Epidemiology

Gestational diabetes is high blood sugar (diabetes) that starts or is first detected during pregnancy. Most commonly, women with gestational diabetes mellitus are diagnosed using an oral glucose tolerance test at 24 to 28 weeks of gestation, the time of routine screening. For women with pregestational Diabetes Mellitus (DM), glucose control in early pregnancy is vital to a normal organogenesis, necessitating early prenatal care; thereafter patients should see a clinician approximately every 2 weeks to optimise their glucose control.

Furthermore, pregestational diabetes could be Type 1 or Type 2 in the prenatal period, where Type 2 diabetes is usually connected with more adverse events. ^{Reference Clausen, Mathiesen and Ekbom23,Reference Wahabi, Fayed and Esmaeil24} A UAE retrospective cohort study reported that maternal diabetes Type 1 may cause more CHDs in infants of diabetic mothers compared to maternal diabetes type. ^{Reference Alsoufi and AlSuwaidi25} The gestational diabetes mellitus prevalence rate has rapidly elevated up to 53.4% in recent years, which may be attributed to the new diagnostic methods. ^{Reference Agarwal, Dhatt and Shah26,Reference Moses27} The prevalence rate varies according to the population; some countries are at low risk (Sweden with <2% and the USA with 4.8%), while others have a higher risk (Canada with 17.8% and France with 12.1%). Middle East countries have similarly higher prevalence rates, such as 20.6% in UAE, and 16.3% in Qatar. ^{Reference Bener, Saleh and Al-Hamaq28}

In a multicentre cohort study in Saudi Arabia (RAHMA), recruiting 9723 pregnant women, 24.2% had gestational diabetes whereas 4.3% had pregestational diabetes.Reference Wahabi, Fayed and Esmaeil24 These findings were consistent with the preceding studies from the Middle East and other countries. ^{Reference Al-Rubeaan, Al-Manaa and Khoja29–Reference Wahabi, Esmaeil and Fayed31}

Older maternal age and obesity in pregnant women are well-known risk factors. These factors accompany the increased prevalence of pregestational diabetes besides adverse perinatal outcomes. ^{Reference Alsoufi and AlSuwaidi25,Reference Wahabi, Esmaeil and Fayed31–Reference Wahabi, Esmaeil and Fayed33} Genetic factors, socio-economic disparities, and racial differences or ethnicity influence the prevalence of CHDs among infants of diabetic mothers. This may be due to suboptimal blood glucose control of hyperglycaemia caused by unaffordable and demanding access to healthcare services. ^{Reference Chou, Chakradhar and Ghimire34}

Pathophysiology

The pathogenesis of hyperglycaemia in infants inducing cardiac defects is still not fully understood. Previous studies were mainly experiments on animals, whereas human studies were limited to observational documents reporting only hypotheses on the association between diabetic mothers and a higher risk of developing fetal cardiac abnormalities. ^{Reference Asoglu, Gabbay-Benziv and Turan35} The common cardiac defects involve the great arteries, including truncus arteriosus, and double outlet right ventricle, which are found to be more prevalent in infants of diabetic mothers. ^{Reference Narchi and Kulaylat36,Reference Wren, Birrell and Hawthorne8} Normal cardiac development during pregnancy needs insulin for cardiac mass development using cell proliferation and insulin-like growth factor I. ^{Reference Lehtoranta, Vuolteenaho and Laine37} In diabetic women, the high concentration of glucose transferred through the placenta triggers fetal hyperinsulinemia and increases serum levels of growth factors, such as Insulin-like growth factor-1 (IGF-1), resulting in septal hypertrophy. ^{Reference Paulik’s7,Reference Higgins and Mc Auliffe38} The long-lasting fetal hyperinsulinemia may raise the total body weight of the fetus and cause discerning organomegaly consequent to the hypertrophy of the insulin-sensitive tissues, including the heart and affinity of insulin receptors. ^{Reference Boucher, Kleinridders and Kahn39}

