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1.  Neonatal jaundice 
Clinical Evidence  2011;2011:0319.
Introduction
About 50% of term and 80% of preterm babies develop jaundice, which usually appears 2 to 4 days after birth, and resolves spontaneously after 1 to 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 question: 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 February 2010 (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 42 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, immunoglobulin, hospital phototherapy, and tin-mesoporphyrin.
Key Points
About 50% of term and 80% of preterm babies develop jaundice, which usually appears 2 to 4 days after birth, and resolves spontaneously after 1 to 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). Low threshold compared with high threshold phototherapy reduces neurodevelopmental impairment and hearing loss and reduces serum bilirubin on day 5 in extremely low birth weight infants. However, it increases the duration of phototherapy, and there is no effect on mortality or the rate of exchange transfusion.Close phototherapy compared with distant light-source phototherapy reduces the duration of phototherapy in infants with hyperbilirubinaemia.
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 to 4 per 1000 exchanged infants, and 5% to 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 US, 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.
Intravenous immunoglobin reduces the need for exchange transfusion in high-risk infants with haemolytic hyperbilirubinaemia, as well as reduces serum bilirubin levels, the requirement for phototherapy, and the length of hospital stay. Benefits of immunoglobulin were observed when used either alone or in conjunction with phototherapy. No adverse effects were reported. However, we don't know whether immunoglobulin prevents neurodevelopmental sequelae.
PMCID: PMC3217664  PMID: 21920055
2.  Is phototherapy exposure associated with better or worse outcomes in 501–1000 gram birth weight infants? 
Aim
To compare risk-adjusted outcomes at 18–22 months corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.
Methods
Outcomes at 18–22 months corrected age included death, neurodevelopmental impairment (NDI), and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for center and other potentially confounding variables.
Results
Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501–1000 g BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI 0.60 –1.20), death, or adverse neurodevelopmental endpoints. However, among infants 501–750 g BW, the rate of significant developmental impairment with MDI<50 was significantly higher for NoPTx (29%) than PTx (12%) (p=0.004).
Conclusions
Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded due to bias from deaths before reaching conservative treatment threshold. The higher rate of MDI<50 in the 501–750g BW NoPTx group is concerning, and consistent with NRN Trial results.
doi:10.1111/j.1651-2227.2011.02175.x
PMCID: PMC3505994  PMID: 21272067
3.  A randomized trial of aggressive versus conservative phototherapy for hyperbilirubinemia in infants weighing less than 1500 g: Short- and long-term outcomes 
Paediatrics & Child Health  2007;12(10):853-858.
OBJECTIVE
Treatment regimens for hyperbilirubinemia vary for very low birth weight infants. The present study seeks to determine whether the initiation of conservative phototherapy is as effective as aggressive phototherapy in reducing peak bilirubin levels without increasing adverse effects.
STUDY DESIGN
The present randomized, controlled study included infants with birth weights between 500 g and 1500 g, stratified into two birth weight groups. In one group, aggressive phototherapy was commenced by 12 h of age, while in the other group, conservative phototherapy was commenced if serum bilirubin levels exceeded 150 μmol/L. The primary outcome variables were peak serum bilirubin levels and hours of phototherapy. Secondary outcomes were age at peak bilirubin levels, number of infants with rebound hyperbilirubinemia, and number of adverse short- and long-term outcomes.
RESULTS
Of 174 eligible infants, 95 consented to participate −49 in the conservative arm and 46 in the aggressive arm. Ninety-two infants completed the study. There was no significant difference in peak bilirubin levels except in infants who weighed less than 1000 g −171.2±26 μmol/L (conservative) versus 139.2±46 μmol/L (aggressive); P<0.02. There was no difference in duration of phototherapy or rebound hyperbilirubinemia. There were no differences in short-term adverse outcomes. Of the 87 infants who survived until hospital discharge, 82 (94%) had some follow-up and 75 (86%) attended follow-up until 18 months corrected age. The incidence of cerebral palsy, abnormal mental developmental index at 18 months corrected age, or combined outcome of cerebral palsy and death did not significantly differ between the two groups.
CONCLUSIONS
In infants weighing less than 1000 g, peak bilirubin levels were significantly higher using conservative phototherapy regimens and there was a tendency for poor neurodevelopmental outcome.
PMCID: PMC2532565  PMID: 19043499
Hyperbilirubinemia; Paediatrics; Phototherapy; Population-based; Preterm
4.  The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants 
Pediatric Research  2012;71(1):77-84.
INTRODUCTION
This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g).
RESULTS
BAER latencies of 751–1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501–750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results.
DISCUSSION
The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management.
METHODS
Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.
doi:10.1038/pr.2011.17
PMCID: PMC3326602  PMID: 22289854
5.  Does Aggressive Phototherapy Increase Mortality while Decreasing Profound Impairment among the Smallest and Sickest Newborns? 
Objective
Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low birth weight (ELBW; (≤1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT.
Study Design
ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12–36 hours. The effect of AgPT on outcomes (death; impairment; profound impairment; death or impairment [primary outcome], and death or profound impairment) at 18–22 months corrected age was related to BW stratum (501–750 g; 751–1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses.
Results
Baseline illness severity was well characterized using mechanical ventilation and FiO2 at 24 hours age. Among mechanically ventilated infants ≤750 g BW (n =684), a reduction in impairment and in profound impairment was offset by higher mortality (p for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment.
Conclusions
Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.
doi:10.1038/jp.2012.64
PMCID: PMC3558278  PMID: 22652561
Phototherapy; bilirubin; severity of illness; ELBW infant; impairment; randomized clinical trial; statistical interaction; Bayesian analysis
6.  Comparison of Two Phototherapy Methods (Prophylactic vs Therapeutic) for Management of Hyperbilirubinemia in Very Low Birth Weight Newborns 
Iranian Journal of Pediatrics  2011;21(4):425-430.
Objective
Preterm and low birth weight (LBW) infants are at greater risk of developing bilirubin-associated brain damage compared with term infants. Certainly, phototherapy, if used appropriately, is capable of controlling the bilirubin levels in LBW infants; but there is not a unique phototherapy treatment strategy in LBW infants. This study was designed to compare the prophylactic phototherapy and late treatment of jaundiced newborns weighing 1000-1500 grams.
Methods
Sixty newborns with birth weight 1000–1500 g were studied. They were divided into two groups: the “Prophylactic” group, in which phototherapy started within six hours after birth and continued for at least 96 hours, and the "Treatment" group, which received phototherapy when indicated according to birth weight and suspended when bilirubin level fell below 50% of bilirubin level for blood exchange. Mean value of daily transcutaneous bilirubin (TCB), duration of phototherapy, the need for blood exchange, and the highest TCB value in both groups were analyzed.
