Expert Review of Endocrinology & Metabolism

ISSN: 1744-6651 (Print) 1744-8417 (Online) Journal homepage: http://www.tandfonline.com/loi/iere20

Gestational diabetes risk factors and long-term

consequences for both mother and offspring: a
literature review

Salar Farahvar, Asnat Walfisch & Eyal Sheiner

To cite this article: Salar Farahvar, Asnat Walfisch & Eyal Sheiner (2018): Gestational diabetes
risk factors and long-term consequences for both mother and offspring: a literature review, Expert
Review of Endocrinology & Metabolism, DOI: 10.1080/17446651.2018.1476135

To link to this article: https://doi.org/10.1080/17446651.2018.1476135

Accepted author version posted online: 15

May 2018.

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Article type: review

Gestational diabetes risk factors and long-term consequences for both mother and offspring: a
literature review
Salar Farahvar1, Asnat Walfisch1, Eyal Sheiner1
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Department of Obstetrics and Gynecology, Faculty of Health, Sciences, Soroka University Medical
Center, Ben-Gurion, University of the Negev, POB 151, 84101 Beer Sheva, Israel

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Corresponding author

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Salar Farahvar
Department of Obstetrics and Gynecology, Faculty of Health, Sciences, Soroka University Medical
Center, Ben-Gurion, University of the Negev, POB 151, 84101 Beer Sheva, Israel

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Email: farahvar@post.bgu.ac.il

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Abstract

Introduction: Established risk factors for gestational diabetes mellitus (GDM) include ethnicity, obesity,
and family history of diabetes. Untreated GDM patients have higher rates of maternal and perinatal
morbidity. GDM is an independent risk factor for future longer-term risk of type 2 diabetes mellitus
(T2DM), metabolic syndrome, cardiovascular morbidity, malignancies, ophthalmic, psychiatric, and renal
disease in the mother. Offspring risk long-term adverse health outcomes, including T2DM, subsequent
obesity, impacted neurodevelopmental outcome, increased neuropsychiatric morbidity, and ophthalmic
disease.

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Areas covered: We critically review data from retrospective, prospective, and meta-analysis studies

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pertaining to established GDM risk factors, complications during pregnancy and birth (both mother and
offspring), and long-term consequences (both mother and offspring).
Expert Commentary: Many of the adverse consequences of GDM might be avoided with proper

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management and treatment. Patients belonging to high-risk ethnic groups, and/or with BMI ≥
25kg/m2, and/or known history of diabetes in first-degree relatives may benefit from universal screening
and diagnostic criteria proposed by the International Association of Diabetes and Pregnancy Study

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Group (IADPSG). The IADPSG one-step method has several advantages, including simplicity of execution,
greater patient-friendliness, and higher diagnostic accuracy. Additionally, evidence suggests that the
recent increased popularity of bariatric surgery will help decrease GDM rates over the upcoming 5 years.
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Similarly, metformin may be useful for treating and preventing obstetrical complications in confirmed
GDM patients.

Keywords: gestational diabetes mellitus, risk factors, maternal complications, fetal complications,
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bariatric surgery, metformin
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1. Introduction
Gestational diabetes mellitus (GDM) is defined as glucose intolerance that begins during pregnancy, and
resolves at parturition; however, some instances of GDM may actually be pre-existing cases of diabetes
that were hitherto undiagnosed [1]. The pathophysiology and etiology of GDM are related to hormonal
changes. As gestation progresses, insulin sensitivity decreases, and resting glucose levels increase. To
maintain regulated normative glucose control, the body compensates by increasing insulin secretion.
GDM occurs when the body is no longer able to adapt to its new circumstances, and the endocrine
system is unable to produce sufficient insulin [2]. GDM affects approximately 1-14% of pregnancies in
the United States annually, depending on the characteristics of the population studied, and the

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diagnostics and metrics utilized [3, 4]. The frequency of GDM is a function of multiple characteristics

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pertaining to diet, lifestyle, genetics, and the idiosyncrasies of an individual pregnancy; it also reflects
the frequency of type 2 diabetes mellitus (T2DM) in the population as a whole. Established risk factors
for GDM include ethnicity, obesity, and family history of diabetes [5]. In recent decades, GDM has

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become more common, creating health consequences for mothers and offspring during antepartum,
intrapartum, and postpartum periods. Among the leading health consequences are heightened risks of
preeclampsia, macrosomia, polyhydramnios, and stillbirth [6,7]. This is an exhaustive review of data

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from retrospective, prospective, and meta-analysis studies, whose purpose is to examine the most
established risk factors for GDM, outline the most common complications during pregnancy and birth
for both mother and offspring, and provide an in-depth analysis of the long-term consequences for both
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mother and offspring. Lastly, it states the author’s expert view on the current status of GDM, and
describes critical theories and insights into how treatment of GDM may change in the upcoming five
years.
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2. Risk factors for developing GDM

