You are on page 1of 7

CCA-13819; No of Pages 7

Clinica Chimica Acta xxx (2015) xxxxxx

Contents lists available at ScienceDirect

Clinica Chimica Acta

journal homepage:

Gestational diabetes mellitus: Where are we now?

Eran Ashwal, Moshe Hod
Perinatal Division, Department of Obstetrics and Gynecology, Helen Schneider Hospital for Women, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, Israel

a r t i c l e

i n f o

Article history:
Received 13 September 2014
Received in revised form 24 January 2015
Accepted 24 January 2015
Available online xxxx
Gestational diabetes pregnancy
Type 2 diabetes mellitus

a b s t r a c t
Gestational diabetes mellitus (GDM) is dened as any carbohydrate intolerance rst diagnosed during
pregnancy. The prevalence of GDM is about 25% of normal pregnancies and depends of the prevalence of
same population to type 2 diabetes mellitus. It is associated with adverse outcome for the mother, the fetus,
neonate, child and adult offspring of the diabetic mother. Detection of GDM lies on screening, followed as
necessary by diagnostic measures. Screening can either be selective, based upon risk stratication or universal.
Timely testing enables the obstetrician to assess glucose tolerance in the presence of the insulin-resistant state
of pregnancy and permits treatment to begin before excessive fetal growth has occurred. Once a diagnosis of
GDM was made close perinatal surveillance is warranted. The goal of treatment is reducing fetal-maternal
morbidity and mortality related with GDM. The exact glucose values needed are still not absolutely proved.
The decision whether and when to induce delivery depends on gestational age, estimated fetal weight, maternal
glycemic control and bishop score. Future research is needed regarding prevention of GDM, treatment goals and
effectiveness of interventions, guidelines for pregnancy care and prevention of long term metabolic sequel for
both the infant and the mother.
2015 Elsevier B.V. All rights reserved.

1. Introduction
Gestational diabetes mellitus (GDM) is dened as any carbohydrate
intolerance rst diagnosed during pregnancy [1]. It is associated with
adverse outcome not only for the mother, but also for the fetus, neonate,
child and adult offspring of the diabetic mother. Maternal consequences
include increased rate of operative and cesarean delivery, hypertensive
disorders during pregnancy and future risk for type 2 diabetes mellitus
(T2DM) as well as other aspects of the metabolic syndrome, such as
obesity, cardiovascular morbidities and recurrent GDM [24]. Also,
there are maternal implications secondary to a delivery of a macrosomic
or large for gestational age (LGA) fetus, such as an increased rate of
cesarean delivery, postpartum hemorrhage (PPH), birth trauma and
shoulder dystocia [4,5].
As today, GDM is dened as carbohydrate intolerance of variable
severity with onset or rst recognition during pregnancy. The denition is applicable regardless of whether insulin is used for treatment
or the condition persists after pregnancy. It does not exclude the

Abbreviations: BMI, body mass index; DM, diabetes mellitus; GCT, glucose challenge
test; GDM, gestational diabetes mellitus; IUFD, intrauterine fetal death; LGA, large for gestational age;OGTT, oral glucose tolerance test; PPH, postpartumhemorrhage; T2DM, type2 diabetes mellitus.
Corresponding author at: President Elect EAPM Chairman FIGO GDM Initiative
Committee Professor of Obstetrics and Gynecology Director, Division of Maternal Fetal
Medicine, Helen Schneider Hospital for Women, Rabin Medical Center, Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel. Tel: + 972 3-9377400; fax: + 972-39377402; Mobile: +972 528888899.
E-mail address: (M. Hod).

possibility that unrecognized glucose intolerance may have antedated

the pregnancy [1]. GDM complicates up to 14% of all pregnancies,
resulting in approximately 200,000 cases annually in the United
States. It is a major cause of perinatal morbidity and mortality, as well
as maternal long term morbidity. Of all types of diabetes, GDM accounts
for approximately 9095% of all cases of diabetes in pregnancy [4,6]. The
rst reference to diabetes in pregnancy was made by Bennewitz in 1823
[7]. He considered diabetes to be a transient symptom of pregnancy
and proved his theory when after two pregnancies all symptoms and
glycosuria disappeared. The next signicant milestone in diabetic
research during pregnancy was achieved by Priscilla White. Back in
the early 20th century women with diabetes had low chances for
successful pregnancy outcome. Pricilla was the rst to believe that
diabetes is not a contraindication to pregnancy. In 1949, White
published the rst version of the classication system that had an
immense clinical value to practitioners all over the world [8]. In 1979,
the White Classication underwent its last revision [9]. In 1952, Jorgan
Pedersen pointed out his hyperglycemia [maternal] hyperinsulinism
[fetal] hypothesis. According to his hypothesis maternal hyperglycemia
results in fetal hyperglycemia, and, hence, results in hypertrophy of fetal
pancreatic islet tissue with insulin hyper secretion. The hyperinsulinism
in the presence of more than adequate supplies of glucose, abruptly
eliminated at birth, explains several of the characteristic features
observed in the offspring, [10]. This theory is still in use more than
20 years after Pedersen's death, and is now called the Pedersen Theory.
In 1989, Representatives of Government Health Departments and
patient organizations from all European countries met with diabetes
experts under the aegis of the Regional Ofces of the World Health
0009-8981/ 2015 Elsevier B.V. All rights reserved.

Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015),

E. Ashwal, M. Hod / Clinica Chimica Acta xxx (2015) xxxxxx

Organization and the International Diabetes Federation in Vincent, Italy.

They unanimously agreed upon the need to search for the ways to prevent, treat and cure diabetes. The St. Vincent Declaration highlights the
importance of diabetes related issues and the necessity to address them
on a local, regional and national level. As for today, GDM is a cause of
concern to both health providers and patients. In national audits who
challenged St. Vincent Declaration poor pregnancy outcome was found.

