Summary of Study Protocol

Title:

Efficacy of prophylactic oral calcium supplementation in reducing the need for phototherapy in neonates thirty five weeks or older – A pilot trial

Background:

Neonatal jaundice, or hyperbilirubinemia, is a very common condition, affecting about sixty percent of term and eighty percent of preterm infants during the first week of life. While mostly benign and self-limiting, about five to ten percent of cases require medical intervention to avoid complications such as bilirubin-induced neurologic dysfunction and kernicterus. The causes of neonatal hyperbilirubinemia are multifactorial: high red blood cell turnover, hepatic immaturity, and increased enterohepatic circulation contribute to elevated bilirubin levels. Enterohepatic recycling is intensified by factors such as low gut colonization and elevated beta glucuronidase activity, which leads to reabsorption of unconjugated bilirubin. Although phototherapy remains the standard treatment for significant jaundice, it has disadvantages including prolonged hospitalization, separation of mother and infant, and side effects such as hypocalcemia, particularly with longer durations of phototherapy. Calcium phosphate binds intestinal unconjugated bilirubin, converting it into a non-absorbable ionic form, disrupting enterohepatic circulation. Previous studies have shown that oral calcium supplementation during phototherapy can reduce its duration and incidence of rebound hyperbilirubinemia. However, there is limited evidence on preventive or prophylactic use of calcium to reduce the need for phototherapy in the first place. This study aims to assess whether oral calcium phosphate given prophylactically can reduce the incidence and duration of phototherapy in neonates thirty five weeks or older, and also to see its impact on hypocalcemia and readmission rates for jaundice.

Problem Statement:

Despite its effectiveness, phototherapy carries risks and resource burdens. There is a need to explore preventive interventions to reduce its necessity, especially in settings with limited resources.

Rationale:

Prophylactic calcium phosphate may reduce bilirubin reabsorption via enterohepatic circulation, lowering serum bilirubin levels and decreasing need for phototherapy.

Novelty:

While calcium has been studied as an adjunct to phototherapy, this trial explores its use as a preventive agent, an area that is largely unexplored.

Purpose of the Study

Objectives

Primary Objective: To compare the proportion of neonates requiring phototherapy until discharge between the intervention and control groups.

Secondary Objectives:

To assess the duration of phototherapy if required

To evaluate readmission rates for neonatal jaundice

To assess incidence of hypercalcemia

Study Design and Methodology

Design: Randomized, open label, parallel group controlled trial

Setting and Duration: Postnatal ward at All India Institute of Medical Sciences Patna over twelve months

Participants: Hemodynamically stable, inborn neonates with gestational age of thirty five weeks or older

Inclusion Criteria: 

Gestational age thirty five weeks or older

Hemodynamically stable

Exclusion Criteria:

Neonatal intensive care unit admission

Cephalohematoma or subgaleal hematoma

Major congenital anomalies

Isoimmune hemolytic anemia

Parental refusal

Randomization and Blinding:

Computer generated block randomization sequences, blocks of four or six

Allocation concealed in sealed opaque envelopes

Clinical staff assessing jaundice will be blinded to group assignment

Intervention:

Intervention Group: Oral calcium phosphate forty to fifty milligrams per kilogram per day of elemental calcium, in two daily doses, started within six hours of birth and continued for six days

Control Group: Routine postnatal care without calcium supplementation

Assessment and Monitoring:

Clinical jaundice assessed by blinded staff using Kramers rule

If jaundice is suspected, total serum bilirubin measured and compared to American Academy of Pediatrics nomogram thresholds. Phototherapy administered as per standard protocol if indicated. Serum calcium measured on day three of life

Interim Exit Criteria:

If serum calcium exceeds eleven milligrams per decilitre, calcium supplementation will be stopped

Outcome Measures:

Primary Outcome: Proportion of neonates requiring phototherapy during hospital stay

Secondary Outcomes:

Duration of phototherapy

Rate of readmission within seven days

Incidence of hypercalcemia

Sample Size:

Eighty neonates, forty per group, allowing for a twenty percent dropout rate, as this is a pilot trial to assess safety and preliminary efficacy.

Data Collection:

Includes antenatal (mother blood group, indirect Coombs test, ultrasound anomalies), natal (birth weight, gestational age, appropriate or small or large for gestational age), postnatal (baby blood group, direct Coombs test, phototherapy), and maternal (gestational diabetes mellitus, preeclampsia, hypothyroidism, sepsis, delivery mode)

Statistical Analysis:

Intention to treat analysis will be performed using JAMOVI. Categorical variables compared using chi square or Fishers exact test. Continuous variables analyzed using Students t test or Mann Whitney U test depending on distribution.

Risks and Benefits:

Benefits

Potential reduction in phototherapy need

Possible prevention of phototherapy induced hypocalcemia

Risks

Minimal risk of hypercalcemia from calcium supplementation, which will be monitored and managed