Diabetes mellitus (DM) is a systemic chronic metabolic disorder characterized by increased insulin resistance and/or β- cell defects. It affects all ages from the foetal life, neonates, childhood to late adulthood. Gestational diabetes is a critical risk factor for congenital heart diseases (CHDs). Moreover, the risk increases with low maternal education, high body mass index at conception, undiagnosed pre-gestational diabetes, inadequate antenatal care, improper diabetes control, and maternal smoking during pregnancy. Maternal DM significantly affects the foetal heart and foetal–placental circulation in both structure and function. Cardiac defects, myocardial hypertrophy are three times more prevalent in infants of diabetic mothers (IDMs). Antenatal evaluation of the cardiac function and structures can be performed with foetal electrocardiography and echocardiography. Postnatal cardiac evaluation can be performed with natal and postnatal electrocardiography and echocardiography, detection of early atherosclerotic changes by measuring aortic intima-media thickness, and retinal vascular changes by retinal photography. Ameliorating the effects of diabetes during pregnancy on the offspring depends mainly on pregestational and gestational diabetes prevention. However, other measures to reduce the risk, such as using medications, nutritional supplements, or probiotics, still need more research. This review discusses the mechanism of foetal sequels and the risk factors that increase the prevalence of CHDs in gestational DM, the various cardiac outcomes of gestational DM on the foetus and offspring, cardiac evaluation of foetuses and IDMs, and how to alleviate the consequences of gestational DM on the offspring.

Diabetes mellitus (DM) is a systemic chronic metabolic disorder characterized by increased insulin resistance and/or β- cell defects. It is a microvascular disease that affects all ages, from foetal life to late adulthood. Diabetes during pregnancy could be a de novo that arises during pregnancy for the first time and could disappear or persist after delivery (gestational DM) or could start as pregestational, before the onset of pregnancy. The incidence of impaired glucose tolerance in pregnancy ranges between 3-10% and varies according to the average incidence of diabetes in the general population[1]. The risk of gestational diabetes increases with maternal overweight and obesity, advanced maternal age at conception (> 30 years), presence of glucosuria on more than two occasions, previous history of gestational diabetes, family history of type-2 DM, polycystic ovary syndrome, polyhydramnios, male foetus, multiple pregnancy, previous big baby (> 4 kg), ethnicity (non-white ancestry), lifestyle (physical inactivity before and during pregnancy), environmental (as cigarette smoking, persistent organic pollutants, and endocrine disruptors), and psychosocial factors (as depression in the first or second trimester)[2]. In a normal pregnancy, there is a 30% increase in basal endogenous glucose production (primarily hepatic) by the end of pregnancy despite the high fasting insulin levels. However, hypoglycaemia could occur in early pregnancy due to increased plasma volume (dilutional hypoglycaemia) and in late pregnancy due to increased glucose utilization. In addition, peripheral insulin sensitivity may decrease by approximately 50% by late gestation, which induces an increase in insulin secretion by 2–3-folds in women with normal glucose tolerance and may disturb the maternal amino acids and lipid metabolism[3,4]. In gestational diabetes, β- cell dysfunction could occur because of the additional stress on β- cells due to excessive gestational weight gain and the uprising insulin resistance; or due to β- cells damage caused by autoantibodies against specific β- cell antigens. In gestational DM, the rate of insulin-stimulated glucose uptake is reduced by 54% compared to the normal pregnancy[5].

