Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e14

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Best Practice & Research Clinical

Obstetrics and Gynaecology
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12

The offspring of the diabetic mother e

Short- and long-term implications
D. Mitanchez, MD, PhD a, C. Yzydorczyk, PhD b,
B. Siddeek, PhD b, F. Boubred, MD, PhD c,
M. Benahmed, MD, PhD b, d, U. Simeoni, MD, NSH b, *
a
Division of Neonatology, Department of Perinatology, Armand Trousseau Hospital, 75012 Paris & Sorbonne
Universit
es UPMC University Paris 06, Paris, France
b
Division of Pediatrics & DOHaD Laboratory, CHUV University Hospital and UNIL, Lausanne, Switzerland
c
Department of Neonatology, University Hospital, Marseille, France
d
INSERM Nice, France

Keywords:
gestational diabetes
obesity
cardiovascular diseases
macrosomia
hypoglycemia
breast-feeding
pregnancy

In the 1980s, David Barker and Colleagues proposed that the major
causes of cardiovascular and metabolic diseases have their roots in
early development. There is now robust evidence that an hyperglycemic intrauterine environment is responsible not only for
signicant short-term morbidity in the fetus and the neonate but
also for an increased risk of developing diabetes as well as other
chronic, noncommunicable diseases at adulthood. The risk is
higher in pregestational diabetes, but unrecognized and/or poorly
managed gestational diabetes (GDM) may have similar consequences. Although a relatively clear picture of the pathogenesis of
the fetal and neonatal complications of maternal diabetes and of
their interrelationship is available today, the intimate molecular
mechanisms involved in the long term are far from being understood. While the rate of GDM is sharply increasing in association
with the pandemic of obesity and of type 2 diabetes over the
world, we review here the current understanding of short- and
long-term outcomes of fetuses exposed to a diabetic environment.
2014 Elsevier Ltd. All rights reserved.

* Corresponding author.
E-mail address: umberto.simeoni@chuv.ch (U. Simeoni).

http://dx.doi.org/10.1016/j.bpobgyn.2014.08.004
1521-6934/ 2014 Elsevier Ltd. All rights reserved.