2. Epidemiology

The prevalence of GDM in the United States is up to 14% and it

accounts for 9095% of diabetes in pregnancy [4,5]. The prevalence of
GDM is directly related to the prevalence of type 2 diabetes mellitus
(DM) in a given population. Risk factors for GDM are outlined in
Table 1, and the risk increases as cumulative factors exist [11,12]. Infants
of diabetic mothers are at an increased risk for future insulin resistance.
This association, along with the increased prevalence of obesity and
type 2 DM, may lead to a signicant rise in GDM, throwing future
generations to a cycle of obesity, insulin resistance, diabetes and various
metabolic complications [13,14].

diabetic population is 79%, rising to 2045% in GDM [20,23]. This

is chiey associated with the maternal glycemic prole [24].
Neonatal hypoglycemia occurs in 25% of newborns, and it depends
on maternal glycemic control at time of delivery [25,26].
Neonatal hypocalcaemia is reported in 1020% of infants to GDM
mothers and it's related to severity of maternal diabetes [21,27].
Neonatal polycythemia has been reported in 5% of infants of GDM
mothers. It is also, partly associated to infant hyperbilirubinemia,
which is more common in infants to diabetic mothers [21,28].
Neonatal respiratory distress is more frequently encountered in
infants to diabetic mothers [29] and is caused mainly because of
respiratory distress syndrome, but also due to transient tachypnea
of the newborn, meconium aspiration syndrome, polycythemia
and hypertrophic cardiomyopathy.
The child of a diabetic mother, mainly prediabetic, remains at
increased risk for obesity, impaired glucose tolerance and diminished neurobehavioral capacities [3032].

4. Screening & diagnosis

3. Morbidity and mortality
Adverse maternal outcome can be short term, such as hypertension,
preeclampsia and an increased risk of cesarean section. Long term
concerns are mainly the increased risk of developing diabetes later in
life. There is a higher rate of hypertensive complications in diabetic
pregnancies compared to normal pregnancies. The risk for preeclampsia rises from 57% to 1520% [15], and it is inuenced by GDM
severity, glucose control and pre-pregnancy BMI [16]. Prepregnancy
obesity and diabetes independently increase the risk for cesarean
delivery [17]. Women with GDM have an increased risk of type 2
diabetes later in life; ranging from 2080% [18,19].
The infants of GDM women are at an increased risk for stillbirth,
aberrant fetal growth, birth trauma and various metabolic and electrolyte disturbances:
Congenital anomalies and spontaneous abortions are not a major
concern as in pre-gestational diabetes. Due to the relatively high
rate of undiagnosed type 2 DM (10%), there should be an effort to
rule out the presence of congenital malformations.
Early, albeit awed studies, showed a 4-fold increase in perinatal
mortality in GDM. These studies did not control for variables affecting perinatal mortality such as fetal malformations, maternal history
of stillbirth and advanced maternal age. Other studies also showed
increased risk for perinatal mortality up to a relative risk of 4.3
over control [2022].
Macrosomia and its partner complications (cesarean section, shoulder dystocia and brachial plexus injury) are the most studied perinatal outcomes in GDM. The overall rate of macrosomia for the non-

Table 1
Risk factors for gestational diabetes mellitus.
Advanced maternal age
Maternal obesity
High parity
Previous delivery of a macrosomic infant
Family history of type 2 diabetes mellitus.
Maternal short stature
Polycystic ovary disease
High levels of saturated fat in the diet
Prior GDM
Prior neonatal death
Prior cesarean delivery
Previous stillbirth or congenital malformations
High blood pressure during pregnancy
Multiple pregnancy

Detection of GDM lies on screening, followed as necessary by

diagnostic measures. Screening can either be selective, based upon
risk stratication (Table 2) or universal [33]. Risk factors should be
determined as early as the rst prenatal meeting, and screening for
GDM in recommended for all pregnant patients unless they are considered at low risk for diabetes.
4.1. Screening
Approaches for screening tests include either fasting glucose, random glucose or, more commonly, glucose challenge test. The test was
developed by O'Sullivan and Mahan in 1950 [34] and involves administration of 50 g glucose load, without consideration from the time of the
last meal, and a determination of plasma glucose levels after 60 min.
Using a cut-off of 140 mg/dl (7.8 mmol/L) will detect 8090% of
women with GDM and will require that an oral glucose tolerance test
(OGTT) be performed for 15% of patients. Lowering the cut off to
130 mg/dl (7.2 mmol/L) will increase the sensitivity to 90100% but
will require OGTT in nearly 25% of all patients. It is generally agreed
that a value of 200 mg/dl (11.1 mmol/L) on glucose challenge test
(GCT) is likely to be associated with the diagnosis of GDM, and therefore
OGTT need not be performed. Women who have positive GCT will need
to be diagnosed for GDM, by performing a 100 g or 75 g oral glucose
tolerance test (Table 3).
4.2. Diagnosis
Initially, O'Sullivan established the criteria for diagnosis of GDM in
1964 [34]. These cutoffs were established to predict the subsequent
development of diabetes and not to identify pregnancies with an
adverse outcome. GDM was dened arbitrarily as 2 or more standard
deviations above the mean. The National Diabetes Data Group (NDDG)
[35] advised in 1979 that plasma should be the preferred sample for
glucose analysis and not in whole blood as was measured according
O'Sullivan. However, due to measurement concerns, Carpenter and
Coustan [36] further modied the cutoffs. In contrast to the 2-step
procedures outlined above, the WHO recommended that GDM be
diagnosed by a 1-step procedure that uses the same OGTT performed
to diagnose diabetes in nonpregnant patient; 75 g of glucose, with
only the fasting and 2-h samples analyzed.
Still, even though OGTT is universally used for diagnosis, the exact
criteria for OGTT are far from being a consensus. Controversy exists
regarding the amount of glucose load (100 g vs. 75 g), the test duration

Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015),

E. Ashwal, M. Hod / Clinica Chimica Acta xxx (2015) xxxxxx

Table 2
Risk stratication for selective screening and diagnosis of GDM.








