Risk factors for fetal macrosomia: the importance of a positive

oral glucose challenge test

Giorgio Mello, Elena Parretti, Federico Mecacci, Roberto Lucchetti, Corrado Lagazio
1
, Monica Pratesi
1
and
Gianfranco Scarselli
Institute of Obstetrics and Gynecology and
1
Department of Statistics G. Parenti, University of Florence, Florence, Italy
(Correspondence should be addressed to G Mello, Via Masaccio, 92, 50132 Firenze, Italy)
Abstract
Objective: The aim of this study was to investigate whether minor abnormalities of glucose metabolism
without gestational diabetes are a risk factor for fetal overgrowth.
Design: A sample of 1883 unselected white motherinfant pairs were screened for gestational diabetes
using a 50 g 1-h oral glucose challenge test (GCT) in two periods of pregnancy: early (1620 weeks)
and late (2630 weeks).
Methods: The effects of risk factors (glucose metabolism, previous history of mothers, obesity, multi-
parity and age of mothers) were estimated using a multinomial logit model.
Results: The level of risk was related to gestational age at the appearance of an abnormal GCT. Patients
with an abnormal GCT in the early and late periods of pregnancy (Group 1) had a risk of delivering a
large for gestational age (LGA) infant seven times higher than the control group (normal GCT in both
periods), and patients with a normal GCT in the early period and an abnormal GCT in the late period
(Group 2) showed a risk three times higher than the control group. Among the historical risk factors
for LGA infants, such as maternal obesity, multiparity, previous gestational diabetes and previous
delivery of an infant weighing 4000 g or more, only the latter was associated with fetal overgrowth
with a risk level 4.7 higher than the control group. Group 1 patients had a signicantly higher
incidence of pregnancy-induced hypertension and preterm birth. There were no differences in the
frequency of 5-min Apgar score <7 and metabolic complications among the infants of all groups. We
found a signicantly higher rate of shoulder dystocia in Group 1 infants than in infants in the other
groups.
Conclusions: Our results suggest that a positive GCT at 2630 weeks is the most important risk factor
for fetal overgrowth. This result was strongly enforced in patients who had also shown a positive early
GCT at 1620 weeks.
European Journal of Endocrinology 137 2733
Introduction
Maternal diabetes is only one of the factors associated
with fetal overgrowth; most large for gestational age
(LGA) infants are born to non-diabetic mothers. Several
other conditions frequently associated with fetal over-
growth are maternal obesity, multiparity and previous
delivery of an infant heavier than 4000 g (1). A posi-
tive relationship has been found between maternal
prepregnancy weight and neonatal weightheight
index, in both diabetic and control subjects (2).
There is an increased incidence of LGA infants, not
only in pregnant women who equal or exceed the
threshold values dening gestational diabetes (GDM) on
an oral glucose tolerance test (OGTT), but also among
women exhibiting lower degrees of glucose intolerance
(3). A previous study (4) showed that patients who
had elevated 1-h glucose screening test values and
normal OGTT results delivered macrosomic neonates
signicantly more often than those with normal glucose
screening results. Another report (5) showed a positive
association between 1-h glucose screening test
values and birth weight. Women who had only one
elevated value on an OGTT had macrosomic neonates
signicantly more often than those having normal
glucose screens (6) and normal OGTT (7, 8). These
ndings support the concept of a continuum of glucose
abnormality and the thesis that an abnormal glucose
challenge test (GCT) in pregnancy is a risk factor for
LGA.
The purpose of the present investigation was to
examine rst the inuence of factors such as maternal
obesity, multiparity, previous GDM, previous delivery of
an infant weighing 4000 g or more and GCT results on
fetal growth, and secondly to evaluate the effect of a
positive GCT in the absence of GDM, both on the
incidence of obstetrical complications (pregnancy-
induced hypertension, intrauterine growth retardation,
European Journal of Endocrinology (1997) 137 2733 ISSN 0804-4643
1997 Society of the European Journal of Endocrinology
polyhydramnios, preterm births) and mode of delivery,
and on neonatal complications (Apgar score, metabolic
complications, respiratory distress syndrome, shoulder
dystocia).
Materials and methods
Universal screening for GDM with the 1-h GCT is used in
the antenatal unit of the Institute of Obstetrics and
Gynecology of the University of Florence.
The present investigation involved 1883 white
motherinfant pairs screened between September
1989 and December 1992. The study received ethical
approval and all the subjects gave their informed
consent. Women were screened in two periods of
pregnancy: early (1620 weeks) and late (2630
weeks). The screening test consisted of a 50 g oral
glucose load followed by plasma determination 1 h later.
