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BMJ Clin Evid. 2007; 2007: 0319.
Published online 2007 June 1.
PMCID: PMC2943774

Neonatal jaundice

Abstract

Introduction

About 50% of term and 80% of preterm babies develop jaundice, which usually appears 2-4 days after birth, and resolves spontaneously after 1-2 weeks. Jaundice is caused by bilirubin deposition in the skin. Most jaundice in newborn infants is a result of increased red cell breakdown and decreased bilirubin excretion.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for unconjugated hyperbilirubinaemia in term and preterm infants? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2006 (BMJ Clinical evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: albumin infusion, exchange transfusion, home phototherapy, hospital phototherapy, tin-mesoporphyrin.

Key Points

About 50% of term and 80% of preterm babies develop jaundice, which usually appears 2-4 days after birth, and resolves spontaneously after 1-2 weeks.

  • Jaundice is caused by bilirubin deposition in the skin. Most jaundice in newborn infants is a result of increased red cell breakdown and decreased bilirubin excretion.
  • Breastfeeding, haemolysis, and some metabolic and genetic disorders also increase the risk of jaundice.
  • Unconjugated bilirubin can be neurotoxic, causing an acute or chronic encephalopathy that may result in cerebral palsy, hearing loss, and seizures.

Phototherapy provided by conventional or fibreoptic lights in hospital reduces neonatal jaundice compared with no treatment (as assessed by serum bilirubin levels), although we don't know which is the best regimen to use.

  • We don't know whether home phototherapy is more or less effective than hospital phototherapy as we found no studies comparing the two treatments.

There is consensus that exchange transfusion reduces serum bilirubin levels and prevents neurodevelopmental sequelae, although we found no studies to confirm this.

  • Exchange transfusion has an estimated mortality of 3-4 per 1000 exchanged infants, and 5-10% permanent sequelae in survivors.
  • We don't know whether albumin infusion is beneficial.

Tin-mesoporphyrin is not currently licensed for routine clinical use in the UK or USA, and further long term studies are warranted to confirm its place in clinical practice.

  • However, tin-mesoporphyrin reduced the need for phototherapy (as assessed by serum bilirubin levels) when given either to preterm infants on the first day, or to jaundiced term or near term infants within the first few days of life.

About this condition

Definition

Neonatal jaundice refers to the yellow coloration of the skin and sclera of newborn babies that results from hyperbilirubinaemia.

Incidence/ Prevalence

Jaundice is the most common condition requiring medical attention in newborn babies. About 50% of term and 80% of preterm babies develop jaundice in the first week of life. Jaundice is also a common cause of readmission to hospital after early discharge of newborn babies. Jaundice usually appears 2-4 days after birth and disappears 1-2 weeks later, usually without the need for treatment.

Aetiology/ Risk factors

Jaundice occurs when there is accumulation of bilirubin in the skin and mucous membranes. In most infants with jaundice, there is no underlying disease, and the jaundice is termed physiological. Physiological jaundice typically presents on the second or third day of life, and results from the increased production of bilirubin (owing to increased circulating red cell mass and a shortened red cell lifespan) and the decreased excretion of bilirubin (owing to low concentrations of the hepatocyte binding protein, low activity of glucuronosyl transferase, and increased enterohepatic circulation) that normally occur in newborn babies. Breast-fed infants are more likely to develop jaundice within the first week of life; this is thought to be an exacerbated physiological jaundice caused by a lower calorific intake and increased enterohepatic circulation of bilirubin. Prolonged unconjugated jaundice, persisting beyond the second week, is also seen in breast-fed infants. The mechanism for this later "breast milk jaundice syndrome" is still not completely understood. Non-physiological causes include blood group incompatibility (Rhesus or ABO problems), other causes of haemolysis, sepsis, bruising, and metabolic disorders. Gilbert's and Crigler-Najjar syndromes are rare causes of neonatal jaundice.

Diagnosis

Jaundice is usually seen first in the face, and progresses caudally to the trunk and extremities. However, visual estimation of the bilirubin levels can lead to errors, and a low threshold should exist for measuring serum bilirubin. There are devices that measure transcutaneous bilirubin, but these are generally for screening purposes.