Findings
In the prophylactic group, the highest daily mean rate of TCB was 7.71±1.84 mg/dl, which happened on the third day. In the treatment group, it was 8.74±1.72 mg/dl on the fourth day after birth. The TCB values in prophylactic group were significantly less than those of the treatment group only on the fourth and fifth days after birth (P<0.001). Although the median duration of phototherapy in the treatment group was shorter than that of the prophylactic group (137.60±57.39 vs 168.71±88.01 hours, respectively), this difference was not statistically significant. Only one neonate needed blood exchange in the treatment group.
Conclusion
The prophylactic phototherapy treatment for babies weighing 1000–1500 g significantly decreases bilirubin levels on the fourth and fifth days after birth but the clinical course of hyperbilirubinemia does not alter in LBW infant, as indicated by the non-significant change in the duration of phototherapy.
PMCID: PMC3446143  PMID: 23056826
Phototherapy; Neonatal jaundice; Preterm Neonate; VLBW infant
7.  Efficacy of phototherapy in non-haemolytic hyperbilirubinaemia. 
Clinical experience of phototherapy for non-haemolytic hyperbilirubinaemia in 3999 infants in Kandang Kerbau Hospital, Singapore, is documented. Phototherapy was most effective in extremely preterm infants with very low birth weight (gestation less than or equal to 32 weeks, birth weight less than or equal to 1500 g) and least effective in full term infants with very low birth weight (gestation greater than or equal to 37 weeks, birth weight less than or equal to 1500 g) and large preterm infants (gestation less than 37 weeks, birth weight greater than 2270 g). Overall, phototherapy was effective in almost all the infants, with a failure rate of only 2.00/1000 infants. No characteristic features common to all the failures could be detected. The bilirubin rebound was usually mild; repeat phototherapy was required in only 30 infants (7.50/1000), with the response to the second exposure comparable to that to the first. No infant required a third exposure. All the infants tolerated phototherapy well, none developing any illness that could be attributed to the treatment. This clinical experience shows that phototherapy for the treatment of nonhaemolytic hyperbilirubinaemia is effective and safe.
PMCID: PMC1342066  PMID: 3098349
8.  Neonatal jaundice 
Clinical Evidence  2007;2007:0319.
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.
PMCID: PMC2943774  PMID: 19454091
9.  Effect of White Plastic Cover around the Phototherapy Unit on Hyperbilirubinemia in Full Term Neonates 
Iranian Journal of Pediatrics  2013;23(2):143-148.
Objective
Jaundice is a common problem in neonatal period. Phototherapy is the most common treatment for neonatal jaundice. The purpose of this study was to determine the effect of adding white plastic cover around the phototherapy unit on hyperbilirubinemia in full term neonates with jaundice.
Methods
In this randomized controlled trial, over 12 months (October 2009 – September 2010), 182 term neonates with uncomplicated jaundice, admitted to neonatal unit of Imam Reza Hospital (AS) in Kermanshah province of Iran, were selected. They were randomized in two groups. Control group received conventional phototherapy without cover around the apparatus and covered group received conventional phototherapy with plastic cover around the unit. After enrolment, total serum bilirubin was measured every 12 hours. Phototherapy was continued until the total serum bilirubin decreased to or less than 12.5 mg/dl.
Findings
There were no significant differences between the two groups for gestational age, birth weight, postnatal age, weight (at admission), serum level of hemoglobin, hematocrit and reticulocyte count. Total serum bilirubin in covered group, during the first 48 hours of treatment, declined significantly than in control group (P. value=0.003). The cover around the phototherapy unit not only did not increase the side effects of phototherapy, but also had a positive impact in reducing duration of jaundice (P. value <0.0001) and duration of hospitalization (P. value <0.0001).
Conclusion
The study results showed that using white plastic cover around the phototherapy unit can increase the therapeutic effect of phototherapy.
PMCID: PMC3663303  PMID: 23724173
Phototherapy; Jaundice; Neonate; Hyperbilirubinemia
10.  Impact of Universal Bilirubin Screening on Severe Hyperbilirubinemia and Phototherapy Use 
Pediatrics  2009;124(4):1031-1039.
OBJECTIVE
The goal was to assess the impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use.
METHODS
In this retrospective cohort study of 358 086 infants of ≥35 weeks and ≥2000 g born between January 1, 1995, and June 30, 2007, we obtained demographic data, bilirubin levels, and codes for inpatient phototherapy from existing databases. We compared the incidence of high total serum bilirubin (TSB) levels and phototherapy before and after implementation of universal screening and examined risk factors for high TSB levels.
RESULTS
A total of 38 182 infants (10.6%) were born at facilities that had implemented universal bilirubin screening. Compared with infants born at facilities that were not screening, these infants had a 62% lower incidence of TSB levels exceeding the American Academy of Pediatrics exchange guideline (0.17% vs 0.45%; P < .001), received twice the inpatient phototherapy (9.1% vs 4.2%; P < .001), and had slightly longer birth hospitalization lengths of stay (50.9 vs 48.7 hours; P < .001). Of those receiving phototherapy, 56% after initiation of universal screening had TSB levels at which phototherapy was recommended by the guideline, compared with 70% before screening. The adjusted odds ratio for developing TSB levels exceeding the guideline value was 0.28 (95% confidence interval: 0.20–0.40) for those born at a facility using TSB screening and 0.28 (95% confidence interval: 0.19–0.42) for those born at a facility using transcutaneous bilirubin screening.
CONCLUSIONS
Universal bilirubin screening was associated with a significantly lower incidence of severe hyperbilirubinemia but also with increased phototherapy use.
doi:10.1542/peds.2008-2980
PMCID: PMC2858633  PMID: 19786442
bilirubin; jaundice; newborn; phototherapy; screening
11.  Efficacy of phototherapy for neonatal jaundice is increased by the use of low‐cost white reflecting curtains 
Objective
To determine whether the addition of low‐cost reflecting curtains to a standard phototherapy unit could increase effectiveness of phototherapy for neonatal jaundice.
Design
Randomised controlled clinical trial.
Setting
Level‐one nursery of the Hospital Universiti Sains Malaysia, Kelantan, Malayasia.
Patients
Term newborns with uncomplicated neonatal jaundice presenting in the first week of life.
Interventions
Phototherapy with white curtains hanging from the sides of the phototherapy unit (study group, n = 50) was compared with single phototherapy without curtains (control group, n = 47).
Main outcome measures
The primary outcome was the mean difference in total serum bilirubin measured at baseline and after 4 h of phototherapy. The secondary outcome was the duration of phototherapy.
Results
The mean (standard deviation) decrease in total serum bilirubin levels after 4 h of phototherapy was significantly (p<0.001) higher in the study group (27.62 (25.24) μmol/l) than in the control group (4.04 (24.27) μmol/l). Cox proportional hazards regression analysis indicated that the median duration of phototherapy was significantly shorter in the study group (12 h) than in the control group (34 h; χ2 change 45.2; p<0.001; hazards ratio 0.20; 95% confidence interval 0.12 to 0.32). No difference in adverse events was noted in terms of hyperthermia or hypothermia, weight loss, rash, loose stools or feeding intolerance.