2.1 Ethnicity
Ethnicity is the most grounded non-modifiable risk factor for GDM. Recent data show that the
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prevalence rate for GDM has increased by 10-100% for the past 20 years among different ethnic groups
[5]. Women of specific ethnicities have long been considered as a risk factor for developing GDM. These
at-risk ethnic groups are Australian Aboriginal women, Middle Eastern women, and Pacific Islander
women [5,8]. Studies have shown that immigrants to western nations have a higher GDM rate than first-
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generation citizens of the same ethnicity [9,10]. As in the United States, African-American, Asians, and
Hispanic women are more vulnerable to GDM than are non-Hispanic white women [5,8]. In Europe,
Asian women are at a higher risk for GDM than European women. In Australia, the prevalence rate for
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GDM was higher among women of Chinese or Indian nationality as compared to the Native European or
Northern Africans [11,12]. The rate of GDM pregnancies among Asian women in their native countries is
lower than among women of that same ethnicity on other continents [13]. For Asian ethnicities, GDM
pervasiveness varies significantly. For instance, a New York study showed that South Asian (Indian,
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Fijian, Sri Lankan, Pakistani) women have a higher prevalence of GDM than South-East Asian (Khmer,
Vietnamese, Laotian, Filipino, Malaysian) or East Asian (Chinese, Korean, Taiwanese, Japanese) [10]. In
another study, Asian women showed a higher risk of GDM than other ethnicities, regardless of body
mass index [14]. This population is inclined to have a more central or visceral fat—a risk factor for
cardiovascular disease and insulin resistance [15]. Table 1 summarizes selected studies regarding ethnic
groups at-risk for GDM.

2.2 Body mass index

Being obese or overweight pre-pregnancy is considered a significant GDM risk factor [16]. GDM
prevalence for American obese and/or overweight women has risen in recent decades [16]. A South
Carolina study found that overweight or obese women are at a significantly increased risk of developing
GDM, regardless of race/ethnicity [17]. In earlier studies, researchers found a positive correlation
between GDM and increased pre-gravid body mass index (BMI) [16, 18-22]. A meta-analysis conducted
by Chu et al. Showed an increase in the risk of GDM twofold among overweight women with BMI of
25.0-30.0 kg/m2, fourfold for those with BMI of 30.0-35.0 kg/m2, and eightfold for those with BMI of
over 35kg/m2 [23]. In other studies, researchers examined self-reported weight change from 18 years to
just before pregnancy. Two studies revealed that a weight gain of 10.0 kg or more was associated with
increased risk of GDM [24,25]. According to Solomon et al., gaining 5.0-9.9 kg of weight between the
ages of 18 years to shortly before pregnancy led to a 67% increase in risk of self-reported GDM; women

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who gained 10.0-19.9 kg reported a 2.5-fold increase in GDM risk; and women with constant weight (±

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4.9 kg) had decreased vulnerability [24]. In a more recent study, Rudra et al. Showed women who
gained 10.0 kg of weight or more when they were 18 years to pregnancy had a 3-fold increased risk of
GDM, even after adjustment for baseline BMI and other confounders [25]. Studies have also assessed

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the weight gain between pregnancies for women who had two pregnancies. According to Glazer et al.,
obese women with a weight gain of at least 4.5 kg between their pregnancies had a 47% risk of GDM;
those who lost at least 4.5 kg had a reduced risk of 37% when compared to those with a stable weight

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[26]. Villamor et al. Found that, among women with two consecutive pregnancies, inter-pregnancy
weight gain resulting in an increase of 3 or more BMI units was associated with a doubled GDM risk.
They also found that the increase in GDM risk was higher among women who were not overweight at
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the first pregnancy, indicating that the association with rate of weight gain was strongest among women
not overweight at baseline [27]. These results suggest that even modest weight gain among women who
are not overweight can increase GDM risk. Another study examined gestational weight gain and GDM
risk, concluding higher gestational weight gain in the first trimester was positively correlated with
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increased GDM risk—particularly in non-white and overweight women [28]. Finally, there was a study
about the interaction between BMI, maternal age, and racial origin. The odds ratio revealed that the
development of GDM was much higher in Caucasian women who were 30 years or older, African women
who were older than 25 years, and South-Asian women who were older than 20 years. The study also
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found that most of the South-Asians and Africans were at high risk of being diagnosed with GDM
regardless of their BMI [29]. Table 2 summarizes selected studies regarding the association between
obesity and GDM.
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2.3 Family history of diabetes

The pathophysiology of type 2 diabetes mellitus (T2DM) is closely related to that of GDM [30]. A family
history of T2DM is considered a significant risk factor for GDM development. Even postpartum, patients
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with a history of GDM are more vulnerable to T2DM as they age [31,32]. Different prospective,
retrospective, and cross-sectional studies have highlighted the above relationship in detail. These
studies found a close relationship between the familial history of T2DM to GDM [33-35]. According to
Williams et al., diabetes in a first-degree relative indicated a high chance of GDM, regardless of whether
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it is a parent or a sibling [36].

Cianni et al. Studied the rate of GDM among patients with familial history of T2DM compared to those
without, and found a high-risk rate of 14.5% against 7.3% [37]; similarly, the same line of discussion,
Yang et al. Found that women with familial history of T2DM showed twice the risk of GDM, compared to
women without [38]. A separate cross-sectional study by Kim et al. Demonstrated that familial history of
T2DM was closely related to increased odds of a history of GDM. More specifically, they found that a
monoparental diabetes history could double or triple the history of GDM risk, compared to no family
history; a biparental diabetes history did not significantly differ in history of GDM risk from a
monoparental history, although it did increase the T2DM risk. Conversely, a sibling history of diabetes
was linked to higher odds of history of GDM than was a parental history [39]. In a study of Korean
women, researchers found that T2DM history among first-degree relatives was closely related to
increased risk of GDM. GDM risk was increased 2-fold by parental T2DM history, 5-fold for sibling, and
6.5-fold for parental and sibling together [40]. Shirazian et al.'s study of 924 expectant Iranian women
revealed that GDM complications increase with age above 30 years, BMI above 30, and history of family
diabetes [41]. Table 3 summarizes selected studies regarding the significance of family history of
diabetes for the development of GDM.