Recommended screening

Normal weight at birth & prior to pregnancy

Age b25 years
No known diabetes in rst-degree relatives
No history of abnormal glucose metabolism
No history of poor obstetric outcome
Not a member of a high prevalence ethnic group
(Hispanic-American, Native American, Asian
American, African American, Pacic Islander)
Not classied as low/high risk
Detected as high risk at early pregnancy and
did not have GDM in early pregnancy
First degree family history of type 2 DM
Previous history of GDM
Known Glucose intolerance outside of pregnancy

All criteria need to be met

No challenge test is required for screening or diagnosis of diabetes

Challenge test is required at 2428 weeks

Should be tested in a single (OGTT) or two stage manner (GCT & OGTT),
as soon as possible in pregnancy, and if diabetes is not diagnosed, testing
should be repeated at 2428 weeks or if clinical suspicion arises

(2 h vs. 3 h), the actual cutoffs and whether 1 or 2 high values are
necessary [37].
One of the major controversies is the determination of the diabetic
threshold in screening and diagnosis. Previous studies have shown
that the current criteria, may lead to under diagnosis and that treating
women with lower hyperglycemic levels, that are not diagnostic for
diabetes, can lower associated morbidity [3841].
The major aw in the GDM diagnostic criteria is that they have been
based on the risk of future hyperglycemia, and not merely on clinical
squeal. In order to address this issue, the Hyperglycemia and Adverse
Pregnancy Outcome (HAPO) study rst demonstrated an association
between increasing levels of fasting, 1-hour and 2-hour plasma glucose
post a 75 g OGTT to outcomes of birth weight above the 90th percentile,
cord blood serum C-peptide level above the 90th percentile, primary
cesarean delivery, neonatal hypoglycemia, preterm delivery, shoulder
dystocia, intensive neonatal care admission, hyperbilirubinemia and
preeclampsia. Since the results show that there is no apparent glycemic
level cut off for complications but rather a continuum [42]. The International Association of Diabetes and Pregnancy Study Groups (IADPSG)
developed recommendations for the diagnosis and classication of
hyperglycemia in pregnancy to translate the HAPO results into clinical
practice [43]. On the basis of the HAPO data, the panel suggested that
a 75-g OGTT be performed and that GDM be diagnosed if any one of
the values for fasting plasma glucose, 1-h glucose, or 2-h glucose
equaled or exceeded the diagnostic threshold in Table 2. Even though
these recommendations were the rst evidence-based guidelines for
GDM which correlate maternal glucose concentrations to perinatal
outcomes, they have not achieved universal acceptance; they were
endorsed by the American Diabetes Association and by the National
Academy of Clinical Biochemistry [44] along with several countries.
However, the American College of Obstetricians and Gynecologists
recommends that GDM be diagnosed with either the NDDG or the
Carpenter and Coustan criteria [5]. Of note, an NIH Consensus Development Conference was held in 2013 to assess the available data regarding

GDM diagnosis [45], the panel concluded that although international

standardization is benecial, there is insufcient evidence to endorse
the IADPSG recommendations due to the lack of evidence that the
additional women diagnosed will have improved outcomes and the
considerable higher cost by the large increase in the number of
women diagnosed with GDM (prevalence of GDM would increase
from approximately 7% to 18% in the US). The panel supported the
continuation of the 2-step approach.
5. Treatment
The single most important step to achieve minimal morbidity and
mortality is to establish near to normal metabolic control. Several
studies, have tried to establish the optimal glucose levels. However,
pointing out such a threshold is difcult, since the diagnosis, as the
key for successful treatment of diabetes lies in the understanding that
there is a continuum of optimal glucose levels for each outcome,
rather than a single cutoff value [4648]. Table 4 shows glucose values
that are closely related to a risk, similar to that of non-diabetics.
5.1. Diet & behavioral adjustments
The cornerstone of treating a pregnant woman with diabetes is a
well-adjusted diet, combined with patient education and an adapted
physical exercise routine. This may prevent the need for insulin or oral
hypoglycemic agents for some of the patients [49]:
Total daily caloric intake the total amount of calories is calculated
according to current and ideal body weight. Underweight women
(BMI b19.8 kg/m2) should consume 3540 Kcal/kg/day of the ideal
body weight, normal body weight women (BMI 19.829.9 kg/m2)
need a caloric intake of 3032 Kcal/kg/day of the ideal body weight,
and for overweight women (BMI 30 kg/m2) only 2425 Kcal/kg/
day of the ideal body weight, is recommended [50,51].

Table 3
Diagnosis of GDM by an oral glucose tolerance test.

Coustan and Carpenter



Increased values to
consider pathology

Glucose load (g)



Glucose threshold




90 (5.0)
105 (5.8)
95 (5.3)
126 (7.0)
92 (5.1)

165 (9.2)
190 (10.6)
180 (10.0)

180 (10.0)

145 (8.1)
165 (9.2)
155 (8.6)
140 (7.8)
153 (8.5)

125 (6.9)
145 (8.1)
140 (7.8)

*adapted from Vandorsten et al.

IADPSG The International Association of Diabetes and Pregnancy Study Groups; NDDG The National Diabetes Data Group; WHO World Health Organization.
The American College of Obstetricians and Gynecologists endorses either the NDDG or Coustan and Carpenter criteria.

Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015),

E. Ashwal, M. Hod / Clinica Chimica Acta xxx (2015) xxxxxx

Table 4
Goals of glycemic control during pregnancy.
Time of glucose measurement

1 h postprandial
2 h postprandial

Target value




Caloric distribution insulin resistance is highest in the morning as

a result of physiological secretion of crotisol, and during pregnancy
this physiological status is enhanced. Postprandial glucose is inuenced directly by the amount of carbohydrate in the consumed
food. Therefore, carbohydrate based calories, should be consumed
in later parts of the day, rendering breakfast as a small meal. Lunch
and dinner, should each account for about 30% of the daily caloric intake, and the rest should be distributed as snacks throughout the
day. On the total, the diet should consist of three meals a day and
four snacks. The regimen of smaller, frequent meals lead to better
satiety and compliance, with a reduction of postprandial glucose
Nutritional component management the diet should contain 50
60% carbohydrate, 1020% protein, and 2530% fat [51].
Weight gain the recommendation for weight gain, are based on
the prepregnancy weight. Overweight women, with a BMI over
29 Kg/m2 need to gain only 7 Kg during pregnancy. Underweight
women, with a BMI under 19.8 Kg/m2 should gain up to 18 Kg.