Conclusion
Hanging white curtains around phototherapy units significantly increases efficacy of phototherapy in the treatment of neonatal jaundice without evidence of increased adverse effects.
doi:10.1136/adc.2006.095687
PMCID: PMC2672760  PMID: 16877479
12.  Treatment of neonatal jaundice with filtered sunlight in Nigerian neonates: study protocol of a non-inferiority, randomized controlled trial 
Trials  2013;14:446.
Background
Severe neonatal jaundice and its progression to kernicterus is a leading cause of death and disability among newborns in poorly-resourced countries, particularly in sub-Saharan Africa. The standard treatment for jaundice using conventional phototherapy (CPT) with electric artificial blue light sources is often hampered by the lack of (functional) CPT devices due either to financial constraints or erratic electrical power. In an attempt to make phototherapy (PT) more readily available for the treatment of pathologic jaundice in underserved tropical regions, we set out to test the hypothesis that filtered sunlight phototherapy (FS-PT), in which potentially harmful ultraviolet and infrared rays are appropriately screened, will be as efficacious as CPT.
Methods/design
This prospective, non-blinded randomized controlled non-inferiority trial seeks to enroll infants with elevated total serum/plasma bilirubin (TSB, defined as 3 mg/dl below the level recommended by the American Academy of Pediatrics for high-risk infants requiring PT) who will be randomly and equally assigned to receive FS-PT or CPT for a total of 616 days at an inner-city maternity hospital in Lagos, Nigeria. Two FS-PT canopies with pre-tested films will be used. One canopy with a film that transmits roughly 33% blue light (wavelength range: 400 to 520 nm) will be used during sunny periods of a day. Another canopy with a film that transmits about 79% blue light will be used during overcast periods of the day. The infants will be moved from one canopy to the other as needed during the day with the goal of keeping the blue light irradiance level above 8 μW/cm2/nm.
Primary outcome: FS-PT will be as efficacious as CPT in reducing the rate of rise in bilirubin levels. Secondary outcome: The number of infants requiring exchange transfusion under FS-PT will not be more than those under CPT.
Conclusion
This novel study offers the prospect of an effective treatment for infants at risk of severe neonatal jaundice and avoidable exchange transfusion in poorly-resourced settings without access to (reliable) CPT in the tropics.
Trial registration
ClinicalTrials.gov Identifier: NCT01434810
doi:10.1186/1745-6215-14-446
PMCID: PMC3879162  PMID: 24373547
Filtered sunlight phototherapy; Hyperbilirubinemia; Developing country; Low-cost technologies; Irradiance; Africa
13.  Ultraviolet Phototherapy Management of Moderate-to-Severe Plaque Psoriasis 
Executive Summary
Objective
The purpose of this evidence based analysis was to determine the effectiveness and safety of ultraviolet phototherapy for moderate-to-severe plaque psoriasis.
Research Questions
The specific research questions for the evidence review were as follows:
What is the safety of ultraviolet phototherapy for moderate-to-severe plaque psoriasis?
What is the effectiveness of ultraviolet phototherapy for moderate-to-severe plaque psoriasis?
Clinical Need: Target Population and Condition
Psoriasis is a common chronic, systemic inflammatory disease affecting the skin, nails and occasionally the joints and has a lifelong waning and waxing course. It has a worldwide occurrence with a prevalence of at least 2% of the general population, making it one of the most common systemic inflammatory diseases. The immune-mediated disease has several clinical presentations with the most common (85% - 90%) being plaque psoriasis.
Characteristic features of psoriasis include scaling, redness, and elevation of the skin. Patients with psoriasis may also present with a range of disabling symptoms such as pruritus (itching), pain, bleeding, or burning associated with plaque lesions and up to 30% are classified as having moderate-to-severe disease. Further, some psoriasis patients can be complex medical cases in which diabetes, inflammatory bowel disease, and hypertension are more likely to be present than in control populations and 10% also suffer from arthritis (psoriatic arthritis). The etiology of psoriasis is unknown but is thought to result from complex interactions between the environment and predisposing genes.
Management of psoriasis is related to the extent of the skin involvement, although its presence on the hands, feet, face or genitalia can present challenges. Moderate-to-severe psoriasis is managed by phototherapy and a range of systemic agents including traditional immunosuppressants such as methotrexate and cyclospsorin. Treatment with modern immunosuppressant agents known as biologicals, which more specifically target the immune defects of the disease, is usually reserved for patients with contraindications and those failing or unresponsive to treatments with traditional immunosuppressants or phototherapy.
Treatment plans are based on a long-term approach to managing the disease, patient’s expectations, individual responses and risk of complications. The treatment goals are several fold but primarily to:
1) improve physical signs and secondary psychological effects,
2) reduce inflammation and control skin shedding,
3) control physical signs as long as possible, and to
4) avoid factors that can aggravate the condition.
Approaches are generally individualized because of the variable presentation, quality of life implications, co-existent medical conditions, and triggering factors (e.g. stress, infections and medications). Individual responses and commitments to therapy also present possible limitations.
Phototherapy
Ultraviolet phototherapy units have been licensed since February 1993 as a class 2 device in Canada. Units are available as hand held devices, hand and foot devices, full-body panel, and booth styles for institutional and home use. Units are also available with a range of ultraviolet A, broad and narrow band ultraviolet B (BB-UVB and NB-UVB) lamps. After establishing appropriate ultraviolet doses, three-times weekly treatment schedules for 20 to 25 treatments are generally needed to control symptoms.
Evidence-Based Analysis Methods
The literature search strategy employed keywords and subject headings to capture the concepts of 1) phototherapy and 2) psoriasis. The search involved runs in the following databases: Ovid MEDLINE (1996 to March Week 3 2009), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2009 Week 13), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 1999 and March 31, 2009. Search alerts were generated and reviewed for relevant literature up until May 31, 2009.
English language reports and human studies
Ultraviolet phototherapy interventions for plaque-type psoriasis
Reports involving efficacy and/or safety outcome studies
Original reports with defined study methodology
Standardized measurements on outcome events such as technical success, safety, effectiveness, durability, quality of life or patient satisfaction
Non-systematic reviews, letters, comments and editorials
Randomized trials involving side-to-side or half body comparisons
Randomized trials not involving ultraviolet phototherapy intervention for plaque-type psoriasis
Trials involving dosing studies, pilot feasibility studies or lacking control groups
Summary of Findings
A 2000 health technology evidence report on the overall management of psoriasis by The National Institute Health Research (NIHR) Health Technology Assessment Program of the UK was identified in the MAS evidence-based review. The report included 109 RCT studies published between 1966 and June 1999 involving four major treatment approaches – 51 on phototherapy, 32 on oral retinoids, 18 on cyclosporin and five on fumarates.. The absence of RCTs on methotrexate was noted as original studies with this agent had been performed prior to 1966.
