Ep 13: Cardiac Lesions in IDM

Learning Objectives

By the end of this episode, NICU Grads will be able to:
1. Describe the proposed pathogenesis of congenital cardiac malformations in IDM
2. Discuss the epidemiology, pathophysiology, clinical presentation, and prognosis of neonatal transient hypertrophic cardiomyopathy associated with maternal diabetes
3. Understand the prevention and treatment of symptomatic neonatal transient HCM

Guest Speakers
Adam S. Bauer, MD FAAP (he/him/his)
Neonatologist, University of Wisconsin School of Medicine and Public Health
Neonatology Consultant to the Fetal Cardiology Clinic
Assistant Professor of Pediatrics
Pediatrics Residency Associate Program Director
Twitter- @BauerHour15, @WiscPediatrics
Website- www.pediatrics.wisc.edu

Dr. Adam S. Bauer earned his medical degree at University of Iowa Carver College of Medicine. He completed his pediatric residency training at University of Wisconsin Hospital and Clinics in Madison, WI, where he remained to complete his neonatal-perinatal medicine fellowship and later joined on as faculty. In addition to working as a Neonatologist, he is one of the Pediatrics Residency Associate Program Directors and director of the Pediatrics Internship Prep Course. Adam’s professional interests include medical education, simulation, and point of care ultrasound. Outside of work, he loves spending time with his wife Shandra, and kiddos, Brynn, Ethan, and Silas. He loves all things Wisconsin—Packers, Brewers, ice fishing/fishing, camping, hiking, and just being outdoors. 

Megan Derrer, MD FAAP
Neonatal-Perinatal Fellow, University of Wisconsin Hospital in Madison, WI

Dr. Megan Derrer earned her medical degree from St. George’s University School of Medicine and completed her pediatric residency training at OSF St Francis Medical Center in Illinois. She moved to Madison for neonatal-perinatal medicine fellowship. During fellowship, she investigated the heart rate variability scores of term babies with HIE and whether there was any correlation with elevated scores and neurodevelopmental outcome. She feels passionate about babies in general, but especially improving neurodevelopmental outcome, palliative care, and advocacy. Outside the NICU, Megan loves to spend time with her husband Matt, daughter Mia, and fur babies Dixie and Max. They are big fans of exploring all of the outdoor beauty that Wisconsin has to offer. 

Pathogenesis

• Maternal glucose freely crosses the placenta (BOARD PEARL)
• Maternal insulin does not cross the placenta (BOARD PEARL)
• Before 20 weeks gestation, the fetal islet cells do not have the ability to produce insulin and regulate glucose levels
• After 20 weeks gestation, the fetus has a functioning pancreas and is responsible for its own glucose homeostasis
• Maternal hyperglycemia leads to fetal hyperinsulinism
  • Abnormal overgrowth
    • Organomegaly
    • Cardiac hypertrophy
    • Macrosomia

• Maternal hyperglycemia –> abnormal metabolic pathways –> inappropriate apoptosis –> malformations
  • Altered lipid metabolism
    • Hyperglycemia alters lipid metabolism –> disrupt many critical cellular functions and negatively impact cell membrane function
  • Mitochondrial dysfunction
    • Hyperglycemia stimulates production of excess superoxide by mitochondria –> necrosis or apoptosis
  • Apoptosis
    • Excess mitochondrial reactive oxygen species production activates apoptosis signal
  • Fetal hyperinsulinemia –> increased metabolic rates –> increased oxygen demand/fetal hypoxemia
    • Fetal hypoxemia promotes erythropoietin synthesis –>polycythemia and increased catecholamine production
    • The iron redistribution from polycythemia may lead to iron deficiency in other developing organs (potentially related to cardiomyopathy)
  • Fetal hyperinsulinemia –> increased fat/glycogen in myocardial cells and increased oxidative stress –> abnormal cardiac remodeling/cardiac hypertrophy

Incidence

• True incidence is unknown as routine echocardiography on well babies is not performed
• Retrospective studies have found that up to 5% of infants of diabetic mothers will have cardiac malformations
• Up to 30% may have pathologic ventricular hypertrophy
• Other cardiac lesions include:
  • PDA
  • ASD
  • VSD
  • TGA
  • DORV
  • Truncus arteriosus
  • Tricuspid atresia
• 5% will suffer from congestive heart failure

