease the incidence of fetal macrosomia in those pregnancies complicated by significant hyperglycemia, the magnitude of any effect on maternal and neonatal health remains uncertain. Moreover, the Task Force report noted that insufficient evidence exists to determine if a health benefit accompanies treatment for the large number of women with GDM with milder degrees of hyperglycemia. A randomized controlled trial is necessary to answer this question (2). With mild GDM affecting 1-3% of pregnancies, ∼50-100,000 women annually are being identified and treated for this diagnosis, making this an important clinical issue. Most recently, Crowther et al. (19) reported results on a 10-year multicenter randomized trial designed to determine whether treatment of GDM reduces the risk of perinatal complications. The primary outcome of this study was a composite of perinatal morbidity and mortality (stillbirth, shoulder dystocia, bone fractures, nerve palsy, neonatal intensive care unit admission, and jaundice). The authors found the composite rate of "serious" perinatal complications was lower among the infants of the 490 treated women compared with the 510 infants in the routine care group (1 vs. 4%). This study represents the first large-scale randomized treatment trial for GDM. The sample size is remarkably similar to the ongoing MFMU trial; however, the Crowther study is different with respect to design and analysis of outcome data. Most importantly, the criteria used for the Crowther study include women with more significant hyperglycemia than the MFMU trial. Thus, our study should provide additional information regarding the effect of treatment of women with milder GDM. The perinatal outcome composite in Crowther's study includes shoulder dystocia, a subjective diagnosis, which in turn weighed heavily on the composite difference observed among study groups. An increased rate of admission to the neonatal intensive care unit was observed in the treatment group; however, no difference was observed in the rate of hypoglycemia (secondary outcome) requiring intravenous therapy. Finally, details regarding several antepartum stillbirths suggest these may not have been related to untreated GDM such that the overall conclusion of a reduction in "serious" perinatal complications in treated GDM must be interpreted with caution. In contrast to the Crowther study, the MFMU Network trial primary outcome includes two markers of fetal response to maternal hyperglycemia: neonatal hypoglycemia and cord C-peptide levels. These outcomes should allow for a meaningful interpretation of any treatment effect in the subset of GDM with mild disease. To date, few additional studies have examined the effectiveness of intensive treatment among women with mild GDM. A summary of four trials including 612 women with mild GDM found no benefit in dietary treatment in preventing adverse health outcomes (20). The ongoing population-based Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study is designed to determine levels of carbohydrate intolerance during pregnancy associated with adverse perinatal outcomes. Specifically, at what level of maternal glycemia is there fetal and/or maternal risk? A continuum of risk is anticipated as a likely result in the Hyperglycemia and Adverse Pregnancy Outcome study. The previously cited Crowther study and the ongoing MFMU trial address whether treatment of GDM is effective at reducing perinatal risk. Given that the MFMU Network trial considers only women with normal fasting glucose levels, it should help clarify whether a benefit exists to treatment of mild GDM. The trial should also complement the Hyperglycemia and Adverse Pregnancy Outcome study data in arriving at some consensus for selecting thresholds for diagnosis and treatment of carbohydrate intolerance during pregnancy.
Article
OBJECTIVE: Our purpose was to assess maternal-fetal outcomes in patients with increasing carbohydrate intolerance not meeting the current criteria for the diagnosis of gestational diabetes.STUDY DESIGN: We conducted a prospective analytic cohort study in which nondiabetic women aged ≥24 years, receiving prenatal care in three Toronto teaching hospitals, were eligible for enrollment. A glucose challenge test and an oral glucose tolerance test were administered at 26 and 28 weeks' gestation, respectively; risk factors for unfavorable maternal-fetal outcomes were recorded. Caregivers and patients were blinded to glucose values except when test results met the current criteria for gestational diabetes.RESULTS: Of 4274 patients screened, 3836 (90%) continued to the diagnostic oral glucose tolerance test. The study cohort was formed by the 3637 (95%) patients without gestational diabetes, carrying singleton fetuses. Increasing carbohydrate intolerance in women without overt gestational diabetes was associated with a significantly increased incidence of cesarean sections, preeclampsia, macrosomia, and need for phototherapy, as well as an increased length of maternal and neonatal hospital stay. Multivariate analysis showed that increasing carbohydrate intolerance is an independent predictor for various unfavorable outcomes.CONCLUSION: Increasing maternal carbohydrate intolerance in pregnant women without gestational diabetes is associated with a graded increase in adverse maternal-fetal outcomes.