Of the 51 RCT studies involving phototherapy, 22 involved UVA, 21 involved UVB, five involved both UVA and UVB and three involved natural light as a source of UV. The RCT studies included comparisons of treatment schedules, ultraviolet source, addition of adjuvant therapies, and comparisons between phototherapy and topical treatment schedules. Because of heterogeneity, no synthesis or meta-analysis could be performed. Overall, the reviewers concluded that the efficacy of only five therapies could be supported from the RCT-based evidence review: photochemotherapy or phototherapy, cyclosporin, systemic retinoids, combination topical vitamin D3 analogues (calcipotriol) and corticosteroids in combination with phototherapy and fumarates. Although there was no RCT evidence supporting methotrexate, it’s efficacy for psoriasis is well known and it continues to be a treatment mainstay.
The conclusion of the NIHR evidence review was that both photochemotherapy and phototherapy were effective treatments for clearing psoriasis, although their comparative effectiveness was unknown. Despite the conclusions on efficacy, a number of issues were identified in the evidence review and several areas for future research were discussed to address these limitations. Trials focusing on comparative effectiveness, either between ultraviolet sources or between classes of treatment such as methotrexate versus phototherapy, were recommended to refine treatment algorithms. The need for better assessment of cost-effectiveness of therapies to consider systemic drug costs and costs of surveillance, as well as drug efficacy, were also noted. Overall, the authors concluded that phototherapy and photochemotherapy had important roles in psoriasis management and were standard therapeutic options for psoriasis offered in dermatology practices.
The MAS evidence-based review focusing on the RCT trial evidence for ultraviolet phototherapy management of moderate-to-severe plaque psoriasis was performed as an update to the NIHR 2000 systemic review on treatments for severe psoriasis. In this review, an additional 26 RCT reports examining phototherapy or photochemotherapy for psoriasis were identified. Among the studies were two RCTs comparing ultraviolet wavelength sources, five RCTs comparing different forms of phototherapy, four RCTs combining phototherapy with prior spa saline bathing, nine RCTs combining phototherapy with topical agents, two RCTs combining phototherapy with the systemic immunosuppressive agents methotrexate or alefacept, one RCT comparing phototherapy with an additional light source (the excimer laser), and one comparing a combination therapy with phototherapy and psychological intervention involving simultaneous audiotape sessions on mindfulness and stress reduction. Two trials also examined the effect of treatment setting on effectiveness of phototherapy, one on inpatient versus outpatient therapy and one on outpatient clinic versus home-based phototherapy.
Conclusions
The conclusions of the MAS evidence-based review are outlined in Table ES1. In summary, phototherapy provides good control of clinical symptoms in the short term for patients with moderate-to-severe plaque-type psoriasis that have failed or are unresponsive to management with topical agents. However, many of the evidence gaps identified in the NIHR 2000 evidence review on psoriasis management persisted. In particular, the lack of evidence on the comparative effectiveness and/or cost-effectiveness between the major treatment options for moderate-to-severe psoriasis remained. The evidence on effectiveness and safety of longer term strategies for disease management has also not been addressed. Evidence for the safety, effectiveness, or cost-effectiveness of phototherapy delivered in various settings is emerging but is limited. In addition, because all available treatments for psoriasis – a disease with a high prevalence, chronicity, and cost – are palliative rather than curative, strategies for disease control and improvements in self-efficacy employed in other chronic disease management strategies should be investigated.
RCT Evidence for Ultraviolet Phototherapy Treatment of Moderate-To-Severe Plaque Psoriasis
Phototherapy is an effective treatment for moderate-to-severe plaque psoriasis
Narrow band PT is more effective than broad band PT for moderate-to-severe plaque psoriasis
Oral-PUVA has a greater clinical response, requires less treatments and has a greater cumulative UV irradiation dose than UVB to achieve treatment effects for moderate-to-severe plaque psoriasis
Spa salt water baths prior to phototherapy did increase short term clinical response of moderate-to-severe plaque psoriasis but did not decrease cumulative UV irradiation dose
Addition of topical agents (vitamin D3 calcipotriol) to NB-UVB did not increase mean clinical response or decrease treatments or cumulative UV irradiation dose
Methotrexate prior to NB-UVB in high need psoriasis patients did significantly increase clinical response, decrease number of treatment sessions and decrease cumulative UV irradiation dose
Phototherapy following alefacept did increase early clinical response in moderate-to-severe plaque psoriasis
Effectiveness and safety of home NB-UVB phototherapy was not inferior to NB-UVB phototherapy provided in a clinic to patients with psoriasis referred for phototherapy. Treatment burden was lower and patient satisfaction was higher with home therapy and patients in both groups preferred future phototherapy treatments at home
Ontario Health System Considerations
A 2006 survey of ultraviolet phototherapy services in Canada identified 26 phototherapy clinics in Ontario for a population of over 12 million. At that time, there were 177 dermatologists and 50 geographic regions in which 28% (14/50) provided phototherapy services. The majority of the phototherapy services were reported to be located in densely populated areas; relatively few patients living in rural communities had access to these services. The inconvenience of multiple weekly visits for optimal phototherapy treatment effects poses additional burdens to those with travel difficulties related to health, job, or family-related responsibilities.
Physician OHIP billing for phototherapy services totaled 117,216 billings in 2007, representing approximately 1,800 patients in the province treated in private clinics. The number of patients treated in hospitals is difficult to estimate as physician costs are not billed directly to OHIP in this setting. Instead, phototherapy units and services provided in hospitals are funded by hospitals’ global budgets. Some hospitals in the province, however, have divested their phototherapy services, so the number of phototherapy clinics and their total capacity is currently unknown.
Technological advances have enabled changes in phototherapy treatment regimens from lengthy hospital inpatient stays to outpatient clinic visits and, more recently, to an at-home basis. When combined with a telemedicine follow-up, home phototherapy may provide an alternative strategy for improved access to service and follow-up care, particularly for those with geographic or mobility barriers. Safety and effectiveness have, however, so far been evaluated for only one phototherapy home-based delivery model. Alternate care models and settings could potentially increase service options and access, but the broader consequences of the varying cost structures and incentives that either increase or decrease phototherapy services are unknown.
Economic Analyses
The focus of the current economic analysis was to characterize the costs associated with the provision of NB-UVB phototherapy for plaque-type, moderate-to-severe psoriasis in different clinical settings, including home therapy. A literature review was conducted and no cost-effectiveness (cost-utility) economic analyses were published in this area.