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Introduction
The incidence of gestational diabetes (GDM) is dramatically increasing in the context of the
pandemic in obesity and type 2 diabetes (T2D) observed in high-income as well as in emerging and
developing countries [1,2]. The real incidence of GDM in low-income countries is underestimated
because of the poor involvement of public health policies in the screening for this disease during
pregnancy and even in nonpregnant populations. Much of the currently available knowledge on the
consequences of maternal diabetes on the neonate has been provided by studies on pregestational
diabetes, while GDM is much more frequent. GDM exposes the fetus and the neonate to short-term
complications that need to be claried in order to improve and to adapt neonatal management
[3,4], especially in developing countries where maternal screening and treatment are decient. Indeed,
recent meta-analyses showed that the treatment of GDM improves neonatal outcomes [5,6]. Moreover,
converging clinical and experimental data suggest that the offspring of diabetic mothers is further
exposed to an increased risk of developing diabetes as well as other chronic, noncommunicable diseases at adulthood, with potential trans-generational effects involved in the pandemic [7]. The
mechanisms by which exposure to altered intrauterine milieu or unsuitable early neonatal care induce
such consequences are not fully understood. Subtle phenomena may act during perinatal life and
impair long-term outcome. In the 1980s, David Barker and his colleagues proposed that the major
causes of cardiovascular mortality in adulthood in industrialized countries have their roots in early
development [8].
Obstetricans and pediatricans are faced in the rst line today with this crucial epidemiologic
context. This article evaluates the currently available knowledge on the short-term and long-term
effects of diabetes in pregnancy on the offspring.
Fetal overnutrition: macrosomia
The consequence of fetal overnutrition is macrosomia. The main conditions during pregnancy that
expose the fetus to excess of nutrients are maternal diabetes and obesity but also excess of gestational
weight gain (GWG). Maternal obesity is tightly linked to GDM or preexisting T2D. The risk of GDM is
2.14-fold higher in overweight pregnant women, 3.56-fold higher in obese pregnant women, and 8.56fold higher in severely obese pregnant women compared to pregnant women with normal weight [9].
The current worldwide pandemic of T2D has devastating effects, and nowadays T2D represents up to
25% of pregnancies with pregestational diabetes [10].
The prevalence of macrosomia in developed countries is between 5% and 20%; however, an increase
of 15e25% has been reported in the last decades, associated with an increase of maternal obesity and
diabetes [11].
The mechanisms of the impact of maternal diabetes and obesity on fetal and neonatal physiology are
still incompletely understood. The Pedersen's hypothesis, formulated more than 50 years ago, suggested
that fetal overgrowth was related to increased transplacental transfer of maternal glucose, stimulating
the release of insulin by the fetal pancreatic beta cells. Because insulin is a major fetal growth factor,
subsequent macrosomia occurs [12]. Indeed, different studies have characterized the link between
maternal glycemia and neonatal macrosomia or fat mass [13]. Other interrelated mechanisms play a role
in the modication of fetal nutrition and metabolism and may have an impact on the long-term
outcome. In GDM, apart from hyperglycemia, the maternal metabolic environment is characterized
by insulin resistance (IR) and inammation [14]. Both conditions increase placental availability of nutrients to the fetus, not only glucose but also amino acids and free fatty acids, and inuence fetal growth.
IR facilitates maternal hypertriglyceridemia that enhances substrates availability to the fetus. Other
mechanisms inuence nutrients supply to the fetus. The placental transcriptome has been showed to be
a target of the altered environment of diabetic pregnancy. For example, genes for lipids transport have
been shown to be upregulated in the placenta of women with GDM, as are genes for inammatory
pathways [15,16]. Such alterations directly or indirectly change the availability of substrates, other than
glucose, to the fetus either by increasing their source or by modifying the maternofetal interface.
Additionally, placental epigenetic changes were recently reported at gene loci involved in energy
metabolism regulation such as those of adipokines [17]. Such epigenetic adaptation to detrimental in
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utero environment may have an impact on the short- and the long-term metabolic regulations in the
newborn. Maternal pregestational overweight or obesity, a condition frequently associated to GDM or
T2D, may also increase lipid availability and modulate delivery of lipid substrates to the fetus. Indeed, it
was shown that prepregnancy overweight/obesity increases the risk of macrosomia and subsequent
offspring overweight and obesity [18]. The increase in birth weight (BW) in obese pregnancy is attributable primarily to an increase in neonate's fat mass, but not in lean mass [19].
The inuence of maternal substrates on fetal growth is illustrated by the association between excess
of GWG and high BW. The comparison of differences in BW between sibling pairs allowed showing that
for every additional kilogram an individual woman gained during pregnancy, the BW of her offspring
increased by about 25 g [20]. In a large prospective multicentric study, excessive GWG was an independent valuable predictor of macrosomia [21].
The concept of excessive fetal growth is expressed either by the word macrosomia or by the
expression large for gestational age (LGA). Depending on study, different cutoffs to dene macrosomia have been proposed: a BW between 4000 and 4500 g, or >3500 g, or above the 90th percentile
for gestational age (GA). The term LGA corresponds to a BW
90th percentile or > 2SD (>97th
percentile) for GA. This more precise denition takes into consideration GA at birth and allows premature newborns with excessive fetal growth to be identied. Macrosomia in newborns of diabetic
mothers is characterized by an excess in body fat, an increase in muscle mass and organomegaly
without increased brain size. There is a linear and continuous relationship between percentage body
fat in newborns, maternal glycemia, and fetal insulin levels [22].
Maternal diabetes during pregnancy, whatever its type, is a risk factor for macrosomia. Treatment of
GDM signicantly reduces the rate of macrosomia [5,6]. In the case of type 1 diabetes (T1D), a satisfying
glycemic control during pregnancy (i.e., HbA1c  7.0%) does not preclude a high incidence of fetal
macrosomia. Various studies have found that third-trimester HbA1c is an independent risk indicator
for macrosomia, but with a weak predictive capacity. HbA1c does not reect intermittent hyperglycemia, mainly postprandial hyperglycemic episodes, that may be involved in accelerated fetal growth
[23]. The frequency of macrosomia or LGA is not different in T2D with respect to T1D [24], even if in
T2D, HbA1c is lower at booking and throughout gestation [25].
Macrosomia, regardless of the cause, is in itself a risk factor for adverse perinatal outcomes, such as
asphyxia and perinatal death, birth injury, respiratory distress and hypoglycemia [26,27]. These risks
increase as the BW or the birth percentile rise. The main risk of being macrosomic is shoulder dystocia
and subsequent birth injuries. This last risk is the highest for infants with a BW 4.500e4.999 g and
>5.000 g, (ORs 2.4 (2.2e2.5) and 3.5 (3.0e4.2), respectively) [26]. Among infants with Erb's palsy in the
general population in the British Isles, 53% were LGA [28]. Erb's palsy is tenfold higher in case of
pregestational diabetes [29].
As discussed below, macrosomia is also in itself a risk factor for long-term altered outcomes.
Short-term complications in the offspring of diabetic mother
Congenital malformations
Maternal diabetes, mainly pregestational diabetes, has huge consequences on the incidence of
congenital anomalies. Eight million infants (185,000 in the United States) are born each year worldwide with major congenital anomalies [30]. Babies from pregestational diabetic mothers are more
likely to suffer cardiac malformations (transposition of great arteries, ventricular or atrial septal defects, and coarctation of the aorta), caudal regression syndrome, central nervous system defects (neural
tube defect (NDT), including anencephaly), gastriceintestinal malformations (duodenal and
analerectal atresia, hypoplastic left colon), and skeletal and genitaleurinary tract anomalies [31]. Poor
maternal glycemic control in the periconceptional period increases the risk of malformations, particularly in the case of preexisting diabetes. Rates of fetal malformations appear to be similar for maternal