3. Complications during pregnancy and birth

Earlier studies have shown that women with untreated GDM have higher rates of maternal and

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perinatal morbidity and mortality [42,43]. Substantial evidence suggests that aggressive treatment of

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GDM can significantly reduce these complications [44]. GDM places mothers at increased risk for
gestational hypertension, preeclampsia and cesarean section [45]. Gorgal et al. Reported that GDM is a
risk factor for non-elective cesarean section after controlling for maternal age, pre-pregnancy BMI,

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gestational weight gain, previous cesarean section, gestational age at delivery, and birthweight. Women
with GDM have a 52% higher risk of non-elective cesarean section than those without GDM [46]. A
cohort study of 422,672 Alberta women without pre-existing diabetes examined the association

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between GDM and preeclampsia, and found significantly increased risk of preeclampsia among women
with GDM [47]. Bryson et al. Concluded that GDM is commonly associated with preeclampsia and
gestational hypertension; women with GDM are at an increased risk (1.5 times) of developing a
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hypertensive disorder of pregnancy. They also examined associations between GDM and risk of
pregnancy-induced hypertension among different maternal ethnic groups, and concluded GDM was
highest among mothers of Black ethnicity, followed by Hispanic, and Caucasian [48]. Additionally, fetal
complications of GDM pregnancies include increased risk of macrosomia, shoulder dystocia, neonatal
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hypoglycemia and hyperbilirubinemia, and operative delivery [49]. The Hyperglycemia and Adverse
Pregnancy Outcome (HAPO) study found positive associations between increasing plasma glucose levels
and five secondary outcomes (premature delivery, shoulder dystocia or birth injury, intensive neonatal
care, hyperbilirubinemia, and preeclampsia) [50]. It is suggested by Pedersen-Freinkel’s hypothesis that
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hyperglycemia in mothers can cause increased transplacental glucose transfer, which leads to fetal
hyperinsulinism; since insulin is a major growth factor, this leads to macrosomia [51], of which one
frequent complication is shoulder dystocia. According to Kc et al. A common adverse outcome of GDM is
fetal macrosomia, which increases the risk of shoulder dystocia, clavicle fractures, and brachial plexus
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injury—and, concomitantly, the rate of admissions to neonatal intensive care units (nicus) [52]. One of
the most common, serious and potentially life-threatening perinatal complications related to GDM is
respiratory complications in the neonate [53]. The global incidence of respiratory complications in
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infants of GDM mothers is as high as 34%, with a 4–6% incidence of respiratory distress syndrome (RDS).
Moreover, the risk of transient tachypnea of newborn (TTN) is also increased compared to infants from
non-diabetic pregnancies [54]. Furthermore, a retrospective study indicated a higher prevalence of
macrosomia, preeclampsia, and emergency cesarean sections in Asian Indian women with GDM.
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Additionally, they found that GDM women who were treated with medical nutrition therapy and insulin
had lower rates of macrosomia, preeclampsia, and emergency cesarean section than those treated with
medical nutrition therapy alone [55]. In a randomized clinical trial by Crowther et al., aggressive
multipartite treatment of GDM patients—including comprehensive dietary advice, blood glucose
monitoring, and insulin therapy — reduced the rate of severe perinatal and postnatal outcomes (defined
as death, shoulder dystocia, bone fracture, and nerve palsy) from 4% to 1% [56].

4. Maternal long-term consequences of GDM

Not only is GDM associated with adverse pregnancy outcomes (both perinatally and postnatally), it
significantly increases the long-term risk of disease in the mother. Recent research has shown that GDM
continues to affect maternal health long after the index pregnancy, and can be exacerbated in later
pregnancies.

4.1 Recurrence of GDM in subsequent pregnancies

One of the major risk factors for GDM is having had a previous GDM pregnancy. GDM has a recurrence
rate ranging from 30% to 84% in subsequent pregnancies [62,63]. In a systematic review, Kim et al.
Found that GDM's recurrence rate during subsequent pregnancies varied markedly across studies. As
such, the most consistent predictor of future recurrence appeared to be ethnicity—albeit with the
caveat that the racial breakdowns within a study were not always explicit. Minority populations had a

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markedly higher recurrence of GDM than did non-Hispanic white, even after preexisting diabetes before

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the subsequent pregnancy was considered [62]. A study of predominantly Japanese women showed that
65.6% experienced GDM recurrence in subsequent pregnancies [64]. Similarly, in a study of primarily
Hispanic (85%) patients, who were older and more parous, the GDM recurrence rate was 69% [65].

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Among Korean women, it was demonstrated by Kwak et al. That 45.0% experienced GDM recurrence in
subsequent pregnancies [66]. In summary, women with a history of GDM have an increased risk of GDM
recurrence, with ethnicity being an important predictor.

