Efficacy & Safety of Oral Adjuvants to Phototherapy in Neonatal Hyperbilirubinemia

Efficacy and Safety of Oral Zinc Sulphate and Ursodeoxycholic Acid as Adjuvants to Phototherapy in Management of Neonatal Non-Hemolytic Unconjugated Hyperbilirubinemia

Neonatal jaundice, or neonatal hyperbilirubinemia, is a common medical issue in the first two weeks of life, causing prolonged hospitalization and readmissions. It results from elevated total serum bilirubin (TSB) and is manifested as yellowish discoloration of the skin, sclera, and mucous membrane. Clinical jaundice appears in about 60% of term neonates and 80% of preterm infants within the first week of life. Pathologic hyperbilirubinemia occurs when bilirubin levels increase by more than 5 mg/dL/day or 0.2 mg/dL/hour, or when jaundice lasts longer than two to three weeks in full-term infants. In preterm infants, unconjugated hyperbilirubinemia is of particular concern due to their permeable blood-brain barrier and underdeveloped brain. Phototherapy is widely used to reduce or prevent the rise of serum unconjugated bilirubin levels and reduce the need for exchange transfusions. However, phototherapy has both immediate and long-term side effects, and it can only decrease accumulated UCB but does not prevent its accumulation. There is a growing potential to explore novel adjuvant treatments to increase bilirubin clearance, decrease phototherapy duration, and decrease exchange transfusion rate.

Study Overview

• Status: Recruiting
• Conditions: Neonatal Hyperbilirubinemia
• Intervention / Treatment: Drug: Zinc sulfate; Drug: Ursodeoxycholic acid

Detailed Description

Neonatal jaundice, or neonatal hyperbilirubinemia, is the most common medical issue in the first two weeks of life and is a frequent cause of prolonged hospitalization and readmission to the hospital after birth. It results from elevated total serum bilirubin (TSB) and is clinically manifested as yellowish discoloration of the skin, sclera, and mucous membrane. Increased enterohepatic circulation of indirect bilirubin is one of the elucidated mechanisms implicated in the pathophysiology of neonatal hyperbilirubinemia.

Clinical jaundice appears in about 60% of term neonates and 80% of preterms within the first week of life. In most cases, it is a mild, transient, and self-limiting condition that resolves spontaneously and is referred to as "physiological jaundice.". When bilirubin levels increase by more than 5 mg/dL/day or more than 0.2 mg/dL/hour, or when jaundice lasts longer than two to three weeks in full-term infants, pathologic hyperbilirubinemia is said to have occurred. In preterm infants, unconjugated hyperbilirubinemia is of particular concern, given that their blood-brain barrier is more permeable, and their underdeveloped brain is more susceptible to bilirubin-induced neurotoxicity.

Scavenging unconjugated plasma bilirubin can be done, conveniently, non-invasively, and effectively by phototherapy. Phototherapy is universally recognized as the mainstay for the treatment of neonatal jaundice and is widely used in neonatal units and postnatal wards. It is a safe and effective method for decreasing or preventing the rise of serum unconjugated bilirubin levels, and it reduces the need for exchange transfusions in neonates.

However, phototherapy has both immediate and long-term side effects, such as rash, bronze baby syndrome, and circadian rhythm modification. This is coupled with social side effects like parental concern because of the infant's increased hospitalization, broken mother-infant attachment, and high cost of care. Moreover, phototherapy can only decrease already accumulated UCB but does not prevent its accumulation. Exchange transfusion therapy, which is generally performed after the failure of phototherapy, may lead to severe complications, such as embolism, sepsis, necrotizing enterocolitis, or even death.

Consequently, there is a growing potential to explore novel adjuvant treatments that can help to increase bilirubin clearance, decrease phototherapy duration, and decrease exchange transfusion rate.

One of the methods used to treat indirect hyperbilirubinemia is to use a zinc solution. Studies have shown that chronic or acute use of zinc salts can reduce serum bilirubin levels by inhibiting the enterohepatic cycle of indirect bilirubin. Oral administration of zinc (Zn) sulfate increases bilirubin excretion and decreases its serum level.

Oral administration of Zn salts is possible in two dose ranges: low (10 mg/day) and high (11-20 mg/day). Given that some of the medication is absorbed in the proximal ileum, giving a high dose may be desirable. Zn salts are safe, and studies treating several children and newborns with diarrhea, measles, pneumonia, the common cold, and malaria have demonstrated the safety of oral Zn sulfate administration. Studies conducted on the effectiveness of Zn salts on serum indirect bilirubin levels in newborns have yielded different results, all calling for further research. Additionally, neonates with hyperbilirubinemia appear to have lower serum Zn levels than other well-term neonates.

The efficacy of ursodeoxycholic acid as an adjuvant to phototherapy has also been examined in a few studies. Ursodeoxycholic acid (UDCA), or ursodiol, is a bile acid commonly used to manage cholestatic liver disease. UDCA helps in improving endogenous bile secretion, reducing the reducing the displacement of more toxic components of endogenous bile acids, and reducing enterohepatic circulation. Because of its anti-apoptotic, anti-inflammatory, and antioxidant characteristics, UDCA also has hepatoprotective and neuroprotective effects.