The foetal heart is targeted by the pre-existing and gestational maternal DM through complex multi-factorial pathogenesis that affects both the foetal heart and foetal–placental circulation in both structure and function. The severity of the foetal cardiac damage is related to the type of DM, the level of HbA1c in early pregnancy, and the degree and duration of hyperglycaemia and hyperketonaemia. Both hyperglycaemia and hyperketonaemia are toxic to the developing embryo inducing and modifying multiple biochemical and signal transduction pathways and increasing the production of excess free oxidative radicles. Hyperglycaemia also increases apoptosis and impairs autophagy, cell homeostasis, proliferation, and migration of neural crest cells, which are critical to the developing heart and brain[6,7]. The teratogenic effect of hyperglycaemia is prominent in the first six weeks of pregnancy (period of organogenesis), especially in mothers with pregestational diabetes, inducing diabetic fetopathy with glucose-mediated disturbances of left-right patterning, congenital cardiac malformations, foetal cardiomyopathy, foetal venous thrombosis, altered placental villi vascularization, and pathological foetal heart rates even with tight maternal glycaemic control[8]. Intrauterine chronic hyperglycaemia induces reflex chronic foetal hyperinsulinemia that increases the total body weight and causes selective organomegaly because of hypertrophy of the insulin-sensitive tissues, including the heart and increased expression and affinity of insulin receptors[9] (Figure 1).

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Figure 1 Possible mechanisms of foetal cardiac damage in gestational diabetes. IGF-І: insulin-like growth factor-І.

The effects of maternal DM are related to the metabolic derangements and the induction of epigenetic changes affecting the expression of specific placental genes in response to diabetes-induced chronic stress and inflammation. These effects have an essential role in the development of maternal diabetes-induced embryopathy[10]. Hypoglycaemia is a potential teratogen and a common complication during the management of gestational DM. It contributes to the development of diabetic embryopathy as it disrupts normal cardiogenesis and alters morphology, function, metabolism, and expression of specific proteins in the developing heart[11]. Maternal diabetes-induced placental vasculopathic abnormalities and the relative immaturity of the placenta cause a state of chronic foetal hypoxemia, which in turn causes compensatory polycythaemia and changes in foetal circulation[12]. The foetal hyperinsulinemia present in gestational DM causes foetal macrosomia. In foetal macrosomia, there is an increase in the cardiac mass due to a larger mass of myocardial nuclei, increased cell number, and hypertrophy of myocardial fibres, which in turn induces underdeveloped foetal ventricular compliance and consequently diastolic dysfunction secondary to a thickened cardiac wall. The foetal macrosomia and the associated ventricular hypertrophy could occur very early, even before 20 wk of gestation. Moreover, accelerated growth of the foetal heart occurs in the second and third trimesters compared to foetuses of non-diabetic pregnancies[13].

Gestational diabetes per se is a significant risk factor to develop congenital heart diseases (CHD). Moreover, other factors may increase CHD risk in the infants of diabetic mothers (IDMs). Low maternal education (less than high school level) is an additional factor that increases CHD risk[14]. High body mass index (BMI) at conception and possibly undiagnosed pre-gestational diabetes are also significant risk factors that increase the risk of CHD in gestational diabetes[15]. Infants born to mothers with pregestational diabetes have higher risks of mortality and morbidity than gestational DM. In a cohort of two million births over 34-year, Øyen et al[15] found a four-times increase in the offspring risk of CHDs in maternal pre-gestational DM (both types 1 and 2). Gestational DM was only weakly associated with increased risk[16]. Inadequate antenatal care and improper diabetes control are also critical confounding factors, increasing the risk. Todorova et al[17] showed a strong association of the foetal abnormalities with higher glycated haemoglobin levels, especially in the first trimester of pregnancy. They also found that pregnancies with poor first trimester glycaemic control were more prone to the presence of foetal heart disease[18]. Studies had confirmed that women who have close monitoring and proper glycaemic control in a normal range at the time of conception and early in pregnancy had a markedly lower risk of having an infant with CHD than women with poor control. Maternal smoking during pregnancy may increase the risk of CHDs by itself. Moreover, maternal tobacco smoking and pregestational diabetes intensify the effects of each other on preterm birth and the risk of congenital anomalies, including CHDs[19]. On the other side, studies showed that early antenatal antioxidants administration (such as lipoic acid, vitamin C, and N-acetylcysteine) in diabetic mice was associated with decreased risk of CHDs[20].

