Implementing transcutaneous bilirubinometry in

jaundiced newborns: a randomized controlled trial

R.M.C. Pepping

November, 2015

Supervisor

J. Bekhof, M.D. PhD.

Paediatrician

Medicine, Master year 3

Research Clerkship

Department of Paediatrics, Isala hospital, Zwolle

Student number: 1720805

1

Abstract Introduction: Evaluation of hyperbilirubinemia in jaundiced neonates is performed by

determining serum bilirubin (SB) through painful blood sampling. The use of non-invasive

transcutaneous bilirubinometry instead, may reduce this need for blood sampling, herewith

decreasing pain and stress.

Methods: A randomized controlled trial including hospitalized jaundiced neonates ≥32weeks

gestational age was performed. The intervention group used a transcutaneous bilirubinometer

(Dräger Jaundice Meter-103, JM-103) measurement (TcB) on the sternum and the control

group used standard care, where the decision to obtain SB was based on visual and clinical

assessment. Indication for phototherapy or exchange transfusion was made according to the

international guidelines of the American Academy of Pediatrics. When TcB was less than

50µmol/L below the threshold for phototherapy, SB was obtained. The decision to start

treatment was always based on an SB value.

Results: A total of 176 neonates were randomized. In the intervention group (n=86), 60

neonates (69.8%) had at least one SB taken, versus 87 (96.7%) in the control group (n=90)

(difference 26.9; 95%CI 11.7 - 42.0; p<0.001). The number of blood samples per neonate in

the intervention group (1.3, SD1.3), was 27% lower than in the control group (1.9, SD1.0)

(difference -0.51; 95%CI -0.81 - -0.17; p=0.003). The highest SB value was higher in the

intervention group (232 µmol/L, SD53L) than in the control group (209 µmol/L, SD60;

95%CI 4.72 - 42.55; p=0.015). Though this was not considered as clinically relevant; we

found no difference in need to treatment, nor treatment duration or hospitalization length,

exchange transfusions did not occur.

Conclusion: The use of transcutaneous bilirubinometry is safe, feasible and reduces invasive

blood sampling in jaundiced neonates with 27%.

Samenvatting Introductie: Beoordeling van hyperbilirubinemie bij gele pasgeborenen gebeurt door middel

van bepaling van het serum bilirubine (SB) na een bloedafname. Een non-invasieve

transcutane bilirubinemeter zou het aantal bloedafnames kunnen verminderen met als gevolg

minder pijnsensaties en stressreacties voor de pasgeborene.

Methode: In een gerandomiseerde gecontroleerde trial werden gele pasgeborenen ≥32weken

amenorroeduur geïncludeerd. In de interventiegroep werd een transcutane bilirubinemeter

(Dräger Jaundice Meter-103, JM-103) op het sternum geplaatst voor een transcutane

bilirubinemeting (TcB). In de controlegroep werd na visuele en klinische beoordeling

besloten of een SB bepaling nodig was. De indicatie voor fototherapie of wisseltransfusie

werd gesteld aan de hand van internationale richtlijnen van de American Academy of

Pediatrics. Indien de TcB minder dan 50µmol/L van de drempelwaarden voor fototherapie

werd gemeten, volgde een SB bepaling. Behandeling werd gestart op basis van SB.

Resultaten: In totaal zijn 176 pasgeborenen gerandomiseerd. In de interventiegroep (n=86)

werd bij 60 pasgeborenen (69,8%) minimaal één SB bepaald, versus 87 (96,7%) in de

controlegroep (n=90) (verschil 26.9; 95%BI 11.7 - 42.0; p<0.001). Het aantal bloedafnames

per pasgeborene in de interventiegroep (1.3, SD1.3) was 27,4% lager dan in de controlegroep

(1.9, SD1.0) (verschil -0.51; 95%BI -0.81tot-0.17; p=0.003). De hoogste serum

bilirubinewaarde was hoger in de interventiegroep (232µmol/L, SD53) dan in de

controlegroep (209µmol/L, SD60; 95%BI 4.72 - 42.55 p= 0.015). Dit verschil was niet

klinisch relevant: we vonden geen verschil in de noodzaak tot behandeling, noch in de

behandelduur of opnameduur, wisseltransfusies waren niet nodig.