It has been reported that newborns from diabetic mothers with poor or good glycaemic management may develop ventricular septal hypertrophy of the heart. ^{Reference Arslan, Oran and Vatansev40} Thus, fluctuation in the expression of CHD, due to maternal diabetes, is ramified. This could be attributed to reactive oxygen species (ROS), which impact heart structure by influencing cell migration, proliferation, apoptosis, and differentiation pathways. ROS also mediate alterations in molecular pathways involved in cardiac development, such as Wnt, Notch, TGF-β, and HIF-1α, as a result of maternal hyperglycemia and associated oxidative stress. Additionally, epigenetic mechanisms may modify the expression of critical genetic material essential for heart development. ^{Reference Basu and Garg41,Reference Basu, Zhu and LaHaye42}

The placental disorder is mainly caused by the placenta vessels variation resulting from poor glycaemic management of maternal diabetes or other causes. It can result in fetal cardiac dysfunction. ^{43,Reference Goulopoulou, Hannan and Matsumoto44} The type of diabetes significantly influences placental vascular development. Gestational diabetes primarily affects the late second trimester, impacting angiogenesis and microvascular remodeling, but it does not influence earlier stages of development. In contrast, pregestational diabetes can affect the entire placental and fetal development process, including vasculogenesis. ^{Reference Pisaneschi, Boldrini and Genazzani45}

Another pathomechanism is that infants of diabetic mothers may inherit intrauterine growth retardation, which in turn can enhance the risk of cardiovascular disorder throughout life. ^{Reference Cvitic, Desoye and Hiden46,Reference Stuart, Amer-Wåhlin and Persson20} Infants of diabetic mothers cause numerous adverse events, together with complex metabolic and endocrine disturbances. It can cause respiratory distress, and birth trauma and can even lead to admissions to neonatal ICUs (NICUs). ^{Reference Yajnik47}

Fetal heart assessment

After birth, the heart function is usually evaluated using echocardiography with M-mode by quantifying the fractional echocardiography with left ventricles. These measurements are ejection phase indicators of systolic activity and are used to determine accurately cardiac manifestations even in adults. However, several studies reported that M-mode and additional conventional markers, including fractional shortening, are relatively insensitive in the fetus and may present some difficulties. ^{Reference Cordero, Paetow and Landon48,Reference Barnes-Powell49} The myocardial performance index is considered a widely used alternative method to reflect systolic and diastolic myocardial activity using the ratio of (isovolumic contraction time with isovolumic relaxation time)/ejection time. In infants, myocardial performance index is based on blood flow Doppler. ^{Reference Chou, Chiou and Liang6} (Table 1)

Table 1. Assessment parameters of fetal cardiac function

A heart murmur is one of the most used tools in detecting CHD; however, its presence or absence is not definitive for a normal or abnormal blood flow of the heart. A study showed that 61.3% of neonates with diabetic mothers presenting with low murmur in the first days of life have structural heart defects. ^{Reference Chu, Gui, Ren and Shi50} Two-dimensional speckle-tracking echocardiography could offer an additional benefit over conventional echocardiography to detect subclinical unfavourable changes in myocardial function in this population. ^{Reference Garcia-Flores, Jañez and Gonzalez51,Reference Al-Biltagi, El Razaky and El Amrousy52,Reference Samanth, Padmakumar and Vasudeva53}

Structural heart defects

There are different complexities on the anatomopathological level, resulting in more or less severe pathophysiological consequences. CHD has been presented as a gross heart defect or great vessel transposition at birth. For this reason, early diagnosis of CHD with the optimal intervention plays a critical part, and in some of these cases, is lifesaving. According to the severity and site of the lesion, the clinical findings of CHD can differ, and the most frequent manifestations are respiratory distress, cyanosis, feeding difficulties, and poor cardiac output. ^{Reference Chu, Gui, Ren and Shi50}

The fetal cardiac malformation is a broad definition that primarily includes atrial septal defect, ventricular septal defect, transposition of great arteries, patent ductus arteriosus, patent foramen oval, and hypertrophic cardiomyopathy. ^{Reference Cordero, Paetow and Landon48,Reference Barnes-Powell49} Atrial septal defect, patent ductus arteriosus, ventricular septal defect, and patent foramen oval account for the highest percentage in prevalence and can differ according to the geographic region (Table 2). ^{Reference Korra, Ezzat and Bastawy2,Reference Begum and Dey54,Reference Muhammad, Khan, Khan and Anwar56,Reference Abu-Sulaiman and Subaih57}