DM, with its hyperglycaemic milieu before conception and during the first trimester, is associated with diabetic embryopathy in the developing foetus, as it affects the heart, the great vessels, and the neural tube[21]. Diabetic fetopathy is still a common clinical problem correlated with high neonatal morbidity and mortality. The foetal heart is more prone to the development of congenital malformations in both pre-existing and gestational DM. Cardiac defects and myocardial hypertrophy are three times more prevalent in the offspring of women with DM. Maternal DM significantly affects the foetal heart and foetal–placental circulation in both structure and function and alters the placental villi vascularization with a wide range of cardiac anomalies ranging from small septal defects to major complex heart diseases. These effects on the foetal, neonatal, and child heart are summarized in Table 1.

Gestational diabetes primarily affects placental circulation. Alteration of the placental development and subsequent vascular dysfunction occurs in six out of seven women with various diabetic severity. The typical placental changes in gestational diabetes include villous immaturity, villous fibrinoid necrosis, infarcts, intervillous thrombosis, increased syncytial knotting, chorangiosis, and increased angiogenesis. These placental changes cause uteroplacental circulation/maternal vascular mal perfusion. The types and effects of the dysfunction depend on how early in pregnancy hyperglycaemia occurs[24]. In addition to the pregnancy induced-hypercoagulability states, maternal hyperglycaemia increases the thrombogenic status. When combined with hyper coiling of the cord, it causes vascular stasis and ischemia resulting in thrombosis in the foetal vascular tree leading to foetal growth restriction and increased perinatal morbidity and mortality[25]. In addition, the umbilical vessels showed pathological changes in line with early atherosclerosis, including focal intimal thickening and glycogen accumulations in the intima and the media cells. The presence of a thin umbilical cord with a single umbilical artery is associated with increase adverse foetal outcome in gestational diabetes[26]. The associated foetal hypoxia contributes to increased erythropoiesis, polycythaemia and promotes catecholamines production, which causes hypertension and cardiac hypertrophy; and may contribute to the 20%–30% of stillbirth seen in poorly controlled diabetic pregnancies[27]. An altered response of the foetal autonomic nervous system to the metabolic stress in pregnancies with complicated gestational diabetes increases the mean foetal heart rate. It impairs the heart rate variability[28].

The main structural alteration in the foetus of a pregnant diabetic mother is myocardial hypertrophy which can lead to transient subaortic stenosis and occasionally causes congestive heart failure (CHF). Chronic foetal hyperinsulinemia causes foetal macrosomia and increases the cardiac mass due to a larger mass of myocardial nuclei, increased cell number, and hypertrophy of myocardial fibres secondary to an increase in the synthesis of proteins and fats, independent of the amount of glycogen deposition, resulting from the increased presence of insulin receptors in the foetal heart[29]. Hypertrophic cardiomyopathy (HCM) is the most common cardiac malformation in up to 40% of diabetic pregnancies. HCM is more common in pre-gestational DM than gestational DM. This myocardial hypertrophy is characterized by the thickening of the interventricular septum and ventricular walls. It is usually asymptomatic in the foetus but may present with systolic and diastolic dysfunction of the neonatal heart.

In addition, the left ventricular mass and contractility are increased with left ventricular outflow tract (LVOT) obstruction due to apposition of the anterior leaflet of the mitral valve to the interventricular septum during systole. As a result, cardiac output is significantly reduced, secondary to reduced stroke volume and is directly related to the degree of septal hypertrophy. Moreover, it may result in CHF in the immediate postnatal period (with tachypnoea, tachycardia, gallop rhythm and hepatomegaly). However, this is uncommon and transient, and cardiac hypertrophy may disappear around 6-24 mo after birth[30]. This asymmetric septal thickening, with a disproportionally hypertrophic septum, is an anabolic result of foetal hyperinsulinemia triggered by maternal hyperglycaemia during the third trimester[31]. Therefore, we should rule out other causes of HCM (infections, other metabolic derangements, neurologic affections, syndromes).

