doi:10.1111/j.1447-0756.2011.01681.x J. Obstet. Gynaecol. Res. Vol. 38, No.

1: 208–214, January 2012

Gestational diabetes and pre-pregnancy overweight:

Possible factors involved in newborn macrosomia

Pablo Roberto Olmos1,5, Gisella Rosa Borzone2, Roberto Ignacio Olmos1,

Claudio Nicolás Valencia1, Felipe Andrés Bravo1, María Isabel Hodgson3,
Cristián Gastón Belmar4, José Andrés Poblete4, Manuel Orlando Escalona1 and
Bernardita Gómez1
Departments of 1Nutrition, Diabetes and Metabolism and 2Respiratory Diseases and 3Pediatrics and 4Obstetrics and
Gynecology, College of Medicine, and 5Department of Electrical Engineering, College of Engineering, Pontificia Universidad
Católica de Chile, Santiago, Chile

Abstract jog_1681 208..214

Aim: Good glycemic control in gestational diabetes mellitus (GDM) seems not to be enough to prevent
macrosomia (large-for-gestational-age newborns). In GDM pregnancies we studied the effects of glycemic
control (as glycosylated hemoglobin [HbA1c]), pre-pregnancy body mass index (PP-BMI) and gestational
weight gain per week (GWG-W) on the frequency of macrosomia.
Methods: We studied 251 GDM pregnancies, divided into two groups: PP-BMI < 25.0 kg/m2 (the non-
overweight group; n = 125), and PP-BMI ⱖ 25.0 kg/m2 (the overweight group; n = 126). A newborn weight
Z-score > 1.28 was considered large-for-gestational-age. Statistical analysis was carried out using the Student’s
t-test and c2-test, receiver–operator characteristic curves and linear and binary logistic regressions.
Results: Prevalence of macrosomia was 14.9% among GDM (n = 202/251, 88.4%) with good glycemic control
(mean HbA1c < 6.0%), and 28.1% in those with mean HbA1c ⱖ 6.0% (n = 49/251, P < 0.025). Macrosomia rates
were 10.4% in the non-overweight group and 24.6% in the overweight group (P = 0.00308), notwithstanding
both having similar mean HbA1c (5.48 ⫾ 0.065 and 5.65 ⫾ 0.079%, P = 0.269), and similar GWG-W
(0.292 ⫾ 0.017 and 0.240 ⫾ 0.021 kg/week, P = 0.077). Binary logistic regressions showed that PP-BMI
(P = 0.012) and mean HbA1c (P = 0.048), but not GWG-W (P = 0.477), explained macrosomia.
Conclusions: Good glycemic control in GDM patients was not enough to reduce macrosomia to acceptable
limits (<10% of newborns). PP-BMI and mean HbA1c (but not GWG-W) were significant predictors of
macrosomia. Thus, without ceasing in our efforts to improve glycemic control during GDM pregnancies,
patients with overweight/obesity need to be treated prior to becoming pregnant.
Key words: diabetes, gestational, macrosomia, obesity, overweight.

Introduction rosomia that is due to gestational diabetes mellitus

There is a worldwide consensus that delivery of a mac-
rosomic or large-for-gestational-age (LGA) infant is
associated with increased frequencies of prolonged
labor, operative delivery, shoulder dystocia and bra-
chial plexus trauma.1 In the particular case of the mac-
(GDM), maternal hyperglycemia – and its conse-
quence, fetal hyperinsulinemia – are positively corre-
lated to neonatal excess body mass.2 However, tight
glucose control seems not to be enough to prevent
macrosomia in GDM, as other variables have emer-
ged as independent factors of excessive fetal growth,

Received: October 21 2010.

