Intensive Phototherapy vs. Exchange Transfusion for Neonatal Hyperbilirubinemia

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Intensive Phototherapy vs. Exchange Transfusion for the Treatment of Neonatal Hyperbilirubinemia: A Multicenter Retrospective Cohort Study

Neonatal hyperbilirubinemia, characterized by elevated bilirubin levels, is one of the most common clinical conditions affecting newborns, occurring in approximately 60% of term and 80% of preterm infants. While most cases resolve without intervention, approximately 10% develop clinically significant hyperbilirubinemia requiring medical treatment. Extreme hyperbilirubinemia, defined by total serum bilirubin (TSB) levels reaching or exceeding exchange transfusion (ET) thresholds or presenting signs of bilirubin encephalopathy (BE), carries risks of neurological damage, including cerebral palsy, auditory complications, and long-term neurodevelopmental impairments. Historically, intensive phototherapy (IPT) and ET have been the primary treatments, but evidence guiding their optimal thresholds and comparative effectiveness remains limited. This multicenter retrospective cohort study aimed to compare the efficacy, safety, and clinical outcomes of IPT and ET in treating extreme hyperbilirubinemia, with a focus on refining treatment thresholds and informing clinical guidelines.

Background and Rationale

Extreme hyperbilirubinemia poses significant risks due to bilirubin’s neurotoxic potential. Unconjugated bilirubin crossing the blood-brain barrier can lead to bilirubin-induced neurological dysfunction (BIND) and acute bilirubin encephalopathy, which manifests as lethargy, seizures, and, in severe cases, kernicterus. The American Academy of Pediatrics (AAP) provides consensus-based thresholds for initiating ET, but these lack robust clinical evidence. In practice, clinicians in developing countries often rely on IPT to avoid ET’s risks, even when TSB levels exceed guideline-based thresholds. This study sought to address critical gaps by evaluating whether IPT alone could safely and effectively treat extreme hyperbilirubinemia without increasing complications or long-term sequelae.

Study Design and Methodology

Patient Population and Inclusion Criteria

The retrospective cohort analysis included 1,164 neonates from seven centers in China (January 2015–January 2018). Infants with gestational age ≥35 weeks and TSB levels meeting ET thresholds per the 2014 Chinese Pediatric Society guidelines (aligned with AAP criteria) were enrolled. Exclusion criteria included congenital anomalies, genetic disorders, hypoxic-ischemic brain injury, and incomplete follow-up data. Patients were stratified into risk subgroups:

  • Low-risk: ≥38 weeks gestation, no risk factors (e.g., isoimmune hemolysis, sepsis, acidosis).
  • Medium-risk: ≥38 weeks with risk factors or 35–37 weeks without risk factors.
  • High-risk: 35–37 weeks with risk factors.

Interventions and Propensity Score Matching

  • IPT involved LED devices (450–480 nm) delivering irradiance >30 mW/cm²/nm at 40 cm distance. TSB was monitored every 4–6 hours, with step-down to conventional phototherapy (8–10 mW/cm²/nm) once TSB fell below ET thresholds.
  • ET was performed using peripheral arteriovenous exchange (150–160 mL/kg), with reconstituted blood products (3:1 red blood cells:plasma ratio).

Propensity score matching (PSM) was applied to balance baseline characteristics (gestational age, birth weight, TSB, albumin use, BE signs) between the IPT-only (n=699) and IPT+ET (n=465) groups. A 1:1 matching ratio with a caliper width of 0.2 standard deviations yielded 296 matched pairs.

Outcomes Measured

  • Primary outcome: Incidence of BE during hospitalization.
  • Secondary outcomes: Hospital readmission within two weeks, hospitalization duration, costs, and complications (e.g., gastrointestinal hemorrhage, sepsis, fever).
  • Follow-up at 3 years: Mortality, auditory deficits, seizures, enamel dysplasia, and neurodevelopmental delays (assessed via the Gesell Development Diagnosis Scale).