If the plasma glucose level was 7.5 mmol/l or greater, a
3-h OGTT was performed within 1 week. After the
fasting plasma sample was withdrawn, a 100 g oral
glucose load was given and plasma samples were
collected after 1, 2 and 3 h. Interpretation of OGTT
results was made in accordance with the criteria
established by Carpenter & Coustan (9). Anyone with
an early negative GCT or an early positive GCT followed
by a negative OGTT underwent a second screening
test in the later period of pregnancy. All glucose
determinations were conducted using the glucose
oxidase method.
By using a threshold of 7.5 mmol/l, we hoped to
identify almost all the cases of GDM whilst avoiding the
performance of a 3-h OGTT in most of our patients.
Carpenter & Coustan (9) found that the screening test
sensitivity at this threshold is closer to unity, that is, the
proportion of gravid women with GDM missed by the
screening test is reduced to nearly zero. OSullivan et al.
(10) reported the prevalence of GDM among pregnant
women with screening test (plasma) values below
7.9 mmol/l to be 0.7%. It is reasonable to assume
that the prevalence is substantially smaller below
7.5 mmol/l. There may be uncommon occasions of
patients with a test value below 7.5 mmol/l and an
abnormal glucose tolerance test.
In our population, the incidence of GDM was 4.4%
(83 of 1883) in the early period and 7.6% (137 of
1800) in the late period. The overall incidence was
therefore 11.7% (220 of 1883).
In order to investigate the effect of abnormalities of
glucose metabolism on fetal overgrowth, we used GCT
and OGTT results to classify women into seven groups,
each representing a different pattern of glucose
metabolism.
Group 1: patients with abnormal GCT but absence of
GDM in both periods of pregnancy.
Group 2: patients with normal GCT in the early period
and abnormal GCT but absence of GDM in the late
period.
Group 3: patients with abnormal GCT but absence of GDM
in the early period and normal GCT in the late period.
Group 4: patients with normal GCT in both periods.
Group 5: patients with GDM in the early period.
Group 6: patients with normal GCT in the early period
and GDM in the late period.
Group 7: patients with abnormal GCT but normal OGTT
in the early period and GDM in the late period.
Patients with GDM (Groups 5, 6 and 7) received their
antenatal care and delivered at the Institute of
Obstetrics and Gynecology of the University of Florence.
All patients were taught self-monitoring of blood
glucose levels with a memory-based reectance. Study
participants performed a 24-h glycemic prole, con-
sisting of one measurement every 2 h, twice a week.
Insulin therapy was introduced in patients with a
fasting capillary glucose level greater than 5.3 mmol/l
or postprandial capillary glucose levels greater than
6.7 mmol/l. Patients were asked to return to the
metabolic study unit at 2-week intervals to have
adjustments made to their insulin therapy or diet
mode to optimize control.
Plasma glucose values during OGTT, both in early
and in late pregnancy, in each of the seven groups are
presented in Table 1.
Several characteristics were collected at the time of
the rst screening for each patient: these consisted of a
sociodemographic prole and a summary of past
obstetric and medical data, including traditional risk
factors associated with GDM and fetal overgrowth. The
previous history of the mothers identied three groups
of patients: (a) patients with previous GDM; (b) patients
with previous delivery of an infant weighing 4000 g or
more, but in the absence of previous GDM; and (c)
patients with neither previous GDM nor previous
delivery of an infant weighing 4000 g or more. Obesity
was dened as prepregnancy body mass index (BMI)
greater than 25.0 kg/m
2
(11). Multiparity was dened
as a parity greater than two. Gestational age was
assigned by the last menstrual period with conrmation
by rst trimester ultrasound. In cases of late prenatal
care, we used ultrasound to assign gestational age. In
our study no patient was allowed to progress beyond 42
weeks of gestation. Infants were considered to be
appropriate for gestational age (AGA) when their birth
weight ranged between the 90th and the 10th
percentile, LGA when their birth weight was equal to
or greater than the 90th percentile and small for
gestational age (SGA) when their birth weight was
equal to or less than the 10th percentile on the basis of
growth standards developed for our population (12).
Some descriptive statistics of maternal characteristics
and neonatal outcomes are reported in Table 2.