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4.2 Type 2 diabetes mellitus
Women with previous GDM have been shown to exhibit substantially increased risk for the
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development of T2DM, even though most return to a euglycemic state shortly postpartum [57-59].
There is substantial evidence to support this association, but the magnitude of the risk varies among
studies; this is primarily the result of methodological differences, including length of follow-up
examination, number of participants in follow-up, ethnicity of participants, and diagnostic criteria [60]. A
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systematic review of 20 collated research studies conducted by Bellamy et al. Found that GDM patients
have an approximately 7-fold increase in risk of T2DM compared to women with a normoglycemic
pregnancy [57]. A population-based study found that 18.9% of women with previous GDM developed
T2DM within 9 years after the index pregnancy; this was much higher than among women without GDM
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(2.0%). The rate of T2DM development increased in the first nine months postpartum, and remained
relatively constant thereafter. More specifically, 3.7% of patients had developed T2DM within nine
months [58]. Lastly, a study conducted by Herath et al. Compared 119 Sri Lankan women with previous
GDM to 240 without, and found that GDM mothers have a 10-fold higher risk of developing T2DM
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during a 10-year follow-up period. GDM patients in the study developed T2DM at a much higher rate
(almost 28% within the first two years) [61]. In summary, GDM is one of the most predictive factors for
later T2DM development.
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4.3 Metabolic syndrome and cardiovascular disease

GDM may also increase postpartum risk of metabolic syndrome and cardiovascular disease. Metabolic
syndrome is characterized by several risk factors, including central obesity, hypertension, insulin
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resistance, and dyslipidemia [67]. Several population-based studies have demonstrated an association
between GDM and risk of subsequent maternal cardiovascular morbidity [68-70]. More precisely,
women with previous GDM have an increased risk of cardiovascular risk factors such as hypertension,
dyslipidemia, obesity and metabolic syndrome [70-72]. GDM is also found to be an independent risk
factor for long-term maternal risk of noninvasive diagnostic procedures, simple cardiovascular events,
and cardiovascular hospitalizations [68]. Goueslard et al. Compared incidence of long-term maternal
cardiovascular morbidity in women with GDM history to those without. They reviewed 1,518,990
deliveries, of which 4.1% (n = 62,958) were in GDM women. After 7 years of follow-up, it was found that
women with GDM history had significantly higher incidence of cardiovascular morbidity (e.g., angina
pectoris, myocardial infarction (MI), and ischemic stroke including TIA) compared to controls, after
adjusting for age, DM, obesity, and hypertensive disorders in pregnancy [69]. Di Cianni et al. Studied the
prevalence of metabolic syndrome and other cardiovascular risk factors in 166 women with a history of
GDM and found, 16 months postpartum, significantly higher rates of metabolic syndrome, and higher
levels of related inflammatory markers (e.g., C-reactive protein) [72]. Bo et al. Followed women with
GDM 6.5 years postpartum, and found they had significantly higher levels of vascular endothelial
dysfunction markers than women with normal pregnancies. The authors concluded that GDM mothers
experience a higher risk of future cardiovascular diseases than do normoglycemic mothers [73]. Lastly,
one study reported that when even slight glucose intolerance (regardless of overt GDM) exists, a dose-
response effect can be seen between glucose level during pregnancy and postpartum atherosclerotic

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morbidity. The study also suggested that a greater proportion of pregnant women with glucose levels

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greater than 5.5 mmol/L eventually developed long-term severe atherosclerotic morbidity [74].

4.4 Malignancies

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Women with a history GDM might have a higher future long-term risk for the development of
malignancies. A study by Fuchs et al. Demonstrated that hospitalizations due to malignancies years after
postpartum were increased in women with GDM. They followed GDM women up to 26 years and found

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a significant association (but definitely not causation) between GDM and risk of developing ovarian,
endometrial, and/or breast cancer [75]. A Scottish study with a cohort of 753 pregnant women
examined the association between maternal gestational glucose intolerance and the long-term risk of
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malignant neoplasms. Subjects underwent glucose testing during pregnancy and were followed up to 20
years. The results showed a positive association between higher glucose levels during pregnancy and
increased risk of breast cancer [76]. Israeli women with prior GDM diagnoses were also observed to
have an elevated risk of breast cancer at 50 years of age and higher [77]. Perrin et al., with a follow-up
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of 28–40 years, documented five cases of pancreatic cancer in women with GDM history, and an
adjusted relative risk of 7.1 was documented [78]. Similarly, another study with a short follow-up period
(5–19months), indicated that GDM women were more likely to be diagnosed with pancreatic cancer. It
also found a 4.5-fold risk of hematologic neoplasms, specifically non-Hodgkin’s lymphoma, in GDM
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women with more than five years of follow-up [79].

4.5 Ophthalmic disease

GDM has also been reported to be a significant risk factor for long-term ophthalmic morbidity.
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Beharier et al. Compared incidence of long-term maternal ophthalmic morbidity in women with GDM
history to those without. They reviewed 104,751 deliveries, of which 9.4% (n = 9888) were in GDM
women. Women with GDM history had significantly higher incidence of ophthalmic morbidity (e.g.,
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glaucoma, diabetic retinopathy, retinal detachment) compared to controls [80]. Interestingly, a

significantly higher incidence of ophthalmic complications were documented in women with
simultaneous diagnoses of GDM and preeclampsia compared to patients with only GDM [80]. The
association between GDM and future T2DM is well established [57]. A significant number of women
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who experience GDM will develop T2DM years following postpartum. Retinopathy will have already
affected up to 20% of women at the time of T2DM diagnosis; some degree of retinopathy will develop in
most women over the following decades [81].

4.6 Renal disease

GDM seems like a significant risk factor for long-term renal morbidity. The most common future renal
diagnoses were hypertensive renal disease without renal failure, hypertensive renal disease with renal
failure, chronic renal failure, and end-stage renal disease [82]. Studies monitored microalbuminuria, a
marker of impaired glomerular filtration rate, years postpartum. In one study by Friedman et al., a
cohort of 72 patients were followed for 5-8 years after their last GDM development, and a higher risk for
microalbuminuria was reported in women with GDM history than in the control group [83]. In a second
study by Bomback et al., a cohort study of 571 women with GDM vs. 25,045 women without was
conducted based on self-report data. They found that GDM without subsequent T2DM is a risk factor for
future development of microalbuminuria. In addition to microalbuminuria, patients with GDM history
had increased risk for developing future chronic kidney disease [84].