Table 2. Type of CHDs in infants of diabetic mothers in different countries

Hyperglycaemia during pregnancy can prevent the expression of genes that are responsible for the septation of the conotruncus in the neural crest cells. The absence of their expression can inhibit the septation of the conotruncus resulting in cardiac outflow tract disorders such as truncus arteriosus, tetralogy of Fallot, outflow tract occlusion, and transposition of great arteries. It has been proven in different studies that infants of diabetic mothers have a higher risk of developing ventricular septal defects (Table 3); they are at significant risk of all types of intracardiac defects. ^{Reference Asoglu, Gabbay-Benziv and Turan35,Reference Ferdousi, Sarker and Jahan55} Furthermore, an experimental study on embryonic chick showed that mutations in cellular proliferation in the endocardial cushions all through the crucial phases of cardiac development contribute to malformations in the outflow tract, resulting in modifications in blood flow patterns and leading to imperative abnormalities in the vasculature. ^{Reference Øyen, Diaz, Leirgul and Boyd58}

Table 3. Comparative table of ventricular septal defect prevalence in different countries

Functional heart defects

As about 90% of the cardiac lesions can be identified prenatally, detailed fetal echocardiography in all diabetic women during pregnancy has been recommended. ^{Reference Lawson, Scott-Drechsel and Chivukula59,Reference Meyer-Wittkopf, Simpson and Sharland60,Reference Wheller, Reiss and Allen61} Heart rhythm is theorised as a predictor for the early detection of infant cardiac manifestations in gestational diabetes. ^{Reference Kinda, Millogo and Koueta62} Tachycardia is one of the less common presentations in infants of diabetic mothers reported. ^{Reference Costa, Nomura and Reynolds63}

Fetal hypertrophic cardiomyopathy is the most frequent disorder that mutates cardiac functions due to fetal hyperinsulinism, sometimes resulting in the obstruction of left ventricular outflow. ^{Reference Roodpeyma, Rafieyian and Khosravi64,Reference Paauw, Stegeman and de Vroede65}

Diastolic dysfunction is another fetal heart function defect resulting from pregestational diabetes. It is mainly induced by pathological interventricular septal hypertrophy. This impaired filling of the ventricle can appear in a range between 20 and 30% of diabetic pregnancies. It is detected when the E/A ratio is abnormal through mitral or tricuspid valve inflow, along with a higher isovolumetric relaxation time, using conventional Doppler imaging. The septal wall thickening causes rapid ventricular filling, creating mitral inflow disorder. ^{Reference Balli, Pac and Ece66,Reference Zielinsky and Piccoli67} Serious intrauterine myocardial hypertrophic modifications can also cause diastolic dysfunction in infants of diabetic mothers. ^{Reference Dawid, Węgrzynowski and Kwiatek68}

Maternal diabetes could result in important adverse perinatal manifestations other than heart defects that can be related to each other such as macrosomia, acute respiratory distress syndrome, birth trauma, transient tachypnoea, cyanosis, and metabolic and endocrine disorders. ^{Reference Garcia-Flores, Jañez and Gonzalez51,Reference Osterholm, Barthell, Georgieff, Buonocore, Bracci and Weindling69,Reference Al-Qahtani70} Infants of poorly controlled diabetic mothers showed a significant reduction in left ventricular global strain rate, higher incidence of neonatal hypoglycaemia, prolonged neonatal ICU stay, and persistent fetal transitional cardiac shunt in comparison to infants of adequately controlled diabetic mothers. ^{Reference Samanth, Padmakumar and Vasudeva53} In another case-control study, between-group infant cardiac function was determined. Intraventricular pressure difference and intraventricular pressure gradient, using M-mode Doppler imaging, were higher in Infant of Gestational Diabetic Mother (IGDM) than in the controls, as well as the global circumferential strain by speckle-tracking echocardiography technology was also higher in IGDM than in the controls. ^{Reference Iwashima, Hayano and Murakami71}

Therefore, a strong association between maternal diabetes and cardiovascular disease in infants is established (Table 4). ^{Reference Bogo, Pabis and Bonchoski72–Reference Lookzadeh, Alipour, Vakili-Zarch and Ekraminasab78} Diabetes prevention, screening, and treatment among women of reproductive age could help to reduce the risk of cardiovascular disease in infants. ^{Reference Yu, Arah and Liew22}

Table 4. Select recent studies reporting cardiac findings in the offspring of diabetic mothers