Risk factors

• Type of diabetes mellitus (DM)
  • DM complicates 6% to 7% of all pregnancies in the US
  • 1-2% of cases – Type 1 DM 
  • 8% of cases- Type 2 DM with insulin-resistance
  • 90% of cases of gestational DM (GDM)
  • GDM is typically not associated with an increased risk of fetal malformations given that GDM occurs in second half of pregnancy, at which point organogenesis is complete (BOARD PEARL)
  • Literature has changed over time – newer information that GDM is also associated with malformations
  • Reports of increased congenital malformations if GDM requires insulin treatment
• Severity of DM
  • Timing, duration and control of DM impacts severity of DM and as a result impacts the incidence of malformation in IDM
  • Early presence of DM in pregnancy, prolonged exposure to maternal hyperglycemia, and poor maternal glycemic control –> greater risk of congenital malformations with increased risk of perinatal mortality (BOARD PEARL)
  • Women with pre-pregnancy DM or DM early in pregnancy have a greater risk of having an infant with birth defects (BOARD PEARL).
  • Hemoglobin A1c levels > 10% is associated with high rates of fetal malformations (cardiac + non-cardiac) (10%-25%)
  • Decreased risk of major malformations if HbA1C is <6.5 at the time of conception
  • Decreased risk of symptomatic cardiac hypertrophy with better glycemic control throughout the third trimester
• Degree of maternal obesity in women with pre-pregnancy DM 
  • Does NOT correlate with the incidence of congenital birth defects

Diagnosis

• Growth parameters
• Vitals
• Clinical exam
• CXR
  • May or may not have cardiomegaly
• ECHO
  • Assess cardiac anatomy and function

Management

• Supportive therapy
  • Oxygen
  • Mechanical ventilation
  • Diuretics
  • Correction of electrolyte abnormalities
  • Beta blockers such as propranolol (short-acting like esmolol preferred)
    • Use non-specific beta blockers with caution in infants with pulmonary hypertension
    • Concern for hypoglycemia as a side-effect
  • Avoid digoxin and positive inotropic agents as this may worsen diastolic filling due to LVOT obstruction and poor diastolic function
• For structural anomalies, IDM may require surgical intervention

Prevention

• Women with pre-existing diabetes, regardless of type, should maintain strict glycemic control prior to and at the time of conception and during pregnancy to minimize the severity of possible malformations

Prognosis

• Prior to seeking better glycemic control of pregnant women, IDM had up to a 65% mortality rate
• Major malformations now account for 30-50% of perinatal death in IDM after maintaining normal glucose levels
• Cardiac hypertrophy
  • Symptomatically recover in a couple of weeks
  • Most infants will have a normal ECHO by 6 months of age
• Congenital heart disease requiring surgical intervention
  • Dependent upon severity of lesion and surgical complications

References

1. Cowett R. The Infant of the Diabetic Mother. NeoReviews.2002;3(9):e173-e189; DOI: 10.1542/neo.3-9-e173
2. Barnes-Powell, L. L. (2007). Infants of diabetic mothers: The effects of hyperglycemia on the fetus and neonate. Neonatal Network : NN, 26(5), 283-290.
3. Loffredo CA, Wilson PD, Ferencz C. Maternal diabetes: an independent risk factor for major cardiovascular malformations with increased mortality of affected infants. Teratology. 2001 Aug;64(2):98-106. doi: 10.1002/tera.1051
4. Narchi H, Kulaylat N. Heart disease in infants of diabetic mothers. Images Paediatr Cardiol. 2000;2(2):17-23.
5. Yeh J, Berger S. Cardiac Findings in Infants of Diabetic Mothers. NeoReviews. 2015;16(11):e624-e630;DOI: 10.1542/neo.16-11-e624. 
6. Paauw, N.D., Stegeman, R., de Vroede, M.A.M.J. et al. Neonatal cardiac hypertrophy: the role of hyperinsulinism—a review of literature. Eur J Pediatr 179, 39–50 (2020). https://doi.org/10.1007/s00431-019-03521-6
7. Elmekkawi SF, Mansour GM, Elsafty MS, Hassanin AS, Laban M, Elsayed HM. Prediction of Fetal Hypertrophic Cardiomyopathy in Diabetic Pregnancies Compared with Postnatal Outcome. Clin Med Insights Womens Health. 2015 Dec 1;8:39-43. doi: 10.4137/CMWH.S32825. PMID: 26664250; PMCID: PMC4667560.
8. Richard J. Martin, Avroy A. Fanaroff, Michele C. Walsh. (2015). Fanaroff and Martin’s neonatal-perinatal medicine: diseases of the fetus and infant. Philadelphia, PA: Elsevier/Saunders.
9. Brodsky, Dara, and Camilia Martin. Brodsky and Martin’s Neonatology Review Series. 3rd ed., Lulu, 2020.
10. Brodsky, Dara. Neonatology Review: Q&A. 3rd ed., Lulu, 2016.
11. Chess, Patricia. Avery’s Neonatology Board Review: Certification and Clinical Refresher. 1 ed., Elsevier, 2019.
12. Polin, Richard A., and Mervin C. Yoder. Workbook in Practical Neonatology. 5th ed., Saunders, 2014.

Credits

• Written and Produced by: Neena Jube-Desai MD, MBA FAAP
• Cover Art by: Neena Jube-Desai MD, MBA FAAP
• Host: Neena Jube-Desai MD, MBA FAAP
• Editor: Neena Jube-Desai MD, MBA FAAP
• Guests: Adam S. Bauer, MD FAAP and Megan Derrer, MD FAAP