Key Findings

Baseline Characteristics

After PSM, groups were well-balanced across all risk subgroups. For example, in the low-risk subgroup (n=94 pairs), mean TSB was comparable (IPT-only: 491.12 ± 58.34 µmol/L vs. IPT+ET: 489.37 ± 60.83 µmol/L, P=0.841). Similar homogeneity was observed in medium- and high-risk subgroups.

Efficacy of IPT vs. IPT+ET

Low-Risk Subgroup

  • BE incidence: 8.5% (IPT) vs. 16.0% (IPT+ET), P=0.118.
  • Hospitalization: IPT-only had shorter stays (4 vs. 6 days, P<0.001) and lower costs (5,573.6 vs. 11,996.2 CNY, P<0.001).
  • Complications: No significant differences in sepsis, fever, or hemorrhage.
  • 3-year outcomes: No mortality; delayed language/motor development rates were comparable (2.1–6.4%, P=0.219).

Medium-Risk Subgroup

  • BE incidence: 14.8% (IPT) vs. 22.5% (IPT+ET), P=0.03.
  • Hospitalization: IPT-only reduced stays (4 vs. 7 days, P<0.001) and costs (6,902.8 vs. 14,165.0 CNY, P<0.001).
  • Complications: Higher fever rates in IPT+ET (11.5% vs. 4.9%, P=0.031).
  • 3-year outcomes: Mortality (0.5% both groups); neurodevelopmental delays were similar.

High-Risk Subgroup

  • BE incidence: 10.0% (IPT) vs. 5.0% (IPT+ET), P≥0.999.
  • Hospitalization: Trends favored IPT-only (4 vs. 7 days, P=0.152; costs 6,260.6 vs. 13,149.0 CNY, P=0.052).
  • 3-year outcomes: One mortality in IPT-only; no significant differences in auditory or motor deficits.

Threshold Curve Analysis

The study derived new ET threshold curves based on age-TSB relationships:

  • Low-risk: TSB = 57.6 ln(days) + 372.4 (R²=0.8577).
  • Medium-risk: TSB = 45.8 ln(days) + 358.2 (R²=0.8216).
  • High-risk: TSB = 56.1 ln(days) + 327.6 (R²=0.5697).

These thresholds were consistently higher than AAP guidelines. For example, on day 4, low-risk thresholds were 24.3 µmol/L higher than AAP recommendations.

Clinical Implications and Discussion

Safety and Efficacy of IPT

The study demonstrated that IPT alone achieved comparable or superior outcomes to IPT+ET, particularly in low- and medium-risk infants. Notably, IPT reduced hospitalization duration and costs without increasing BE risk or complications. Fever rates were higher in IPT+ET groups, likely due to procedural risks. Long-term follow-up revealed no significant differences in neurodevelopmental outcomes, underscoring IPT’s safety.

Reassessing ET Thresholds

The derived threshold curves suggest current AAP guidelines may be overly conservative. For instance, medium-risk infants on day 4 had a study-derived threshold 45.5 µmol/L higher than AAP’s. However, clinicians must remain vigilant for risk factors (e.g., hemolysis, sepsis) that predispose to BE, necessitating contingency plans for emergency ET.

Limitations and Future Directions

  • Sample size: High-risk subgroups had limited participants (n=20 pairs), warranting larger studies.
  • Generalizability: Findings reflect Chinese populations; global validation is needed.
  • Gestational age: Excluded infants <35 weeks, necessitating preterm-specific research.

Conclusion

This study provides robust evidence supporting IPT as a first-line therapy for extreme neonatal hyperbilirubinemia. By reducing unnecessary ET, clinicians can minimize procedural risks, healthcare costs, and hospitalization time. Revised ET thresholds derived from the data advocate for more individualized, risk-stratified approaches. Future guidelines should incorporate these findings while emphasizing close monitoring and readiness for ET in high-risk scenarios.

doi.org/10.1097/CM9.0000000000001962

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