T1D and T2D [32]. The risk for congenital malformations in preexisting diabetes is 1.9e10-fold higher
than that in the total population and slightly increased in the case of GDM compared to the general
population (ORs between 1.1 and 1.3), but this risk is much lower than in women with pregestational
diabetes [33]. Maternal hyperglycemia results in excess glucose metabolism in the developing embryo
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that may alter various molecular chain reactions: 1) altered cell lipid metabolism, notably the production of prostaglandin E2 involved in the patency of the ductus arteriosus in utero [34]; 2) high
glucose levels induce an excess production of reactive oxygen species (ROS) which has been shown to
cause oxidative stress (OS) and subsequently increase the risk for fetal malformations, notably NDT
[35]; and also 3) high glucose induces the activation of many proteins involved in apoptotic cell death,
including members of the caspase families [36]. Although it is increasing, the understanding of the
molecular bases of diabetic embryopathy mechanisms is still incomplete [30].
Perinatal death
Both types of pregestational diabetes are associated with an increased risk of stillbirth. In T1D, such
risk is increased threefold to vefold in various countries [37] and more than 75% of perinatal deaths
are attributed to congenital anomalies or complications of prematurity. In T2D, the risk of perinatal
mortality seems even higher than in T1D (OR 1.5 (1.15e1.96)) [25], and the deaths are mainly due to
stillbirth, chorioamnionitis, or birth asphyxia [38]. A strict glycemic control has been shown to reduce
the number of stillbirths in women with TD1 and TD2 [39].
The risk for stillbirth may be slightly increased in GDM, less than in T1D and T2D [37]. According to
the available data, the increased risk of perinatal death in case of GDM, reported in some studies, is
possibly attributable to undiagnosed T2D [38].
Hypertrophic cardiomyopathy
Fetuses exposed to maternal hyperglycemia and hyperinsulinism are prone to develop hypertrophic
cardiomyopathy (most often asymptomatic). Myocardiopathy primarily affects the interventricular
septum, but can extend to the myocardium and sometimes lead to severe morbidity and mortality,
according to the severity of aortic obstruction and the extension of cardiac hypertrophy.
Myocardial hypertrophy has been reported in both pregestational diabetes and GDM. Frequencies
between 25 and 75% have been reported in infants born to diabetic mothers. The incidence is lower in
pure GDM compared to pregestational diabetes [40]. The most recent studies showed that a proper
maternal glycemic control does not entirely preclude interventricular septum hypertrophy and minor
fetal cardiac function impairment, whatever is the type of diabetes [41,42].
Intrauterine growth restriction and preterm birth
Intrauterine growth restriction has been less associated with maternal diabetes but has been reported in cases with severe vascular complications of advanced diabetes and poor placental perfusion
[43]. A relationship between preconceptional HbA1c and a reduced fetal weight at birth has been found
[44]. The hypothesis is that high glucose levels in early pregnancy do harm placental development,
especially when they are associated with microvascular disease. Placental growth is reduced and
placental functions are impaired, resulting in fetal growth restriction.
This situation induces a risk of preterm birth as well. In pregestational diabetes, the rate of premature birth is increased up to 25%, consisting mostly of late preterm birth (34e36 weeks of gestation
(WG)) [45]. In T1D, pregestational hypertension (HT) is related to preterm birth whereas in T2D, thirdtrimester glycosylated hemoglobin (HbA1c) is a predictor of prematurity [46]. GDM and glucose
intolerance are risk factors for spontaneous preterm birth independently on other diabetes complications [47], while the mean maternal glucose level has been related to the risk of preterm birth [48].
Neonatal respiratory distress syndrome
Newborns to diabetic mothers are at increased risk of neonatal respiratory distress syndrome (RDS),
a major cause of admission in neonatal intensive care units.
The principal mechanism of this complication relies in altered lung surfactant synthesis, due to fetal
hyperinsulinism. Insulin has been shown to alter prenatal surfactant synthesis also after 34 weeks GA.
The risk of RDS between 36 and 37 GA has been shown to be higher [49] particularly in cases of
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pregestational diabetes [50]. Therefore, late preterm birth associated with RDS is a particular characteristic of intrauterine exposure to diabetes and these infants are at greater risk of neonatal morbidity
than term infants.
Besides RDS, infants born to diabetic mothers are also exposed to an increased risk of transient
tachypnea of the newborn, particularly in the context of caesarean birth, due to delayed reabsorption of
alveolar liquid at birth. Furthermore, increased risk for meconium aspiration has been reported after
diabetic pregnancy, together with increased risk of perinatal asphyxia. However, such complication
affects mainly pregnancies complicated by severe preexisting diabetes [51].
Neonatal hypoglycemia
A correlation exists between macrosomia, increased cord C-peptide levels, and neonatal hypoglycemia, as conrmed by the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Infants
with excessive size at birth were more likely to develop hypoglycemia and hyperinsulinemia [52].
Transient hyperinsulinism at birth prevents the normal activation of metabolic pathways producing
glucose and ketone bodies, and causes increased glucose consumption by tissues.
It seems reasonable to consider that LGA (>90th percentile) or growth-restricted infants (<10th
percentile) born to a diabetic mother benet from a blood glucose concentration check at 3e6-h intervals during the rst day of life. On the other hand, normal-grown infants of mothers with dietcontrolled GDM may not be systematically monitored.
Early and frequent breast-feeding remains key in preventing hypoglycemia, whatever the infant's
BW, as far as he/she is able to feed autonomously. Therefore, infants of diabetic mothers should be kept
aside their mother, in the absence of signicant complications requiring a transfer to a special care
neonatal unit, which is the case in the majority of the cases in high-income countries. Even in mildly or
moderately symptomatic infants with low blood glucose levels, sustained breast-feeding, or eventually
formula supplements, should be tried rst, provided a satisfactory clinical response is obtained [4].
Neonatal hypocalcemia
The evidence for neonatal hypocalcemia in the case of maternal diabetes remains poor in the
literature. An incidence of up to 30% has been reported after poorly maternal controlled diabetes [53].
The mechanism is still unclear but seems to involve an abnormal calcium phosphorus metabolism
during pregnancy with decreased calcemia and vitamin D concentrations especially during the third
trimester. The severity may be related to the degree of maternal diabetes control. There is growing
evidence that women who develop GDM are more likely to be vitamin D decient [54]. Other factors
like prematurity and perinatal asphyxia can contribute to low calcium levels.
Neonatal polycythemia and hyperbilirubinemia
Relative fetal hypoxia, secondary to insulin-induced high glucose uptake and metabolic rate, causes
increased erythropoietin secretion and as a consequence, increased fetal red cell production (Fig. 1).
The incidence and the severity of polycythemia are associated with poor maternal glycemic control.
Normovolemic polycythemia seen in infants from a diabetic mother can lead to blood hyperviscosity. Early symptoms are unspecic: feeding problems, plethoric aspect, cyanosis, lethargy, hypotonia, respiratory distress, jitteriness and irritability, seizures (due to multiple cerebral infarcts),
necrotizing enterocolitis, hyperbilirubinemia, and hypoglycemia have all been found associated. Renal
thrombosis and other vein thrombosis are more frequent in infants of diabetic mothers.
Hyperbilirubinemia has been traditionally considered as a neonatal complication of maternal diabetes. It is not a serious complication if potentially toxic levels are treated which is usually the case. The
danger is in the risk of hyperbilirubinemic encephalopathy and kernicterus, which is not classically
reported in cases of maternal diabetes. In the HAPO study, hyperbilirubinemia was weakly associated
with maternal blood glucose levels [13]. Polycythemia is considered as one of the causes of hyperbilirubinemia, but additional mechanisms, such as preterm birth, poor liver conjugation are likely to be
involved.
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Intra-uterine exposure to maternal diabetes