In order to meet the second aim of the analysis,
pregnancies were considered to be complicated in
the presence of pregnancy-induced hypertension,
intrauterine growth retardation, polyhydramnios
and preterm delivery. Criteria for the diagnosis of
28 G Mello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137
pregnancy-induced hypertension were based on the
classication of Davey & MacGillivray (13). Diagnosis of
intrauterine growth retardation was based on a
pathologic decrease in the rate of fetal growth (14).
Polyhydramnios was dened as an amniotic uid index
greater than the 95th percentile for gestational age
(15). Any delivery occurring before 37 completed weeks
from the rst day of the last menstrual period was
considered to be a preterm birth (16).
Neonatal complications considered in the study were:
5-min Apgar score <7, hyperbilirubinemia, hypo-
calcemia, hypoglycemia, respiratory distress syndrome,
shoulder dystocia. Hypoglycemia (capillary heel blood)
was diagnosed if any two consecutive values of plasma
glucose were less than 1.7 mmol/l. Hyperbilirubinemia
was characterized by plasma values equal to or greater
than 204 mmol/l. Hypocalcemia (equal to or less than
1.7 mmol/l) was assessed when clinically indicated
(jitters, tremors, etc.). The diagnosis of respiratory
distress syndrome was based on clinical signs, blood
gas values, need for respiratory assistance, and X-ray
ndings typical of this syndrome. None of the newborns
were born from multiple pregnancies or had congenital
anomalies and there were no macrosomic newborns
(birth weight greater than 4000 g) associated with
post-date (more than 42 weeks) pregnancies.
Statistical analysis
The rst aim of the analysis was to assess the effects of
the risk factors on the distribution of infants among the
three fetal growth categories (AGA, LGA, SGA). Since
the response variable is classied on three nominal
levels we used a multinomial logit model to evaluate the
inuence of the risk factors on fetal overgrowth (17).
The risk factors involved in the specication of the model
were glucose metabolism (seven different patterns
identied by the previous classication), previous history
of the mothers, obesity, multiparity and mothers older
than 35 years.
In our specication of the model the reference
category of the response variable was the AGA class.
Therefore the inuence of risk factor levels on fetal
overgrowth can be read through two parameters: one
contrasting LGA with AGA infants, the other SGA with
AGA infants. The parameter associated with a level of a
risk factor can be interpreted as the logarithm of the
odds ratio between that level and the reference category.
The odds are the probability of being LGA (or SGA) over
the probability of being AGA, given the level of the risk
factor. Therefore, the risk of fetal overgrowth can be
measured by the exponential of the parameter value. An
odds ratio greater than 1 indicates a higher relative
frequency of LGA (or SGA) for the corresponding risk
factor level with respect to the reference category.
The model selection (i.e. the choice of signicant
factors) was based on the likelihood ratio test;
condence intervals for each odds ratio were con-
structed using the normal approximation. Single odds
ratios are considered statistically signicant if the
correspondent 95% condence interval does not cover
unity. The application was conducted using the GLIM
package (18).
In order to evaluate the effect of a positive GCT in the
absence of GDM on maternal (pregnancy-induced
hypertension, intrauterine growth retardation, poly-
hydramnios, preterm birth, operative delivery) and
neonatal (Apgar score, metabolic complications,
respiratory distress syndrome, shoulder dystocia) out-
comes, attention was focused on the rst four groups
previously dened on the basis of GCTand OGTT results.
Differences in incidence of maternal and neonatal
complications among groups were evaluated with x
2
analysis and Fishers exact tests. Statistical signicance
was dened as P<0.05.
Results
Table 3 shows the odds ratios and the 95% condence
intervals for each level of the factors considered.
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 Fetal macrosomia and testing 29
Table 1 MeanS.D. glucose plasma values (mmol/l) in early (1620 weeks) and late (2630 weeks) GCT and OGTT tests.
