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Hypertrophic cardiomyopathy in an extremely preterm infant
  1. Apoorva Aiyengar,
  2. Claire Howarth and
  3. Sujith Pereira
  1. Neonatal Unit, Homerton University Hospital NHS Foundation Trust, London, UK
  1. Correspondence to Dr Apoorva Aiyengar; a.aiyengar{at}nhs.net

Abstract

We present a case of an extreme preterm infant (Baby X) born at 24-week gestation. The echocardiogram showed evidence of hypertrophic cardiomyopathy (HCM) and a patent ductus arteriosus (PDA). There are a number of well-known causes of neonatal HCM including genetic, metabolic and endocrine. PDA is commonly present in preterm infants, and this can contribute to cardiac remodelling and result in cardiac changes mimicking HCM. Furthermore, medications such as steroids can also cause HCM through various mechanisms. A careful consideration of all the different aetiologies for HCM is important for appropriate management of such cases. This report examines the evidence in the literature for the above differential diagnoses and highlights the challenges in diagnosing the underlying cause of HCM in a preterm infant.

  • cardiovascular medicine
  • paediatrics (drugs and medicines)
  • obstetrics
  • gynaecology and fertility
  • neonatal intensive care

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Background

Neonatal hypertrophic cardiomyopathy (HCM) is a well-recognised condition with multiple causes including endocrine, metabolic and genetic.1–3 We present a case of an extremely preterm infant (Baby X) who had evidence of HCM on echocardiogram.

The majority of preterm infants have a persistent patent ductus arteriosus (PDA). This can often complicate their respiratory and cardiovascular course. When managing Baby X, a key query was whether he suffered from a primary cardiac disease (neonatal HCM) or whether the observed changes were secondary to a PDA causing cardiac muscle remodelling through left ventricle (LV) volume loading.

One review quotes the annual incidence of new cases of HCM in the paediatric population to be between 0.24 and 0.47 per 100 000.3 The aim of this case report is to outline the various aetiologies of neonatal HCM including lesser known causes in preterm infants including antenatal and postnatal exposure to steroids,4–9 which may be useful for other clinicans working in neonatology and paediatrics.

Case presentation

Baby X was born at 24 weeks gestation weighing 460 g via spontaneous vaginal delivery following a pregnancy complicated by bleeding since the 18th week of gestation. There was suspicion of premature prolonged rupture of membranes due to oligohydramnios seen on antenatal scans. His mother received a complete course of antenatal steroids and magnesium sulfate prior to delivery.

He was born with APGAR scores of 1 at 1 min, 6 at 5 min and 9 at 10 min, was intubated and received 120 mg of surfactant in the labour room.

He had evidence of respiratory distress syndrome (RDS), but he tolerated weaning of ventilation. At 1 week of life, cardiovascular examination showed easily palpable peripheral pulses, and his non-invasive blood pressure was 53/27 (mean 35) mm Hg. On auscultation, a murmur was noted. A baseline echo showed a structurally normal heart with the presence of a PDA (1.7 mm) with mild left ventricular dilatation (LVD) and left ventricular hypertrophy (LVH).

At 2 weeks of age, his ventilation requirements increased coinciding with a septic episode for which he received a course of antibiotics. Following the episode of sepsis, a repeat echocardiogram was performed on day 22 due to persistent high oxygen requirement, which showed LVH (see figure 1A,B) with evidence of systolic anterior motion of the mitral valve (see online supplemental video 1) and intracavitary dynamic obstruction (Vmax 4.3 m/s and pressure gradient of 73 mm Hg). Of note, the aortic valve itself appeared normal. The non-restrictive PDA measured 2.3 mm with left to right flow (Vmax 1 m/s), and there was reversed end-diastolic flow in the descending aorta distal to the aortic origin of the PDA. A differential diagnosis of HCM was considered and investigated.

Supplementary video

Figure 1

(A) Parasternal long axis view illustrating interventricular septal hypertrophy. (B) Continuous-wave Doppler spectrogram obtained using the apical five-chamber view demonstrating the pressure gradient along the left ventricular outflow tract. Ao, aorta; IVS, interventricular septum; LA, left atrium; LV, left ventricle; RV, right ventricle.

In terms of genetic causes, HCM is associated most commonly with Noonan Syndrome.1 3 There was no recorded family history of Noonan Syndrome or congenital cardiac conditions in baby X’s parents, and there were no obvious dysmorphic features on examination. Genetic testing was carried out, and baby X tested negative for Noonan Syndrome. Other genetic causes include Williams-Beuren10 and Beckwith-Wiedemann syndromes.2 Maternal diabetes is associated with neonatal HCM. Maternal hyperglycaemia causes fetal hyperinsulinism in utero which is thought to cause myocardial hypertrophy directly via action of insulin on receptors on cardiomyocytes.2 There was no evidence of hypercalcaemia. Baby X’s mother had no history of diabetes, and there was no clinical or laboratory evidence of hyperinsulinism or unstable blood sugar levels during baby X’s stay on our unit. Metabolic conditions such as Pompe disease (glycogen storage disease type II) and mitochondrial disorders can result in a multisystem disease with cardiac involvement and in particular cardiac hypertrophy.3 Baseline metabolic tests were performed; however, baby X had no clinical features such as ongoing lactic acidosis or hepatosplenomegaly to suggest an underlying metabolic condition. In addition, the changes seen on echocardiography were only confined to the left side of the heart making this group of disorders unlikely.3 The results of urine organic and amino acids did not point towards any specific metabolic condition but were in keeping with samples taken from a sick infant.