Hospital, Clinic, and Home Costs of Phototherapy
Costs for NB-UVB phototherapy were based on consultations with equipment manufacturers and dermatologists. Device costs applicable to the provision of NB-UVB phototherapy in hospitals, private clinics and at a patient’s home were estimated. These costs included capital costs of purchasing NB-UVB devices (amortized over 15-20 years), maintenance costs of replacing equipment bulbs, physician costs of phototherapy treatment in private clinics ($7.85 per phototherapy treatment), and medication and laboratory costs associated with treatment of moderate-to-severe psoriasis.
NB-UVB phototherapy services provided in a hospital setting were paid for by hospitals directly. Phototherapy services in private clinic and home settings were paid for by the clinic and patient, respectively, except for physician services covered by OHIP. Indirect funding was provided to hospitals as part of global budgeting and resource allocation. Home therapy services for NB-UVB phototherapy were not covered by the MOHLTC. Coverage for home-based phototherapy however, was in some cases provided by third party insurers.
Device costs for NB-UVB phototherapy were estimated for two types of phototherapy units: a “booth unit” consisting of 48 bulbs used in hospitals and clinics, and a “panel unit” consisting of 10 bulbs for home use. The device costs of the booth and panel units were estimated at approximately $18,600 and $2,900, respectively; simple amortization over 15 and 20 years implied yearly costs of approximately $2,500 and $150, respectively. Replacement cost for individual bulbs was about $120 resulting in total annual cost of maintenance of about $8,640 and $120 for booth and panel units, respectively.
Estimated Total Costs for Ontario
Average annual cost per patient for NB-UVB phototherapy provided in the hospital, private clinic or at home was estimated to be $292, $810 and $365 respectively. For comparison purposes, treatment of moderate-to-severe psoriasis with methotrexate and cyclosporin amounted to $712 and $3,407 annually per patient respectively; yearly costs for biological drugs were estimated to be $18,700 for alefacept and $20,300 for etanercept-based treatments.
Total annual costs of NB-UVB phototherapy were estimated by applying average costs to an estimated proportion of the population (age 18 or older) eligible for phototherapy treatment. The prevalence of psoriasis was estimated to be approximately 2% of the population, of which about 85% was of plaque-type psoriasis and approximately 20% to 30% was considered moderate-to-severe in disease severity. An estimate of 25% for moderate-to-severe psoriasis cases was used in the current economic analysis resulting in a range of 29,400 to 44,200 cases. Approximately 21% of these patients were estimated to be using NB-UVB phototherapy for treatment resulting in a number of cases in the range between 6,200 and 9,300 cases. The average (7,700) number of cases was used to calculate associated costs for Ontario by treatment setting.
Total annual costs were as follows: $2.3 million in a hospital setting, $6.3 million in a private clinic setting, and $2.8 million for home phototherapy. Costs for phototherapy services provided in private clinics were greater ($810 per patient annually; total of $6.3 million annually) and differed from the same services provided in the hospital setting only in terms of additional physician costs associated with phototherapy OHIP fees.
Keywords
Psoriasis, ultraviolet radiation, phototherapy, photochemotherapy, NB-UVB, BB-UVB PUVA
PMCID: PMC3377497  PMID: 23074532
14.  Bilirubin Neurotoxicity in Preterm Infants: Risk and Prevention 
Hemolytic conditions in preterm neonates, including Rhesus (Rh) disease, can lead to mortality and long-term impairments due to bilirubin neurotoxicity. Universal access to Rh immunoprophylaxis, coordinated perinatal-neonatal care, and effective phototherapy has virtually eliminated the risk of kernicterus in many countries. In the absence of jaundice due to isoimmunization and without access to phototherapy or exchange transfusion (in 1955), kernicterus was reported at 10.1%, 5.5%, and 1.2% in babies <30, 31-32, and 33-34 wks gestational age, respectively. Phototherapy initiated at 24±12 hr effectively prevented hyperbilirubinemia in infants <2,000 g even in the presence of hemolysis. This approach (in 1985) reduced exchange transfusions from 23.9% to 4.8%. Now with 3 decades of experience in implementing effective phototherapy, the need for exchange transfusions has virtually been eliminated. However, bilirubin neurotoxicity continues to be associated with prematurity alone. The ability to better predict this risk, other than birthweight and gestation, has been elusive. Objective tests such as total bilirubin, unbound or free bilirubin, albumin levels, and albumin-bilirubin binding, together with observations of concurrent hemolysis, sepsis, and rapid rate of bilirubin rise have been considered, but their individual or combined predictive utility has yet to be refined. The disruptive effects of immaturity, concurrent neonatal disease, cholestasis, use of total parenteral nutrition or drugs that alter bilirubin-binding abilities augment the clinical risk of neurotoxicity. Current management options rely on the “fine-tuning” of each infant's exposure to beneficial antioxidants and avoidance of silent neurotoxic properties of bilirubin navigated within the safe spectrum of operational thresholds demarcated by experts.
doi:10.4103/2249-4847.116402
PMCID: PMC3775137  PMID: 24049745
Bilirubin neurotoxicity; hyperbilirubinemia; jaundice; kernicterus; preterm
15.  Value of Twelfth Hour Bilirubin Level in Predicting Significant Hyperbilirubinemia in Preterm Infants 
Background
As hyperbilirubinemia is a significant cause of brain injury, it is important to predict the cases who are at risk. Data for preterm infants are scarce. The aim of this study is to predict significant hyperbilirubinemia in preterm infants by measuring capillary bilirubin at 12th hour of life.
Methods
One hundred and fifty neonates born ≤ 35 weeks were included in the study. They were categorized into two groups according to their birth weights (group 1: 1,000 - 1,499 g; group 2: 1,500 - 2,000 g). Their bilirubin levels were measured at 12th hour and daily thereafter for 5 days. Risk nomograms were generated based on their bilirubin measurements and postnatal ages. On the age-specific percentile-based nomogram, the zone above the 90th percentile was determined as high risk and those below the fifth percentile as low risk. Infants who had bilirubin levels over the limits defined according to their postnatal ages and birth weights were accepted to have significant hyperbilirubinemia and received phototherapy and predictive value of the 12th hour bilirubin was asssessed.
Results
Fifty-four of 57 infants (94.7%) in group 1 and 75/93 infants (80.7%) in group 2 received phototherapy. Capillary bilirubin levels of 3.55 mg/dL and 4.55 mg/dL for group 1 and group 2 measured at the 12th hour of life had the highest sensitivity, negative and positive predictive value to predict the neonates who will develop significant hyperbilirubinemia.
Conclusion
Bilirubin levels of preterm infants should be monitored closely. More attention should be paid to the ones who had 12th hour bilirubin level above the cutoff values.
doi:10.14740/jocmr1639w
PMCID: PMC3985561  PMID: 24734145
Hyperbilirubinemia; Neonate; Preterm; Phototherapy
16.  Neonatal Hyperbilirubinemia in infants with G6PD c.563C > TVariant 
BMC Pediatrics  2012;12:126.
