Diabetes mellitus is a common maternal morbidity, associated with higher body mass index, higher maternal age, and sedentary lifestyle, affecting 9–25% of pregnancies.1–4 The term “infant of a diabetic mother (IDM)” refers to neonates born to a woman with persistently elevated blood sugar during pregnancy.⁵ Infants of diabetic mothers, even with good glycemic control, are at five times increased risk of both morphological and functional cardiac changes because of characteristic fetal metabolic abnormalities such as hyperglycemia and hyperinsulinemia.^5–7. Fetal exposure to these conditions often contributes to neonatal morbidity, which may be transient or permanent and predispose to cardiovascular disease in adulthood.^1,8 Even asymptomatic infants may have subclinical functional impairment.⁵

Congenital heart disease, including septal defects, transposition of the great arteries, persistent truncus arteriosus, and patent ductus arteriosus (PDA), is associated with maternal diabetes.¹ Cardiomyopathy including hypertrophic obstructive cardiomyopathy, is identified in 13–44% of cases, with the greatest risk associated with maternal type 1 diabetes.^9,10 Hypertrophic cardiomyopathy is described as a combination of asymmetric septal hypertrophy and diastolic dysfunction.^9,11 These cardiac structural changes may be due to hyperglycemia, activating a cascade of cellular events and changes in gene expression.¹ They have also been found to be associated with hyperinsulinemia and IGF-1, which promotes hypertrophy in cardiomyocytes, leading to decreased myocardial compliance.¹ Asymmetric septal hypertrophy is typically due to a greater density of insulin receptors in this region as compared to other areas of the cardiac muscle. This may lead to left ventricular outflow tract (LVOT) obstruction and systolic anterior mitral valve displacement.¹⁰ Although good maternal glycemic control may improve heart development and mitigate the risk of increased ventricular thickness compared to infants of poorly controlled diabetic mothers,⁵ it does not eliminate the risk of septal hypertrophy.¹²

Echocardiography can be utilized to demonstrate structural and functional changes commonly found in IDMs; specifically, it is useful to examine the interventricular septum and posterior wall thickness and measure left ventricular (LV) systolic and diastolic function.^13,14 Biomarkers such as cardiac-specific troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) may also be used to predict HOCM and LV dysfunction. cTnI is an inhibitory protein involved in cardiac muscle relaxation released in settings of myocardial injury. Serum levels are correlated with the degree of septal hypertrophy, which may be due to suboptimal coronary artery oxygen delivery to compensate for high myocardial oxygen demand.¹⁵

IDM are at increased risk of respiratory distress syndrome because fetal hyperinsulinemia impairs surfactant production.^16,17 Lung disease may lead to secondary acute pulmonary hypertension (PH); however, animal studies have also shown increased muscularization of pulmonary arteries and fewer pulmonary vessels at birth, suggesting that a predisposition to pulmonary vascular disease may exist in the absence of lung disease. Maternal diabetes is also associated with chronic fetal hypoxia and polycythemia, which are risk factors for PAH at birth.^18,19 Katheria et al. demonstrated that even following well-controlled DM during pregnancy, the IDM is at risk of abnormal transitional hemodynamics. This was supported by lower right ventricular output compared to controls.⁸ These data are also consistent with the report by Seppänen et al., who showed that the closure of the ductus arteriosus and postnatal decrease in pulmonary artery pressure are delayed in IDMs when compared with control infants during the first postnatal days.⁶ The consequences of hypertrophic cardiomyopathy may include impaired systemic blood flow and hyperdynamic LV systolic function, which is often observed to coexist with diastolic dysfunction.⁸ However, even in the absence of hypertrophic cardiomyopathy, functional cardiac changes may be evident. As compared to well-controlled DM pregnancies and healthy controls, IDMs following poor control during pregnancy showed a significant reduction in LV global strain and strain rate. This suggests glycemic control influences the degree of impairment in myocardial systolic function, which persists at least through 6 months postnatal age. Additionally, persistence of the ductus arteriosus may be more prevalent among IDMs following poor glycemic control,⁵ which may have important implications for preterm IDMs. Interestingly, early functional impairment itself has been suggested to induce cardiac hypertrophy.¹

The potential benefit of evaluating fetal cardiac function may lie in its prognostic value for long-term cardiovascular health. Fetal studies have shown that in utero reprogramming of genes involved in metabolic processes can occur secondary to maternal diabetes, especially when associated with a high-fat diet.²⁰ Several biochemical markers associated with adult cardiovascular disease have been identified as higher among IDMs than control infants. These include increased cellular adhesion molecules, markers of endothelial damage, and dysfunctional endothelial colony-forming cells. Elevated levels of angiotensin II, which potentiates stronger vasoconstriction in the presence of endothelin 1, and apoptosis of umbilical venous endothelial cells have been demonstrated in human IDMs.¹² While limited longitudinal data specific to the heart is available, these findings may provide biological support to epidemiological studies suggesting a greater burden of cardiovascular disease among IDMs later in life.