Accepted: May 6 2011.
Reprint request to: Dr Pablo R. Olmos, Department of Nutrition, Diabetes and Metabolism, College of Medicine, Pontificia
Universidad Católica de Chile, Alameda 340, Santiago 6513492, Chile. Email: polmos@med.puc.cl

208 © 2011 The Authors

Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology

particularly maternal overweight and obesity (body
mass index [BMI] of 25 or greater).3
In fact, in the last 2 decades, evidence has accumu-
lated showing that maternal obesity is a risk factor for
adverse pregnancy outcomes in general (i.e., even in
the absence of GDM), and LGA infants in particular.4,5
In 2004, a large review of maternal and neonatal data
in the USA6 showed that the statistical association
between GDM and LGA infants strengthened as pre-
gravid BMI increased, thus suggesting that maternal
overweight was an independent risk factor for LGA
newborns among those patients. One year later, Ricart
et al.7 showed that a pregravid BMI above 26.1 kg/m2
was a risk factor for LGA that not only was inde-
pendent from the presence of GDM, but was also a
stronger predictor for LGA than the degree of hyper-
glycemia as determined by the results of the oral
glucose tolerance test (OGGT).
Apart from pre-pregnancy overweight and obesity,
little is known about the impact that weight gain
during pregnancy might have on excessive fetal
growth in the particular case of gestational diabetes, as
recent studies have shown that a single recommenda-
tion of weight gain is not feasible based on current
data. In fact, although the subject seemed to be settled
in 1990 when the US Institute of Medicine established
their gestational weight gain recommendations,8 a 2009
review on outcomes of gestational weight gain, despite
finding a positive correlation between weight gain and
risk of LGA infants,9 also revealed that the quality of
published data was inadequate for providing a single
recommendation of gestational weight gain to all cases
– in agreement with the conclusions of a contemporary
review of 189 studies.10 In other words, adjusting ges-
tational weight gain to pre-pregnancy maternal nutri-
tional status is not enough, as other confounding
variables and comorbidities need to be taken into
consideration – one of which is GDM.
In this context, the aim of our study was to establish
in women with GDM whether, in addition to glycemic
control, pregravid overweight and/or pregnancy
weight gain have an impact on the newborn’s weight
and the frequency of LGA.
Materials and Methods
This study on GDM included 251 pregnancies (in 245
mothers), all of which had been referred by their
obstetrician to our diabetes and pregnancy team. The
‘Healthcare Network’ of our College of Medicine
includes six Obstetrics and Gynecology outpatient cli-
© 2011 The Authors
Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology
Macrosomia and gestational diabetes
nics in Santiago, where faculty and staff carry out the
evaluation and follow up of pregnant mothers, who in
due course are admitted for delivery at the teaching
hospital of our institution. We assumed a 4% rate of
GDM, which is the arithmetic mean of the figures from
two references, that is, 4.1% published in 2004 by Cata-
lano et al.6 and 4.0% (central value of a 2–6% range)
given in the year 2010 by Galtier.11 With this consensus
figure of 4.0%, plus an average of 2200 deliveries per
year in our hospital, we expected to recruit a maximum
of 88 new cases of GDM per year, that is, 968 GDM
pregnancies between 1998 and 2009, the period during
which the recruitment and follow up of our patients
was made. A total of 251 GDM pregnancies were
referred to our diabetes and pregnancy team, that is,
26% of the expected patients. During these 11 years,
however, the GDM referral rate has increased steadily
(up to 80% of the expected number of cases in the year
2008). Our data does not include multiple pregnancies.
The diagnosis of GDM was confirmed by a World
Health Organization OGGT, using a 75-g oral glucose
load, with basal and 2-h venous plasma glucose mea-
surements.12,13 Referral of GDM mothers was done after
the 24th week, which is the date at which the OGGT is
carried out in all pregnancies in Chile.
The diet consisted of 25–30 kilocalories per kg of
ideal pre-pregnancy bodyweight for women with
normal bodyweight, aiming to an increase of 11–12 kg
during pregnancy. The kilocalories allowance was
moderately reduced in obese women (i.e., a pre-
pregnancy BMI ⱖ 30 kg/m2) in order to limit the
weight gain to 6–7 kg. Approximately 40–50% of total
calories were carbohydrates, excluding saccharose,
grapes and ‘diet’, ‘light’ or ‘zero’ products (sweet car-
bonated beverages, ice-creams and jams). Each of the
GDM mothers received an individualized diet both
verbally and as a detailed letter written and printed
during the outpatient visit by the endocrinologist.
Compliance to the diet was assessed in each medical
visit, and appropriate counseling was given in case
errors were detected.
Recommended results for glucose (mg/dL) self-
monitoring were as follows: before breakfast = 70–90;
1 h after breakfast = 90–120; before the midday
meal = 90–105; 1 h after the midday meal = 90–120;
before the evening meal = 90–105; and 1 h after the