Background
There is a strong correlation between glucose-6-phosphate dehydrogenase (G6PD) deficiency and neonatal hyperbilirubinemia with a rare but potential threat of devastating acute bilirubin encephalopathy. G6PD deficiency was observed in 4–14% of hospitalized icteric neonates in Pakistan. G6PD c.563C > T is the most frequently reported variant in this population. The present study was aimed at evaluating the time to onset of hyperbilirubinemia and the postnatal bilirubin trajectory in infants having G6PD c.563C > T.
Methods
This was a case–control study conducted at The Aga Khan University, Pakistan during the year 2008. We studied 216 icteric male neonates who were re-admitted for phototherapy during the study period. No selection was exercised. Medical records showed that 32 were G6PD deficient while 184 were G6PD normal. Each infant was studied for birth weight, gestational age, age at the time of presentation, presence of cephalhematoma, sepsis and neurological signs, peak bilirubin level, age at peak bilirubin level, days of hospitalization, whether phototherapy or exchange blood transfusion was initiated, and the outcome. During hospital stay, each baby was tested for complete blood count, reticulocyte count, ABO and Rh blood type, direct antiglobulin test and quantitative G6PD estimation [by kinetic determination of G6PDH]. G6PDgenotype was analyzed in 32 deficient infants through PCR-RFLP analysis and gene sequencing.
Results
G6PD variants c.563C > T and c.131 C > G were observed in 21 (65%) and three (9%) of the 32 G6PD deficient infants, respectively. DNA of eight (25%) newborns remained uncharacterized. In contrast to G6PD normal neonates, infants with c.563C > T variant had significantly lower enzyme activity (mean ± 1SD; 0.3 ± 0.2 U/gHb vs. 14.0 ± 4.5 U/gHb, p < 0.001) experienced higher peak levels of total serum bilirubin (mean ± 1SD; 16.8 ± 5.4 mg/dl vs. 13.8 ± 4.6 mg/dl, p = 0.008) which peaked earlier after birth (mean ± 1SD 2.9 ± 1.6 vs. 4.3 ± 2.3 days, p = 0.007). No statistically significant difference was observed in mean weight, age at presentation, hemoglobin, reticulocyte count, TSH level, hospital stay or in the frequency of initiation of phototherapy or blood exchange between the two groups.
Conclusions
We concluded that infants with G6PD c.563C > T variant developed jaundice earlier than infants with normal G6PD enzyme levels. Compared to G6PD normal infants, G6PD c.563C > T carrying infants had significantly low G6PD activity.
doi:10.1186/1471-2431-12-126
PMCID: PMC3529675  PMID: 22906047
17.  Neonatal physiological correlates of near-term brain development on MRI and DTI in very-low-birth-weight preterm infants 
NeuroImage : Clinical  2014;5:169-177.
Structural brain abnormalities identified at near-term age have been recognized as potential predictors of neurodevelopment in children born preterm. The aim of this study was to examine the relationship between neonatal physiological risk factors and early brain structure in very-low-birth-weight (VLBW) preterm infants using structural MRI and diffusion tensor imaging (DTI) at near-term age.
Structural brain MRI, diffusion-weighted scans, and neonatal physiological risk factors were analyzed in a cross-sectional sample of 102 VLBW preterm infants (BW ≤ 1500 g, gestational age (GA) ≤ 32 weeks), who were admitted to the Lucile Packard Children's Hospital, Stanford NICU and recruited to participate prior to routine near-term brain MRI conducted at 36.6 ± 1.8 weeks postmenstrual age (PMA) from 2010 to 2011; 66/102 also underwent a diffusion-weighted scan. Brain abnormalities were assessed qualitatively on structural MRI, and white matter (WM) microstructure was analyzed quantitatively on DTI in six subcortical regions defined by DiffeoMap neonatal brain atlas. Specific regions of interest included the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, the thalamus, and the globus pallidus. Regional fractional anisotropy (FA) and mean diffusivity (MD) were calculated using DTI data and examined in relation to neonatal physiological risk factors including gestational age (GA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and sepsis, as well as serum levels of C-reactive protein (CRP), glucose, albumin, and total bilirubin.
Brain abnormalities were observed on structural MRI in 38/102 infants including 35% of females and 40% of males. Infants with brain abnormalities observed on MRI had higher incidence of BPD (42% vs. 25%) and sepsis (21% vs. 6%) and higher mean and peak serum CRP levels, respectively, (0.64 vs. 0.34 mg/dL, p = .008; 1.57 vs. 0.67 mg/dL, p= .006) compared to those without. The number of signal abnormalities observed on structural MRI correlated to mean and peak CRP (rho = .316, p = .002; rho = .318, p= .002). The number of signal abnormalities observed on MRI correlated with thalamus MD (left: r= .382, p= .002; right: r= .400, p= .001), controlling for PMA-at-scan. Thalamus WM microstructure demonstrated the strongest associations with neonatal risk factors. Higher thalamus MD on the left and right, respectively, was associated with lower GA (r = −.322, p = .009; r= −.381, p= .002), lower mean albumin (r = −.276, p= .029; r= −.385, p= .002), and lower mean bilirubin (r = −.293, p= .020; r= −.337 p= .007).
Results suggest that at near-term age, thalamus WM microstructure may be particularly vulnerable to certain neonatal risk factors. Interactions between albumin, bilirubin, phototherapy, and brain development warrant further investigation. Identification of physiological risk factors associated with selective vulnerability of certain brain regions at near-term age may clarify the etiology of neurodevelopmental impairment and inform neuroprotective treatment for VLBW preterm infants.
Highlights
•Biomarkers of inflammation in preterm infants correlated with brain abnormalities detected on near-term structural MRI.•Biomarkers of inflammation in preterm infants correlated with near-term WM microstructure assessed on DTI.•Signal abnormalities observed on near-term structural MRI correlated with increased thalamus MD.
doi:10.1016/j.nicl.2014.05.013
PMCID: PMC4110350  PMID: 25068107
MRI; Diffusion tensor imaging; White matter microstructure; Brain development; Risk factors; Preterm infants; VLBW, very-low-birth-weight; GA, gestational age; PMA, post-menstrual age; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, mean diffusivity; CC, corpus callosum; IC, internal capsule; ALIC, anterior limb of the internal capsule; PLIC, posterior limb of the internal capsule; GloP, globus pallidus
18.  Is the light-emitting diode a better light source than fluorescent tube for phototherapy of neonatal jaundice in preterm infants? 
Background:
Light-emitting diodes (LEDs) are light sources recently used for phototherapy in neonatal jaundice. We compared the efficacy and safety of LEDs with fluorescent phototherapy in the treatment of indirect hyperbilirubinemia.