Glucose plasma (mmol/l)
Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 Total
Early period
GCT after 1h 8:5 0:8 6:3 0:9 8:2 0:5 5:6 1:5 9:3 1:3 6:4 1:1 8:7 0:9 6:4 1:7
OGTT initial value 4:6 0:4 4:6 0:5 5:1 0:6 4:7 0:5 4:8 0:5
OGTT after 1h 8:1 1:2 7:3 1:4 11:0 1:3 8:9 1:3 8:8 1:8
OGTT after 2h 6:7 1:0 6:4 1:1 9:4 1:1 6:9 1:1 7:4 1:6
OGTT after 3h 5:6 3:3 5:3 1:2 7:0 1:6 5:4 1:4 5:9 2:6
Late period
GCT after 1h 8:7 0:9 8:3 0:8 6:6 0:7 6:2 0:9 8:8 0:9 9:7 1:3 7:1 1:5
OGTT initial value 4:7 0:4 4:6 0:4 5:0 0:5 5:1 0:6 4:7 0:5
OGTT after 1h 8:6 1:1 8:4 1:2 10:7 1:1 10:9 1:2 8:9 1:5
OGTT after 2h 7:3 1:0 7:0 1:0 9:4 1:1 9:4 1:2 7:6 1:4
OGTT after 3h 5:9 1:1 5:8 2:4 7:1 1:6 7:0 1:5 6:1 2:1
Different patterns of glucose metabolism and the
previous history of mothers showed a signicant
inuence on birth weight, while multiparity, obesity
and age of mothers seemed not to be signicant factors.
The interactions between all the considered factors were
not statistically signicant and are not reported in
Table 3.
Patients belonging to Groups 1, 2 and 6 showed a
signicant increase in the risk of fetal overgrowth
(LGA) with respect to patients with normal glucose
metabolism (reference category). The highest level of
risk was achieved by patients in Group 1: the estimated
odds ratio indicated a risk seven times higher than in
the control group. This high level was not due to the
higher incidence of previous GDM and the higher
maternal age of patients in Group 1 (see Table 2), since
the parameters measuring the interaction between
glucose metabolism and previous history and age of
mothers were not signicant. Patients with previous
delivery of an infant of 4000 g or more showed a risk 4.7
times greater than patients having a normal history. In
our analysis, the absence of interactions between
glucose metabolism and the previous history of the
mothers indicated that the risk due to previous delivery
of an infant of 4000 g or more does not signicantly
differ among groups.
Obstetrical complications, mode of delivery and
neonatal complications of Groups 1, 2, 3 and 4 (control
group) are shown in Table 4. Patients of Group 1 had a
signicantly higher incidence of pregnancy-induced
hypertension. Comparable rates of intrauterine growth
retardation and polyhydramnios were found between
the four groups. A signicantly higher rate of preterm
births was found in Group 1 compared with Group 3
and the control group. There was no signicant
difference in the frequency of normal spontaneous
delivery, Cesarean section and vacuum extraction.
There was no difference in the frequency of 5-min
Apgar scores <7. Comparison of metabolic com-
plications, such as hyperbilirubinemia, hypocalcemia
and hypoglycemia revealed no signicant differences
among the four groups. No signicant difference was
found also in the incidence of respiratory distress
syndrome. There was a signicantly higher risk for
shoulder dystocia for the infants of Group 1 compared
with those of the control group.
Discussion
The results of this study are consistent with previous
reports that minor abnormalities of glucose metabolism
without GDM are a signicant risk factor for fetal
overgrowth (3, 4, 68, 19). The level of risk is related to
gestational age at the onset of abnormal maternal
glucose metabolism. Patients with abnormal GCT in the
early and late periods of pregnancy (Group 1) had a risk
of LGA infants seven times higher than the control
30 G Mello and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137
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group and patients with normal GCT in the early
period and abnormal GCT in the late period (Group 2)
showed a risk three times greater than the control
group. The patients of Group 3 did not differ signi-
cantly from the control group. Our results suggest that a
positive GCT at 2630 weeks is the most important risk
factor for fetal overgrowth. This result is strongly
enforced in patients who also have a positive early
GCT at 1620 weeks.
The current study supports the consideration of a
positive 1-h glucose screen itself as a marker of
abnormal carbohydrate metabolism with effects on
fetal growth. Leikin et al. (4) showed that minor
carbohydrate intolerance in subjects with an elevated
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 Fetal macrosomia and testing 31
Table 3 Odds ratios (OR) with 95% condence intervals (CI) obtained from multinomial logit model for the associations between selected
variable and fetal growth.
LGA SGA
Parameter OR 95% CI OR 95% CI
Glucose metabolism
Group 1 7.06 4.7710.44 0.42 0.101.81
Group 2 3.04 2.174.25 0.49 0.211.11
Group 3 2.38 0.946.02
a

a
Group 4 1.00 1.00
Group 5 1.03 0.462.30 1.18 0.393.52
Group 6 2.09 1.094.00 0.31 0.042.37
Group 7 1.45 0.613.41 1.39 0.404.87
Previous history of mothers
Normal 1.00 1.00
Previous gestational diabetes 0.60 0.201.87
a

a
Previous delivery infant > 4000g 4.74 1.7512.85
a

a
Obesity
No 1.00 1.00
Yes 1.03 0.701.51 1.24 0.612.55
Multiparity
No 1.00 1.00
Yes 2.10 0.994.46 0.89 0.117.37
Maternal age > 35 years
No 1.00 1.00
Yes 1.22 0.871.72 0.95 0.452.00
a
Not estimated because of lack of observations.