Although UDCA is an off-label treatment in neonates, it is widely used in conjugated hyperbilirubinemia and liver disorders. UDCA has also been investigated for its possible role in indirect hyperbilirubinemia. It is thought to function by inhibiting the reabsorption of bilirubin from the intestines. UDCA is often tolerated well. In studies on healthy-term neonates, ill neonates, and neonates with G6PD deficiency, UDCA was reported to be useful in shortening the length of phototherapy.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Amira M. Fouly, Demonstrator; Phone Number: +20 102 303 3092; Email: amira.mohamed@ecu.edu.eg
• Study Contact Backup: Name: Dina K. Abou El Fadl, lecturer; Phone Number: +20 100 544 2855; Email: Dkhaled@fue.edu.eg

Study Locations

• Egypt
  • Cairo Governorate
    • Cairo, Cairo Governorate, Egypt
      • Recruiting
      • Neonatal Intensive Care Unit (NICU) of Ain Shams University Hospitals
      • Contact: Yasmin A. Farid; Phone Number: 01001449558; Email: Yasmin_Ali_Farid@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• neonates with both genders
• neonates with gestational age ≥ 32 weeks
• neonates who can tolerate enteral feeding
• diagnosed with unconjugated non-hemolytic hyperbilirubinemia
• Phototherapy is required within the first week of life.

Exclusion Criteria:

• Neonates with seizures, hydrops fetalis, hypoxic-ischemic encephalopathy, or major congenital anomalies
• Neonates who have had an exchange transfusion within 24 hours
• neonates have evidence of hemolytic causes of jaundice (e.g., ABO and RH
• incompatibility, glucose 6-phosphate dehydrogenase deficiency)
• neonates who have reported hypersensitivity to zinc sulfate or ursodeoxycholic acid.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: preterm: control; phototherapy only
Experimental: preterm: low dose of oral zinc sulfate; Neonates will receive oral Zn sulfate solution in low doses (10 mg/day) given as 5 mg twice daily.	Drug: Zinc sulfate; Neonates will receive oral Zn sulfate solution in either low doses (10 mg/day) or high doses (20 mg/day) given twice daily.; Other Names: zinc origin
Experimental: preterm: high dose of oral zinc sulfate; Neonates will receive oral Zn sulfate solution in a high dose (20 mg/day) given as 10 mg twice daily.	Drug: Zinc sulfate; Neonates will receive oral Zn sulfate solution in either low doses (10 mg/day) or high doses (20 mg/day) given twice daily.; Other Names: zinc origin
Experimental: preterm: low dose of oral UDCA; Neonates will receive oral UDCA solution at 10 mg/kg twice daily.	Drug: Ursodeoxycholic acid; Neonates will receive oral UDCA solution at 10 mg/day given as 5 mg twice daily.; Other Names: Livagoal
No Intervention: full-term: control; phototherapy only
Experimental: full-term: low dose of oral zinc sulfate; Neonates will receive oral Zn sulfate solution in low doses (10 mg/day) given as 5 mg twice daily.	Drug: Zinc sulfate; Neonates will receive oral Zn sulfate solution in either low doses (10 mg/day) or high doses (20 mg/day) given twice daily.; Other Names: zinc origin
Experimental: full-term: high dose of oral zinc sulfate; Neonates will receive oral Zn sulfate solution in a high dose (20 mg/day) given as 10 mg twice daily.	Drug: Zinc sulfate; Neonates will receive oral Zn sulfate solution in either low doses (10 mg/day) or high doses (20 mg/day) given twice daily.; Other Names: zinc origin
Experimental: full-term: low dose of oral UDCA; Neonates will receive oral UDCA solution at 10 mg/kg twice daily.	Drug: Ursodeoxycholic acid; Neonates will receive oral UDCA solution at 10 mg/day given as 5 mg twice daily.; Other Names: Livagoal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
serum bilirubin level.	Assessing the effect of oral administration of zinc sulfate (at low and high doses) and ursodeoxycholic acid on serum bilirubin levels during the treatment of neonatal non-hemolytic unconjugated hyperbilirubinemia.	10 days
duration of phototherapy needed.	Assessing the effect of oral administration of zinc sulfate (at low and high doses) and ursodeoxycholic acid on the duration of phototherapy during the treatment of neonatal non-hemolytic unconjugated hyperbilirubinemia.	10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
monitoring adverse effects	assessing the possible side effects of both drugs	10 days
serum zinc level	evaluate the level of serum zinc before and after interventions.	10 days
length of NICU stay.	assess if the intervention will affect the duration of the NICU stay.	10 days

Collaborators and Investigators

• Sponsor: Amira Adel Fouly
• Collaborators: Ain Shams University; Egyptian Chinese University
• Investigators: Study Director: Ehab R. Bendas, professor, Future University in Egypt; Study Director: Yasmin A. Farid, Ain Shams University; Study Director: Dina K. Abou El Fadl, Lecturer, Future University in Egypt; Study Director: Sarah S. Hesham, Lecturer, Egyptian Chinese University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: July 18, 2024
• First Submitted That Met QC Criteria: July 18, 2024
• First Posted (Actual): July 24, 2024

Study Record Updates

• Last Update Posted (Actual): March 18, 2026
• Last Update Submitted That Met QC Criteria: March 16, 2026
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Phototherapy; Ursodeoxycholic acid; Zinc sulfate; exchange transfusion; Neonatal hyperbilirubinemia
• Additional Relevant MeSH Terms: Pathologic Processes; Infant, Newborn, Diseases; Hyperbilirubinemia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Hyperbilirubinemia, Neonatal; Sulfur Compounds; Polycyclic Compounds; Inorganic Chemicals; Steroids; Fused-Ring Compounds; Sulfur Acids; Sulfates; Sulfuric Acids; Zinc Compounds; Deoxycholic Acid; Cholic Acids; Bile Acids and Salts; Cholanes; Ursodeoxycholic Acid; Zinc Sulfate
• Other Study ID Numbers: REC-FPFUE-31/2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No