5.2. Oral hypoglycemic agents

The use of oral anti-diabetic agents was historically contraindicated
during pregnancy, mainly due to concern over fetal anomalies, and
inducing fetal and neonatal hypoglycemia [52,53]. Studies on human
placental models have demonstrated that the trans-placental passage
of glyburide is negligible [54]. Also, several studies have demonstrated
the efcacy of the drugs, to be comparable to that of insulin, in lowering
glucose levels and pregnancy adverse outcomes [5558]. Oral medication for GDM is becoming the drug of choice in GDM not controlled by
diet. The decision to begin pharmacological therapy depends on the
level of glycemic control achieved with diet, and on gestational age.
Measurement of the fetal abdominal circumference early in the third
trimester can be considered another indicator to dene the need to
start pharmacological therapy [59]. Patients with a fasting plasma
glucose of b 95 mg/dl may be candidates for a trial of diet therapy for a
23 week period before initiation of pharmacological therapy, however,
nearly 30% will fail to achieve the desired levels of glycemic control and
will require pharmacological therapy. Patients with a fasting plasma
glucose of N95 mg/dl are assigned to pharmacological therapy. Criteria
for the selection of glyburide over insulin includes: gestational age of
1133 weeks; fasting glucose on 3-hour OGTT under 110 mg/dl, and
no known sulfa allergy. For women who do not meet these criteria,
insulin is recommended [6062].

5.2.2. Metformin
Oral metformin is the second option for pharmacological noninsulin treatment for GDM. Metformin crosses the placenta and could
affect fetal physiology directly. It improves insulin sensitivity, probably
by activating adenosine monophosphate kinase, and is not associated
with weight gain or hypoglycemia [65]. Reported outcomes of its use
during pregnancy have been favorable [66,67] except for one small,
retrospective cohort study [68] that showed increased rates of perinatal
loss and preeclampsia as compared with insulin treatment.
5.3. Insulin
Approximately 15% of GDM patients will not meet glycemic targets
with diet alone and will require medical intervention with insulin or a
hypoglycemic agent. As mentioned earlier, other than glycemic target
values, after 2930 weeks of gestation (up until which glucose level
were the sole indicator for insulin initiation) the fetal abdominal
circumference can be also used as an indicator for the need to initiate
insulin (or medical) therapy. An abdominal circumference above the
70th percentile should evoke insulin therapy as an additional mean to
the dietary plan [69]. Regular human insulin is mostly prescribed, however, either human regular insulin or rapid acting analogues can be
used, through multiple daily injections or subcutaneous infusion.
Preliminary studies suggest also, that long acting insulin analogues
(e.g. glargine) have a good safety prole during pregnancy [70].
5.3.1. Insulin starting dose
Insulin is dosed according to body weight, between 0.71.0 Units/kg.
With advancing gestational age, the patient becomes more insulin resistant and insulin requirements increase. Between 2032 weeks there is
up to 50% increase from the starting dose of insulin. The average dose
in the rst trimester is 0.7 Units/Kg, 0.8 Units/Kg in the second
trimester, and 0.91 Units/Kg along the third trimester.
5.3.2. Multiple daily injections
There are several protocols to distribute insulin throughout the day,
in several timed daily injections, and according to the glycemic control.
One common regimen involves giving two thirds of the total calculated
insulin dose in the morning (fasting, pre-breakfast), made up of two
parts intermediate-acting to one part regular insulin. The remaining
one third of the total daily insulin dosage should be divided equally as
regular insulin (to be given before dinner) and intermediate-acting
insulin (to be given at bedtime). Another option would be a protocol
of 4 injections a day, combing three doses of regular insulin before
each meal and an intermediate insulin dose before bedtime [71].
5.3.3. Continuous subcutaneous infusion
This mode of administration is as effective as various regimens of
multiple daily injections, in terms of glycemic control, with a lesser
risk of maternal hypoglycemia and an improvement in adverse pregnancy outcome. However, limited data suggests an increased risk for
neonatal hypoglycemia, diabetic ketoacidosis, maternal weight gain
and diabetic retinopathy with the use of an insulin pump [7274].
5.4. Treatment during delivery

5.2.1. Glyburide
The drug increases insulin secretion and diminishes insulin resistance by lowering glucose toxicity. Its onset of action is ~4 h, and duration of action is ~ 10 h. Thus, after achieving the targeted therapeutic
level, glyburide covers the basal requirement as well as postprandial
glucose excursions. The starting dose is 2.5 mg in the morning, increasing to 5 mg if target glucose levels are not met. After 37 days, another
dose of 5 mg in the evening can be added and thereafter, 5 mg increments to a maximum of 20 mg/day. If the patient does not achieve
targeted levels of glycemic control, add long-acting insulin to the regimen or assign the patient to insulin therapy alone [63,64].

Good glycemic control before and during delivery is important to

reduce immediate fetal complications. For diet treated women, an
intravenous infusion of saline solution at a rate of 100150 ml/h and
regular glucose monitoring are advised. In the case of woman on
medical treatment, an intravenous insulin infusion of 12 units of
short acting insulin per hour together with a 5% glucose solution or a
saline solution at a rate of 100150 ml/h is recommended. Blood
glucose should be evaluated every hour and the insulin infusion rate
should be adjusted in order to obtain glucose level of 70130 mg/dl
(3.97.2 mmol/L) [75].

Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015),

E. Ashwal, M. Hod / Clinica Chimica Acta xxx (2015) xxxxxx

5.5. Evaluation of treatment

There is no consensus, as to how often glucose levels should be
checked during the day. Data exists that supports an intensied
approach to treat and monitor diabetes during pregnancy. One of the
key components of this approach, other than stringent glycemic control
and adherence to an established criterion for insulin initiation is veried and documented glucose data, based upon measuring glucose
seven times per day before and after each meal (breakfast, lunch,
dinner) and at bedtime. Rates of macrosomia, shoulder dystocia, cesarean delivery, and neonatal hypoglycemia are reduced by this approach,
compared to women who were monitored and treated less often [5].
Continuous glucose monitoring is a novel system measures glucose
levels in subcutaneous interstitial tissue, takes a glucose measurement
every 1-sec and stores an average value every 5 min, for a total of 288
measurements each day. Monitoring glucose level can help us detect
times of hyperglycemia or hypoglycemia that are not witnessed by
intermittent blood glucose monitoring. Continuous glucose monitoring
system detects a markedly higher proportion of GDM mothers needing
anti-hyperglycemic medication compared with self-monitoring of
plasma glucose. Continuous glucose monitoring could serve as a useful
tool for the long-term management of diabetic pregnancies; however,
the clinical implications and effect on outcome still require evidence
from large prospective trials [76].
6. Timing and mode of delivery
The decision whether to induce labor in pregnancies complicated
with gestational diabetes is controversial. There is still no clear evidence
based medicine to show advantage in induction of labor versus expectant management. The supporting evidence to induce labor is based
on two factors rst, the fear of intrauterine fetal death (IUFD) and
second, expected high rate of macrosomia and an associated increase
of cesarean deliveries and shoulder dystocia. Fetal demise in the pregnant diabetic is a result of the fetal metabolic acidosis in the presence
of abnormal glucose level. GDM patients, have 4-fold higher perinatal
mortality, compared to non-diabetic pregnancy [20]. However, this is
debatable as other studies have demonstrated no association between
IUFD and maternal diabetes. The risk for shoulder dystocia in diabetic
pregnancies is higher than for non-diabetic women for the same fetal
weight, a difference that can be explained by anthropometric differences. In non-diabetic women, macrosomia is constitutional in origin
thus resulting in a proportionally larger infant. In contrast, for the diabetic infant, its overgrowth is due to continuous fetal hyperinsulinemia
resulting in disproportional growth and organomegaly, in the majority
of organs except for the brain therefore, much of the excess weight
is distributed in the trunk and shoulders. This increased chesthead
and shoulderhead size discrepancy results in a higher risk for shoulder
dystocia [77,78]. In order to prevent one case of permanent brachial
plexus injury in babies weighing b4500 g would necessitate performing
153 cesarean deliveries in diabetic mothers and 419 in non-diabetic. If a
cutoff of 4000 g is used, then 169 cesarean sections would be required in
diabetics and 654 in non-diabetic [79]. For women with uncomplicated
insulin treated GDM, expectant management beyond 38 weeks gestation does not reduce the incidence of cesarean delivery, as compared
to predicted high cesarean section rate due to failed induction, and
there is an increased prevalence of large-for-gestational-age infants
(23% vs. 10%) and shoulder dystocia (3% vs. 0%) [80]. Also, induction
of labor at term has a success rate of 80%, with a signicantly higher
CS rate compared to uncomplicated pregnancies [81].
7. Postpartum maternal follow up
In all women with history of GDM and particularly in with obesity
and insulin treated GDM, a recommendation for a 75-g OGTT, should
be performed 6 weeks after delivery [5]. If the blood glucose levels are

normal, another evaluation should be done after 3 years. Patients should

be educated on symptoms of hyperglycemia and they should be advised
to seek medical attention if they should develop such symptoms. They
should also be educated on the need for family planning to ensure
optimal glycemia control from the start of any subsequent pregnancy.
8. Future aspects
Across the past few decades, evidence has emerged regarding the
inuence of the lifetime risk of developing morbidities as obesity, diabetes and cardiovascular disease by exposures that occur in utero and in
childhood. It is yet, unclear whether these explorations reect causal
processes or are confounded by genetic and environmental and social
factors. It is hypothesized that during critical episodes in the human
development, dysmetabolic programming events occur which predispose the offspring to detrimental effects as adults, and that these
processes may be mediated by epigenetic processes that give rise to
trans-generational inheritance [82].
Epidemiological data demonstrated the link between the higher risk
for developing diabetes later in life and the offspring of diabetic pregnancies. In a study of 1436 children to 911 non-diabetic mothers, the
adjusted hazard rate ratio for offspring risk of diabetes per standard
deviation maternal glucose (~ 1.3 mmol/L) was 1.6 (95% condence
interval 1.32.0, P b 0.0001). This relationship was approximately
dose dependent and was reected by a 56 g higher offspring birth
weight per standard deviation unit maternal glucose (P = 0.0002)
[83]. Additionally, in a prospective analysis of 28,358 motherinfant
pairs who enrolled in the National Collaborative Perinatal Project
between 1959 and 1965. Consequently, the offspring were followed
until age 7. Even after adjustment for infant birth weight, the offspring
of mothers with GDM at age 7 had higher weight and BMI compared
to the offspring of mothers without GDM at that age (all P b 0.05). Furthermore, the offspring of mothers with GDM had a 61% higher odds of
being overweight at the age of seven compared to the offspring of
mothers without GDM even after adjustment for maternal BMI, pregnancy weight gain, family income, race and birth weight (OR = 1.61
(95% CI:1.07, 1.28)) [82].
Studies are now being employed in order to inspect the impact of
intervening during pregnancy in order to improve the long term prognosis in those considered at high risk, usually dened on the basis of
the mother's pre- or early pregnancy BMI or glucose tolerance [61].
9. Conclusion
GDM is dened as carbohydrate intolerance of variable severity
with onset or rst recognition during pregnancy. The prevalence of
GDM is about 25% of normal pregnancies and it depends of the prevalence of same population to type 2 DM. The pathogenesis of GDM is
combined of insulin resistance (of normal pregnancy and a chronic
form in GDM patients), B cell dysfunction of autoimmune origin and/
or from genetic mutations and is associated with chronic insulin resistance, genetic changes and placental transport differences in GDM and
non-diabetic pregnant women. The pathogenesis of GDM resembles
that of type 2 DM. indeed, large percentage of GDM patients turn in to
type 2 DM in the upcoming years after pregnancy.
GDM has both maternal and fetal complications: for the mother the
risk is mainly long term the progress to type 2 DM and metabolic
syndrome. For the fetus there are both short and long term complications IUFD, aberrant fetal growth mainly macrosomia with its effect
on delivery and risk of shoulder dystocia and metabolic hematologic
changes (hypoglycemia, hypokalemia, hyperbilirubinemia, hypocalcemia, polycythemia and respiratory distress syndrome). The long term
risks for the fetus are adverse neurological and cognitive outcomes
and mainly early onset metabolic syndrome.
For most women, glucose screening should be conducted at
2428 weeks gestation with use of a 50-g oral glucose load. A value of

Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015),

E. Ashwal, M. Hod / Clinica Chimica Acta xxx (2015) xxxxxx

140 mg/dl or greater necessitates a full diagnostic 100-g OGTT. Testing

at this time not only enables the obstetrician to assess glucose tolerance
in the presence of the insulin-resistant state of pregnancy but, should
GDM be diagnosed, permits treatment to begin before excessive fetal
growth has occurred. Those women who seem to be at high risk for
GDM should be tested by OGTT as fast as possible. If the initial screen
is negative, they should be retested at 2428 weeks gestation.
Once a diagnosis of GDM was made the women should be under
close perinatal surveillance. Diet treatment is advised to all. The goal
of treatment is reducing fetal maternal morbidity and mortality related
with GDM. The exact glucose values needed to do so are still not
absolutely proved. The decision to start pharmacological treatment
depends at the glycemic control with diet treatment and gestational
age at diagnosis. The options for pharmacological treatment are insulin,
which is considered the most accepted treatment, or oral anti-diabetic
drugs such as metformin and glyburide. It is extremely important to
keep good glycemic control in order to reduce maternal and fetal
morbidity and mortality during pregnancy and surrounding delivery.
Concerning time and mode of delivery there is a higher rate of cesarean
section in GDM women. The decision whether and when to induce
delivery depends on gestational age, estimated fetal weight and maternal glycemic control and bishop score. The main reasons for timed delivery are fear of IUFD and shoulder dystocia. When estimated fetal weight
is 4500 g or more, cesarean delivery may be considered because it may
reduce the likelihood of permanent brachial plexus injury in the infant.
Future research is needed regarding prevention of GDM, treatment
goals and effectiveness of interventions, guidelines for pregnancy care
and prevention of long term metabolic sequel for both the infant and
the mother.

[1] Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of
the Fifth International Workshop Conference on gestational diabetes
mellitus. Diabetes Care 2007;30(Suppl. 2):S25160.
[2] Estampador AC, Franks PW. Genetic and epigenetic catalysts in early-life programming
of adult cardiometabolic disorders. Diabetes Metab Syndr Obes 2014;7:57586.
[3] Barahona MJ, Sucunza N, Garcia-Patterson A, et al. Period of gestational diabetes
mellitus diagnosis and maternal and fetal morbidity. Acta Obstet Gynecol Scand
[4] American Diabetes A. Standards of medical care in diabetes 2009. Diabetes Care
2009;32(Suppl. 1):S1361.
[5] American College of Obstetrics and Gynecologists. Gestational diabetes mellitus;
2013[Practice Bulletin number 137].
[6] Landon MB, Gabbe SG. Gestational diabetes mellitus. Obstet Gynecol 2011;118:
[7] Hadden DR, Hillebrand B. The rst recorded case of diabetic pregnancy (Bennewitz HG,
1824, University of Berlin). Diabetologia 1989;32:625.
[8] White P. Pregnancy complicating diabetes. Am J Med 1949;7:60916.
[9] White P. Classication of obstetric diabetes. Am J Obstet Gynecol 1978;130:22830.
[10] Pedersen J. Diabetes and pregnancy; blood sugar of newborn infants during fasting and
glucose administration. Ugeskr Laeger 1952;114:685.
[11] Xiong X, Saunders LD, Wang FL, Demianczuk NN. Gestational diabetes mellitus: prevalence, risk factors, maternal and infant outcomes. Int J Gynaecol Obstet 2001;75:
[12] Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its
association with type 2 diabetes. Diabet Med 2004;21:10313.
[13] Reece EA. Perspectives on obesity, pregnancy and birth outcomes in the United States:
the scope of the problem. Am J Obstet Gynecol 2008;198:237.
[14] Bristow S, Rowan J, Rush E. Obesity and gestational diabetes mellitus: breaking
the cycle. N Z Med J 2009;122:129.
[15] Yogev Y, Xenakis EM, Langer O. The association between preeclampsia and the severity
of gestational diabetes: the impact of glycemic control. Am J Obstet Gynecol 2004;191:
[16] Ehrenberg HM, Durnwald CP, Catalano P, Mercer BM. The inuence of obesity
and diabetes on the risk of cesarean delivery. Am J Obstet Gynecol 2004;191:96974.
[17] Ehrenberg HM, Mercer BM, Catalano PM. The inuence of obesity and diabetes on the
prevalence of macrosomia. Am J Obstet Gynecol 2004;191:9648.
[18] Lauenborg J, Hansen T, Jensen DM, et al. Increasing incidence of diabetes after
gestational diabetes: a long-term follow-up in a Danish population. Diabetes Care
[19] Bian X, Gao P, Xiong X, Xu H, Qian M, Liu S. Risk factors for development of diabetes
mellitus in women with a history of gestational diabetes mellitus. Chin Med J (Engl)