Cardiovascular malformations are among the most common malformations in the IDMs, accounting for 3%-9% of diabetic pregnancies and about 2.5-10 times higher than observed in normal pregnancies. The highest relative risk for major cardiovascular defects occurs if the mother has gestational diabetes and develops insulin resistance in the 3^rd trimester[31]. The reported complications incidence was 3.4% with maternal HbA1c levels lower than 8.5, and 22.4 % with HbA1c levels higher than 8.5%. Infants born to mothers with an HbA1c level of more than 10% in late pregnancy tend to have neonatal complications[32].

There is an increased risk of laterality and cardiac looping defects (heterotaxia), cardiac outflow tract anomalies, atrioventricular and membranous ventricular septal defects but no increased risk of muscular ventricular septal defects and atrial septal defects[21]. The most common cardiac defects that occur in foetuses of diabetic mothers include ventricular septal defect, transposition of great arteries (TGA), patent ductus arteriosus, aortic stenosis, pulmonary atresia, dextrocardia, and conotruncal defects (tetralogy of Fallot, truncus arteriosus and double outlet right ventricle)[33,34].

Immediately after delivery, the neonate starts a critical process to adapt to the extra-uterine life during the first 6 to 8 h of life, known as the transitional period. Changes in the cardiovascular system are the most important changes when the foetal bypass shunts close, and blood normally circulates[35]. Metabolic alterations of the intrauterine environment in gestational diabetes cause foetal cardiac dysfunctions that can persist after birth and impair neonatal transitional haemodynamics even in asymptomatic neonates[36]. They have a prolonged isometric contraction phase of right ventricle (RV) with elevated RV pre-ejection period (RVPEP)/RV ejection time (RVET) ratio (RVPEP/ RVET Ratio). This ratio correlates closely with pulmonary vascular resistance (PVR) and pulmonary artery diastolic pressure suggesting an abnormality of the transitional pulmonary circulation. The persistence of foetal circulation syndrome is found with a higher frequency in IDMs, leading to cardiorespiratory distress in the first 24 h of life. There is delayed closure of the ductus arteriosus and delayed postnatal decrease in pulmonary artery pressure in these neonates, causing right-to-left shunting through a patent ductus arteriosus and/or patent foramen oval, which could explain the increased frequency of respiratory disorders and the delay in the recovery of these infants. Cardiomegaly, venous congestion, hepatomegaly, and pleural effusion may be seen radiographically. It is not well understood why high pulmonary resistance persists. It could be related to hyperviscosity, hypoglycaemia, atypical respiratory distress syndrome, and/or idiopathically[37].

Primary pulmonary hypertension may be due to increased muscularization of small pulmonary arteries. It also associated with and aggravated by polycythaemia which is frequently present in these neonates[31]. The persistence of foetal shunts and decreased RV output in IDMs suggest that even those with reasonable gestational glycaemic control have impaired transitional haemodynamics[38]. Cardiomegaly could present in IDMs without hypertrophic cardiomyopathy due to persistent foetal circulation or transient increase in pulmonary pressure due to increased interstitial pulmonary fluids, which causes transient tachypnoea of the newborn (because of increased incidence of Caesarean section). Neonatal hypoglycaemia, which is more frequent in IDMs, could lead to cardiomegaly and electrocardiographic abnormalities[39]. Studies also showed that about 8% of IDMs have bradycardia[40]. The neonates should also be monitored for the possible occurrence of bradycardia because of using βeta-blockers like propranolol to treat symptomatic hypertrophic cardiomyopathy.

Gestational diabetes does not only affect the foetus or the neonates but could also affect the offspring till adulthood. Exposure to hyperglycaemia in utero may program future diseases risk via changes in critical developmental pathways because of altered gene expression. Current evidence suggests that atherosclerosis and cardiovascular risks begin in utero and are compounded by postnatal influences. According to some studies, maternal gestational diabetes, especially with a complicated pregnancy, induces the development of many recognised cardiovascular risk factors in their progeny with an adverse risk profile that persists into early adulthood. Increased rates of hypertension, hyperglycaemia, and overweight in young adults suggest that this group is at an increased risk of developing cardiac sequelae in later life (up to 40 years)[23].