4.7 Psychiatric disease

A New Jersey study found that prevalence of depression during pregnancy and/or postpartum was 15.2
% in women with pre-pregnancy or gestational diabetes and 8.5 % in women without diabetes. The

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study further indicated that GDM women without depression during the prenatal period might be at

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increased risk of new onset depression during the postpartum period [85]. Similarly, a Bangladeshi study
found a significant difference between the prevalence of depression in women with and without GDM
(25.92% vs 10.38%) [86].

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In summary, GDM is an independent risk factor for future T2DM, metabolic syndrome, cardiovascular
morbidity, vascular endothelial dysfunction, malignancies, and ophthalmic, psychiatric, and renal
disease. The risks of these outcomes can be lessened with proper prevention and interventions.

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However, most women with GDM do not undergo postpartum evaluation. One study indicated that only
19% of women (4486 of 23,999) with GDM underwent testing for T2DM within six months postpartum
[87]. Another study reported that women with GDM rarely followed dietary and physical activity
recommendations postpartum [88].
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5. Long-term consequences in offspring of mothers with GDM
Long-term adverse health outcomes reported among offspring of GDM mothers include sustained
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impairment of glucose tolerance, subsequent obesity, impacted neurodevelopmental outcome and
increased neuropsychiatric morbidity, and ophthalmic disease.

5.1 Glucose intolerance

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Maternal diabetic intrauterine environment is strongly associated with T2DM development in offspring.
In a multiethnic population (African-American, Hispanic, and non-Hispanic) aged 10-22 years, it was
found that 30.4% of youth with T2DM had been exposed to maternal diabetes, compared to 6.3% of
nondiabetic youth controls [89]. In another multiethnic cohort of obese adolescents, Holder et al. Found
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that 31.1% of obese children with normal glucose tolerance who had been exposed to GDM developed
impaired glucose tolerance/diabetes over a relatively short follow-up period (avg. < 3 years). The results
indicate that offspring of mothers with GDM history have at least 5 times greater risk of developing
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impaired glucose tolerance than those not exposed to gestational diabetes [90]. Similarly, in a cohort of
primarily Caucasians aged 18-27 years, 21% of youth with either T2DM or pre-diabetes (impaired
glucose tolerance or impaired fasting glucose) were offspring of women with diet-treated GDM,
compared to 4% of women from the background population [91]. Studies of Pima Indians illustrate the
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consequences of exposure to diabetes in utero on childhood obesity and risk of T2DM. For genetic
reasons, the Pima have exceptionally high rates of obesity and T2DM. T2DM prevalence in Pima children
is up to 6 times greater in those with diabetic or prediabetic mothers; T2DM in childhood and
adolescence occurs almost exclusively among the offspring of diabetic and prediabetic mothers [92].
There is evidence that the higher frequency of diabetes and obesity in the offspring of diabetic Pima
women is not only due to genetic susceptibility to obesity and diabetes. Studies including sibling pairs
with one sibling born before the onset of maternal diabetes, and one after, have brought interesting
data [93]. Being born after the mother developed diabetes led to a significantly higher risk of diabetes in
offspring; as well, mean BMI was 2.6 kg/m2 higher in offspring of diabetic pregnancies than in non-
diabetic [94].
5.2 Obesity
The relationship between childhood BMI z score and maternal diabetes was examined in a
comprehensive meta-analysis, and a strong relationship was found between prenatal exposure to
maternal diabetes and increased childhood BMI [96]. In the HAPO study, higher levels of maternal
glucose tolerance were found to be positively associated with high birth weight, fetal hyperinsulinemia,
and neonatal adiposity [97]. In one study, Deierlain et al. Measured blood glucose concentration at
around 27 weeks of gestation, and found an association between maternal glucose concentration ≥130
mg/dl and a significantly increased risk of children being overweight or obese at 3 years, independent of

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maternal pre-pregnancy BMI [98]. A Danish study found a significant association between offspring birth

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size and obesity risk at 7 years of age and fasting plasma glucose concentrations during pregnancy in
women with GDM, even after adjusting for maternal pre-pregnancy BMI. This significant association was
not relevant during infancy [99]. Zhao et al. Using multinational data, found an association between

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maternal GDM and childhood obesity. They found that maternal GDM was associated with an increased
risk of childhood obesity among children aged 9–11 years from 12 countries (Australia, Brazil, Canada,
China, Colombia, Finland, India, Kenya, Portugal, South Africa, the UK and the USA). However, they also