Maternal excess circula ng
glucose, lipids, amino-acids

Fetal susbtrates transfer

Fetal hyperinsulinemia
Fetal substrate uptake

Hypoxia

Altered oxygen
delivery

Erythropoe n
S llbirth,
Perinatal
Asphyxia

Lung surfactant
synthesis

Macrosomia

Tissue oxygen consump on

Myocardiopathy

Polycythaemia
Hyperbilirubinemia

Respiratory distress
syndrome

Fig. 1. Short-term complications of intrauterine exposure to maternal diabetes in the offspring.

The sequence relating the various short-term complications possibly observed in infants born to
diabetic mothers is shown in Fig. 1.
Long-term effects in the offspring
Obesity and T2D
The consequences of exposure to diabetes in utero on childhood overweight and obesity and the
risk of T2D have been illustrated by studies in Pima Indians. Pima Indians have an exceptionally high
prevalence of obesity and T2D due to genetic reasons. The prevalence of T2D in offspring of Pima
women increases up to sixfold in those with diabetic or prediabetic mothers, and diabetes during
childhood and adolescence occurred almost exclusively among the offspring of diabetic and prediabetic mothers [55]. In the same way, the offspring of mothers with pregestational T2D or GDM are
heavier at birth and at every age than those born to nondiabetic mothers. There is evidence that the
higher frequency of diabetes and obesity in the offspring of diabetic Pima women is not only due to a
genetic susceptibility to obesity and diabetes. Studies including sibling pairs in which one sibling was
born before and the other after the onset of maternal diabetes have brought interesting data [56]. The
risk of diabetes was signicantly higher in siblings born after the mother developed diabetes than in
those born before the mother's diagnosis of diabetes (odds ratio 3.7, P 0.02) and the mean body mass
index (BMI) was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies
(P 0.003) [57]. On the other hand, in a US nationwide study, Gillman et al. have shown that 9.7%
children overweight at early adolescence were born to mothers with GDM compared with only 6.6% in
the absence of GDM [58]. In a large prospective Swedish cohort study, BMI of men at 18 years of age
whose mothers had diabetes mellitus during their pregnancy was on average 0.94 kg/m2 greater (95%
CI, 0.35e1.52) than in their brothers born before their mother was diagnosed with diabetes, after
adjustment for maternal age, parity, and education [59].
It must be underlined that most studies have encountered major difculties in separating the roles
of fetal exposure to maternal hyperglycemia, from that of coexisting maternal manifestations such as
overweight/obesity.
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In a multiethnic group of youths aged 10e22 years, exposure to maternal diabetes (OR 5.7 (95% CI
2.4e13.4)) and exposure to maternal obesity (2.8 (95% CI 1.5e5.2)) were independently associated with
T2D in the offspring. Exposure to maternal diabetes in utero resulted in an attributable risk of only 4.7%,
although 47.2% of T2D in youth could be attributed to intrauterine exposure to maternal diabetes and
obesity together [60]. Concerning the link between in utero diabetes and overweight and obesity in the
offspring, the literature provides contradictory results. After adjusting on maternal prepregnancy BMI,
the association between maternal diabetes and offspring BMI was no longer signicant in some studies
[61,62]. Although convincing data exist in the literature on the effect of maternal diabetes on offspring
health, many unanswered questions remain regarding the size effect of maternal intrauterine exposure
compared with shared genetic traits. These, in turn, are difcult to distinguish from inuences of the
child's postnatal environment and lifestyle.
Cardiovascular and renal diseases
When compared with controls, offspring exposed to maternal diabetes have a worse cardiovascular
risk prole, with increased levels of circulating cellular adhesion molecules, which are biomarkers of
adverse endothelium perturbation. These markers are related to the earliest preclinical stages of
atherosclerosis and diabetes [63]. Offspring of Pima mothers who had diabetes during pregnancy also
had higher systolic blood pressure (SBP) than offspring of mothers who did not develop T2D until after
pregnancy: this was independent on adiposity [64]. A recent systematic review conrmed the association between exposure to maternal diabetes and SBP in childhood. However, this association was
only signicant in male offspring. Furthermore, there is evidence that this association may be inuenced by maternal prepregnancy BMI [65].
Endothelial dysfunction (ED) is thought to be critical in the development of vascular disease,
notably in HT [66]. ED can be characterized by a loss of regulatory functions related to vascular tone,
inammation, and OS, but also by impaired vasculogenesis and capacity of repair mediated by circulating endothelial progenitor cells. These cells are now considered as a strong biomarker to assess ED
and have been identied as endothelial colony-forming cells (ECFCs). Ingram et al. showed in vitro and
in vivo that hyperglycemia or exposure to a diabetic intrauterine environment of ECFCs (from newborns of diabetic pregnancies) reduced ECFCs colony formation and capillary-like tube formation [67]
and increased senescence and reduced proliferation [68]. Therefore, infants born to diabetic mothers
are predisposed to develop ED and cardiovascular diseases (CVD) later in life.
Angiotensin II (AngII) can also be involved in the impairment of endothelial and vascular functions.
Experimental models have shown that AngII increased vasoconstriction in response to endothelin-1
[69], and in human, induced apoptosis of umbilical venous endothelium cells [70]. An increase in
cord blood AngII concentration has been observed in offspring from mothers with GDM [71].
Exposure to a diabetic intrauterine environment is also considered as a strong risk factor for renal
disease. Diabetic nephropathy is the major cause of end stage renal disease [72]. In Pima Indians,
increased urinary albumin excretion (UAE) has been observed in the offspring of diabetic mothers: UAE
was 58% in offspring of mothers with GDM, 43% in offspring of mothers who develop diabetes after
pregnancy, and only 40% in offspring of nondiabetic mothers [73]. These functional changes might result
in damage to developing glomeruli possibly related to a similar process of nephron number decreased [2].
Mechanisms: role of oxidative stress
Among possible factors involved in the development of cardiometabolic diseases in offspring from
diabetic mother, OS and epigenetic alterations have been proposed. Epigenetic factors are discussed in
a different chapter in this issue.
A hyperglycemic environment is associated with OS, notably in women with GDM who have an
overproduction of free radicals and a decrease of radical scavenger. Hyperglycemia induces OS through
several metabolic mechanisms as the polyol pathway, the formation of advanced glycation end products,
the activation of protein kinase C, the hexosamine pathway, and enhanced ROS production by mitochondria. Therefore, a hyperglycemic intrauterine milieu from mother GDM exposed the fetus to OS. In
fact, an increase in malondialdehyde levels (end product of lipid peroxidation) and a decrease in
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superoxide dismutase (enzyme responsible for the superoxide anion scavenging) activity has been
mentioned in cord blood of infants born to GDM mothers [74]. Shortened telomere length is associated
with an increased risk of CVD, HT, obesity, and diabetes. OS seems to have a possible implication in
telomere attrition. A shorter telomere length has been observed in infants born to GDM women suggesting that shortened telomere length may increase the risk of cardiometabolic diseases in adulthood of
GDM offspring [75]. AngII has also been involved in the enhancement of ROS levels [76], which can affect
vascular function by scavenging or inactivating endothelium-relaxing factors, such as NO or prostacyclin,
and by producing peroxynitrite, a potent constrictor [77]. Therefore, AngII may participate in endothelium dysfunction and later increase in blood pressure (BP) observed in offspring of GDM mothers.
Consequence of being LGA on long-term outcomes
A number of studies reported a link between high BW and obesity in childhood to early adulthood. A
meta-analysis showed that BW
4000 g increases twofold the risk for obesity, and this risk is
increased about 2.5-fold when BW exceeds 90th percentile [78].
Being LGA (BW > 90th percentile) in association with GDM or maternal obesity increases the risk of
metabolic syndrome (MS) in childhood. A longitudinal cohort study analyzed the prevalence of MS in
children aged 6e11 years; accordingly, they were LGA or adapted for gestational age (AGA, BW 10e90th
percentile), and their mothers did or did not have GDM. The prevalence at any time of at least two
components of MS was higher for the LGA/GDM group (50%), compared to the LGA/control group (29%),
AGA/GDM group (21%), and AGA/control group (18%). The risk of developing MS with time was
signicantly different between LGA and AGA offspring in the GDM group, with a 3.6-fold greater risk
among LGA children by 11 years. In this study, children exposed to maternal obesity were also at
increased risk of developing MS [79].