Materials and Methods:
This controlled trial was conducted on preterm infants hospitalized in neonatal intensive care unit of Shahid Beheshti Hospital in Isfahan (Iran) who needed conventional phototherapy for uncomplicated indirect hyperbilirubinemia. Neonates received phototherapy through devices with LEDs or special blue fluorescent tubes. Primary outcomes included the rate of fall of total serum bilirubin (TSB, mg/dL/hour) and duration of phototherapy (hours). Secondary outcomes were treatment failure and side effects.
Results:
A total of 64 infants with gestational age of 33.5 ± 1.2 weeks, chronological age of 73.0 [SE = 7.3] hours, and weight of 1757.5 ± 147.6 gram were enrolled. The rates of fall of TSB were 0.20 [SE = 0.03] and 0.12 [SE = 0.01] mg/dL/hour in the LED and fluorescent groups, respectively (P = 0.472). Treatment duration was 37.5 ± 26.8 and 45.3 ± 32.1 hours in the LED and fluorescent groups, respectively (P = 0.292). There was no treatment failure in the two groups. Mild hyperthermia was occurred in 3.1% and 28.1% of infants in the LED and fluorescent groups, respectively (P = 0.006).
Conclusions:
LED light source is as effective as fluorescent tubes for phototherapy of preterm infants with indirect hyperbilirubinemia. Considering less frequent side effects, less energy consumption, longer life span, and lower costs, LED phototherapy seems to be a better option than current conventional phototherapy.
doi:10.4103/2277-9175.100158
PMCID: PMC3544129  PMID: 23326782
Hyperbilirubinemia; jaundice; premature infant; phototherapy
19.  Influence of Clinical Status on the Association Between Plasma Total and Unbound Bilirubin and Death or Adverse Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
Objectives
To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
Method
Total plasma biirubin and unbound biirubin were measured in 1,101 extremely low birth weight infants at 5±1 day of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.
Results
Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants.
Conclusions
In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma and unbound bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.
doi:10.1111/j.1651-2227.2010.01688.x
PMCID: PMC2875328  PMID: 20105142
Plasma bilirubin; unbound bilirubin; Extremely low birth weight infants; Neurodevelopmental outcomes
20.  Neurodevelopmental Outcomes of Triplets or Higher-Order Extremely Low Birth Weight Infants 
Pediatrics  2011;127(3):e654-e660.
BACKGROUND:
Extremely low birth weight twins have a higher rate of death or neurodevelopmental impairment than singletons. Higher-order extremely low birth weight multiple births may have an even higher rate of death or neurodevelopmental impairment.
METHODS:
Extremely low birth weight (birth weight 401–1000 g) multiple births born in participating centers of the Neonatal Research Network between 1996 and 2005 were assessed for death or neurodevelopmental impairment at 18 to 22 months' corrected age. Neurodevelopmental impairment was defined by the presence of 1 or more of the following: moderate to severe cerebral palsy; mental developmental index score or psychomotor developmental index score less than 70; severe bilateral deafness; or blindness. Infants who died within 12 hours of birth were excluded. Maternal and infant demographic and clinical variables were compared among singleton, twin, and triplet or higher-order infants. Logistic regression analysis was performed to establish the association between singletons, twins, and triplet or higher-order multiples and death or neurodevelopmental impairment, controlling for confounding variables that may affect death or neurodevelopmental impairment.
RESULTS:
Our cohort consisted of 8296 singleton, 2164 twin, and 521 triplet or higher-order infants. The risk of death or neurodevelopmental impairment was increased in triplets or higher-order multiples when compared with singletons (adjusted odds ratio: 1.7 [95% confidence interval: 1.29–2.24]), and there was a trend toward an increased risk when compared with twins (adjusted odds ratio: 1.27 [95% confidence: 0.95–1.71]).
CONCLUSIONS:
Triplet or higher-order births are associated with an increased risk of death or neurodevelopmental impairment at 18 to 22 months' corrected age when compared with extremely low birth weight singleton infants, and there was a trend toward an increased risk when compared with twins.
doi:10.1542/peds.2010-2646
PMCID: PMC3304548  PMID: 21357334
extremely low birth weight; triplets; neurodevelopmental outcomes
21.  Oxygen consumption and resting energy expenditure during phototherapy in full term and preterm newborn infants 
Fok, T | Gu, J | Lim, C | Ng, P | Wong, H | So, K
OBJECTIVES—To determine the effect of phototherapy on the oxygen consumption and resting energy expenditure of term and preterm newborn infants.
METHODS—A total of 202 infants (gestation 30-42 weeks; body weight 1270-4100 g) requiring phototherapy for the treatment of neonatal hyperbilirubinaemia were enrolled in a randomised crossover study. In random sequence, the oxygen consumption and resting energy expenditure were measured twice in each infant by indirect calorimetry, once at the end of six hours of continuous phototherapy and once after a control period of at least six hours without phototherapy. Anterior abdominal wall temperature was servocontrolled at 36.5°C throughout the study.
RESULTS—At the end of six hours of continuous phototherapy, oxygen consumption (mean (SD): 6.21 (1.35) v 6.26 (1.51) ml/kg, p = 0.555) and resting energy expenditure (178.11 (37.62) v 180.37 (43.14) kJ/kg/24 h, p = 0.382) did not differ significantly from those measured after the control period. There were also no significant differences in heart rate, respiratory rate, or rectal temperature. Subgroup analysis of those of gestation < 37 weeks or < 34 weeks also showed no effect of phototherapy on either oxygen consumption or resting energy expenditure.
CONCLUSION—Phototherapy has no effect on the metabolic rate of thermally stable term or preterm infants.


doi:10.1136/fn.85.1.F49
PMCID: PMC1721262  PMID: 11420323
22.  SYNCHRONIZED NASAL INTERMITTENT POSITIVE PRESSURE VENTILATION AND NEONATAL OUTCOMES: A RETROSPECTIVE STUDY 
Pediatrics  2009;124(2):517-526.
Background
Current literature suggests that use of synchronized nasal intermittent positive pressure ventilation (SNIPPV), following extubation, reduces the rate of reintubation compared to nasal continuous positive airway pressure (NCPAP). However, there is limited information available on the outcomes of infants managed with SNIPPV.
Objectives
To compare the outcomes of infants managed with SNIPPV (postextubation or for apnea) to infants not treated with SNIPPV at 2 sites.
Methods
Clinical retrospective data was used to evaluate the use of SNIPPV in infants ≤1250 g birth weight (BW); and 3 BW subgroups (500 –750, 751–1000, and 1001–1250 g, decided a priori). SNIPPV was not assigned randomly. Bronchopulmonary dysplasia (BPD) was defined as treatment with supplemental oxygen at 36 weeks’ postmenstrual age.
