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 significant 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.
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 . 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 clarified in order to improve and to adapt neonatal management , especially in developing countries where maternal screening and treatment are deficient. Indeed, recent meta-analyses showed that the treatment of GDM improves neonatal outcomes . 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 . 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 .
Obstetricans and pediatricans are faced in the first 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 8.56-fold higher in severely obese pregnant women compared to pregnant women with normal weight . The current worldwide pandemic of T2D has devastating effects, and nowadays T2D represents up to 25% of pregnancies with pregestational diabetes .
The prevalence of macrosomia in developed countries is between 5% and 20%; however, an increase of 15–25% has been reported in the last decades, associated with an increase of maternal obesity and diabetes .
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 . Indeed, different studies have characterized the link between maternal glycemia and neonatal macrosomia or fat mass . Other interrelated mechanisms play a role in the modification 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 inflammation . Both conditions increase placental availability of nutrients to the fetus, not only glucose but also amino acids and free fatty acids, and influence fetal growth. IR facilitates maternal hypertriglyceridemia that enhances substrates availability to the fetus. Other mechanisms influence 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 inflammatory pathways . 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 . Such epigenetic adaptation to detrimental in 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 . 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 .
The influence 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 . In a large prospective multicentric study, excessive GWG was an independent valuable predictor of macrosomia .
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 define 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 definition takes into consideration GA at birth and allows premature newborns with excessive fetal growth to be identified. 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 .
Maternal diabetes during pregnancy, whatever its type, is a risk factor for macrosomia. Treatment of GDM significantly reduces the rate of macrosomia . 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 reflect intermittent hyperglycemia, mainly postprandial hyperglycemic episodes, that may be involved in accelerated fetal growth . The frequency of macrosomia or LGA is not different in T2D with respect to T1D , even if in T2D, HbA1c is lower at booking and throughout gestation .
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 . 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 4.500–4.999 g and >5.000 g, (ORs 2.4 (2.2–2.5) and 3.5 (3.0–4.2), respectively) . Among infants with Erb’s palsy in the general population in the British Isles, 53% were LGA . Erb’s palsy is tenfold higher in case of pregestational diabetes .
As discussed below, macrosomia is also in itself a risk factor for long-term altered outcomes.
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 8.56-fold higher in severely obese pregnant women compared to pregnant women with normal weight . The current worldwide pandemic of T2D has devastating effects, and nowadays T2D represents up to 25% of pregnancies with pregestational diabetes .
The prevalence of macrosomia in developed countries is between 5% and 20%; however, an increase of 15–25% has been reported in the last decades, associated with an increase of maternal obesity and diabetes .
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 . Indeed, different studies have characterized the link between maternal glycemia and neonatal macrosomia or fat mass . Other interrelated mechanisms play a role in the modification 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 inflammation . Both conditions increase placental availability of nutrients to the fetus, not only glucose but also amino acids and free fatty acids, and influence fetal growth. IR facilitates maternal hypertriglyceridemia that enhances substrates availability to the fetus. Other mechanisms influence 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 inflammatory pathways . 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 . Such epigenetic adaptation to detrimental in 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 . 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 .
The influence 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 . In a large prospective multicentric study, excessive GWG was an independent valuable predictor of macrosomia .
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 define 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 definition takes into consideration GA at birth and allows premature newborns with excessive fetal growth to be identified. 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 .
Maternal diabetes during pregnancy, whatever its type, is a risk factor for macrosomia. Treatment of GDM significantly reduces the rate of macrosomia . 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 reflect intermittent hyperglycemia, mainly postprandial hyperglycemic episodes, that may be involved in accelerated fetal growth . The frequency of macrosomia or LGA is not different in T2D with respect to T1D , even if in T2D, HbA1c is lower at booking and throughout gestation .
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 . 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 4.500–4.999 g and >5.000 g, (ORs 2.4 (2.2–2.5) and 3.5 (3.0–4.2), respectively) . Among infants with Erb’s palsy in the general population in the British Isles, 53% were LGA . Erb’s palsy is tenfold higher in case of pregestational diabetes .
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 . 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), gastric–intestinal malformations (duodenal and anal–rectal atresia, hypoplastic left colon), and skeletal and genital–urinary tract anomalies . 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 . The risk for congenital malformations in preexisting diabetes is 1.9–10-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 . Maternal hyperglycemia results in excess glucose metabolism in the developing embryo 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 ; 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 ; and also 3) high glucose induces the activation of many proteins involved in apoptotic cell death, including members of the caspase families . Although it is increasing, the understanding of the molecular bases of diabetic embryopathy mechanisms is still incomplete .