The management of acute PH and/ or shock in the infant of a diabetic mother requires modification from routine neonatal intensive care strategies if significant septal hypertrophy is identified, particularly in the presence of LVOT obstruction. The most appropriate approach depends on the degree of obstruction to left heart outflow. If the dominant clinical concern is hypoxia and LVOT obstruction is mild or absent, treatment of PH with strategies that reduce pulmonary vascular resistance (PVR) such as inhaled nitric oxide (iNO) is the most appropriate. Conditions in which the left heart is preload compromised result in closer approximation of the septum and the mitral valve and therefore may exacerbate obstruction. This includes excessive mean airway pressure, particularly in the setting of high-frequency ventilation, where diastolic filling time may be limited. In addition, vasodilator drugs, such as milrinone, should be avoided. Positive inotropes (epinephrine, dobutamine, and dopamine) are contraindicated as more forceful contraction may worsen obstruction and, by inducing tachycardia, may reduce diastolic time, hence further limiting filling. For neonates with hypotension and moderate or severe LVOT obstruction, in whom adequate augmentation of LV filling is not possible, a strategy in which the PVR is kept elevated, and the right heart (via right-to-left ductal shunt) is temporarily used to supply systemic circulation may be the only way to accomplish adequate systemic blood flow. In this case prostaglandin E1 (PGE-1) to maintain ductal patency and avoidance of pulmonary vasodilators is warranted. Veno-arterial extracorporeal membrane oxygenation may be an alternative for neonates with refractory shock, though there is limited published evidence.^24,25 In the short term therapeutic hypothermia, which is associated with reduced HR, may be advantageous for these patients; however, this requires prospective study. The changes in heart rate, upon rewarming, in the setting of hypoxic-ischemic encephalopathy and therapeutic hypothermia, may negatively impact the physiology of these patients.

Long-term management may be required, though hypertrophic cardiomyopathy in infants of diabetic mothers is transient and typically resolves over 3–6 months. Beta-blockers may improve left heart filling based on their ability to reduce heart rate and for their negative inotropic properties.⁹ In the acute phase, however, beta-blockers can precipitate symptomatic PH crisis, which may adversely affect LA filling; therefore caution should be exercised. Calcium channel blockers (e.g., verapamil, diltiazem) may also be used to reduce myocardial stiffness. Drugs that reduce systemic afterload (e.g., nitrates, angiotensin-converting enzyme inhibitors, milrinone) should be avoided in this population as they may worsen LVOT obstruction. Diuretics should be used with caution when hypertrophic cardiomyopathy is severe enough to cause pulmonary edema as dehydration may compromise LV filling.

There is evidence of a strong association between maternal diabetes and impaired fetal cardiac function in IDMs. Studies directly demonstrating the relationship between fetal cardiac diastolic dysfunction on ultrasound and future cardiovascular health are lacking. There is a need for further longitudinal studies aimed at demonstrating the plausible association between maternal diabetes and fetal cardiac function in utero, in relation to clinical outcomes and offspring development.¹ Cardiovascular management is focused on maintenance of LV filling by liberal use of volume boluses and judicious use of vasopressin as the first-line agent for systemic hypotension. In the situation where filling is refractory to fluid and vasopressin, maintenance of ductal shunt to support pulmonary blood flow (and indirectly load the LA) or systemic blood flow (if maintained right-to-left in the setting of severe LVOT obstruction) may be warranted.

In utero, severe decompensation is rare because the low resistance of the cerebral VGAM is balanced by the low resistance of the placenta, which ensures perfusion of the peripheral organs. With loss of the placenta at birth, up to 80% of cardiac output is directed to the cerebral circulation due to high blood flow through the low-resistance fistula.26–28 Therefore the volume overload caused by VGAM worsens after birth. Patel et al showed superior vena caval flow in this condition may be 10 times higher than that of normal values in their description of three infants with VGAM.²⁶ Higher cardiac output has been associated with higher mortality in the fetus with this condition and may be a useful prognostic indicator in the postnatal period. The right ventricle (RV) suffers from both volume and pressure overload; however, “high-output cardiac failure” is a biological misnomer for the clinical presentation with end-organ dysfunction of patients with VGAM. A more accurate term may be pseudocoarctation because the high flow to the brain acts functionally like an anatomic juxta-ductal obstruction. The high blood flow through the low-resistance fistula can reduce blood flow to the remainder of the body and may result in progressive hypotension, which may be profound secondary to pseudocoarctation physiology.²⁹ Pseudocoarctation physiology is a result of intracranial steal with low coronary root pressure and retrograde transverse and descending aortic arch flow. This means blood flow to the remainder of the body is reduced and can lead to multi-organ ischemia-mediated failure and death. Moreover, myocardial ischemia and infarction have been previously described in these infants. The ischemic myocardial damage stems from a decrease in right coronary blood flow and contributes to the cardiac decompensation.