The best way to ameliorate the effect of gestational diabetes on the offspring is to prevent the development of diabetes itself. If not possible, we must strictly control the disease during pregnancy, aiming to achieve adequate glycaemic control and avoid harming the future offspring. Prevention of gestational diabetes could be attained through pre-pregnancy prevention of obesity, weight management, increased physical activity, and good nutritional strategies. The role of antenatal dietary supplementation with Myo-inositol (a derivative of secondary messengers involved in several signalling pathways, including the insulin pathway) in the prevention of gestational diabetes still unclear and needs more studies[69]. Although probiotics have a potentially beneficial role in glucose metabolism outside pregnancy, their role in preventing gestational diabetes is debatable. There is no firm evidence supporting the use of probiotics for the prevention of gestational DM[70]. Higher levels of physical activity both before and during early pregnancy seem to protect against the development of gestational diabetes[71]. Observational studies conducted in large population-based cohorts suggest that women who are the most active before pregnancy are less likely to have insulin-resistant in late pregnancy and have lower rates of gestational diabetes[72].

Optimizing screening for gestational diabetes in pregnant mothers by strictly following International Association of Diabetes and Pregnancy Study Groups (IADPSG) guidelines and recommendations on the diagnosis and classification of hyperglycaemia in pregnancy will significantly increase the number of women who are diagnosed with and treated for gestational DM[73]. Diagnosing and treating gestational diabetes can reduce perinatal complications, especially cardiovascular complication closely linked to strict glycaemic control. Nutritional management is the cornerstone of treatment. We can use Insulin, glyburide, and metformin to intensify the nutritional treatment. Since metformin has anti-cell growth and pro-apoptotic effects, there are persistent concerns over its use in early pregnancy. However, metformin may be chosen in selected cases, depending on the convenience and the cost[74]. Diet should ensure sufficient intake of micronutrients and macronutrients, including > 175 g of carbohydrates daily and minimizing the glycaemic excursions by intake of low- glycaemic-index carbohydrates and high fibres divided over several meals and snacks daily[75]. Foetal measurements support maternal glucose measurements in identifying pregnancies that need more intensification with a target to keep the fasting blood glucose ≤ 5.3 mmol/L, 1-h post-meal ≤ 7.8 mmol/L and 2-h post-meal 6.7 mmol/L[76].

After delivery, encouragement of breastfeeding can modify the risk in the IDMs. Breastfeeding has “dose-response” effects in reducing hypertension, insulin resistance, type 2 diabetes, dyslipidaemia, and obesity in IDMs. The beneficial effects of breastfeeding are mediated through the bioactive nutrients present only in the breast milk, the higher protein content, and the slower postnatal growth pattern compared to formula-fed infants. In addition, breastfeeding for six months or longer is associated with a significantly lower BMI, waist circumference, and visceral and subcutaneous adipose tissue at 6–13 years of age[77,78].

Gestational diabetes is a significant risk factor for CHDs. The risk increases in the presence of low maternal education, high BMI at conception, undiagnosed pregestational diabetes, inadequate antenatal care, improper diabetes control, and maternal smoking during pregnancy. Maternal DM significantly affects the foetal heart and foetal–placental circulation in both structure and function. CHDs, as well as myocardial hypertrophy, are three times more common in IDMs. Evaluation of the foetal cardiac structure and function can be performed using foetal electrocardiography and echocardiography. Postnatal cardiac evaluation can be performed by natal and postnatal electrocardiography, postnatal echocardiography, measuring aortic IMT, and retinal photography. Ameliorating the effects of gestational diabetes on the offspring depends mainly on pregestational and gestational diabetes prevention. However, other measures to reduce these effects, such as nutritional interventions, medications or probiotics, require more research.