evening meal = 90–120.14 Whenever these parameters
could not be met by diet and self-monitoring of blood
glucose, patients were admitted to the institutional
hospital, where they were started on intensified insulin
therapy (IIT).
209
P. R. Olmos et al.
In general, ‘glycemic control’ – also known as
‘quality of glycemic control’ – is defined as the extent to
which serum glucose of a given patient falls within
recommendations. The variable that gives the best
measure of glycemic control is the glycosylated hemo-
globin (HbA1c). The HbA1c was measured every
2 weeks throughout, by means of high-performance
liquid chromatography, using a Variant-II HPLC
system, with a normal range of 4.27–6.07%, and a stan-
dard deviation of 0.45%. In this manuscript, ‘mean
HbA1c’ is the arithmetic mean of all measurements of
HbA1c that have been done in a given patient during
the entire pregnancy.
Another variable reflecting glucose control is the
mean blood glucose, which is the arithmetic mean of
all capillary glucose measurements of a given patient
from diagnosis of GDM to delivery.
IIT consisted of two injections (before breakfast and
at bedtime) of neutral protamine hagedorn (NPH)
human insulin (Humulin-N or Insuman-N), plus three
injections of regular (rapid-acting) insulin (Humulin-R
or Insuman-R). All patients attended follow-up
appointments by an endocrinologist and an obstetri-
cian every 1–2 weeks.
We used the 2004 percentile curves for fetal weight of
the Chilean Ministry of Health.15 The fetuses and
newborn infants whose weights were between the 10th
and 90th percentiles were considered adequate for
gestational age, those below the 10th percentile were
small-for-gestational-age, and those above the 90th
percentile (i.e., weight Z-Score > 1.28) were classified
as LGA.
Gestational weight gain of the mother (GWG) was
calculated by subtracting the pre-pregnancy body-
weight from the antepartum bodyweight, whereas
the gestational weight gain per week (GWG-W, in
kg/week) was calculated by dividing the GWG by the
duration of pregnancy.
Unless stated otherwise, results are reported as the
mean ⫾ one standard error of the mean. The statistics
package used was pasw Statistics 18, version 18.0.2,
dated 18 April 2010 (with WinWrapBasic, Copyright
1993–2007 Polar Engineering and Consulting (http://
www.winwrap.com/.). Comparisons of means were
carried out using the Student’s t-test. Categorical vari-
ables were compared using the c2-test. Linear regres-
sions were carried out, calculating the ‘R’ coefficient
and a P-value. Binary logistic regression with forward-
conditional method was used to assess the impact of
multiple variables on newborn macrosomia. Akaike
information criterion was used to select the model with
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Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology
the best combination of variables. In order to determine
the capacity of a continuous variable for discriminating
LGA from non-LGA newborns, receiver–operator
characteristic (ROC) curves were constructed to find
the best possible trade-off between sensitivity and
‘1-specificity’ (false positive) rates. The area under the
ROC curve was also calculated.
A P-value below 0.05 was considered significant
throughout. Bonferroni correction was used as needed
for multiple comparisons.
Results
In 251 pregnancies with GDM, 17.7% were LGA
newborns. Prevalence of macrosomia was 14.9%
among GDM (n = 202/251, 88.4%) pregnancies having
good glycemic control (mean HbA1c < 6.0%), and
28.1% in those with mean HbA1c ⱖ 6.0% (n = 49/251,
P < 0.025).
Figure 1a shows the correlation between pre-
pregnancy BMI and the Z-Score of the newborn weight
in all 251 pregnancies with GDM. The data fit a linear
regression function with a positive slope. Figure 1b
shows the ROC curve for pre-pregnancy BMI as a pre-
dictor of macrosomia in the newborn. A cut-off point of
24.5 kg/m2 for pre-pregnancy BMI had a sensitivity of
0.83, a ‘1-specificity’ (false positive rate) of 0.53, and an
area under the ROC curve of 0.703.
Considering that the aforementioned cut-off point
was very similar to the upper limit of the normal BMI
in adults (25.0 kg/m2), we decided to divide the
cohort of 251 GDM pregnancies into two groups
(Table 1): the pre-pregnancy BMI < 25 kg/m2 (the
non-overweight [NOW] group; n = 125) and the pre-
pregnancy BMI ⱖ 25 kg/m2 (the overweight [OW]
group; n = 126). The OW group had a rate of macroso-
mia of 24.6%, which was 2.5 times higher than that in
the NOW group (10.4%, P = 0.00308), despite having a
similar mean HbA1c (P = 0.209) and similar GWG-W
(P = 0.077).
In Table 2, binary logistic regression, limited to the
NOW pregnancies only, shows that macrosomia is
explained just by mean HbA1c, leaving out of the
model both GWG-W and mean blood glucose.
In Table 3, binary logistic regression, restricted only
to OW pregnancies, showed that macrosomia is
explained just by mean HbA1c, thus leaving out of the
model both GWG-W and mean blood glucose.
Binary logistic regression (Table 4) applied to the
whole cohort of 251 GDM pregnancies, showed that
both pre-pregnancy BMI (P = 0.012) and mean HbA1c
© 2011 The Authors
 Macrosomia and gestational diabetes