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added that these associations were not entirely independent of maternal BMI [100]. Data regarding the
relation between maternal GDM and offspring BMI in childhood might be interpreted as a result of a
common genetic potential, rather than to intrauterine programming secondary to the exposure of a
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hyperglycemic intrauterine environment. However, a study of Swedish men included analysis of sibling
pairs (280,866 men from 248,293 families), and found that, at a mean age of 18 years, men born to
GDM mothers had a BMI on average 0.94 kg/m2 greater than their brothers born to pre-GDM mothers.
The difference in BMI was similar within brothers and between non-siblings [101].
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5.3 Neurodevelopmental outcome and neuropsychiatric morbidity
Previous literature suggests convincing evidence that offspring of diabetic mothers are at risk of
impaired neurodevelopmental outcome [102,103]. Dionne et al. Compared the language development
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of 221 Canadian children of GDM mothers (age 18 months to 7 years) to 2612 controls. They found that
infants of GDM mothers scored significantly lower in expressive language scores at several time points,
including middle childhood [103]. A systematic review and meta-analysis compared cognitive function in
children of diabetic mothers and of nondiabetic mothers, and indicated that infants of diabetic mothers
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have lower mental and psychomotor development than their counterparts in the first few years of life
[104]. One study examined the development of neural systems associated with facial expression
recognition in children of diabetic mothers and in controls, for a 12-month period. The results suggest
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that the neural development of facial expression recognition among children of diabetic mothers
deviates from that of controls across the first few years of life [105]. Deboer et al. Investigated the
impact of abnormal fetal environment on explicit memory performance. After controlling for differences
in gestational age and global cognitive functioning, they found that, at one year of age, children of
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diabetic mothers perform worse on delayed recall tasks than do controls [106]. Additionally, an
extensive population-based study conducted in southern Israel investigated long-term neuropsychiatric
morbidities in offspring exposed to GDM. Neuropsychiatric illnesses included in this study were autistic
spectrum disorder, eating disorders, cerebral palsy, obstructive sleep apnea, epilepsy, and infantile
spasms [107]. During the study period 231,271 deliveries met the inclusion criteria; 5.4% of the births
were to mothers diagnosed with GDM (n = 12,642), of these 4.3% had GDM type A1 (n = 10,076) and
1.1% had GDM type A2 (n = 2566). During the follow-up period, a significant linear association was
noted between the severity of the gestational diabetes (no gestational diabetes, gestational diabetes
mellitus A1, gestational diabetes mellitus A2) and neuropsychiatric disease of the offspring (1.02% vs
1.36% vs 1.68%, respectively, P < .001). Additionally, children exposed to GDM who developed
neuropsychiatric disease did so at a younger age than their unexposed counterparts: A Kaplan-Meier
curve demonstrated that children born to women with gestational diabetes mellitus had higher
cumulative incidence of neuropsychiatric morbidity. Using a generalized estimating equation
multivariable logistic regression model, controlling for time-to-event, maternal age, gestational age at
delivery, maternal obesity, maternal preeclampsia and fertility treatments, maternal GDM was found to
be an independent risk factor for long-term neuropsychiatric disease of the offspring (gestational
diabetes mellitus A1 [adjusted odds ratio, 1.83; 95% confidence interval, 1.53-2.19] and gestational
diabetes mellitus A2 [adjusted odds ratio, 1.64; 95% confidence interval, 1.18-2.27]). Additionally,
children exposed to GDM who developed neuropsychiatric disease did so at a younger age than their

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unexposed counterparts. Within the limits of their database, the findings also point to a possible

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association between in utero exposure to GDM and autistic spectrum disorder of the offspring (adjusted
odds ratio, 4.44; 95% confidence interval, 1.55-12.69), which was found significant also after controlling
for time-to-event, maternal age, gestational age at delivery, and offspring weight at birth [107]. In

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summary, in the first few years of life, offspring of diabetic mothers are at risk of impaired linguistic,
mental, and psychomotor development, as well as impairment of neural development of facial
expression, and explicit memory performance. Lastly, they are at increased risk of developing

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neuropsychiatric diseases such as autistic spectrum disorder, eating disorders, cerebral palsy,
obstructive sleep apnea, epilepsy, and infantile spasms.
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5.4 Ophthalmic disease
A recent study investigated whether children born to mothers with GDM are at increased risk to develop
pediatric ophthalmic morbidity. Mothers were defined as either having no GDM, having diet treated
GDM, or medically treated GDM. Outcomes were defined as different ophthalmic morbidities of the
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offspring until the age of 18. During the study period, 238, 622 deliveries met the inclusion criteria, of
those 4.0% (n = 9601) of mothers were diagnosed with GDM treated by diet, and an additional 1.0% (n =
2398) were diagnosed with GDM treated by medication. Offspring of patients with GDM treated by
medication had a higher cumulative incidence of ophthalmic morbidity when compared to the other
ed

groups (Kaplan-Meier log rank test p = 0.038). GDM treated by medication was found to be an
independent risk factor for long-term ophthalmic morbidity, in a cox multivariable model (adjusted HR:
1.5, 95% CI: 1.05-2.1, p = 0.025). Authors concluded that GDM treated by medication was associated
with an increased risk for long-term pediatric ophthalmic morbidity [108].
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6. Expert commentary
Worldwide, the prevalence of obesity and morbid obesity in women of childbearing age has been on the
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rise. There is an increased risk of GDM in overweight and obese women leading to complications during
pregnancy and birth, as well as long-term maternal and neonatal complications. The clinical
management of GDM and obese women is a challenge, and puts additional burden on the healthcare
system. Prevention and early detection are essential. A systematic review of 19 randomized controlled
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trials, with a total of 6633 women, indicated possible reduced risk of GDM in women who received
standard care and undertook dietary and exercise programs, as compared to those who received
standard care without dietary and exercise programs [109]. Many of the adverse short and long-term
consequences listed in this review might be avoided with proper management and treatment. It is
imperative for physicians to know the most common risk factors for GDM so that they may intervene
early and, if not prevent its development, at least mediate its short and long-term consequences.
Additionally, effective communication between physician, patient, and primary care provider is
essential. At-risk patients should be informed about the importance of proactive lifestyle choices such as
exercise, weight loss, and a healthy diet, before, during, and after pregnancy. Unfortunately, there is no
international agreement regarding screening method and the optimal cut-off points for diagnosis of
GDM. In the US, two different (one-step and two-) approaches to screening and diagnosing at-risk
patients are commonly used. The two-step approach is the most widely used approach in the US. The
first step is to administer the glucose challenge test (GCT): a 50-gram oral glucose load is given
irrespective of last meal, and plasma glucose is measured one hour later. A positive screening test is
anywhere from ≥130 mg/dl to ≥140 mg/dl. Positive patients proceed to the second step, a 100-gram,
three-hour oral glucose tolerance test (GTT). GTT is diagnostic for gestational diabetes. The one-step
approach omits GCT screening, and simplifies testing by performing only a 75-gram, two-hour oral
GTT. In 2010, the International Association of Diabetes and Pregnancy Study Group (IADPSG) consensus
panel proposed new screening and diagnostic criteria for GDM. The IADPSG defined thresholds for the