Prognosis

In the newborn baby, unconjugated bilirubin can penetrate the blood-brain barrier and is potentially neurotoxic. Acute bilirubin encephalopathy consists of initial lethargy and hypotonia, followed by hypertonia (retrocollis and opisthotonus), irritability, apnoea, and seizures. Kernicterus refers to the yellow staining of the deep nuclei of the brain — namely, the basal ganglia (globus pallidus); however, the term is also used to describe the chronic form of bilirubin encephalopathy, which includes symptoms such as athetoid cerebral palsy, hearing loss, failure of upward gaze, and dental enamel dysplasia. The exact level of bilirubin that is neurotoxic is unclear, and kernicterus at autopsy has been reported in infants in the absence of markedly elevated levels of bilirubin. Recent reports suggest a resurgence of kernicterus in countries in which this complication had virtually disappeared. This has been attributed mainly to early discharge of newborns from hospital.

Aims of intervention

To prevent the development of bilirubin associated neurodevelopmental sequelae; to reduce serum bilirubin levels, with minimal adverse effects.

Outcomes

Primary outcomes: Mortality; hearing loss; incidence of kernicterus and other neurodevelopmental sequelae; adverse events caused by treatment (including effects on parent-infant bonding); duration of treatment; failure of treatment (defined as the need to use other different treatments; length of hospital stay; need for transfusion. Secondary outcomes: A reduction in serum bilirubin levels.

Methods

BMJ Clinical Evidence search and appraisal November 2006. This review focuses on interventions for treating unconjugated hyperbilirubinaemia. Specific treatment of the underlying causes is not covered. Conjugated hyperbilirubinaemia, a condition that may indicate an underlying liver or biliary tract disorder, is beyond the scope of this review. The following databases were used to identify studies for this review: Medline 1966 to November 2006, Embase 1980 to November 2006, and The Cochrane Library and Cochrane Central Register of Controlled Clinical Trials Issue 4, 2006. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language and containing more than 20 individuals (at least 10 per intervention if multiple intervention study) of whom more than 80% were followed up. There was no minimum length of follow up required to include studies. Considering the population and nature of the interventions involved we also included studies described as "open", "open label", or "not blinded". In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for neonatal jaundice

Glossary

Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low-quality evidence
Any estimate of effect is very uncertain

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

References

1. Kumar RK. Neonatal jaundice. An update for family physicians. Aust Fam Physician 1999;28:679–682. [PubMed]
2. Gale R, Seidman DS, Stevenson DK. Hyperbilirubinemia and early discharge. J Perinatol 2001;21:40–43. [PubMed]
3. Ip S, Chung M, Kulig J, et al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 2004;114:e130–e153. [PubMed]
4. Turkel SB, Guttenberg ME, Moynes DR, et al. Lack of identifiable risk factors for kernicterus. Pediatrics 1980;66:502–506. [PubMed]
5. Hansen TWR. Kernicterus in term and near-term infants – the specter walks again. Acta Paediatr 2000;89:1155–1157. [PubMed]
6. Brown AK, Kim MH, Wu PYK, et al. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics 1985;75:393–400. [PubMed]
7. Martinez JC, Maisels MJ, Otheguy L, et al. Hyperbilirubinaemia in the breast-fed newborn: a controlled trial of four interventions. Pediatrics 1993;91:470–473. [PubMed]
8. Lipsitz PJ, Gartner LM, Bryla DA. Neonatal and infant mortality in relation to phototherapy. Pediatrics 1985;75:422–426. [PubMed]
9. Scheidt PC, Bryla DA, Nelson KB, et al. Phototherapy for neonatal hyperbilirubinemia: six-year follow-up of the National Institute of Child Health and Human Development clinical trial. Pediatrics 1990;85:455–463. [PubMed]
10. Mills JF, Tudehope D. Fibreoptic phototherapy for neonatal jaundice (Cochrane Review). In: The Cochrane Library, Issue 4, 2005. Chichester, UK: John Wiley & Sons, Ltd. Search date 2000; primary sources Cochrane Controlled Trials Register, Medline, Embase, reference lists, conference proceedings, and personal communications with authors.
11. Sarici SU, Alpay F, Dundaroz MR, et al. Fibreoptic phototherapy versus conventional daylight phototherapy for hyperbilirubinemia of term newborns. Turk J Pediatr 2001;43:280–285. [PubMed]
12. Romagnoli C, Zecca E, Papacci P, et al. Which phototherapy system is most effective in lowering serum bilirubin in very preterm infants? Fetal Diagn Ther 2006;21:204–209. [PubMed]
13. Nuntnarumit P, Naka C. Comparison of the effectiveness between the adapted-double phototherapy versus conventional-single phototherapy. J Med Assoc Thai 2002;85:S1159–S1166. [PubMed]
14. Sarin M, Dutta S, Narang A. Randomized controlled trial of compact fluorescent lamp versus standard phototherapy for the treatment of neonatal hyperbilirubinemia. Indian Pediatr 2006;43:583–590. [PubMed]
15. French S. Phototherapy in the home for jaundiced neonates. Clayton, Victoria: Centre for Clinical Effectiveness (CCE). 2003. 15. Centre for Clinical Effectiveness (CCE).
16. Martinez JC, Garcia HO, Otheguy LE, et al. Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. Pediatrics 1999;103:1–5. [PubMed]
17. Kappas A, Drummond GS, Henschke C, et al. Direct comparison of Sn-mesoporphyrin, an inhibitor of bilirubin production, and phototherapy in controlling hyperbilirubinemia in term and near-term newborns. Pediatrics 1995;95:468–474. [PubMed]
18. Valaes T, Petmezaki S, Henschke C, et al. Control of jaundice in preterm newborns by an inhibitor of bilirubin production: studies with tin-mesoporphyrin. Pediatrics 1994;93:1–11. [PubMed]
2007; 2007: 0319.
Published online 2007 June 1.