Article
A matched control study of 126 women equally divided into three groups (normal oral glucose tolerance test, one abnormal test value, and gestational diabetes mellitus) was undertaken to examine the relationships among oral glucose tolerance test results, glycemic control in pregnancy, and adverse perinatal outcome. Characterization of metabolic control for the one abnormal oral glucose tolerance test value and the gestational diabetes mellitus groups (before treatment) showed no significant difference. After the start of treatment, however, a significant (p less than 0.01) difference between the groups in level of control was found. While no significant difference in the average birth weight between the three groups was discovered, the incidence of large infants (macrosomia and large for gestational age) was found to be significantly higher in the one abnormal oral glucose tolerance test group when compared with the normal (34% versus 9%; p less than 0.01) and gestational diabetes mellitus group (34% versus 12%; p less than 0.01). No significant difference for the incidence of an infant large for gestational age was found between the normal group and the patients with gestational diabetes mellitus after treatment. Neonatal metabolic disorders were found to be significantly higher for the one abnormal oral glucose tolerance test group (15%) when compared with the control and the gestational diabetes mellitus groups (3%). We conclude that, if left untreated, one abnormal value on an oral glucose tolerance test is strongly associated with adverse perinatal outcome.
Article
The purpose of this study was to determine the distribution of values for the 75 gm glucose tolerance test in pregnancy and to define glucose intolerance by the relationship between maternal glucose values and neonatal macrosomia. A total 3505 unselected pregnant women were given a 75 gm, 2-hour glucose tolerance test. Diet or insulin therapy was offered only to patients with a fasting plasma glucose level > or = 105 mg/dl or a 2-hour post-glucose-load value > or = 200 mg/dl. Birth weights of live-born singletons delivered from 36 to 42 weeks whose mothers had a fasting plasma glucose level < 105 mg/dl and 2-hour post-glucose-load value < 200 mg/dl were used to calculate relationships between glucose levels and birth weights. At 24 to 28 weeks' gestation the mean and SD plasma glucose values were fasting 83.6 (8.9) mg/dl, 1 hour 128.4 (32.9) mg/dl, and 2 hour 108.4 (24.8) mg/dl. In a multiple logistic regression model the factors found to be statistically significantly associated with macrosomia were maternal race, parity, prepregnancy body mass index, weight gain, gestational age at testing, fasting plasma glucose level, and 2-hour post-glucose-load value. A positive association was found between maternal glucose values and birth weight percentiles. No clinically meaningful glucose threshold values relative to birth weight or macrosomia were found. In the absence of a meaningful threshold relationship between glucose tolerance test values and clinical outcome, criteria defining gestational diabetes will probably be established by consensus.
Article
To evaluate the maternal and neonatal complications rates of mild gestational hyperglycaemia (MGH) compared to a control group in France. A systematic screening by a 50-g glucose challenge test was offered to all women between 24 and 28 weeks of gestation in 15 maternity units. If the 50-g glucose challenge test was > or = 7.2 mmol/l, a 100-g 3-h oral glucose tolerance test (OGTT) was performed. MGH (n = 131) was defined by one abnormal value on the 3-h OGTT (Carpenter and Coustan criteria). The control group (n = 108) was defined by a 50-g glucose challenge test below 7.2 mmol/l. Women with MGH received no treatment or specific advice during the pregnancy. Large for gestational age (LGA) was defined by a birth weight of at least the 90th percentile on French standard growth curves. Women with MGH were older than the controls (28.8 (5.8) vs. 27.0 (5.2); P < 0.05) and had a higher body mass index (24.8 (4.8) vs. 23.0 (3.9); P < 0.01). The rate of pregnancy-induced hypertension and Caesarean section were not different between the MGH and control group. The rate of LGA was significantly higher in the MGH group than the control group (22.1% vs. 11.4%; P < 0.05). After adjustment for confounding factors of macrosomia (pre-pregnancy body mass index > 27, maternal age > 35, multiparity and educational level), there was a persistent relationship between LGA and MGH (odds ratio 2.50; 95% confidence interval (1.16-5.40); P < 0.05). MGH was more frequently associated with adverse maternal and fetal outcome than in the controls (53.4% vs. 28.7%; P < 0.01). This study suggested that the increased rate of adverse maternal and fetal outcome, especially LGA, was associated with untreated mild gestational hyperglycaemia women compared to a control group. This link to lower degrees of hyperglycaemia during pregnancy is independent of confounding factors.
