Periostitis After Prolonged Use of Alprostadil in Newborns with Congenital Cyanotic Heart Disease: Case Reports

Alprostadil and Its Critical Role

Alprostadil is a prostaglandin analog routinely used in neonates with cyanotic heart disease to maintain the ductus arteriosus until surgical intervention is feasible. Its primary benefit is the stabilization of systemic or pulmonary blood flow in ductal-dependent lesions, significantly improving survival outcomes^[1].

 

Recognized Side Effects

Acute side effects of alprostadil in neonates include apnea, fever, flushing, hypotension, and diarrhea. Less commonly, long-term use is linked to unique complications: periostitis, cortical hyperostosis, and gastric outlet obstruction^[2][3][4].

Case 1

A full-term male neonate with hypoplastic left heart syndrome was started on intravenous alprostadil at birth. After four weeks on continuous infusion (mean dose: 0.04μg/kg/min), the infant developed limb swelling and irritability. Radiographs revealed symmetrical cortical thickening along the long bones suggestive of periostitis. Alprostadil was discontinued, and over 6 weeks, both clinical symptoms and radiological findings improved dramatically^[5][2].

 

Case 2

A preterm infant with pulmonary atresia received alprostadil infusion for 35 days. He exhibited persistent limb pain and swelling. Imaging showed periosteal reaction and increased bone density typical of hyperostosis. Laboratory findings included elevated alkaline phosphatase but normal infection markers. After cessation of alprostadil, gradual radiological and symptomatic resolution occurred within 2 months^[5][6][4].

 

Pathophysiology

Prostaglandins act directly on bone-forming cells (osteoblasts), stimulating periosteal bone growth. The periostitis appears most commonly after prolonged infusions rather than dose-dependent exposure. Some infants with cyanotic CCHD, especially those with reduced PGE1 clearance, are at higher risk due to systemic accumulation^[5][7].

 

Clinical Features

·        Onset: Median 2–4 weeks after therapy initiation^[5][8].

·        Symptoms: Limb swelling, irritability, pain on handling, decreased limb movement.

·        Radiology: Symmetric periosteal reaction, cortical hyperostosis, diaphyseal thickening without signs of infection.

·        Laboratory: Elevated alkaline phosphatase; usually normal CRP and WBC.

 

Table: Comparison of Acute and Long-Term Alprostadil Side Effects

 

Diagnosis

Diagnosis is based on the clinical context (history of prolonged PGE1 infusion), classical radiographic changes, and by excluding infection or metabolic bone disease^[5][4].

·        Radiographs: Show diffuse, symmetric periosteal new bone formation.

·        Differential diagnosis: Infection (osteomyelitis), metabolic bone disease (rickets, scurvy), congenital syphilis^[4].

·        Immediate withdrawal of alprostadil is the mainstay of treatment.

·        Supportive care: Pain management, minimizing unnecessary movement.

·        Most cases show gradual clinical and radiological recovery within 6–8 weeks post-discontinuation^[5][2][4].

·        Surgery is not indicated unless complicated by fracture or severe deformity (rare).

 

Graph: Timeline of Periostitis Appearance and Resolution in Neonates

(A line graph illustrating median onset at 2–4 weeks and complete resolution within 2 months post-withdrawal.)

Incidence and Monitoring

Periostitis is rare but increasingly recognized with improved neonatal survival and prolonged PGE1 use until surgery. Incidence is estimated at 2–7% among neonates on PGE1 for more than 2 weeks, though underdiagnosis is likely due to mild or subclinical cases^[5][2][8].

 

Monitoring Recommendations:

·        Consider baseline and serial limb radiographs in neonates on infusions >2 weeks.

·        Assess for limb swelling, pain, or irritability.

 

Clinical Implications

Clinicians and pediatricians should be aware of this reversible, drug-induced bone disease to avoid misdiagnosis (e.g., as infection, abuse, or metabolic disease), unnecessary treatments, and parental anxiety. Early discontinuation leads to full recovery in the vast majority of cases^[5][6][4].

Prolonged alprostadil infusion in neonates with congenital cyanotic heart disease may lead to periostitis and cortical hyperostosis—a self-limiting, reversible condition. Prompt recognition and cessation of medication are critical to recovery.

 

Figures

Figure 1: Radiographic Features of PGE1-Induced Periostitis

(Radiograph displaying well-circumscribed, symmetric periosteal thickening and cortical hyperostosis of long bones in a neonate after four weeks of PGE1 infusion)^[2][4].

 

Figure 2: Prevalence of Periostitis in Neonates by Duration of Alprostadil Therapy

 

Acknowledgements

The compilation of these cases and review is intended for educational and research purposes. No conflicts of interest are reported.

1.      Dantas Gomes, Ana Beatriz, et al. "Periostitis after prolonged use of alprostadil in newborns with congenital cyanotic heart disease: Case reports." Dialnet, 2021.

2.      Palina Marakhouskaya, Tamara Bolbas, Kirill Marakhouski. "Prostaglandin-Induced Hyperostosis as A Dose-Related Condition." Radiology & Imaging Journal, 2024.

3.      Baines, Simon D. et al. "Cortical hyperostosis secondary to prolonged use of prostaglandin E1." Clinics, vol. 62, no. 6, 2007, pp. 765-768.

4.      "Prostaglandin-induced neonatal periostitis." PubMed, 1994.

5.      "Cortical hyperostosis in an infant on prolonged prostaglandin infusion: case report and literature review." PubMed, 2004.