Baby X deteriorated further on day 24 and was extremely difficult to oxygenate despite optimising his respiratory and circulatory support. Multiple ventilation strategies were used including High Frequency Oscillatory Ventilation (HFOV) with no improvement in oxygenation. Both preductal and postductal saturations were low, and his echocardiogram continued to show a structurally normal heart but with evidence of HCM. Given his poor oxygenation and concerns about the PDA, he received medical treatment for PDA (paracetamol). He was commenced on rescue steroids (dexamethasone as per the DART protocol) and antibiotics were escalated to cover for sepsis, but he remained extremely unwell and continued to deteriorate with persistent severe hypoxia and severe metabolic acidosis. His C reactive protein rose to 34 mg/L, and it was felt that he was clinically septic although his blood culture was negative.

OUTCOME AND FOLLOW-UP

After discussions with his family, his parents decided for redirection of goals of care and baby X sadly died on day 28.

DISCUSSION

Neonatal HCM has a varied aetiology with idiopathic causes contributing to more than 50% of cases presenting under the age of one.3 When managing a case of suspected HCM in a preterm infant, it is important to investigate the cause, as it may have potential implications for management and prognosis. If there is an underlying genetic cause, determining this will be useful for counselling parents for future pregnancies.

The cardiac effects of antenatal steroids, in particular LVH and systolic function in neonates, have been extensively investigated. The benefits of antenatal steroid administration include not only a reduction in the risk of Respiratory Distress Syndrome (RDS) but also a substantial reduction in mortality and intraventricular haemorrhage.4 Prior to delivery, mother of baby X received one full course of antenatal steroids, to expedite lung maturity prior to delivery. Vural et al5 examined the effect of a single course of antenatal steroid exposure on the myocardium including LVH and systolic function in preterm infants. There was no difference in these parameters among infants who were exposed and not exposed to antenatal steroids.5 Furthermore, preterm infants (<32 weeks) exposed to repeated courses of prenatal steroids did not have higher blood pressure or significantly increased myocardial wall thickness in the first few days after birth.6 In the case of baby X, he was exposed to only one course of prenatal steroids and had LVH changes on echo observed on day 8 of life; therefore, the cardiac hypertrophy was unlikely to be induced by exposure to prenatal steroids.

Postnatal steroids are often administered to preterm infants to facilitate weaning from the ventilator when there is evidence of evolving or established chronic lung disease. There is a strong association between preterm infants receiving steroids and developing LVH and also a small proportion developing LV outflow tract obstruction.7 8 There are reports of such changes being reversible following discontinuation of steroids.7 9 The mechanism by which postnatal steroids result in cardiac hypertrophy is unclear. A suggested hypothesis is the resulting hypertension after steroid use can cause direct hypertrophy of the heart.9 At a cellular level, cardiac hypertrophy is due to increased size of myocytes following synthesis of intracellular proteins.7 This could be in response to stimulation of receptors, for example, insulin receptors or insulin-like growth factor-1 and dexamethasone is thought to activate these pathways, similar to infants of diabetic mothers.7 However, the presence of HCM in our patient preceded the rescue dexamethasone given to optimise ventilation.

Baby X was discussed with our paediatric cardiology colleagues, and the most likely cause of our patient’s HCM was felt to be secondary to the effects of PDA; hence, they recommended medical treatment. Spontaneous ductal closure during the neonatal period is less common in extreme preterm babies, and they are more likely to suffer from the effects of a PDA, which includes pulmonary oedema and need for escalating respiratory support. This could also explain baby X’s course particularly in the last week of his life when his ventilation and oxygenation became a challenge. A PDA can result in increased pulmonary blood flow and eventual LVD and remodelling resulting in LVH,11 as noted on baby X’s scan. A study investigating cardiac remodelling in preterm infants with exposure to PDA showed that ventricular wall thickness increases 4 weeks after exposure to PDA-related volume overload.12 The systolic anterior motion of the mitral valve along with the LVH resulted in the intracavitary obstruction in this case.13

Our working diagnosis was that baby X had LVH from volume loading secondary to PDA and extreme prematurity. He developed sepsis causing severe hypoxia and metabolic acidosis which ultimately led to his death.

Conclusion

Neonatal HCM in a preterm infant presents a diagnostic challenge because of its broad aetiology. PDA, which is frequently seen in extremely preterm infants, can be responsible for the observed picture and acts as a confounding factor. Rare causes of neonatal HCM should be suspected and their diagnosis facilitated through early referral to a specialist centre in order to achieve the best outcomes for the infant and family.

Learning points

  • Neonatal hypertrophic cardiomyopathy (HCM) can be due to variety of aetiologies including genetic, endocrine or metabolic; however, 50% of cases presenting under 1-year old can be idiopathic.

  • HCM can occur following exposure to steroids; however, these changes can spontaneously reverse 2–5 weeks following discontinuation of treatment.

  • Patent ductus arteriosus (PDA) is common in extremely preterm infants. Cardiac remodelling including left ventricular dilatation and left ventricular hypertrophy occurs after 4 weeks of exposure to volume overload secondary to PDA.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Contributors AA prepared and edited manuscript. CH and SP supervised, reviewed and edited manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.