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75-gram two-hour oral GTT, based primarily on outcome data reported in the HAPO study (a prospective

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observational study of more than 23,000 pregnancies evaluated with a 75-gram two-hour oral GTT at 24
to 32 weeks gestation) [109]. According to these criteria, GDM is diagnosed if there is at least one
abnormal value (≥92, 180 and 153 mg/dl for fasting, one-hour and two-hour plasma glucose

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concentration respectively), after a 75-g oral glucose tolerance test. These thresholds represent the
glucose values at which the odds of infant birth weight, cord C-peptide, and neonatal percent body fat
>90 percentile were 1.75 times the estimated odds of these outcomes at mean glucose levels, based on

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fully-adjusted logistic regression models. The use of IADPSG resulted in increased rate of GDM (35.5%,
versus 10.6% with two-step procedure) and resulted in a significant improvement in pregnancy outcome
in their population and appeared cost-effective [110]. It seems that there is a need for universal
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screening in patients belonging to high-risk ethnic groups, BMI of 25kg/m2 or more, and/or known
history of diabetes in first-degree relatives. The IADPSG criteria may diagnose and treat GDM earlier.
This one-step method has several advantages, including simplicity of execution, greater patient-
friendliness, and higher accuracy of diagnosis [111].
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7. Five-year view
7.1 Bariatric surgery
Bariatric surgery (BS), a highly effective treatment for morbid obesity and many of its associated medical
ed

conditions [112], is gaining popularity among obese and morbidly obese females of reproductive age,
and may ultimately help decrease rates of GDM over the upcoming 5 years.
Increasing numbers of women of reproductive age have already undergone BS. Currently, >50,000
American women aged 18-45 undergo inpatient bariatric surgical procedures each year [113]. Bariatric
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surgeries can be subcategorized as restrictive, malabsorptive, or combined [114]. More than half of BS
patients experience sustained improvement of glycemic control, and are able to end their diabetic
treatment [115,116]. Additionally, post-BS pregnancy appears to be generally safer than pregnancy
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while obese [117, 118]. BS can significantly reduce the likelihood of pre-gestational and gestational
diabetes, and of obesity-related reproductive complications [113,115,118-122]. The risk of obstetrical
complications, especially hypertensive disorders and fetal macrosomia, is likewise reduced; however,
this may result in neonates born small-for-gestational-age [123-128]. A study by Aricha-Tamir et al. Of
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144 women who each had bariatric surgery before subsequent pregnancies found a significant reduction
in hypertensive disorders post-BS, as compared to their pre-BS pregnancies [117]. Similarly, a study by
Weintraub et al. Of 301 preoperative and 507 postoperative pregnancies demonstrated a reduction in
hypertension and severe preeclampsia in postoperative women [118]. Additionally, the major finding of
one population-based study was that previous bariatric surgery was not associated with adverse
perinatal outcome: perinatal death, congenital malformations, and Apgar scores were similar in patients
with and without a history of previous bariatric surgery [129]. Amsalem et al. Demonstrated a reduced
rate of GDM persisting into the next post-BS pregnancy [130]. If a post-BS woman does develop GDM
during a subsequent pregnancy, current research has not revealed a significantly increased risk to the
mother or fetus as compared to non-BS women with GDM [128]. The BS subtype may also affect
postoperative time to conception. Sheiner et al. Found a shorter mean time to conception after
restrictive procedures (36.2 months) than after malabsorptive procedures (57.4 months) [127]. Current
recommendations are to avoid conception for 12 – 24 months post-BS, so as to avoid potential nutrient
fluctuations during the 6-to-18-month period of rapid weight loss that typically results [131-133].
7.2 Metformin
While there is compelling evidence of the merits of pre-pregnancy bariatric surgery, more recent studies
have indicated that metformin may be useful for treating and preventing obstetrical complications in
confirmed GDM patients [135,136]. Metformin was originally introduced as an antidiabetic agent;
however, its therapeutic roles now include treatment of prediabetes mellitus, GDM, and polycystic

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ovarian syndrome. More recent experimental studies and observations in randomized clinical trials

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suggest that it could be used to treat or prevent preeclampsia [136]. Additionally, the efficacy and safety
of metformin in managing GDM was compared to that of insulin. Gui et al. Published a systematic
review and meta-analysis showing metformin to be superior to insulin in reducing maternal weight gain

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during pregnancy and frequency of gestational hypertension; however, it did not change the frequency
of hypoglycemia, preeclampsia, or either large- or small-for-gestational-age fetuses [137]. Additionally,
according to Butalia et al. Metformin significantly decreased the frequency of neonatal hypoglycemia,