Hospital phototherapy

Summary

NEED FOR EXCHANGE TRANSFUSION Conventional phototherapy compared with no treatment: Conventional phototherapy may reduce the need for exchange transfusion compared with no treatment in infants with non-haemolytic jaundice ( low-quality evidence ). Conventional phototherapy compared with fibreoptic phototherapy: Conventional phototherapy may be as effective as fibreoptic phototherapy at reducing the need for exchange transfusion ( very low-quality evidence ). Double phototherapy compared with single phototherapy: Double phototherapy may be no more effective than single phototherapy at reducing the need for exchange transfusion ( very low-quality evidence ). NOTE We found no clinically important results about fibreoptic phototherapy compared with no active treatment, or about compact fluorescent light (CFL) compared with standard-length tube light (STL) phototherapy.

Benefits

Conventional phototherapy versus no treatment:

We found one systematic review (search date 2001), which included two RCTs, although their results were not combined statistically. None of these studies assessed the primary outcomes of this review. The largest RCT identified by the review compared conventional phototherapy using daylight fluorescent lamps versus no treatment in three birth weight groups: less than 2000 g; 2000–2499 g; and 2500 g and over. Exchange transfusion was given at predetermined serum bilirubin levels in each group. The RCT examined prevention of hyperbilirubinaemia in the lowest birth weight group, and treatment of established hyperbilirubinaemia in the remaining two groups. Only the results of treatment of established hyperbilirubinaemia are reported here. The RCT found that in the 2000–2499 g birth weight group (141 infants, serum bilirubin ≥ 171 µmol/L, average 212 µmol/L), phototherapy significantly reduced the proportion of infants with higher maximal serum bilirubin levels compared with no treatment (serum bilirubin ≥ 257 µmol/L: 18.6% with phototherapy v 42.3% with no treatment; P = 0.002). For this group, it found that phototherapy significantly decreased the proportion of infants who needed exchange transfusion compared with no treatment (4.3% with phototherapy v 25.4% with no treatment; P < 0.001). The RCT found that, in the 2500 g or over birth weight group (276 infants, serum bilirubin ≥ 222 µmol/L, average 267–268 µmol/L), phototherapy significantly reduced mean serum bilirubin levels until 24 hours after stopping treatment compared with no treatment (results presented graphically; P value not reported). The RCT found no significant difference between phototherapy and no treatment in the proportion of infants who needed exchange transfusion (10.0% with phototherapy v 16.9% with no treatment; reported as not significant). In both birth weight groups, subgroup analysis suggested that, in infants with non-haemolytic jaundice, phototherapy significantly decreased exchange transfusion compared with no treatment (infants 2000–2499 g: 1.9% with phototherapy v 27.5% with no treatment, P = 0.0002; infants ≥ 2500 g: 2.9% with phototherapy v 17.3% with no treatment, P = 0.05), but there was no evidence of effectiveness in preventing exchange transfusion in infants with haemolytic jaundice. A subsequent report of the RCT noted that there were two deaths before hospital discharge (2000–2499 g group: 1 with phototherapy v 1 with no treatment; ≥ 2500 g group: none). A further follow up report of the RCT found no significant difference in cerebral palsy or other motor abnormalities (clumsiness, hypotonia, abnormal movement) after 1 and 6 years in either of the birth weight groups. The smaller RCT identified by the review compared the effect of four interventions on hyperbilirubinaemia (serum bilirubin > 291 µmol/L) on 125 term breastfed infants. The four interventions were: continue breastfeeding and observe (25 infants); substitute formula feed (26 infants); continue breast feeding and administer phototherapy (36 infants); and substitute formula and administer phototherapy (38 infants). Phototherapy resulted in a smaller proportion of infants whose serum bilirubin rose above 342 µmol/L (8.1% of 74 infants receiving phototherapy v 21.6% of 51 infants not receiving phototherapy; RR 0.34, 95% CI 0.15 to 0.95; see comment).