Results
Overall, infants who were treated with SNIPPV had significantly lower mean BW (863g vs. 964g) and gestational age (26.4 weeks vs. 27.9 weeks), more frequently received surfactant (85% vs. 68%), and had a higher incidence of BPD or death (39% vs. 27%) (all p<0.01), compared to infants treated with NCPAP. In the subgroup analysis, SNIPPV was associated with lower rates of BPD (43% vs 67%, P = .03) and BPD/death (51% vs 76%, P = .02) in the 500- to 750g infants, with no significant differences in the other BW groups. Logistic regression analysis, adjusting for significant covariates, revealed infants with 500 –700-g BW who received SNIPPV were significantly less likely to have the outcomes of BPD (OR: 0.29 [95% CI: 0.11– 0.77]; P = .01), BPD/death (OR: 0.30 [95% CI: 0.11– 0.79]; P = .01), neurodevelopmental impairment (NDI) (OR: 0.29 [95% CI: 0.09–0.94]; P = .04), and NDI/death (OR: 0.18 [95% CI: 0.05– 0.62]; P = .006).
Conclusion
SNIPPV use in infants at greatest risk of BPD or death (500-750g) was associated with decreased BPD, BPD/death, NDI, and NDI/death when compared to infants managed with NCPAP.
doi:10.1542/peds.2008-1302
PMCID: PMC2924622  PMID: 19651577
premature newborn; respiratory distress syndrome; non-invasive ventilation
23.  Numbers Needed to Treat With Phototherapy According to American Academy of Pediatrics Guidelines 
Pediatrics  2009;123(5):1352-1359.
OBJECTIVES
Our aims were to estimate the efficacy of hospital phototherapy for neonatal jaundice and the number needed to treat to prevent one infant from reaching the exchange transfusion level.
METHODS
From a cohort of 281 898 infants weighing ≥2000 g born at ≥35 weeks’ gestation at 12 Northern California Kaiser hospitals from 1995 to 2004, we identified 22 547 who had a “qualifying total serum bilirubin level” within 3 mg/dL of the American Academy of Pediatrics 2004 guideline phototherapy threshold. We used multiple logistic regression to estimate the efficacy of hospital phototherapy within 8 hours at preventing the bilirubin level from exceeding the 2004 guideline’s exchange transfusion threshold within 48 hours. We combined this efficacy estimate with other predictors of risk to estimate the numbers needed to treat at different values of covariates.
RESULTS
Of the 22 547 eligible newborns, 5251 (23%) received hospital phototherapy within 8 hours of their qualifying bilirubin level. Only 354 (1.6%) ever exceeded the guideline exchange transfusion threshold; 187 (0.8%) did so within 48 hours. Among infants who did not have a positive direct antiglobulin test, hospital phototherapy within 8 hours was highly effective (adjusted odds ratio, 0.16; 95% confidence interval, 0.07–0.34). For infants with bilirubin levels 0–0.9 mg/dL above the phototherapy threshold, the estimated number needed to treat at mean values of covariates was 222 (95% CI: 107–502) for boys and 339 (95% CI: 154–729) for girls, ranging from 10 (95% CI: 6–19) for <24-hour-old, 36-week gestation boys to 3,041 (95% CI: 888–11 096) for ≥3-day-old 41-week girls. Hospital phototherapy was less effective for infants direct antiglobulin test-positive infants (adjusted odds ratio 0.55; 95% CI: 0.21–1.45; P = 0.01 for the direct antiglobulin test × phototherapy interaction).
CONCLUSIONS
While hospital phototherapy is effective, the number needed to treat according to current guidelines varies considerably across different infant subgroups.
doi:10.1542/peds.2008-1635
PMCID: PMC2843697  PMID: 19403502
hyperbilirubinemia; jaundice; phototherapy; exchange transfusion; clinical guidelines; cohort studies; kernicterus; risk assessment
24.  Antioxidant status in neonatal jaundice before and after phototherapy 
Phototherapy has been related to increased oxidative stress and lipid peroxidation. In the present study, thirty full term jaundiced neonates with appropriate weight were analyzed before and after completion of phototherapy for malondialdehyde (MDA), reduced glutathione (GSH), total thiols, vitamin C and superoxide dismutase (SOD) levels in hemolysate and albumin levels in plasma. These parameters were analyzed in cord blood samples of 20 healthy neonates as control. It was observed that levels of MDA were elevated significantly (p<0.001) in patients as compared to controls and that the levels increased significantly after phototherapy (p<0.001). Levels of SOD were also found to be increased significantly as compared to controls and the levels rose after phototherapy (p<0.001). On the other hand, the levels of non-enzymatic antioxidants such as GSH, total thiols and vitamin C were significantly low (p<0.001) as compared to controls and the levels decreased significantly after phototherapy (p<0.001). The plasma albumin levels also were found to be decreased significantly after phototherapy (p<0.01). Therefore, phototherapy increases oxidative stress and should be used with care.
doi:10.1007/BF02913086
PMCID: PMC3453759  PMID: 23105589
Neonatal Jaundice; Oxidative stress; Phototherapy
25.  Hyperbilirubinemia and Neurodevelopmental Outcome of Very Low Birthweight Infants: Results from the LIFT Cohort 
PLoS ONE  2012;7(1):e30900.
Background
Bilirubin-related neurotoxicity is an important clinical issue in very low birthweight (VLBW) infants, and the existing literature is inconsistent.
Objective
To analyze the relationship between maximal serum unconjugated bilirubin levels (SBL) and neurodevelopmental outcome at 2-year corrected age in VLBW infants.
Methods
Phototherapy was initiated in all infants born before 33 weeks of gestation, according to Maisels' recommendations. Neurodevelopmental assessment at 2-year corrected age was performed in all infants that survived. SBLs collected during the first week of life were used to define three tertiles of max-SBL. The first tertile corresponded to infants with the lowest max-SBL.
Results and Conclusions
A total of 724 infants were included in the study, and among them, 631 (87%) were evaluated at two years old. The infants of the first tertile were younger and smaller than the infants of the other two tertiles, in accordance with Maisels' recommendations for very small infants. No difference in the risk of impaired functional outcome among the three groups was observed. However, among infants weighing less than 1001 g, those in the third tertile had a poorer neurodevelopmental prognosis as compared to those in the second tertile (adjusted odds ratio = 6.8, 95% CI: 1.2–36.7, p = 0.03). Considering the results obtained, we propose 196 µmol/L (11.5 mg/dL) when birthweight varies between 1001 and 1500 g, and 170 µmol/L (9.9 mg/dL) when birthweight is less than 1001 g, as recommended max-SBLs (defined as maximal levels of 95th percentile curves of SBLs in infants with an optimal outcome). When Maisels' recommendations were applied, max SBLs were higher in 8% of infants weighing 1001–1500 g and in 15% of infants weighing less than 1001 g. Our data seems to validate Maisels' recommendations in the overall population of infants born before 33 weeks of gestation, but not in infants weighing less than 1001 g.
doi:10.1371/journal.pone.0030900
PMCID: PMC3267748  PMID: 22303470

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