Long-term consequence of being born preterm
Epidemiological studies have described long-term health consequences of prematurity, apart from
physical and neurodevelopmental disabilities. As compared with young adults who had been born at
term (GA comprised between 37.0 and 42.9 weeks), it has been shown that preterm birth with very low
birth weight (LBW) (<1500 g; GA ranged from 24.0 to 35.6 weeks) had signicantly higher fasting
insulin, 2-h insulin, and 2-h glucose concentrations, as well as a higher homeostatic model assessment
(HOMA)-IR index. These differences were not attributable to body size or fat distribution [80]. Other
studies conrmed these ndings notably during childhood (4e10 years old) [81], in young adults (22
years old) [82], and in adulthood (30e60 years old) [83]. A Swedish study has shown that preterm birth
(<37 weeks of GA), including late preterm birth (35e36 weeks of GA), is associated with a slight
increased risk of diabetes in young adulthood (25e37 years old) [84].
Epidemiological studies have also shown that premature infants are prone to increased arterial BP
at young adulthood. An inverse relationship between GA and adult HT has been described in adult born
prematurely [85]. We have recently shown that ECFCs from preterm infants exhibit striking reductions
in their clonogenic and angiogenic properties, an imbalance between angiogenic and anti-angiogenic
factors, as a consequence of an accelerated senescence in comparison with infants born at term. These
alterations result in ECFCs dysfunction and could be involved in the developmental programming of HT
observed in premature infants [86e88].
The effect of breast-feeding
It has been suggested that breast-feeding has benet effects for long-term obesity. A long-term
advantage of breast-feeding was further supported by a doseeresponse effect. A longer duration of
breast-feeding was associated with a lower tendency to later obesity; each month of breast-feeding
was associated with a decrease of 4% (95% CI 6  2%) in obesity risk [89]. The positive effect of
breast-feeding is partly related to a slower pattern of growth compared to formula-fed infants because
an early accelerated postnatal growth or a rapid postnatal catch-up growth during infancy enhances
the risk of obesity and CVD at adulthood [90]. However, the critical window period when nutrition
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inuences the long-term outcomes is not well dened and early growth may correspond to a spectrum
that spans between the rst 2 WG to the rst 2 years of life at least (the rst 1000 days). It was shown
that greater weight gain in the rst week of life can program obesity in adulthood: each 100-g increase
in absolute weight gain during this period was associated with an increase of 28% in the risk of being
overweight (95% CI 8e52%) [91]. On the other hand, a recent meta-analysis of individual-level data on
47,661 participants, from 10 cohort studies from the UK, France, Finland, Sweden, the US, and
Seychelles, has shown that infant weight gain (between birth and 1 year of age) is positively associated
with a subsequent risk of obesity [92].
Adequate breast-feeding (
6 months) also reduces the increase of adiposity levels observed
during childhood after exposure to diabetes in utero. [93] Furthermore, these results were
strengthened by the follow-up of a longitudinal cohort. It was shown that adequate breast-feeding
reduces the overall body size and slows BMI, growth velocity both during infancy as well as in the
childhood period, in offspring of nondiabetic mothers, as well as in offspring of diabetic mothers.
Effects were independent of sex, race/ethnicity, current childhood diet, and physical activity levels.
This study indicates that the favorable effects of breast-feeding on BMI growth patterns extend
throughout the entire childhood period, and are also present in youth at increased risk for obesity
due to intrauterine exposure to maternal diabetes [94]. Others have reported data that favor the
benet of breast-feeding in offspring of diabetic mother, either on the risk of obesity [95] or of
diabetes [96].
Therefore, encouraging diabetic mothers to breast-feed could be a good way to a long-term
protective effect on the offspring, notably to preterm infants. In fact, in a randomized trial
comparing preterm infant assigned human milk versus formula for just 4 weeks, marked benets of
human milk were observed at 13e16 years of age on BP, lipids prole, and IR [97].
Breast-fed babies may control the amount of milk they consume and so learn to self-regulate their
energy intake better than those given formula, although whether this difference persists into adult life
is unknown. Nutritional benets of breast-feeding may include differences in nutrients between
human milk and formulas (lower glucose and protein, concentrations in long-chain polyunsaturated
fatty acids). Differences in early protein intakes that are greater in formula than in human milk could
also affect later adiposity.
Disparities in the world: the burden in low-income countries
The prevalence of risk factors for diabetes during pregnancy is increasing all around the world.
Indeed, a huge increase in the incidence of T2D and obesity in developing countries is observed,
especially in the westernized ones. T2D is an occult disease that can remain undiagnosed especially in
young women of reproductive age. In many low-income countries, no screening program for diabetes
during pregnancy is available, nor are programs of maternal care, especially in rural areas, because of
limited nancial and human resources. A recent study reported an estimated global prevalence of
hyperglycemia in pregnancy worldwide of 17/1000 live births in 2013. A majority of cases occurred in
low- and middle-income countries (91.6%). The Southeast Asia region had the highest prevalence with
23% of live births, followed by the Middle East and North Africa region with 22% [98].
A community-based prospective program in India, with universal screening for GDM, showed that
the prevalence of GDM was 13.9%. The frequency varied widely across urban, semi-urban, and rural
areas, respectively, 17.8%, 13.8%, and 9.9%. The prevalence also varied according to maternal BMI. For
BMI
25 mg/m2, the incidence was up to 28.4%, 23.8%, and 16.1% in urban, semi-urban, and rural areas,
respectively [99].
Then, it can be estimated that the burden of neonatal complications is higher in developing
countries, because of the high incidence of maternal hyperglycemia and the absence of screening and
treatment of maternal diabetes and because of the scarcity of neonatal care.
Indeed, a recent analysis of data from World Health Organization's (WHO's) Global Survey on
maternal and perinatal outcomes in 23 developing countries describes the prevalence of macrosomia,
one of the main complication of maternal diabetes and obesity [100]. In this study, maternal diabetes
and increased gestational BMI were signicantly associated with macrosomia in all regions. For
example, in Algeria, 15% of the babies had a BW
4 kg and 25% of the mothers were obese
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(BMI
30 kg/m2). In other countries in Latin America, maternal obesity was >30% (Argentina, Mexico,
and Paraguay).
The health systems in low-income countries are often insufciently structured to provide adequate
screening and care to diabetic pregnant women. Then, the limited spectrum of available services results in a burden of adverse neonatal outcomes that are higher than in high-income countries. As
discussed above, offspring of diabetic and obese women or macrosomic infants are more likely to be
obese and to have diabetes and CVD at adulthood. Consequently, the long-term consequences of
diabetes in pregnancy also have a main impact in developing countries and supply with the current
pandemic in obesity and T2D.
Summary
While the incidence of T2D and of GDM is increasing worldwide, both short-term and longterm consequences in the offspring need special attention today. Macrosomia is a common
complication in all types of diabetes during pregnancy and also in maternal obesity. It is the main
factor related to most of the neonatal adverse outcomes. Furthermore, it is a strong predictor of
long-term adverse outcomes. The mechanisms involved in the short- and long-term outcomes in
offspring from GDM mothers are increasingly understood. The impact of obesity/overweight
compared to the effects of maternal diabetes on the short- and long-term consequences needs
however a better documentation. The identication of early biomarkers in infants and children
from diabetic mothers may represent an interesting pathway to develop preventive and therapeutic strategies in order to deprogram the long-term effect of exposure to intrauterine hyperglycemic environment.
Macrosomia and subsequently neonatal complications linked to macrosomia can be partly prevented by providing a tight maternal glycemic control. This underlines the importance of developing
strategies for screening and managing women with GDM into public policy and health systems,
particularly in middle- and low-income countries where the burden of maternal hyperglycemia is the
higher. The growing number of women developing obesity and diabetes has major implications not
only for the health of the mother and child but also for global health, as it accentuates the global
diabetes epidemic.