[20] Mitanchez D. Fetal and neonatal complications in gestational diabetes: perinatal mortality, congenital malformations, macrosomia, shoulder dystocia, birth injuries, neonatal complications. Diabetes Metab 2010;36:61727.
[21] Hay Jr WW. Care of the infant of the diabetic mother. Curr Diab Rep 2012;12:415.
[22] Syed M, Javed H, Yakoob MY, Bhutta ZA. Effect of screening and management of
diabetes during pregnancy on stillbirths. BMC Public Health 2011;11(Suppl. 3):S2.
[23] Alberico S, Montico M, Barresi V, et al. The role of gestational diabetes, pre-pregnancy
body mass index and gestational weight gain on the risk of newborn macrosomia: results from a prospective multicentre study. BMC Pregnancy Childbirth 2014;14:23.
[24] Herbison P, Wilson D. Intensied versus conventional management of gestational diabetes. Am J Obstet Gynecol 1995;172:16423.
[25] Ramos GA, Hanley AA, Aguayo J, Warshak CR, Kim JH, Moore TR. Neonatal chemical
hypoglycemia in newborns from pregnancies complicated by type 2 and gestational
diabetes mellitus the importance of neonatal ponderal index. J Matern Fetal
Neonatal Med 2012;25:26771.
[26] Maayan-Metzger A, Lubin D, Kuint J. Hypoglycemia rates in the rst days of life among
term infants born to diabetic mothers. Neonatology 2009;96:805.
[27] Reece EA, Homko CJ. Infant of the diabetic mother. Semin Perinatol 1994;18:45969.
[28] Hopewell B, Steiner LA, Ehrenkranz RA, Bizzarro MJ, Gallagher PG. Partial exchange
transfusion for polycythemia hyperviscosity syndrome. Am J Perinatol 2011;28:
[29] Robert MF, Neff RK, Hubbell JP, Taeusch HW, Avery ME. Association between maternal
diabetes and the respiratory-distress syndrome in the newborn. N Engl J Med 1976;
[30] Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association
with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 2005;
[31] Rizzo T, Metzger BE, Burns WJ, Burns K. Correlations between antepartum maternal
metabolism and child intelligence. N Engl J Med 1991;325:9116.
[32] Langer O. Obesity or diabetes: which is more hazardous to the health of the offspring?
J Matern Fetal Neonatal Med 2015;15.
[33] Tieu J, McPhee AJ, Crowther CA, Middleton P. Screening and subsequent management
for gestational diabetes for improving maternal and infant health. Cochrane Database
Syst Rev 2014;2:CD007222.
[34] O'Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes 1964;13:27885.
[35] Classication and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes 1979;28:103957.
[36] Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J
Obstet Gynecol 1982;144:76873.
[37] Sacks DB. Diagnosis of gestational diabetes mellitus: it is time for international
consensus. Clin Chem 2014;60:1413.
[38] Hartling L, Dryden DM, Guthrie A, Muise M, Vandermeer B, Donovan L. Benets and
harms of treating gestational diabetes mellitus: a systematic review and metaanalysis for the U.S. Preventive Services Task Force and the National Institutes of Health
Ofce of Medical Applications of Research. Ann Intern Med 2013;159:1239.
[39] Falavigna M, Schmidt MI, Trujillo J, et al. Effectiveness of gestational diabetes
treatment: a systematic review with quality of evidence assessment. Diabetes
Res Clin Pract 2012;98:396405.
[40] Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus
on pregnancy outcomes. N Engl J Med 2005;352:247786.
[41] Poolsup N, Suksomboon N, Amin M. Effect of treatment of gestational diabetes
mellitus: a systematic review and meta-analysis. PLoS One 2014;9:e92485.
[42] Group HSCR, Metzger BE, Lowe LP, et al. Hyperglycemia and adverse pregnancy
outcomes. N Engl J Med 2008;358:19912002.
[43] International Association of D, Pregnancy Study Groups Consensus P, Metzger BE, et al.
International association of diabetes and pregnancy study groups recommendations
on the diagnosis and classication of hyperglycemia in pregnancy. Diabetes Care
[44] Sacks DB, Arnold M, Bakris GL, et al. Executive summary: guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus.
Clin Chem 2011;57:7938.
[45] Vandorsten JP, Dodson WC, Espeland MA, et al. NIH consensus development
conference: diagnosing gestational diabetes mellitus. NIH Consens State Sci
Statements 2013;29:131.
[46] Alwan N, Tuffnell DJ, West J. Treatments for gestational diabetes. Cochrane Database
Syst Rev 2009:CD003395.
[47] Hernandez TL. Glycemic targets in pregnancies affected by diabetes: historical
perspective and future directions. Curr Diab Rep 2015;15:565.
[48] Kjos SL, Schaefer-Graf U, Sardesi S, et al. A randomized controlled trial using glycemic
plus fetal ultrasound parameters versus glycemic parameters to determine insulin
therapy in gestational diabetes with fasting hyperglycemia. Diabetes Care 2001;24:
[49] Han S, Crowther CA, Middleton P, Heatley E. Different types of dietary advice for
women with gestational diabetes mellitus. Cochrane Database Syst Rev 2013;3:
[50] Bao W, Bowers K, Tobias DK, et al. Prepregnancy low-carbohydrate dietary pattern
and risk of gestational diabetes mellitus: a prospective cohort study. Am J Clin
Nutr 2014;99:137884.
[51] Franz MJ, Bantle JP, Beebe CA, et al. Nutrition principles and recommendations
in diabetes. Diabetes Care 2004;27(Suppl. 1):S3646.
[52] Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to
oral hypoglycaemic drugs. Lancet 1991;338:8669.
[53] Hellmuth E, Damm P, Molsted-Pedersen L. Congenital malformations in offspring of
diabetic women treated with oral hypoglycaemic agents during embryogenesis.
Diabet Med 1994;11:4714.

Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015),

E. Ashwal, M. Hod / Clinica Chimica Acta xxx (2015) xxxxxx

[54] Pollex EK, Feig DS, Koren G. Oral hypoglycemic therapy: understanding the mechanisms of transplacental transfer. J Matern Fetal Neonatal Med 2010;23:2248.
[55] Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of
glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med
[56] Langer O, Yogev Y, Xenakis EM, Rosenn B. Insulin and glyburide therapy: dosage, severity level of gestational diabetes, and pregnancy outcome. Am J Obstet Gynecol
[57] Ryu RJ, Hays KE, Hebert MF. Gestational diabetes mellitus management with oral hypoglycemic agents. Semin Perinatol 2014;38:50815.
[58] Berggren EK, Boggess KA. Oral agents for the management of gestational diabetes.
Clin Obstet Gynecol 2013;56:82736.
[59] Schaefer-Graf UM, Kjos SL, Fauzan OH, et al. A randomized trial evaluating a predominantly fetal growth-based strategy to guide management of gestational diabetes in Caucasian women. Diabetes Care 2004;27:297302.
[60] Maymone AC, Baillargeon JP, Menard J, Ardilouze JL. Oral hypoglycemic agents for
gestational diabetes mellitus? Expert Opin Drug Saf 2011;10:22738.
[61] Paglia MJ, Coustan DR. The use of oral antidiabetic medications in gestational diabetes mellitus. Curr Diab Rep 2009;9:28790.
[62] Dhulkotia JS, Ola B, Fraser R, Farrell T. Oral hypoglycemic agents vs insulin in management of gestational diabetes: a systematic review and metaanalysis. Am J Obstet
Gynecol 2010;203(457):e4519.
[63] Conway DL, Gonzales O, Skiver D. Use of glyburide for the treatment of gestational
diabetes: the San Antonio experience. J Matern Fetal Neonatal Med 2004;15:515.
[64] Rosenn BM. The glyburide report card. J Matern Fetal Neonatal Med 2010;23:
[65] Hawthorne G. Metformin use and diabetic pregnancy has its time come? Diabet
Med 2006;23:2237.
[66] Lautatzis ME, Goulis DG, Vrontakis M. Efcacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a
systematic review. Metabolism 2013;62:152234.
[67] Balani J, Hyer SL, Rodin DA, Shehata H. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a casecontrol study. Diabet
Med 2009;26:798802.
[68] Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med 2000;17:50711.
[69] Kjos SL, Schaefer-Graf UM. Modied therapy for gestational diabetes using high-risk
and low-risk fetal abdominal circumference growth to select strict versus relaxed
maternal glycemic targets. Diabetes Care 2007;30(Suppl. 2):S2005.
[70] Price N, Bartlett C, Gillmer M. Use of insulin glargine during pregnancy: a casecontrol pilot study. BJOG 2007;114:4537.

[71] Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial. BMJ
[72] Chen R, Ben-Haroush A, Weismann-Brenner A, Melamed N, Hod M, Yogev Y. Level of
glycemic control and pregnancy outcome in type 1 diabetes: a comparison between
multiple daily insulin injections and continuous subcutaneous insulin infusions. Am
J Obstet Gynecol 2007;197(404):e4015.
[73] Mukhopadhyay A, Farrell T, Fraser RB, Ola B. Continuous subcutaneous insulin infusion vs intensive conventional insulin therapy in pregnant diabetic women: a systematic review and metaanalysis of randomized, controlled trials. Am J Obstet
Gynecol 2007;197:44756.
[74] Cyganek K, Hebda-Szydlo A, Katra B, et al. Glycemic control and selected pregnancy
outcomes in type 1 diabetes women on continuous subcutaneous insulin infusion
and multiple daily injections: the signicance of pregnancy planning. Diabetes
Technol Ther 2010;12:417.
[75] de Valk HW, Visser GH. Insulin during pregnancy, labour and delivery. Best Pract Res
Clin Obstet Gynaecol 2011;25:6576.
[76] Kestila KK, Ekblad UU, Ronnemaa T. Continuous glucose monitoring versus selfmonitoring of blood glucose in the treatment of gestational diabetes mellitus. Diabetes Res Clin Pract 2007;77:1749.
[77] Salim R, Hasanein J, Nachum Z, Shalev E. Anthropometric parameters in infants of
gestational diabetic women with strict glycemic control. Obstet Gynecol 2004;104:
[78] McFarland MB, Trylovich CG, Langer O. Anthropometric differences in macrosomic
infants of diabetic and nondiabetic mothers. J Matern Fetal Med 1998;7:2925.
[79] Rouse DJ, Owen J, Goldenberg RL, Cliver SP. The effectiveness and costs of elective
cesarean delivery for fetal macrosomia diagnosed by ultrasound. JAMA 1996;276:
[80] Kjos SL, Henry OA, Montoro M, Buchanan TA, Mestman JH. Insulin-requiring diabetes in pregnancy: a randomized trial of active induction of labor and expectant management. Am J Obstet Gynecol 1993;169:6115.
[81] Yogev Y, Ben-Haroush A, Chen R, Glickman H, Kaplan B, Hod M. Active induction
management of labor for diabetic pregnancies at term; mode of delivery and fetal
outcome a single center experience. Eur J Obstet Gynecol Reprod Biol 2004;114:
[82] Baptiste-Roberts K, Nicholson WK, Wang NY, Brancati FL. Gestational diabetes and
subsequent growth patterns of offspring: the National Collaborative Perinatal Project. Matern Child Health J 2012;16:12532.
[83] Franks PW, Looker HC, Kobes S, et al. Gestational glucose tolerance and risk of type 2
diabetes in young Pima Indian offspring. Diabetes 2006;55:4605.

Please cite this article as: Ashwal E, Hod M, Gestational diabetes mellitus: Where are we now?, Clin Chim Acta (2015),