Fibreoptic phototherapy versus no treatment:

We found one systematic review (search date 2000; term and preterm infants; randomised and quasi-randomised trials; see comment below). The review identified one RCT (46 term infants, haemolysis excluded), which compared fibreoptic phototherapy (Wallaby system) versus no treatment. Conventional phototherapy was commenced if the serum bilirubin reached predetermined levels. The review found that, compared with no treatment, fibreoptic phototherapy significantly increased the percentage change in serum bilirubin per hour (WMD –0.44%, 95% CI –0.21% to –0.67%) and the percentage change after 24 hours of treatment (WMD –10.70%, 95% CI –3.26% to –18.14%). It found that infants in the fibreoptic phototherapy group were less likely to require conventional phototherapy, but this did not reach significance (0/23 [0%] with fibreoptic phototherapy v 3/23 [13%] with no treatment; RR 0.14, 95% CI 0.01 to 2.62).

Conventional versus fibreoptic phototherapy:

We found one systematic review (search date 2000; term and preterm infants; randomised and quasi-randomised trials; see comment below) and two subsequent RCTs. The review found that conventional phototherapy significantly increased the percentage change in serum bilirubin after 24 and 48 hours of treatment compared with fibreoptic phototherapy (24 hours: 5 trials, 203 infants; WMD 3.59%, 95% CI 1.27% to 5.92%; 48 hours: 4 trials, 183 infants; WMD 10.79%, 95% CI 8.33% to 13.26%). It also found that fibreoptic phototherapy significantly increased the use of additional phototherapy compared with conventional phototherapy (8 trials: 52/366 [14%] with fibreoptic v 35/390 [9%] with conventional; RR 1.68, 95% CI 1.18 to 2.38), and also resulted in an increase in duration of phototherapy treatment (6 trials, 562 infants: WMD +13.6 hours, 95% CI +10.1 hours to +17.1 hours). It found no significant difference between fibreoptic and conventional phototherapy in the use of exchange transfusion (3 trials: 4/97 [4%] with fibreoptic v 3/117 [3%] with conventional; RR 1.62, 95% CI 0.38 to 6.93). In a subgroup analysis of preterm babies only, the review found no significant difference between fibreoptic phototherapy and conventional phototherapy in the duration of phototherapy, use of additional phototherapy, percentage change in serum bilirubin after 24 hours of treatment, percentage change in serum bilirubin after 24 hours of treatment, and repeat phototherapy for rebound jaundice (duration of phototherapy: 3 trials, 232 infants; WMD +2.00 hours, 95% CI –3.50 hours to +7.52 hours; use of additional phototherapy: 5 trials, 3/148 [2%] with fibreoptic v 3/156 [2%] with conventional; RR 1.07, 95% CI 0.27 to 4.27; percentage change in serum bilirubin after 24 hours of treatment: 1 trial, 20 infants; WMD +1.7%, 95% CI –2.65% to +6.05%; repeat phototherapy for rebound jaundice: 3 trials, 10/122 [8%] with fibreoptic v 5/121 [4%] with conventional; RR 2.00, 95% CI 0.71 to 5.63). The first subsequent RCT (109 term infants, birth weight ≥ 2500 g, infants with haemolytic jaundice excluded) found that conventional daylight phototherapy significantly increased the rate of decline of serum bilirubin, and decreased treatment duration compared with fibreoptic phototherapy (bilirubin decline rate: 2.6 ± 1.0 µmol/L/hour with conventional v 1.7 ± 0.9 µmol/L/hour with fibreoptic; P < 0.05; duration of phototherapy: 49.4 ± 14.4 hours with conventional v 61 ± 13.1 hours with fibreoptic; P < 0.05). The second subsequent RCT (140 preterm infants, gestation < 31 weeks, infants with haemolytic jaundice excluded) compared single conventional phototherapy, fibreoptic Wallaby phototherapy, fibreoptic BiliBlanket phototherapy, and combined conventional plus fibreoptic Wallaby phototherapy. It found no significant difference in the duration of treatment required for either Wallaby and BiliBlanket fibreoptic phototherapy compared with conventional phototherapy alone (Wallaby: 92 hours; BiliBlanket: 95 hours; conventional: 90 hours; combined Wallaby and conventional: 75 hours; P < 0.05 for combined Wallaby and conventional v either Wallaby or BiliBlanket alone; P < 0.01 for combined Wallaby and conventional v conventional alone).