Practice points
 Maternal diabetes during pregnancy should be screened and treated to improve neonatal
outcomes.
 Maternal obesity/overweight is an additional risk factor for adverse neonatal outcomes.
 Pediatricians should be aware of the neonatal risks associated with diabetes in pregnancy,
especially RDS and hypoglycemia.
 Strategies for screening and managing women with GDM should be developed in middleand low-income countries.

Breast-feeding
 Must be encouraged and started as soon as possible after birth in infants born to diabetic
mothers.
 Reduces the risk of later obesity and decreases childhood adiposity and slows growth velocity during infancy.
 May have a protective effect against the risk of diabetes later in life.

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D. Mitanchez et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e14

11

Macrosomia
 The incidence of macrosomia is increasing in association with an increased incidence of
maternal obesity and diabetes.
 Macrosomia is associated with poor perinatal outcomes, particularly asphyxia, perinatal
death, birth injury, RDS, and hypoglycemia.

Research agenda
Exposure in utero to maternal diabetes:
 More research is needed to better understand the factors that influence fetal growth in case of
maternal diabetes and/or obesity.
 Studies are needed to differentiate the impact of maternal overweight/obesity from that of
maternal diabetes on short-term and long-term outcomes in the mother and in the offspring.
 The mechanisms of the long-term impact of maternal diabetes on embryo, fetal, and
neonatal physiology are not well established.
 Early biomarkers of maternal diabetes imprinting effects in the offspring need to be
identified.

Conict of interest statement

The authors declare no conicts of interest.

References
[1] Anna V, van der Ploeg HP, Cheung NW, et al. Sociodemographic correlates of the increasing trend in prevalence of
gestational diabetes mellitus in a large population of women between 1995 and 2005. Diabetes Care 2008;31:
2288e93.
*[2] Simeoni U, Barker DJ. Offspring of diabetic pregnancy: long-term outcomes. Semin Fetal Neonatal Med 2009;14:
119e24.
*[3] Mitanchez D. Foetal and neonatal complications in gestational diabetes: perinatal mortality, congenital malformations, macrosomia, shoulder dystocia, birth injuries, neonatal complications. Diabetes Metab 2010;36:617e27.
*[4] Mitanchez D. Management of infants born to mothers with gestational diabetes. Paediatric environment. Diabetes
Metab 2010;36:587e94.
[5] Horvath K, Koch K, Jeitler K, et al. Effects of treatment in women with gestational diabetes mellitus: systematic review
and meta-analysis. Bmj 2010;340:c1395.
[6] 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;98:396e405.
*[7] Mitanchez D, Burguet A, Simeoni U. Infants born to mothers with gestational diabetes mellitus: mild neonatal effects,
a long-term threat to global health. J Pediatr 2014;164:445e50.
[8] Barker DJ. Intrauterine programming of adult disease. Mol Med Today 1995;1:418e23.
[9] Chu SY, Callaghan WM, Kim SY, et al. Maternal obesity and risk of gestational diabetes mellitus. Diabetes Care 2007;
30:2070e6.
[10] Bell R, Bailey K, Cresswell T, et al. Trends in prevalence and outcomes of pregnancy in women with pre-existing type I
and type II diabetes. Bjog 2008;115:445e52.
[11] Henriksen T. The macrosomic fetus: a challenge in current obstetrics. Acta Obstet Gynecol Scand 2008;87:134e45.
[12] Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol (Copenh) 1954;16:330e42.
*[13] Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:
1991e2002.
[14] Catalano PM, Hauguel-De Mouzon S. Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic?
Am J Obstet Gynecol 2011;204:479e87.
[15] Radaelli T, Lepercq J, Varastehpour A, et al. Differential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type 1 diabetes mellitus. Am J Obstet Gynecol 2009;201. 209 e201e209 e210.

Please cite this article in press as: Mitanchez D, et al., The offspring of the diabetic mother e Short- and
long-term implications, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://
dx.doi.org/10.1016/j.bpobgyn.2014.08.004