Conclusie: Het gebruik van een transcutane bilirubinemeter is veilig, toepasbaar en zorgt

voor een afname van 27% van invasieve, pijnlijke en stressvolle bloedafnames bij gele

pasgeborenen.

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Table of contents

1. Introduction ............................................................................................................................ 4

1.1 Neonatal icterus ................................................................................................................ 4

1.1.1 Neonatal icterus in the Netherlands ............................................................................ 4

1.2 Bilirubin ............................................................................................................................ 4

1.3 Hyperbilirubinemia ........................................................................................................... 5

1.3.1 Physiology .................................................................................................................. 5

1.3.2 Pathophysiology ......................................................................................................... 5

1.3.3 Clinical presentation and risk factors ......................................................................... 5

1.4 Diagnose ........................................................................................................................... 6

1.4.1 Transcutaneous bilirubinometry ................................................................................. 6

1.5 Treatment of hyperbilirubinemia ...................................................................................... 6

1.5.1 Phototherapy ............................................................................................................... 7

1.5.2 Exchange transfusion .................................................................................................. 7

1.5.3 Pharmalogical interventions ....................................................................................... 7

1.6 Aim of this study ............................................................................................................... 7

2. Methods .................................................................................................................................. 8

2.1 Setting ............................................................................................................................... 8

2.2 Patient population ............................................................................................................. 8

2.3 Transcutaneous bilirubinometry ....................................................................................... 8

2.4 Study protocol ................................................................................................................... 8

2.5 Randomisation, allocation and blinding ........................................................................... 9

2.6 Study approval .................................................................................................................. 9

2.7 Measurements of outcome ................................................................................................ 9

2.8 Data collection ................................................................................................................ 10

2.9 Sample size and statistical analysis ................................................................................. 10

3. Results .................................................................................................................................. 11

3.1 Patients ............................................................................................................................ 11

3.2 Characteristics ................................................................................................................. 12

3.3 Primary outcome variable ............................................................................................... 12

3.4 Secondary outcome variables.......................................................................................... 14

3.4.1 Highest serum bilirubin ............................................................................................ 14

3.4.2 Phototherapy ............................................................................................................. 14

3.4.3 Additional outcome variables ................................................................................... 14

3.4.4 Costs ......................................................................................................................... 15

3.4.5 Escape decision ......................................................................................................... 15

3

3.4.6 Agreement between TcB and serum bilirubin .......................................................... 15

4. Discussion ............................................................................................................................ 17

4.1 Main findings .................................................................................................................. 17

4.2 Comparison with existing literature ................................................................................ 17

4.3 Study limitations and strengths ....................................................................................... 19

4.4 Future research and recommendations ............................................................................ 20

5. Conclusion ............................................................................................................................ 20

6. References ............................................................................................................................ 21

7. Appendix A .......................................................................................................................... 25

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1. Introduction

1.1 Neonatal icterus Neonatal icterus or neonatal jaundice is a very common phenomenon in newborn babies. (1,2)

Jaundice is the observed yellow pigmentation of skin and sclerae, caused by a rise in

concentration of bilirubin (section 1.2). (3) The term neonatal jaundice is therefore used

interchangeably with the term neonatal hyperbilirubinemia. It is important to diagnose

hyperbilirubinemia, as high levels of bilirubin can cause potential, irreversible neurological

damage (section 1.3). (4) To quantify hyperbilirubinemia in visibly jaundiced neonates

appropriately, it is necessary to determine the bilirubin level in the serum by a blood sample

and not to rely only on sight (section 1.4). (4-7) When the bilirubin concentration in the

sample exceeds a certain threshold, according to international guidelines, treatment existing of

phototherapy or even exchange transfusion is required (section 1.5). Many possible causes for

neonatal hyperbilirubinemia exist, whereby the great majority of cases is due to a transient

physiologic jaundice and a minority is caused by pathological conditions (section 1.3.2).