Double versus single phototherapy:

We found one systematic review (search date 2000; term and preterm infants; randomised and quasi-randomised trials; see comment below) and two subsequent RCTs. The systematic review included one RCT (86 term infants, haemolysis excluded) comparing double fibreoptic phototherapy (infants wrapped in 2 BiliBlankets) versus single conventional phototherapy. The RCT included in the review found no significant difference between groups in duration of treatment, percentage change in serum bilirubin per hour, percentage change in serum bilirubin per day, and the use of repeat phototherapy for rebound jaundice (duration of treatment: WMD +2.24 hours, 95% CI –10.68 hours to +15.16 hours; percentage change in serum bilirubin per hour: WMD –0.04%, 95% CI –0.17% to +0.09%; percentage change in serum bilirubin per day: WMD +2.82%, 95% CI –1.84% to +7.48%; and the use of repeat phototherapy for rebound jaundice: RR 1.05, 95% CI 0.07 to 16.22). The review also compared double phototherapy using a combination of fibreoptic plus conventional phototherapy versus conventional phototherapy alone. It found no significant difference between fibreoptic plus conventional phototherapy and single conventional phototherapy in exchange transfusion, additional phototherapy, and percentage change in serum bilirubin after 24 or 48 hours, although it noted a trend favouring the fibreoptic plus conventional group (exchange transfusion, 1 trial: 0/19 [0%] with fibreoptic plus conventional v 2/23 [8%] with conventional alone; RR 0.24, 95% CI 0.01 to 4.72; additional phototherapy, 1 trial: 0/90 [0%] with fibreoptic plus conventional v 4/90 [4%] with conventional; RR 0.11, 95% CI 0.01 to 2.02; percentage change in serum bilirubin after 24 or 48 hours: 1 trial, 26 infants; 24 hours: WMD –3.2%, 95% CI –17.2% to +10.8%; 48 hours: WMD –9.2%, 95% CI –25.02% to +6.62%). It found no significant difference between fibreoptic plus conventional phototherapy and single conventional phototherapy in repeat phototherapy for rebound jaundice (6 trials: 36/232 [16%] with fibreoptic plus conventional v 30/240 [13%] with conventional; RR 1.29, 95% CI 0.85 to 1.95). The first subsequent RCT (51 term infants, birth weight ≥ 2500 g, haemolysis included) compared double conventional phototherapy using daylight fluorescent lamps versus single conventional phototherapy. It found that double conventional phototherapy reduced serum bilirubin at a significantly higher rate during the first 24 hours compared with single conventional phototherapy (3.8 ± 2.1 µmol/L/hour with double v 2.4 ± 1.7 µmol/L/hour with single; P = 0.02). It found a trend for double conventional phototherapy to reduce bilirubin at a higher rate on the second day, but this did not reach significance (P = 0.06). It found that double conventional phototherapy significantly reduced duration of treatment compared with single conventional phototherapy (34.9 ± 12.6 hours with double v 43.7 ± 17.5 hours with single; P = 0.039). It did not report on kernicterus or other long term outcomes. The second subsequent RCT (140 preterm infants, gestation < 31 weeks, infants with haemolytic jaundice excluded) compared single conventional phototherapy, fibreoptic Wallaby phototherapy, fibreoptic BiliBlanket phototherapy, and combined conventional plus fibreoptic Wallaby phototherapy. It found that the combined phototherapy reduced the mean duration of treatment required compared with either of the treatments used alone (Wallaby: 92 hours; BiliBlanket: 95 hours; conventional: 90 hours; combined Wallaby and conventional: 75 hours; P < 0.05 for combined Wallaby and conventional v either Wallaby or BiliBlanket alone; P < 0.01 for combined Wallaby and conventional v conventional alone). It also found that the combination of conventional phototherapy plus Wallaby fibreoptic phototherapy produced a smaller increase in bilirubin levels over the first 24 hours compared with conventional phototherapy alone (16% with conventional plus Wallaby fibreoptic v 27% with conventional alone; P < 0.01).