12

D. Mitanchez et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e14
[16] Radaelli T, Varastehpour A, Catalano P, et al. Gestational diabetes induces placental genes for chronic stress and inammatory pathways. Diabetes 2003;52:2951e8.
[17] Houde AA, Hivert MF, Bouchard L. Fetal epigenetic programming of adipokines. Adipocyte 2013;2:41e6.
[18] Yu Z, Han S, Zhu J, et al. Pre-pregnancy body mass index in relation to infant birth weight and offspring overweight/
obesity: a systematic review and meta-analysis. PLoS One 2013;8:e61627.
[19] Sewell MF, Huston-Presley L, Super DM, et al. Increased neonatal fat mass, not lean body mass, is associated with
maternal obesity. Am J Obstet Gynecol 2006;195:1100e3.
[20] Hutcheon JA, Platt RW, Meltzer SJ, et al. Is birth weight modied during pregnancy? Using sibling differences to
understand the impact of blood glucose, obesity, and maternal weight gain in gestational diabetes. Am J Obstet
Gynecol 2006;195:488e94.
[21] 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.
*[22] Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: associations with neonatal anthropometrics. Diabetes
2009;58:453e9.
[23] Evers IM, de Valk HW, Mol BW, et al. Macrosomia despite good glycaemic control in Type I diabetic pregnancy; results
of a nationwide study in The Netherlands. Diabetologia 2002;45:1484e9.
[24] Lapolla A, Dalfra MG, Fedele D. Pregnancy complicated by type 2 diabetes: an emerging problem. Diabetes Res Clin
Pract 2008;80:2e7.
[25] Balsells M, Garcia-Patterson A, Gich I, et al. Maternal and fetal outcome in women with type 2 versus type 1 diabetes
mellitus: a systematic review and metaanalysis. J Clin Endocrinol Metab 2009;94:4284e91.
[26] Zhang X, Decker A, Platt RW, et al. How big is too big? the perinatal consequences of fetal macrosomia. Am J Obstet
Gynecol 2008;198(517):e511e516.
[27] Weissmann-Brenner A, Simchen MJ, Zilberberg E, et al. Maternal and neonatal outcomes of large for gestational age
pregnancies. Acta Obstet Gynecol Scand 2012;91:844e9.
[28] Evans-Jones G, Kay SP, Weindling AM, et al. Congenital brachial palsy: incidence, causes, and outcome in the United
Kingdom and Republic of Ireland. Arch Dis Child Fetal Neonatal Ed 2003;88:F185e9.
[29] Weindling A. Offspring of diabetic pregnancy: short term outcomes. Semin Fetal Neonatal Med 2009;14:111e8.
[30] Reece EA. Diabetes-induced birth defects: what do we know? what can we do? Curr Diab Rep 2012;12:24e32.
[31] McLeod L, Ray JG. Prevention and detection of diabetic embryopathy. Community Genet 2002;5:33e9.
[32] Macintosh MC, Fleming KM, Bailey JA, et al. Perinatal mortality and congenital anomalies in babies of women with
type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. BMJ 2006;333:177.
[33] Balsells M, Garcia-Patterson A, Gich I, et al. Major congenital malformations in women with gestational diabetes
mellitus: a systematic review and meta-analysis. Diabetes Metab Res Rev 2012;28:252e7.
[34] Schneider DJ, Moore JW. Patent ductus arteriosus. Circulation 2006;114:1873e82.
[35] Chang TI, Horal M, Jain SK, et al. Oxidant regulation of gene expression and neural tube development: insights gained
from diabetic pregnancy on molecular causes of neural tube defects. Diabetologia 2003;46:538e45.
[36] Zhao Z, Yang P, Eckert RL, et al. Caspase-8: a key role in the pathogenesis of diabetic embryopathy. Birth Defects Res B
Dev Reprod Toxicol 2009;86:72e7.
[37] Dudley DJ. Diabetic-associated stillbirth: incidence, pathophysiology, and prevention. Obstet Gynecol Clin North Am
2007;34:293e307 [ix].
*[38] Cundy T, Gamble G, Townend K, et al. Perinatal mortality in Type 2 diabetes mellitus. Diabet Med 2000;17:33e9.
[39] Mathiesen ER, Ringholm L, Damm P. Stillbirth in diabetic pregnancies. Best Pract Res Clin Obstet Gynaecol 2011;25:
105e11.
[40] Ullmo S, Vial Y, Di Bernardo S, et al. Pathologic ventricular hypertrophy in the offspring of diabetic mothers: a
retrospective study. Eur Heart J 2007;28:1319e25.
[41] Garcia-Flores J, Janez M, Gonzalez MC, et al. Fetal myocardial morphological and functional changes associated with
well-controlled gestational diabetes. Eur J Obstet Gynecol Reprod Biol 2011;154:24e6.
[42] Chu C, Gui YH, Ren YY, et al. The impacts of maternal gestational diabetes mellitus (GDM) on fetal hearts. Biomed
Environ Sci 2012;25:15e22.
[43] Vambergue A, Fajardy I. Consequences of gestational and pregestational diabetes on placental function and birth
weight. World J Diabetes 2011;2:196e203.
[44] Glinianaia SV, Tennant PW, Bilous RW, et al. HbA(1c) and birthweight in women with pre-conception type 1 and type
2 diabetes: a population-based cohort study. Diabetologia 2012;55:3193e203.
[45] Yang J, Cummings EA, O'Connell C, et al. Fetal and neonatal outcomes of diabetic pregnancies. Obstet Gynecol 2006;
108:644e50.
[46] Gonzalez-Gonzalez NL, Ramirez O, Mozas J, et al. Factors inuencing pregnancy outcome in women with type 2 versus
type 1 diabetes mellitus. Acta Obstet Gynecol Scand 2008;87:43e9.
[47] Hedderson MM, Ferrara A, Sacks DA. Gestational diabetes mellitus and lesser degrees of pregnancy hyperglycemia:
association with increased risk of spontaneous preterm birth. Obstet Gynecol 2003;102:850e6.
[48] Yogev Y, Langer O. Spontaneous preterm delivery and gestational diabetes: the impact of glycemic control. Arch
Gynecol Obstet 2007;276:361e5.
[49] Piper JM, Xenakis EM, Langer O. Delayed appearance of pulmonary maturation markers is associated with poor
glucose control in diabetic pregnancies. J Matern Fetal Med 1998;7:148e53.
[50] Moore TR. A comparison of amniotic uid fetal pulmonary phospholipids in normal and diabetic pregnancy. Am J
Obstet Gynecol 2002;186:641e50.
[51] Salihu HM, Weldeselasse HE, Rao K, et al. The impact of obesity on maternal morbidity and feto-infant outcomes
among macrosomic infants. J Matern Fetal Neonatal Med 2011;24:1088e94.
[52] Metzger BE, Persson B, Lowe LP, et al. Hyperglycemia and adverse pregnancy outcome study: neonatal glycemia.
Pediatrics 2010;126:e1545e1552.

Please cite this article in press as: Mitanchez D, et al., The offspring of the diabetic mother e Short- and
long-term implications, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://
dx.doi.org/10.1016/j.bpobgyn.2014.08.004