Therefore, it is challenging to decide whether jaundiced non-ill neonate needs an invasive

blood sample taken? (section 1.6)

1.1.1 Neonatal icterus in the Netherlands

In the Netherlands, 50% - 60% of newborns become jaundiced during the first week of life.(8)

The exact incidence of hyperbilirubinemia that requires treatment however, is unknown. (9)

In 2008, the Paediatric Association of the Netherlands (Nederlandse Vereniging voor

Kindergeneeskunde, NVK) made an estimate, based on combining different Dutch registration

systems which state that in 2% - 5% of jaundiced an intervention to treat hyperbilirubinemia

is warranted. The NVK guideline states: “when in doubt, take a blood sample.” (9) As doubt

is often the case, a high number of often needless, painful and stressful blood samples are

taken, as a consequence (section 1.4). (10) Fortunately, new studies show that a valid, non-

invasive alternative method is available, that determinates the bilirubin level in the skin

through transcutaneous bilirubinometry. (4,9,11-14) This method is not only more patient

friendly, but also reduces the need and costs for blood sampling (section 1.4.1). (10,12,15,16)

1.2 Bilirubin Bilirubin is a toxic end product of heme catabolism. (2) Due to this catabolism, which takes

place in the reticuloendothelial system, a red blood cell is broken down and as a result

bilirubin comes into the blood serum. (17) When a red blood cell is broken down, heme is

degraded into biliverdin during heme oxygenase which is found in the liver, spleen and

macrophages. The enzyme biliverdin reductase then converts biliverdin into bilirubin. This

bilirubin is called unconjugated bilirubin or indirect bilirubin, which will bind to albumin and

finally be released into the circulation. (2) As a complex with the albumin, bilirubin is

transported through the hepatocyte membrane to the endoplasmatic reticulum, where

unconjugated bilirubin will be conjugated. (2,8) This conjugation is crucial for efficient

biliary excretion of bilirubin. Conjugated bilirubin or direct bilirubin is excreted into the

duodenum, where intestinal bacteria degrade conjugated bilirubin to urobilinogen and further

into stercobilinogen. These latter two give the normal colour to respectively urine and faeces,

which will be excreted from the body containing bilirubin. (2) Most of the urobilinogen

however, is degraded into unconjugated bilirubin again and reabsorbed from the intestines,

then transported to the liver where it undergoes the so-called enterohepatic circulation.

Therefore, this urobilinogen is one of the major mechanisms responsible for neonatal

icterus.(17)

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1.3 Hyperbilirubinemia 1.3.1 Physiology

Hyperbilirubinemia is caused by a high level of bilirubin in blood serum. Neonates have a

much higher production of bilirubin than adults, which causes hyperbilirubinemia. (2) There

are two main reasons for this. Firstly, there is a postnatal rapid rise due to a combination of a

high bilirubin load and a decreased hepatic excretion. The latter in view of the fact that all

neonates have relatively impaired hepatic function during the transitional period after birth.

(2,3) Secondly, there is a high concentration of haemoglobin containing about 80% foetal

haemoglobin, which will be replaced by adult haemoglobin during the first four months of

life. (2,8) This haemoglobin turnover is a major factor in the excess bilirubin production. But

also bruising during birth and cephalohematomas will contribute to higher bilirubin

concentrations, with hyperbilirubinemia as a result. (2) A neonate is not yet able to cope with

the normal bilirubin concentration, let alone the increased concentrations due to

aforementioned different mechanisms. Consequently, a hint of jaundice can be expected and

this is in most cases a physiological phenomenon.