Article
The objective was to study the clinical impact of mild carbohydrate intolerance in pregnant women with risk factors for gestational diabetes mellitus. This was a historical cohort study of 2904 pregnant women examined for gestational diabetes on the basis of risk factors. Information on oral glucose tolerance test results and clinical outcomes was collected from laboratory charts and medical records. The following outcomes increased significantly with increasing glucose values during the oral glucose tolerance test: shoulder dystocia, macrosomia, emergency cesarean section, assisted delivery, hypertension, and induction of labor. However, when corrections were made for other risk factors, hypertension and induction of labor were only marginally associated with glucose levels. In a group of nondiabetic pregnant women with risk factors for gestational diabetes, there was a graded increase in the frequency of shoulder dystocia and other maternal-fetal complications with increasing glucose levels during an oral glucose tolerance test.
Article
There is extreme variation in the definition of low plasma glucose levels in newborn infants in the first postnatal days, ranging from < 30 to < or = 60 mg/dL. The goal of the present study was to define low thresholds (< or = 5th percentile) of plasma glucose concentrations in full-term normal newborns during the first 72 hours of life. Population meta-analysis was performed on published studies of neonatal hypoglycemia ascertained by MedLine search. One-way analysis of variance was computed across the studies for each of the following four postnatal time periods: 1 to 2 (physiological nadir), 3 to 23, 24 to 47, and 48 to 72 hours. The estimated < or = 5th percentiles of neonatal hypoglycemia during 1 to 2, 3 to 23, 24 to 47, and 48 to 72 hours after birth were < or = 28, < or = 40, < or = 41, and < or = 48 mg/dL, respectively. Based on this statistical definition, we recommend that low thresholds of plasma glucose levels of 28, 40, and 48 mg/dL be adopted in full-term normal newborns at 1 to 2, 3 to 47, and 48 to 72 hours of life, respectively.
Reflections on gestational diabetes mellitus Gestational diabetes Effective care in pregnancy and childbirth
  • Rj Jarrett
  • Djs Hunter
  • Mjnc Keirse
  • Wn Spellacy
  • S Miller
  • A Winegar
  • Pq Peterson
Jarrett RJ. Reflections on gestational diabetes mellitus. Lancet 1981;2:1220-1. Hunter DJS, Keirse MJNC. Gestational diabetes. In: Chalmers I, Enkin M, Kierse M, eds. Effective care in pregnancy and childbirth. Oxford, England: Oxford University Press, 1989:403-10. Spellacy WN, Miller S, Winegar A, Peterson PQ. Macrosomia: maternal characteristics and infant complications. Obstet Gynecol 1985;66:158-61.
Classification of perinatal deaths: development of the Australian and New Zealand classifications International statistical classification of diseases and related health problems revision: ICD-10. Geneva: World Health Organization, 1992
  • A Chan
  • Jf King
  • V Flenady
  • R Haslam
  • D Tudehope
  • Ma Brown
  • Md Lindheimer
  • M De Swiet
  • A Van Assche
  • Jm Moutquin
Chan A, King JF, Flenady V, Haslam R, Tudehope D. Classification of perinatal deaths: development of the Australian and New Zealand classifications. J Paediatr Child Health 2004;40:340-7. International statistical classification of diseases and related health problems, 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 10th revision: ICD-10. Geneva: World Health Organization, 1992. Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy 2001;20: ix-xiv.