Figure 1 (a) Correlation and linear regression between pre-pregnancy body mass index (BMI) and the Z-Score of the
newborn weight in all 251 pregnancies with gestational diabetes mellitus. r = 0.2323, and P = 0.002. (b) Receiver–operator
characteristic (ROC) curve for pre-pregnancy BMI used for prediction of macrosomia in the newborn, defined as
Z-Score > 1.28 (i.e. >90th percentile). A pre-pregnancy BMI with a cut-off point of 24.5 kg/m2 had a sensitivity of 0.83, a
‘1-specificity’ (false positive rate) of 0.53, and an area under the ROC curve of 0.703.

Table 1 Clinical profile (mean ⫾ standard error of the mean) of both patients and newborns divided into two groups
according to the pre-pregnancy weight status of the mother
NOW OW Test P-value
(n = 125) (n = 126)
Age (years) 32.7 ⫾ 0.61 32.8 ⫾ 0.43 Student’s t 0.850
First visit (weeks) 28.9 ⫾ 0.65 27.9 ⫾ 0.59 Student’s t 0.251
Pre-pregnancy BMI (kg/m2) 22.6 ⫾ 0.15 30.0 ⫾ 0.37 Student’s t —
Mean HbA1c (%) 5.48 ⫾ 0.065 5.65 ⫾ 0.079 Student’s t 0.269
Insulin therapy 13 (10.4%) 36 (28.6%) c2 0.00028*
GWG-W (kg/week) 0.292 ⫾ 0.017 0.240 ⫾ 0.021 Student’s t 0.077
Gestational age at delivery [weeks] 37.9 ⫾ 0.16 37.5 ⫾ 0.19 Student’s t 0.163
Cesarean section (n [%]) 35 (28.0%) 43 (34.1%) c2 0.2943
Perinatal mortality (n [%]) 0 0 c2 1.00
Malformations (n [%]) 3 (2.4%) 2 (1.58%) c2 0.6450
Newborn weight >4000 g (n [%]) 6 (4.8%) 15 (11.9%) c2 0.0420
LGA newborn (n [%]) 13 (10.4%) 31 (24.6%) c2 0.00308*
Z-Score of the newborn weight 0.17 ⫾ 0.11 0.61 ⫾ 0.14 Student’s t 0.022
Hypoglycemia (n [%]) 2 (1.6%) 2 (1.6%) c2 1.00
Hyperbilirubinemia (n [%]) 8 (6.4%) 16 (12.7%) c2 0.08979
Admitted, intensive care (n [%]) 12 (9.6%) 28 (22.2%) c2 0.0063
*Statistically significant: P < 0.003125 after Bonferroni correction has been applied. BMI, body mass index; GWG-W, gestational weight gain
per week (kg); HbA1c, glycosylated hemoglobin; LGA, large-for-gestational-age (>90th centile = Z-Score > 1.28); NOW, non-overweight; OW,
overweight.