1.3.2 Pathophysiology

When neonatal icterus appears in the first 24 hours after birth, it is always defined as

pathological, mostly due to active hemolysis, and needs further investigation. This form of

jaundice is by far the most dangerous, as the concentration of unconjugated bilirubin can rise

rapidly to a neurotoxic and damaging level; causing acute bilirubin encephalopathy and in

worst case kernicterus. (2,17,18) Acute bilirubin encephalopathy is the first clinical

presentation of elevated bilirubin concentrations, presenting with central nervous system

symptoms (section 1.3.3). (4,19) Kernicterus is nowadays also called chronic bilirubin

encephalopathy, because it is usually a consequence of severe or untreated acute bilirubin

encephalopathy. Kernicterus is caused by deposits of unconjugated bilirubin in different

nuclei of the brain, turning them yellow, hence kernicterus. Unconjugated bilirubin is water

insoluble and therefore able to cross the blood-brain barrier. (18,19) Bilirubin deposits

develop when the concentration increases to a certain level and cross the blood-brain barrier.

(18) Especially the globus pallidus, subthalamic nucleus and different vulnerable nuclei in the

brainstem, such as the auditory, the oculomotor and the vestibular nuclei, are damaged by

these deposits. (19) Therefore, it is very important to identify the cases of hyperbilirubinemia

that are in need for treatment; in order to prevent (irreversible) neurological damage.

1.3.3 Clinical presentation and risk factors

The clinical presentation of hyperbilirubinemia has a variety of symptoms, is not always clear

and often non-symptomatic. Acute bilirubin encephalopathy is divided into three phases: the

initial phase is characterized by feeding problems, hypotonia, drowsiness and lethargy; the

intermediate phase is characterized by irritability and hypertonia, the latter can cause

retrocollis and ophisthotonus, they may also develop a fever and a high pitched cry. These

symptoms and the symptoms from the initial phase can alternate. When the advanced and last

phase is sustained the neurological damage is generally irreversible; typical symptoms during

this phase are apnoea’s, high fever, stupor to coma, seizures and all aforementioned

symptoms. This phase has unfortunately a high mortality rate. (4,9,19)

Kernicterus will develop if the abovementioned is survived. Classical symptoms are athetotic

cerebral palsy, auditory dysfunction, dental enamel dysplasia, vertical gaze palsy and

sometimes intellectual and other handicaps. (4,9) Luckily, kernicterus is rare and the

incidence for kernicterus is very low worldwide. (20-22)

The major risk factor for developing hyperbilirubinemia is haemolytic diseases of the

newborn, these rapidly increase the level of unconjugated bilirubin. There is a variety of

6

haemolytic diseases, rhesus and AB0 blood group incompatibility being the most frequent

causes of early rising bilirubin levels. (2,4) Sepsis, prematurity, bruises and

cephalohematomas, siblings who received hyperbilirubinemia treatment and exclusive

breastfeeding are other important factors.

1.4 Diagnose The standard method, the gold standard, to determine hyperbilirubinemia is to obtain an

invasive serum bilirubin sample. (7,9) This is, after the routine screening for inborn errors, the

most frequent reason to perform a venous heel prick in neonates. (10,12) These heel pricks are

painful, traumatizing, time-consuming, costly and not to mention a serious cause of distress

for the neonates, as well as for their parents. (7,10,23) There is no way to establish for certain

if it is necessary to obtain a serum bilirubin; it is a subjective decision made by the

professional. (9,24) This decision is in most cases based on a visual assessment of the

jaundice, usually led by Kramer’s rule, which states a cranio-caudal system that correlates

with the serum bilirubin. (25) As a result, 17% to 71% of jaundiced neonates has a blood

sample taken for bilirubin concentration at least one time. (26,27) Whereas, as

aforementioned only 2% - 5% of the jaundiced neonates need actual treatment (section 1.1.1).