Compact fluorescent light phototherapy versus standard length tube light phototherapy:

We found one RCT (100 infants > 34 weeks' gestation, haemolytic jaundice excluded), which found no significant difference between compact fluorescent light (CFL) and standard length tube light (STL) phototherapy in total duration of treatment required (40.66 hours with CFL v 40.78 hours with STL; P = 0.98). It found that CFL significantly reduced the mean total serum bilirubin over 12 hours compared with STL (15.86 mg/dL, 95% CI 15.5 to 16.2 with CFL v 14.23 mg/dL, 95% CI 13.7 to 14.8 with STL; P < 0.001).

Harms

Conventional phototherapy versus no treatment:

The review found no evidence that phototherapy for neonatal hyperbilirubinaemia has any long term adverse neurodevelopmental effects.

Fibreoptic phototherapy versus no treatment:

The review gave no information on adverse effects for this comparison.

Conventional versus fibreoptic phototherapy:

In the systematic review, one small trial (20 infants) found that transepidermal water loss (sweating) was significantly higher in infants treated with fibreoptic devices compared with conventional phototherapy, and one small trial (34 infants) found no significant difference between fibreoptic and conventional phototherapy in mothers developing migraine during their infants' treatment with phototherapy. However, the clinical significance of this is uncertain. One RCT reported transient erythema and mild watery stools not leading to dehydration (erythema: 1/50 [2%] with conventional v 1/50 [2%] with fibreoptic; mild watery stools: 3/50 [6%] with conventional v 3/50 [6%] with fibreoptic). A subsequent RCT found similar levels of transient erythema between conventional phototherapy, fibreoptic Wallaby phototherapy, and fibreoptic BiliBlanket phototherapy (10/35 [29%] with conventional v 9/35 [26%] with Wallaby v 8/35 [23%] with BiliBlanket; significance not assessed).

Double versus single phototherapy:

One RCT found no significant difference between double conventional and single conventional phototherapy in weight reduction, frequency of stooling, or fever. Another RCT found a small increase in rates of transient erythema using the combination of Wallaby and conventional phototherapy compared with one type of phototherapy (12/35 [34%] with combined v 10/35 [29%] with conventional v 9/35 [26%] with Wallaby v 8/35 [23%] with BiliBlanket; significance not assessed).

Compact fluorescent light versus standard length tube light phototherapy:

One RCT found no significant difference in moderate or extreme eye pain caused by glare, moderate or extreme giddiness, and moderate or extreme headache in nursing staff with CFL compared with STL (pain from glare: 38% with CFL v 48% with STL; P = 0.16; giddiness: 14% with CFL v 20% with STL; P = 0.42; headache: 6% with CFL v 8% with STL; P = 1).

Comment

Conventional phototherapy:

The largest RCT comparing phototherapy with no treatment did not use very intensive phototherapy, which probably explains why phototherapy seemed no better than controls in preventing exchange transfusion in the haemolytic subgroup.The RCT of four interventions for jaundice in breast-fed newborns allocated the infants to the groups at random, although there were more infants entered into the groups with phototherapy as one of the interventions. This apparent imbalance was not explained in the text and, therefore, may limit the validity of its conclusions.