Perinatal death
Both types of pregestational diabetes are associated with an increased risk of stillbirth. In T1D, such risk is increased threefold to fivefold in various countries 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 (1.15–1.96)) , and the deaths are mainly due to stillbirth, chorioamnionitis, or birth asphyxia . A strict glycemic control has been shown to reduce the number of stillbirths in women with TD1 and TD2 .
The risk for stillbirth may be slightly increased in GDM, less than in T1D and T2D . 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 .
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 . 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 .
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 . A relationship between preconceptional HbA1c and a reduced fetal weight at birth has been found . 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 (34–36 weeks of gestation (WG)) . In T1D, pregestational hypertension (HT) is related to preterm birth whereas in T2D, third-trimester glycosylated hemoglobin (HbA1c) is a predictor of prematurity . GDM and glucose intolerance are risk factors for spontaneous preterm birth independently on other diabetes complications , while the mean maternal glucose level has been related to the risk of preterm birth .
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 particularly in cases of pregestational diabetes . 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 .
Neonatal hypoglycemia
A correlation exists between macrosomia, increased cord C-peptide levels, and neonatal hypoglycemia, as confirmed by the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study. Infants with excessive size at birth were more likely to develop hypoglycemia and hyperinsulinemia . 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 benefit from a blood glucose concentration check at 3–6-h intervals during the first day of life. On the other hand, normal-grown infants of mothers with diet-controlled 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 significant 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 first, provided a satisfactory clinical response is obtained .
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 . 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 deficient . 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 unspecific: 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 . 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.
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 . 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 . The risk of diabetes was significantly 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/m 2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies ( P = 0.003) . 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 . 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/m 2 greater (95% CI, 0.35–1.52) than in their brothers born before their mother was diagnosed with diabetes, after adjustment for maternal age, parity, and education .
It must be underlined that most studies have encountered major difficulties in separating the roles of fetal exposure to maternal hyperglycemia, from that of coexisting maternal manifestations such as overweight/obesity.
In a multiethnic group of youths aged 10–22 years, exposure to maternal diabetes (OR 5.7 (95% CI 2.4–13.4)) and exposure to maternal obesity (2.8 (95% CI 1.5–5.2)) 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 . 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 significant in some studies . 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 difficult to distinguish from influences 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 profile, 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 . 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 . A recent systematic review confirmed the association between exposure to maternal diabetes and SBP in childhood. However, this association was only significant in male offspring. Furthermore, there is evidence that this association may be influenced by maternal prepregnancy BMI .
Endothelial dysfunction (ED) is thought to be critical in the development of vascular disease, notably in HT . ED can be characterized by a loss of regulatory functions related to vascular tone, inflammation, 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 identified 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 and increased senescence and reduced proliferation . 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 , and in human, induced apoptosis of umbilical venous endothelium cells . An increase in cord blood AngII concentration has been observed in offspring from mothers with GDM .
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 . 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 . These functional changes might result in damage to developing glomeruli possibly related to a similar process of nephron number decreased .
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 superoxide dismutase (enzyme responsible for the superoxide anion scavenging) activity has been mentioned in cord blood of infants born to GDM mothers . 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 . AngII has also been involved in the enhancement of ROS levels , which can affect vascular function by scavenging or inactivating endothelium-relaxing factors, such as NO or prostacyclin, and by producing peroxynitrite, a potent constrictor . 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 .
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 6–11 years; accordingly, they were LGA or adapted for gestational age (AGA, BW 10–90th 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 significantly 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 .
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 significantly 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 . Other studies confirmed these findings notably during childhood (4–10 years old) , in young adults (22 years old) , and in adulthood (30–60 years old) . A Swedish study has shown that preterm birth (<37 weeks of GA), including late preterm birth (35–36 weeks of GA), is associated with a slight increased risk of diabetes in young adulthood (25–37 years old) .
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 . 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 .
The effect of breast-feeding
It has been suggested that breast-feeding has benefit effects for long-term obesity. A long-term advantage of breast-feeding was further supported by a “dose–response” 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 . 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 . However, the critical window period when nutrition influences the long-term outcomes is not well defined and early growth may correspond to a spectrum that spans between the first 2 WG to the first 2 years of life at least (the first 1000 days). It was shown that greater weight gain in the first 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 8–52%) . 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 .
Adequate breast-feeding (≥6 months) also reduces the increase of adiposity levels observed during childhood after exposure to diabetes in utero. 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 . Others have reported data that favor the benefit of breast-feeding in offspring of diabetic mother, either on the risk of obesity or of diabetes .
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 benefits of human milk were observed at 13–16 years of age on BP, lipids profile, and IR .
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 benefits 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.
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