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LGA neonates, and admissions to a NICU compared to insulin [138]. Lastly, considerable evidence
suggests that it is safe during pregnancy. Several meta-analyses have found no teratogenic effect to
metformin; it is currently classified as category B in the United States and as category C in Australia [139-
142].
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8. Key Issues
• Established risk factors for GDM include ethnicity, obesity, and family history of diabetes.
M
• GDM places mothers at increased risk for gestational hypertension, preeclampsia and
emergency cesarean section.
• Fetal complications of GDM pregnancies include increased risk of macrosomia, shoulder
dystocia, operative delivery and respiratory complications.
ed

• GDM is an independent risk factor for future T2DM, metabolic syndrome, cardiovascular
morbidity, vascular endothelial dysfunction, malignancies, and ophthalmic, psychiatric, and
renal disease in the mother.
• Long-term adverse health consequences in offspring of GDM mothers include sustained
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impairment of glucose tolerance, subsequent obesity, impacted neurodevelopmental outcome,

and increased neuropsychiatric morbidity.
• It is imperative for physicians to know the most common risk factors for GDM so that they may
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intervene early and mediate its short and long-term consequences.

• There is a need for universal screening in patients belonging to high-risk ethnic groups, BMI of
25kg/m2 or more, and/or known history of diabetes in first-degree relatives.
• Bariatric Surgery can significantly reduce the likelihood of pre-gestational and gestational
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diabetes, and of obesity-related reproductive complications.

• Metformin might serve as a potential agent in treating and preventing obstetrical complications.
Funding
This paper was not funded.

Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony,
grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant
financial or other relationships to disclose

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 Table 1 Summary of select studies on
ethnicity—a risk factor for GDM
Study Savitz et al [10] McDonald et al [11]
Farrar et al [12] Hunsberger et al [14]

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City/Region New York City, US Australia
Bradford Royal Infirmary, Oregon, US

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UK

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Total 48,853 4610
Number of 9509 357
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Women
with GDM
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Rate of 7.2% N. African 20 % Southeast Asia
GDM by 51% South Asian 16.4% NH Asian
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ethnicity 6.2% East Asia 3.3% East Asia

41% White British 11.7% NH Pacific Island
6.3% Mexico 14.6% South Asia
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8% Other 11.1% Hispanic

14.3% S. Central Asia 7.7% Africa
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8.1% NH Black
6.8% NH Caribbean 0.9% Latin America
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7.9% NH American Indians

4.9% Hispanic Caribbean 1.8% Oceania
6% NH White
4.9% Central American 4.4% Europe and North
America
 6.6% South American 3.0% West and Central
Asia
34.3% African-American 2.4% Arab States
3.6% NH White 41.9% Australia or New
Zealand

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5.9% Sub-Saharan Africa

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8.6% South-East Asia and Pacific Islands

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Table 2 Summary of select studies on BMI—a risk
factor for GDM
Study BMI Range Number of women with
GDM/Total (%) Statistic

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Adjusted Relative Risk (95% CI)
BMI 30.0-34.9 1768/19087 (9.3)
2.3 (2.1-2.4)

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BMI 25.0-29.9 2071/33694 (6.5)
1.6 (1.5-1.7)

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Cavicchia et al [17] BMI 18.5-24.9 2160/57482 (3.8)
1.0
BMI < 18.5 167/5945 (2.8)
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0.9 (0.8-1.0)

Adjusted Odds Ratio (95% CI)

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BMI > 30.0 579/9731 (6.0)

5.2 (4.3-6.2)
BMI 25.0-29.9 464/17438 (2.7)
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2.4 (2.0-2.9)
Baeten et al [19] BMI 20.0-24.9 777/50097 (1.6)
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1.3 (1.1-1.5)
BMI < 20.0 231/18878 (1.2)
1.0
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Adjusted Odds Ratio (95% CI)

BMI ≥ 30.0 155/677 (22.9)
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4.18 (3.42-5.12)
BMI 27.5-30.0 215/1147 (18.7)
3.09 (2.61-3.66)
Leung et al [20] BMI 25-27.4 428/2809 (15.2)
2.45 (2.16-2.77)
BMI 23-24.9 520/4666 (11.1)
1.75 (1.56-1.96)
 BMI 18.5-22.9 1052/17375 (6.1)
1.0
BMI < 18.5 107/2629 (4.1)
0.73 (0.60-0.90)

Adjusted Relative Risk (95% CI)

BMI > 29.0 19/161 (11.8)

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3.25 (1.85-5.71)
BMI 26.1-29.0 3/109 (2.8)
0.74 (0.23-2.40)

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Rudra et al [25] BMI 19.8-26.0 41/1078 (3.8)
1.0

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BMI < 19.8 4/296 (1.4)
0.34 (0.12-0.95)
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Table 3 Summary of select studies on family
history of diabetes—a risk factor for GDM
Study FH of Diabetes Women with GDM (%)
Non-GDM Control Adjusted Odds Ratio (95% CI)

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Yes 112 (37.3)
36 (12.0) 4.4 (2.9-6.6)

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Bhat et al [33] No 188 (62.7)
264 (88.0)

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Yes 38 (33.3)
192 (10.3) 4.34 (2.86-6.60)
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Hossein-Nezhad et al [34] No 76 (66.7)
1670 (89.7)
Yes 116 (16.4)
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1242 (8.0) 2.15 (1.78-2.61)

Yang et al [38] No 592 (83.6)
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14336 (92.0)
Yes 199 (46.2)
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117 (27.4) 2.14 (1.59-2.86)

Rhee et al [40] No 232 (53.8)
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310 (72.6)
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