Table 4 Maternal complications, mode of delivery and neonatal complications.
Group 1 Group 2 Group 3 Group 4
Maternal complications
Pregnancy-induced hypertension (%) 2.9
a
1.5 0.0 0.6
Intrauterine growth retardation (%) 0.6 0.5 0.0 1.6
Polyhydramnios (%) 0.0 0.5 0.0 0.1
Preterm birth (%) 8.0
b
5.3 2.9 4.3
Modes of delivery
Normal spontaneous delivery (%) 81.0 76.2 73.5 80.5
Operative delivery (%)
Cesarean section 16.1 20.0 23.5 16.1
Vacuum extraction 2.9 3.8 2.9 3.4
Neonatal complications
Metabolic complications (%)
Hyperbilirubinemia 4.0 4.8 0.0 3.1
Hypocalcemia 0.0 0.5 0.0 0.5
Hypoglycemia 2.3 0.6 0.0 0.7
Respiratory distress syndrome 2.3 0.6 1.5
Shoulder dystocia 1.7
c
0.5 0.3
a
P < 0
:
01, Group 1 vs Group 4;
b
P < 0
:
05, Group 1 vs Groups 3 and 4;
c
P < 0
:
05, Group 1 vs Group 4.
glucose screen but normal OGTT was associated with
delivery of macrosomic infants, even after correcting for
other variables associated with macrosomia. Another
report showed positive association between 1-h glucose
screen test values and birth weight (5). Berkus et al. (20)
have also found that patients with abnormal 50 g
screen values but normal OGTT had signicantly higher
insulin output and insulinglucose ratios than those with
normal GCT. Landy et al. (21) have shown that a glucose
screen above 103 mmol/l is associated with a probable
diagnosis of GDM and predictive of neonatal macrosomia
and hypoglycemia in their patient population and
suggested the use of this approach in the diagnosis of
GDM without using the 3-h OGTT.
Both mothers with GDM in the early period (Group 5)
and those with an abnormal GCT but a normal OGTT in
the early period and GDM in the late period (Group 7)
showed rates of LGA infants not signicantly higher
than the control group; this may occur because of the
higher proportion of women treated with insulin in
Group 5 and Group 7 (711% and 614% respectively).
In contrast, mothers with normal GCT in the early
period and GDM in the late period (Group 6) showed a
risk 21 times greater than the control group probably
because of the lower proportion (163%) of women
treated with insulin. These ndings, as well as those
from other studies (22, 23), suggest that insulin therapy
may have contributed to the prevention of fetal
overgrowth in our subjects, lowering the rate of LGA
infants independently of the period of the onset of
abnormal maternal glucose metabolism (23).
Among the historical risk factors for LGA infants such
as multiparity, obesity, previous GDM and previous
delivery of an infant weighing 4000 g or more, only the
latter was associated with fetal overgrowth when
controlling for glucose metabolism, with a level of risk
47 times greater than the reference group. The high
frequency of increased birth weights in subsequent
pregnancies is well accepted. Bakketeig et al. (24) found
that the incidence of an LGA infant was 479% in the
second birth if the rst was LGA, compared with 188%
if the rst birth was AGA.
Our nding of an increased risk of pregnancy-induced
hypertension in Group 1 is consistent with the ndings
of Lindsay et al. (6) who observed a signicant increase
in the incidence of this complication in women with
minor degrees of maternal glucose intolerance.
Cesarean delivery rates were similar in Group 1 and the
control group despite very different LGA rates between the
two groups. This may be because of our policy of
performing elective Cesarean section for all infants with
an estimated weight greater than or equal to 4250 g:
among the 70 LGAinfants of Group 1, only 6 (86%) (data
not shown) had a birth weight above this threshold.
A threefold higher rate of shoulder dystocia was
found in Group 1 compared with the other two groups.
This fact may be related to the higher incidence of LGA
infants in this group.
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Received 24 June 1996
Accepted 27 February 1997
EUROPEAN JOURNAL OF ENDOCRINOLOGY (1997) 137 Fetal macrosomia and testing 33