In utero, the fetal vascular bed of infants with VGAM physiology is exposed to substantially more flow than is typical as soon as the capacity of the ductus to shunt blood away from the lung is overcome. This leads to maldevelopment of the pulmonary vascular bed as characterized by pulmonary vascular muscularization and vascular hyperreactivity, which manifests as resistance-mediated pulmonary arterial hypertension (PAH). Intrinsically, patients with VGAM may also present with flow-mediated PAH, given that a substantial volume of blood may fill vessels accustomed to a much smaller volume of flow every minute. It is important to be able to clinically distinguish between these two phenotypes because the principles of management are dichotomous. The former presents with oxygenation failure and typical echocardiographic findings of PAH, while the latter, however, is characterized by a baby who appears generally stable on low (or no) supplemental oxygen but has exclusively or predominantly right-to-left ductal shunt. The lack of compromise to oxygenation relates to the fact these patients have a normal to high right ventricular output (typically low in resistance-mediated PAH), which may be used to distinguish both conditions echocardiographically. A third, mixed phenotype may occur because high pulmonary blood flow over a sustained period can lead to RV dilation and subsequent RV dysfunction due to increased energy demand. This contributes to adverse effects on LV diastolic performance due to abnormal septal configuration and may contribute to left heart–mediated pulmonary edema. The combination of these three cardiovascular phenotypes may lead to multi-factorial oxygenation failure after birth. The presence of supra-systemic PAH may be an indicator of poor prognosis²⁶; however, the relevance of each of these physiologies to a broad population of patients requires further study using comprehensive echocardiography.

Infants with VGAM need to be carefully evaluated for signs of PH and systemic hypoperfusion and managed accordingly. Therapeutic goals are to balance systemic and pulmonary blood flow, maintain RV performance, and monitor for neurological abnormalities. Although embolization is the definitive therapy for flow-mediated PH, correction of other ambient conditions is often necessary to achieve optimal operative stability. An algorithm has been published with this in mind by Giesinger et al, as illustrated in Figure 29.1.²⁹

The development of the pulmonary vasculature is a process that occurs concurrently with development of the lung parenchyma. The proximal pulmonary arteries and veins arise from proliferation of endothelial cells from existing vessels in the developing heart.³⁴ The most distal pulmonary vessels develop from pluripotent mesenchymal cells from blood islands which differentiate into endothelial cells.³⁵ The proximal and distal vessels are joined together between 5 and 17 weeks of gestation, during the pseudoglandular stage of lung development.³⁶ As the lungs continue to develop, pulmonary vessels grow alongside each acinus.³⁴ After 20 weeks of gestation, pulmonary arteries and arterioles have completed development of wall musculature.³⁴ The developing pulmonary arterial system has approximately twice the thickness of musculature as compared to those in adults, and the smallest arterioles have more pronounced musculature³⁶; however, there is animal evidence to suggest that arterial smooth muscle controlling vascular tone is mature in later gestation. Studies in the fetal lamb have suggested that the pulmonary vascular bed does not receive increased cardiac output in response to maternal hyperoxygenation at 20 weeks, suggesting the immature pulmonary vasculature does not vasodilate in response to oxygen.³⁷ As gestation progresses to 30 weeks, however, the vasculature does become responsive to maternal hyperoxygenation, suggesting maturation of the vasoreactivity of these vessels later in gestation.^34,37–39 Importantly, endothelial nitric oxide synthase (eNOS) is present throughout gestation, suggesting that, if stimulated, it would respond to vasodilatory mediators.

Despite the inherent elevated vascular resistance of the fetal pulmonary vessels, several in utero factors may affect the normal development of these vessels and result in a delayed transition or PH following delivery (Figure 29.3). Prolonged premature rupture of membranes and oligohydramnios results in abnormal development of the lungs and alveoli, which in turn leads to poor growth of the pulmonary vasculature with thickened smooth muscle layers.⁴⁰ Abnormal placentation and intrauterine growth restriction lead to decreased alveolarization, pulmonary vessel density, and endogenous nitric oxide production.⁴¹ Maternal factors, including obesity; diabetes mellitus; and use of tobacco, nonsteroidal anti-inflammatory drugs, or selective serotonin reuptake inhibitors, can affect the development of the pulmonary vasculature and its reactivity to endogenous pulmonary vasodilators.^42–45 Finally, factors around the time of delivery, including fetal distress and cesarean delivery (both emergent and elective), can contribute to delayed transition to a neonatal cardiopulmonary physiology.^38,45

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