Acute myocardial infarction in a premature infant on the first day of life

Case report

A 35+5 weeks’ male infant was born to a G4A2P1T0 healthy mother via vaginal delivery after spontaneous onset of labor. Serologies were protective. Vaginal swab was negative for Streptococcus beta hemolytic (GBS), and positive for Ureaplasmaurealyticum. The pregnancy was complicated by preterm premature rupture of membranes at 30 weeks.

The infant required tactile stimulation at birth and administration of O₂ in mask for about 2 min. Cord pH was normal.

At 12 min of life the baby suddenly deteriorated, displaying symptoms of cardiogenic shock (poor perfusion, bradycardia, hypotension) and requiring intubation and cardiopulmonary resuscitation. The infant was resuscitated for about 10 min, after which an heart rate >60/min was detected. Subsequently cardiac frequency (CF) around 80/min was permanently registered, and mechanical ventilation was started.

Electrocardiogram (ECG), performed after resuscitation efforts (while CF was about 80/min), showed signs of complete heart block. Echocardiogram, performed immediately after by a junior medical stuff, revealed normal cardiac and coronary artery anatomy but a global and diffuse hypokinesia. Chest radiography was normal. Intractable systemic hypotension required inotropic support with dopamine, dobutamine and epinephrine, although only minimal response could be elicited. Broad spectrum antibiotic therapy was started. Serial blood gas analysis detected severe metabolic acidosis. Laboratory findings were as follows: troponin T 4098 µg/L (normal <0.014), creatine kinase 4754 ng/mL (normal <100), and B-type natriuretic peptide 845 pg/mL (normal <300). C-reactive protein was negative.

Because of increased blood ammonium levels (472 µg/dL, normal <150), treatment with sodium benzoate and vitamins was started. Ammonium levels normalized within 6 h. Cranial ultrasound showed no signs of intracranial hemorrhage or perfusion defects. The repeat ECG at 12 h of life showed ST depression and wide Qs in leads II and III, avF, suggesting a transmural posteroinferior wall myocardial infraction (MI). On echocardiogram the left ventricle appeared dilated with severely decreased function (ejection fraction 20%, fractional shortening 11%) and moderate to severe atrioventricular valve regurgitation. Posteroinferior and lateral wall segments were almost akinetic.

Given the diagnostic findings, highly suggestive for with MI, antiplatet therapy with aspirin and anticoagulant therapy with heparin were attempted. A coronary angiography could not be performed, given the rapidly evolving disease. Clinical conditions dramatically deteriorated, with the development of disseminated intravascular coagulation and multiorgan failure, leading to death at about 40 h of life.

Post-mortem diagnostic tests confirmed no evidence for sepsis. Metabolic screens came back normal. The initial hyperammonemia seems compatible with transient neonatal hyperammonia.

Genetic screen for thrombosis, including lupus anticoagulant, antithrombin III, protein S and C, factor V Leiden, factor II and MTHFR was positive for an homozygosis mutation on MTHFR A1298C. The parents did not display any prothrombotic mutation, while the brother was heterozygous for MTHFR A1298C.

The autopsy revealed a left coronary predominance but the external inspection of the heart showed a necrotic area in the apex of the right ventricle, measuring 2×2 cm, with its largest axis extending up towards the line of the right coronary artery. The cut surface showed a distinct zone of myocardial necrosis, with deeply congested center and a paler peripheral area (Figure 1). The overlying endocardium was covered with fibrin. The first portion of right coronary artery contained a partially organized, adherent, laminated thrombus. No other anomalies were seen either in the hearth or in other systems.

Figure 1:

Macroscopic features of the myocardial infarction.

The histopathology of the cardiac tissue confirmed widespread necrosis of the myocardium with calcification at the periphery of the necrotic area and mononuclear cell infiltration (Figure 2). The central area of some papillary muscles showed evidence of frank necrosis. The area of the right coronary artery, containing a reddish mass, was found to be occluded more than 70% by a laminated thrombus containing numerous leucocytes showing signs of organization (Figure 3).

Figure 2:

Subendocardial haemorrhagic infarction and necrosis (Ematoxilin&Eosin 2×).

Figure 3:

Coronary thrombosis (Ematoxilin&Eosin 2×).

Upon completion of the case study, it was also performed the examination of the placenta that showed no significant alterations.

Conclusion

We report the case of an acute fatal neonatal MI, caused by an occlusive thrombus of the right coronary artery. Neonatal MI is an extremely rare entity leading to death due to cardiogenic shock in up to 90% of the cases. So far, only a few cases have been described. In the literature more than half of cases of acute neonatal MI are due to a thrombosis but rarely there was an histological demonstration of the thrombosis [1], [2], [3]. Other causes of MI recognized in the perinatal era are: structural heart disease, intrauterine asphyxia, paradoxical embolus and thromboembolism [1]. Cardiac anomalies linked to neonatal MI are aortic stenosis or atresia, hypoplastic left heart syndrome, pulmonary atresia, total anomalous pulmonary venous return, stenosis of the coronary ostium, and anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) [4], [5]. Cardiac dysfunction, of varying severity, is seen in 50%–70% of asphyxiated newborns but is usually more relevant in preterm infants, due to immature myocardial contractility and respiratory distress. An association has been found between perinatal asphyxia and thromboembolic neonatal MI, potentially inducing a state of low-output causing stasis and clot formation. However, the exact physiologic mechanism has yet to be elucidated [6].