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Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology
P. R. Olmos et al.

Table 2 Results in non-overweight pregnancies (n = 125) of binary logistic

regression (method = ‘forward-conditional’) between newborn weight
Z-Score > 1.28 and three covariables: mean HbA1c, GWG-W and MBG
P-value Odds ratio† 95% confidence
interval
Mean HbA1c 0.036 18.214 1.203–275.8
GWG-W 0.929‡ Eliminated —
MBG 0.913‡ Eliminated —
†Odds ratio = e[B]. ‡Out of the three variables introduced, GWG-W and MBG were elimi-
nated from the model on the first stage of the forward-conditional method of the binary
logistic regression. GWG-W, gestational weight gain per week; HbA1c, glycosylated
hemoglobin; MBG, mean blood glucose.

Table 3 Results in overweight pregnancies (n = 126) of binary logistic regression

(method = ‘forward-conditional’) between newborn weight Z-Score > 1.28 and
three covariables: mean HbA1c, GWG-W and MBG
P-value Odds ratio† 95% confidence
interval
Mean HbA1c 0.030 3.201 1.122–9.131
GWG-W 0.590‡ Eliminated —
MBG 0.586‡ Eliminated —
†Odds ratio = e[B]. ‡Out of the three variables introduced, GWG-W and MBG were elimi-
nated from the model on the first stage of the forward-conditional method of the binary
logistic regression. GWG-W, gestational weight gain per week; HbA1c, glycosylated
hemoglobin; MBG, mean blood glucose.

Table 4 Results in all pregnancies (n = 251) of binary logistic regression

(method = ‘forward-conditional’) between newborn weight Z-Score > 1.28 and
three covariables: pre-pregnancy BMI, mean HbA1c, and GWG-W
P-value Odds ratio† 95% confidence
interval
Pre-pregnancy-BMI 0.012 1.150 1.031–1.282
Mean-HbA1c 0.048 2.714 1.031–7.304
GWG-W Eliminated 0.477‡ — —
Constant 0.000 0.000 —
†Odds ratio = e[B]. ‡Out of the three variables introduced, only GWG-W was eliminated from
the model on the first stage of the forward-conditional method of the binary logistic regres-
sion. BMI, body mass index; GWG-W, gestational weight gain per week; HbA1c, glycosy-
lated hemoglobin; MBG, mean blood glucose.

(P = 0.048) explained macrosomia. The third variable,
GWG-W (P = 0.477) had no significant impact.
Discussion
We have reported the study of the follow up and out-
comes of 251 pregnancies treated by us for gestational
diabetes, where the overall neonate LGA rate (17.7%)
was related not only to glycemic control – defined as
mean HbA1c – but also to maternal pre-pregnancy
BMI. In fact, when analyzing the latter by means of a
ROC curve, we found that a pre-pregnancy BMI equal
or above 24.5 kg/m2 had a sensitivity (true positive
rate) of 0.83 (i.e. 83%) in predicting LGA newborns,
thus suggesting that maternal overweight – not even
obesity – was enough to accelerate fetal growth. We say
this because the accepted cut-off point for overweight
in adults is 25.0 kg/m2, a figure that is very near to the
one we obtained in the ROC curve.
Therefore, our results have also shown that among
GDM pregnancies there were two different groups of
patients according to whether the pre-pregnancy BMI
was below or equal to/above 25.0 kg/m2. These two
groups have proved to be different with respect to the