Fibreoptic phototherapy:

The systematic review of fibreoptic phototherapy also included quasi-randomised controlled trials, all of which used alternate or sequential allocation. This may limit the validity of its conclusions. Two different fibreoptic devices were used by trials included in the review: BiliBlanket and Wallaby. The irradiance of the Wallaby phototherapy system and BiliBlanket are different, and the irradiance setting of the BiliBlanket was not the same in different trials. Conventional phototherapy varied between trials, with trials using either halogen or fluorescent lamps, emitting white light, blue light, or a mixture of the two. Inclusion criteria in the trials varied, with some excluding infants with haemolysis and others including them. No trials including infants with haemolysis reported separate data for this group, and the review was unable to do a planned subgroup analysis on this group. Phototherapy was instituted at different serum bilirubin levels in different trials; this review has not addressed the complex question of the bilirubin level at which to commence phototherapy. Outcomes of trials included in the review were reported mainly in terms of changes in serum bilirubin levels; the incidence of kernicterus was not reported in any of the trials, although very large studies would be required to show a reduction in such a rare adverse event. No trials were identified to support or refute the view that fibreoptic devices interfere less with infant care or impact less on parent–child bonding.

Clinical guide:

It is generally accepted that intensive phototherapy applied to reduce the bilirubin levels rapidly (rather than merely to prevent levels rising further) has greatly reduced the need for exchange transfusions in infants with or without haemolysis.

Substantive changes

Hospital phototherapy Two RCTs added, but these did not assess the primary outcomes of this review. One RCT found no significant difference in the duration required for fibreoptic phototherapy compared with conventional phototherapy therapy. The other RCT found that a combination of single conventional phototherapy and fibreoptic phototherapy was more effective than single conventional phototherapy in terms of duration of treatment required. Categorisation unchanged (Beneficial).

2007; 2007: 0319.
Published online 2007 June 1.

Exchange transfusion

Summary

We found no clinically important results about the effects of exchange transfusion for neonatal jaundice.

Benefits

Exchange infusion versus no treatment:

We found no systematic review or RCTs (see comment below).

Exchange infusion versus phototherapy:

We found no systematic review or RCTs.

Harms

Exchange infusion versus no treatment:

We found no RCTs.

Exchange infusion versus phototherapy:

We found no RCTs.

Comment

In most of the RCTs comparing other interventions, exchange transfusion was used as an outcome measure.

Clinical guide:

There is general consensus that exchange transfusion is effective in reducing serum bilirubin levels and preventing neurodevelopmental sequelae. It is generally accepted that this procedure will reduce serum bilirubin levels when other interventions such as phototherapy have failed to control the rise in serum bilirubin. Exchange transfusion is not without risks. It has an estimated mortality of 3–4 per 1000 exchanged infants, and an estimated range of 5–10% permanent sequelae in survivors (aortic thrombosis, intraventricular haemorrhage, pulmonary haemorrhage).

Substantive changes

Exchange transfusion Evidence reassessed. Categorisation changed from Beneficial to Likely to be beneficial.

2007; 2007: 0319.
Published online 2007 June 1.

Albumin infusion

Summary

We found no clinically important results about the effects of albumin infusion in babies with neonatal jaundice.

Benefits

Albumin infusion versus no treatment:

We found no systematic review or RCTs.

Albumin infusion versus other treatment:

We found no systematic review or RCTs.

Harms

Albumin infusion versus no treatment:

We found no RCTs.

Albumin infusion versus other treatment:

We found no RCTs.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0319.
Published online 2007 June 1.

Home phototherapy

Summary

We found no clinically important results about the effects of home phototherapy in babies with neonatal jaundice.

Benefits

Home phototherapy versus no treatment:

We found no systematic review or RCTs.

Home phototherapy versus hospital phototherapy:

We found one systematic review (search date 2003), which identified no RCTs.

Harms

Home phototherapy versus no treatment:

We found no RCTs.

Home phototherapy versus hospital phototherapy:

We found no RCTs.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0319.
Published online 2007 June 1.

Tin-mesoporphyrin

Summary

NEURODEVELOPMENTAL DELAY Compared with placebo: The long-term effects of tin-mesoporphyrin (or stannsoporpfin) on neurodevelopmental delay are unclear ( low-quality evidence ).