In our case normal funicular pH excluding intrauterine asphyxia; cardiorespiratory depression occurred after approximately 10 min and severe acidosis was developed subsequently. On the other hand, sudden unexpected postnatal collapse, described during the first 2 h while the baby start breastfeeding, was also excluded, considering the rapidity and the progressiveness. Our patient showed cardiogenic shock at 12 min of life while he was placed supine and breastfeeding was not yet started. The airways had patency. It clear that neonatal asphyxia was the symptom and not the cause of the coronary arterial occlusion in our newborn.

Inflammatory disease or medial calcification of the coronary arteries, Kawasaki disease, endocarditis, myocarditis, erythroblastosis fetalis, or neonatal thrombosis were also described as cause of MI [3], [7]. A paradoxical embolus usually arises from thrombotic material within the ductus venosus, umbilical cord, or renal veins, especially due to umbilical vein catheterization. In our case no catheter was placed before clinical deterioration.

Possible etiologies for thrombosis are also antithrombin III deficiency, protein S and/or protein C deficiency, factor V Leiden mutation in homozygosis. Finally, maternal cocaine abuse was reported [8], [9], [10]. The patient admitted to our unit was diagnosed post-mortem with MTHFR A1298C mutation. No other associated risk factors for thrombosis or MI were found. To our knowledge, this is the first description of neonatal MI, due to an isolated hypercoagulable state. We speculate may have predisposed the infant to coronary thrombosis.

MTHFR is an crucial enzyme for the folate metabolism which is an integral process or cell metabolism in the DNA, RNA and protein methylation. This enzyme plays a role in the homocysteine to methionine metabolism. Fourteen rare prothrombotic mutations have been identified on the MTHFR gene, the most common being MTHFR C677T and A1298C [11]. Not all homozygous patients will develop high homocysteine levels, thanks to adequate folate levels. However, high homocysteine levels are a risk factor for developing blood clots with consequent higher risks of coronary heart disease and stroke. Folic acid cannot be synthesized by the human body and needs to be introduced with adequate diet. Folate supplementation is recommended during pregnancy because the fetus extrapolates itself circulating folate.

Despite that Nie et al. [12], in a meta-analisys demonstrated that the fetal MTHFR C677T polymorphism is an important risk factor of developing congenital heart diseases but found no statistically significant association between the MTHFR A1298C polymorphism and congenital heart disease, we suppose that the homozygous state of our patient, in the absence of optimal levels of folate (the mother was not taking folate during pregnancy; she was not aware of her heterozygosous state for MTHFR A1298C nor that of her husband), has predispose the patient to susceptibility to the hypercoagulation. The stress of birth may have been the trigger for thrombus formation. This result has proved very useful to couple to the possibility of a prenatal diagnosis targeted for subsequent pregnancies.

In some cases described previously, catheterization or thrombolytic therapy were possible given the clinical condition of the patient. Supportive measures including anti-arrhytmias, diuretics, inotropes and afterload reducing agents were described and were used in this case. In other cases prostaglandin E1 (PGE1) was started to maintain ductal potency and to support systemic circulation. Alternatively, support in extracorporeal membrane oxygenation (ECMO) was started [13] but the coronary must be patent to permit perfusion of the myocardium, which contrasts with the findings in our case. Indeed, in our patient, additional diagnostic tests or transfer to a center for ECMO therapy was impossible due to massive infarction and rapid clinical deterioration. Thrombolytic therapy with r-TPA to restore myocardial perfusion was not undertaken since the diagnosis of MI has been made approximately at 20 h of life when the overall clinical condition had dramatically worsened. As it was, therapy with aspirin and heparin was carried out. Cesna et al. [14] reported a successful case of newborn MI solved by only intracoronary thrombolytic therapy.

In our case, ECG and echocardiography were performed at 30 min of life directly in the delivery room after resuscitation care and major congenital abnormalities were excluded. Signs of complete heart block were reported in our first ECG but other specific signs of MI were seen later (Figures 4 and 5). Other prompt cardiac investigations such as cardiac catheterization and angiography were indicated to confirm the diagnosis and guide management. Despite our promptness performing ECG and echocardiography already in delivery room, we underestimated the potential indirect signs, attributing the overall clinical condition of our baby to a fulminant sepsis, an underlying metabolic disease or a cerebral stroke.

Figure 4:

First ECG, performed at birth, showed signs of complete heart block.

Figure 5:

ECG at 12 hours of life showed ST depression and wide Qs in leads II and III, avF, suggesting a transmural posteroinferior wall MI.

In summary, we report a case of MI that led to cardiac failure occurred at birth in a premature infant without known risk factors. The right dominance and very proximal right coronary artery occlusion would explain deterioration of the right ventricle and possible left ventricular dysfunction. Our case has shown that the possibility to perform ECG and echocardiography directly in the delivery room could be useful in all cases of cardiogenic shock at birth although the classic signs of MI in the newborn period may not be immediately proven. Other cardiac investigations are indicated but, despite supportive measures and fibrinolytic agents, mortality remains high. Complete genetic screen for thrombosis was necessary in these patients and in their family.