D. Mitanchez et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e14

13

[53] Demarini S, Mimouni F, Tsang RC, et al. Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: a randomized study. Obstet Gynecol 1994;83:918e22.
[54] Alzaim M, Wood RJ. Vitamin D and gestational diabetes mellitus. Nutr Rev 2013;71:158e67.
[55] Dabelea D, Pettitt DJ. Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the
offspring, in addition to genetic susceptibility. J Pediatr Endocrinol Metab 2001;14:1085e91.
[56] Dabelea D. The predisposition to obesity and diabetes in offspring of diabetic mothers. Diabetes Care 2007;30(Suppl.
2):S169e74.
[57] Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and
obesity: a study of discordant sibships. Diabetes 2000;49:2208e11.
[58] Gillman MW, Rifas-Shiman S, Berkey CS, et al. Maternal gestational diabetes, birth weight, and adolescent obesity.
Pediatrics 2003;111:e221e226.
[59] Lawlor DA, Lichtenstein P, Langstrom N. Association of maternal diabetes mellitus in pregnancy with offspring
adiposity into early adulthood: sibling study in a prospective cohort of 280,866 men from 248,293 families. Circulation 2011;123:258e65.
[60] Dabelea D, Mayer-Davis EJ, Lamichhane AP, et al. Association of intrauterine exposure to maternal diabetes and
obesity with type 2 diabetes in youth: the SEARCH Case-Control Study. Diabetes Care 2008;31:1422e6.
[61] Kim SY, England JL, Sharma JA, et al. Gestational diabetes mellitus and risk of childhood overweight and obesity in
offspring: a systematic review. Exp Diabetes Res 2011;2011:541308.
[62] Philipps LH, Santhakumaran S, Gale C, et al. The diabetic pregnancy and offspring BMI in childhood: a systematic
review and meta-analysis. Diabetologia 2011;54:1957e66.
[63] West NA, Crume TL, Maligie MA, et al. Cardiovascular risk factors in children exposed to maternal diabetes in utero.
Diabetologia 2011;54:504e7.
[64] Bunt JC, Tataranni PA, Salbe AD. Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic
blood pressure in pima Indian children. J Clin Endocrinol Metab 2005;90:3225e9.
[65] Aceti A, Santhakumaran S, Logan KM, et al. The diabetic pregnancy and offspring blood pressure in childhood: a
systematic review and meta-analysis. Diabetologia 2012;55:3114e27.
[66] Taddei S, Virdis A, Mattei P, et al. Endothelium-dependent forearm vasodilation is reduced in normotensive subjects
with familial history of hypertension. J Cardiovasc Pharmacol 1992;20(Suppl. 12):S193e5.
[67] Ingram DA, Lien IZ, Mead LE, et al. In vitro hyperglycemia or a diabetic intrauterine environment reduces neonatal
endothelial colony-forming cell numbers and function. Diabetes 2008;57:724e31.
[68] Blue EK, DiGiuseppe R, Derr-Yellin E, et al. Gestational diabetes induces alterations in the function of neonatal
endothelial colony-forming cells. Pediatr Res 2014;75:266e72.
[69] Kobayashi T, Nogami T, Taguchi K, et al. Diabetic state, high plasma insulin and angiotensin II combine to augment
endothelin-1-induced vasoconstriction via ETA receptors and ERK. Br J Pharmacol 2008;155:974e83.
[70] Bian YF, Yang HY, Yang ZM, et al. Amlodipine treatment prevents angiotensin II-induced human umbilical vein
endothelial cell apoptosis. Arch Med Res 2011;42:22e7.
[71] Zhang F, Xiao X, Liu D, et al. Increased cord blood angiotensin II concentration is associated with decreased insulin
sensitivity in the offspring of mothers with gestational diabetes mellitus. J Perinatol 2013;33:9e14.
[72] Atkins RC, Zimmet P. Diabetic kidney disease: act now or pay later. Acta Diabetol 2010;47:1e4.
[73] Nelson RG, Morgenstern H, Bennett PH. Intrauterine diabetes exposure and the risk of renal disease in diabetic Pima
Indians. Diabetes 1998;47:1489e93.
[74] Kinalski M, Sledziewski A, Telejko B, et al. Lipid peroxidation, antioxidant defence and acid-base status in cord blood at
birth: the inuence of diabetes. Horm Metab Res 2001;33:227e31.
[75] Xu J, Ye J, Wu Y, et al. Reduced fetal telomere length in gestational diabetes. PLoS One 2014;9:e86161.
[76] Yzydorczyk C, Gobeil Jr F, Cambonie G, et al. Exaggerated vasomotor response to ANG II in rats with fetal programming
of hypertension associated with exposure to a low-protein diet during gestation. Am J Physiol Regul Integr Comp
Physiol 2006;291:R1060e8.
[77] Abe J, Berk BC. Reactive oxygen species as mediators of signal transduction in cardiovascular disease. Trends Cardiovasc Med 1998;8:59e64.
[78] Monasta L, Batty GD, Cattaneo A, et al. Early-life determinants of overweight and obesity: a review of systematic
reviews. Obes Rev 2010;11:695e708.
[79] Boney CM, Verma A, Tucker R, et al. Metabolic syndrome in childhood: association with birth weight, maternal
obesity, and gestational diabetes mellitus. Pediatrics 2005;115:e290e296.
[80] Hovi P, Andersson S, Eriksson JG, et al. Glucose regulation in young adults with very low birth weight. N Engl J Med
2007;356:2053e63.
[81] Hofman PL, Regan F, Jackson WE, et al. Premature birth and later insulin resistance. N Engl J Med 2004;351:2179e86.
[82] Rotteveel J, van Weissenbruch MM, Twisk JW, et al. Infant and childhood growth patterns, insulin sensitivity, and
blood pressure in prematurely born young adults. Pediatrics 2008;122:313e21.
[83] Pilgaard K, Faerch K, Carstensen B, et al. Low birthweight and premature birth are both associated with type 2 diabetes
in a random sample of middle-aged Danes. Diabetologia 2010;53:2526e30.
[84] Crump C, Winkleby MA, Sundquist K, et al. Risk of diabetes among young adults born preterm in Sweden. Diabetes
Care 2011;34:1109e13.
[85] Poplawska K, Dudek K, Koziarz M, et al. Prematurity-related hypertension in children and adolescents. Int J Pediatr
2012;2012:537936.
[86] Vassallo PF, Simoncini S, Ligi I, et al. Accelerated senescence of cord blood endothelial progenitor cells in premature
neonates is driven by SIRT1 decreased expression. Blood 2014.
[87] Ligi I, Simoncini S, Tellier E, et al. A switch toward angiostatic gene expression impairs the angiogenic properties of
endothelial progenitor cells in low birth weight preterm infants. Blood 2011;118:1699e709.
[88] Ligi I, Simoncini S, Tellier E, et al. Altered angiogenesis in low birth weight individuals: a role for anti-angiogenic
circulating factors. J Matern Fetal Neonatal Med 2014;27:233e8.

Please cite this article in press as: Mitanchez D, et al., The offspring of the diabetic mother e Short- and
long-term implications, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://
dx.doi.org/10.1016/j.bpobgyn.2014.08.004

14

D. Mitanchez et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1e14

[89] Harder T, Bergmann R, Kallischnigg G, et al. Duration of breastfeeding and risk of overweight: a meta-analysis. Am J
Epidemiol 2005;162:397e403.
[90] Singhal A, Lanigan J. Breastfeeding, early growth and later obesity. Obes Rev 2007;8(Suppl. 1):51e4.
[91] Stettler N, Stallings VA, Troxel AB, et al. Weight gain in the rst week of life and overweight in adulthood: a cohort
study of European American subjects fed infant formula. Circulation 2005;111:1897e903.
[92] Druet C, Stettler N, Sharp S, et al. Prediction of childhood obesity by infancy weight gain: an individual-level metaanalysis. Paediatr Perinat Epidemiol 2012;26:19e26.
*[93] Crume TL, Ogden L, Maligie M, et al. Long-term impact of neonatal breastfeeding on childhood adiposity and fat
distribution among children exposed to diabetes in utero. Diabetes Care 2011;34:641e5.
[94] Crume TL, Ogden LG, Mayer-Davis EJ, et al. The impact of neonatal breast-feeding on growth trajectories of youth
exposed and unexposed to diabetes in utero: the EPOCH Study. Int J Obes (Lond) 2012;36:529e34.
[95] Mayer-Davis EJ, Rifas-Shiman SL, Zhou L, et al. Breast-feeding and risk for childhood obesity: does maternal diabetes
or obesity status matter? Diabetes Care 2006;29:2231e7.
*[96] Pettitt DJ, Knowler WC. Long-term effects of the intrauterine environment, birth weight, and breast-feeding in Pima
Indians. Diabetes Care 1998;21(Suppl. 2):B138e41.
[97] Singhal A, Cole TJ, Fewtrell M, et al. Breastmilk feeding and lipoprotein prole in adolescents born preterm: follow-up
of a prospective randomised study. Lancet 2004;363:1571e8.
[98] Guariguata L. Contribute data to the 6th edition of the IDF Diabetes Atlas. Diabetes Res Clin Pract 2013;100:280e1.
[99] Seshiah V, Balaji V, Balaji MS, et al. Pregnancy and diabetes scenario around the world: India. Int J Gynaecol Obstet
2009;104(Suppl. 1):S35e8.
*[100] Koyanagi A, Zhang J, Dagvadorj A, et al. Macrosomia in 23 developing countries: an analysis of a multicountry, facilitybased, cross-sectional survey. Lancet 2013;381:476e83.

Please cite this article in press as: Mitanchez D, et al., The offspring of the diabetic mother e Short- and
long-term implications, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://
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