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Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology

frequencies of both macrosomia and insulin treatment
during pregnancy.
The OW pregnancies had significantly higher fre-
quency of LGA newborns than their NOW counter-
parts. At first sight, this difference could be assigned
to the tendency of overweight and obese mothers to
have more severe insulin resistance and hyperglyce-
mia than mothers of normal pre-pregnancy weight –
thus leading eventually to more severe hyperglycemia
– as cytokines produced by the adipose tissues have
been shown to increase insulin resistance. One of
these is tumor necrosis factor-alpha (TNF-a), a mol-
ecule that induces serine phosphorylation in the
insulin receptor substrate-1, thus altering the insulin
signaling within muscular and adipose cells.16 The
combined effects of ‘adipose cytokines’ – TNF-a,
interleukin-6 and leptin – would enhance insulin
resistance in obese mothers more than in their non-
overweight counterparts. This phenomenon could
explain why, in our study, glucose control was more
difficult in the OW group, as evidenced by the 2.77-
fold higher frequency of insulin treatment compared
to the NOW group. Unexpectedly, however, this
mechanism could not explain the higher rate of mac-
rosomia in OW compared to NOW pregnancies, as the
mean HbA1c was similar in both groups.
Thus, the high frequency of LGA in OW could not be
explained only by the classical pathway of maternal
hyperglycemia–fetal hyperglycemia–fetal hyperin-
sulinemia.17 We hypothesize that, in addition to glucose
control as reflected by the HbA1c, a second variable,
maternal pre-pregnancy overweight, has somehow a
role enhancing the transport from the OW mother to
the fetus of nutrients other than glucose, that is, amino
acids and/or lipids.
It has been demonstrated that placental leptin
enhances mother-to-fetus amino acid transport
through the syncytiotrophoblast (STB).17 As leptin
in adults is produced by the adipose tissue,18 one
may be tempted to propose that maternal amino
acids could be responsible for the infant macroso-
mia that was observed in the OW group. However,
others have shown that there is no correlation
between maternal leptin levels and birthweight of
the offspring.18,19
Therefore, only the lipids remain as the nutrients
potentially responsible for fetal overgrowth. Physi-
ologically, placental triglyceride transport during the
third trimester is enhanced by maternal hypertriglyc-
eridemia, which in turn is due to two mechanisms:
the decreased catabolism of very-low-density lipopro-
© 2011 The Authors
Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology
Macrosomia and gestational diabetes
teins (VLDL), plus the enhanced lipolysis, that in turn
increases the substrate fatty acids and glycerol flow
towards the hepatic synthesis of VLDL. Both path-
ways can be enhanced by maternal-overweight-
related insulin resistance. The net result is a sharp
increase in the flow of maternal VLDL towards the
placenta.20–24
This hypothetical ‘lipid overflow’ could certainly
explain the association that we have found bet-
ween pre-gestational overweight and LGA infants in
GDM women notwithstanding near-optimal glycemic
control, as their insulin resistance was certainly made
worse by adiposity. In this context, Schaefer-Graf et al.22
have shown that in GDM, maternal plasma triglycer-
ides and fatty acids, measured in the third trimester,
were independent predictors of LGA infants. Whether
maternal excess of plasma triglycerides could be sec-
ondary to pre-pregnancy overweight is very likely, but
it remains to be established.
Before closing the discussion, it is advisable to
provide a word of caution on ruling out the variable
GWG (Tables 2,3,4). This is because the health-care
team in charge of these 251 pregnancies has made
every effort to keep maternal weight gain within
narrow limits. Thus, we may have unintentionally
reduced the statistical impact of this variable on the
regression models.
Despite our efforts towards tight control of blood
glucose in gestational diabetic patients, the LGA rate
stayed above what is regarded to be an acceptable limit
(i.e., 10% or less). Our results suggest that, in order to
further reduce the incidence of LGA infants in GDM, in
addition to tight glycemic control during pregnancy in
all patients, counseling and treatment for overweight
and obese women is needed,25 encouraging them to
aim for a BMI below 25.0 kg/m2 before becoming
pregnant.
We conclude that in Chilean women with GDM,
both pre-pregnancy BMI and mean HbA1c (but not
GWG-W) are significant predictors of newborn mac-
rosomia. Good glycemic control in GDM pregnancies
was not enough to reduce macrosomia to acceptable
(i.e. <10%) limits, as pre-pregnancy overweight/
obesity (pre-pregnancy BMI > 24.5 kg/m2) remained
as a variable that should be controlled in the
pre-gestational period.26
Acknowledgments
The authors are grateful to Mrs Carolina Torres for her
excellent secretarial support.
213
P. R. Olmos et al.
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