Benefits

Tin-mesoporphyrin versus standard treatment:

We found two RCTs and one non-systematic review of five RCTs, none of which assessed primary outcomes of this review. In the first RCT (84 term infants, haemolysis excluded), infants were given either tin-mesoporphyrin 6 µmol/kg or no treatment if the bilirubin level was raised at 48–96 hours after birth to a level likely to require phototherapy (250–308 µmol/L). In both groups, phototherapy was commenced if the bilirubin level subsequently exceeded 331 µmol/L, and was discontinued when below 230 µmol/L. The RCT found that tin-mesoporphyrin significantly reduced the need for phototherapy compared with no treatment (infants requiring phototherapy: 0/40 [0%] with tin-mesoporphyrin v 12/44 [27%] with no treatment; P = 0.0004). Similarly, in the second RCT (open label, 86 infants, stratified into 44 term [38–42 weeks] and 42 near term [35–37 weeks], excluding haemolytic jaundice), infants 36–84 hours of age received either tin-mesoporphyrin 6 µmol/kg or phototherapy for treatment of hyperbilirubinaemia; phototherapy was started in the group treated initially with tin-mesoporphyrin if serum bilirubin levels exceeded levels outlined in a strict protocol. The RCT found that none of the infants (0/44) who received tin-mesoporphyrin required supplemental phototherapy. In the phototherapy group, the mean length of phototherapy required was less for term infants than near term infants (term infants: 33.2 hours; P < 0.001; near term infants: 48.6 hours; P < 0.03). The non-systematic review of five RCTs undertaken in the same hospital over a 4 year period compared tin-mesoporphyrin given as prophylaxis within 24 hours of birth (range: 1–6 µmol/kg) versus placebo (517 infants, 454 analysed, stratified into preterm infants < 37 weeks, birthweight 1.5–2.5 kg and preterm infants 30–35 weeks; excluding cases of known haemolysis). Phototherapy was commenced if the bilirubin level exceeded 212 µmol/L. It found that tin-mesoporphyrin 6 µmol/kg was the most effective dose (between the range1–6 µmol/kg) to significantly reduce the mean peak bilirubin concentration compared with placebo (160 µmol/L with tin-mesoporphyrin v 197 µmol/L with placebo; 41% reduction, P < 0.01). Tin-mesoporphyrin 6 µmol/kg significantly reduced the number of hours of phototherapy required for each infant compared with placebo (47.8 hours with tin-mesoporphyrin v 77.4 hours with placebo; 76% reduction, P < 0.01). Follow up at 3 and 18 months did not show any significant difference in growth or development between tin-mesoporphyrin and usual care in 336 infants who attended both 3 and 18 month assessments. The meta-analysis undertaken by the non-systematic review was sponsored by the manufacturer.

Harms

Tin-mesoporphyrin versus standard treatment:

One non-systematic review of five RCTs found that phototherapy produced a mild, transient, non-dose dependent erythema in a few infants treated either with or without tin-mesoporphyrin (2/127 [1.6%] with phototherapy alone v 13/262 [5.0%] with tin-mesoporphyrin [129 of these infants also received phototherapy]).

Comment

Tin-mesoporphyrin is not currently licensed for routine clinical use in the UK or USA. All of the RCTs assessed developmental follow up, but follow up data were only reported for 49% of infants. The studies were also limited because tin-mesoporphyrin was used to prevent or reduce the need for phototherapy. Additionally, none of the primary outcomes for this review were assessed by the RCTs included.

Clinical guide:

Further long term studies are needed to confirm the place of tin-mesophorpyrin in clinical practice.

Substantive changes

Neonatal jaundice Tin-mesoporphyrin added as a new option. Tin-mesoporphyrin is not currently licensed for routine clinical use in the UK or USA and further long term studies are needed to confirm its place in clinical practice. However, two RCTs found that tin-mesoporphyrin greatly reduced the need for phototherapy when given to jaundiced term or near term infants within the first few days of life. An additional RCT found that giving tin-mesoporphyrin to preterm infants within the first day of life reduced the peak bilirubin level and the duration of phototherapy required to treat subsequent jaundice. The studies were limited by the fact that tin-mesoporphyrin was used to prevent or reduce the need for phototherapy. None of the studies assessed the primary outcomes of this review. Categorised as Unknown effectiveness.


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