(9,26) Therefore, many of the blood samples, up to 77% - 78%, are unnecessary (24,26,27)

and put neonates each time at risk of complications such as anaemia, infection, needle stick

injuries and even osteomyelitis. (28,29) Moreover, over the past two decades, many studies

demonstrate a poor resemblance between Kramer’s visual rule and the serum bilirubin. (5-

7,10,11,15,26)

1.4.1 Transcutaneous bilirubinometry

Transcutaneous bilirubinometry is a good and reliable, non-invasive screening method to

detect hyperbilirubinemia that requires treatment. Since the 1980s, the use of a transcutaneous

bilirubinometer has already been described to detect hyperbilirubinemia and to decrease heel

pricks and costs. (23) But strangely enough, little use is made of it since then, also in the

Netherlands. (4,9,16,27) Several instruments have been developed over the past three decades

and these have all been extensively studied in comparison to serum bilirubin and Kramer’s

rule. (7,10,11,15,16,21,30,31) This novel method shows excellent results that correlate very

well with serum bilirubin. (7,10,11,15,16,30,32)

One of the best studied devices is the Dräger Minolta/Hill-Rom Air-Shields Transcutaneous

Jaundice Meter 103 (JM-103). This device uses a dual optical path system and two

wavelengths to establish the bilirubin load in the subcutaneous tissue and deeper layers, hence

transcutaneous bilirubin (TcB). (30) The best measuring place to establish the bilirubin load

in the skin is the sternum. (16,30) Measurement of the skin means that transcutaneous

bilirubin is not a reproduction of serum bilirubin but can be used as a screening method; it

helps to make that doubtful decision whether to get a serum bilirubin as well as to indicate

when to worry about a newborn. (21)

Even in neonates with a dark skin the transcutaneous bilirubinometer can be used. (15,33) The

JM-103 has the predominant tendency to overestimate the TcB value in comparison to the

serum bilirubin in black neonates. (30,34) Therefore, the only drawbacks are: the decision to

do a serum bilirubin measurement anyway or an extra follow-up appointment. But more

importantly, it will be unlikely to miss clinically significant hyperbilirubinemia that requires

treatment.

1.5 Treatment of hyperbilirubinemia Established hyperbilirubinemia that exceeds the threshold values will be treated with

phototherapy, whereas severe hyperbilirubinemia will need an exchange transfusion as

7

treatment. The aim of the treatment is to reduce the amount of unconjugated bilirubin and

hereby preventing kernicterus or neurological damage. The thresholds published by the

American Academy of Pediatrics (AAP) are used to asses if there is need for intervention.

(4,26) In the Netherlands, the NVK guidelines are based upon these AAP guidelines. They

suggest four different hour specific nomograms with their own thresholds for specific

gestational age, birth weight and presence of risk factors.

1.5.1 Phototherapy

Phototherapy converts unconjugated bilirubin into more water soluble substances, which can

be excreted from the body without the necessary conjugation by the liver. Phototherapy is

used in the overwhelming majority of newborns. It uses blue or green light with wavelengths

of 430-490 nm; from lamps, a blanket or both. The neonate should be naked during

phototherapy, except for a diaper and covering of the eyes for protection, to expose as much

skin as possible. During the first 24 hours of phototherapy the bilirubin diminishes with 6% -

20%. (4,9) Combined with phototherapy, hyper hydration is indicated. This means a fluid

supplementation of extra breastfeeding or formula, during phototherapy treatment. It

decreases the rate of exchange transfusions but also the duration of phototherapy. (9,35) Like

any other treatment, there is always a risk of side-effects and complications. Common side-

effects are erythema and dehydration; complications are rare but burn wounds, necrotizing

enterocolitis and retinopathy are reported.

1.5.2 Exchange transfusion

Transfusion is used when phototherapy proofs not to be sufficient or directly in case of severe

hyperbilirubinemia. Transfusion is a much faster intervention to decrease the bilirubin

concentration. During transfusion there will be a replacement of 85% of the neonates’

circulation, with a 50% decrease of bilirubin as a result. But, as can be imagined, it comes

with more risks and more dangerous complications. Complications that are reported vary from

metabolic problems, risks of central venous lines, infections, graft versus host-disease to even

death. (2,36)

1.5.3 Pharmalogical interventions

High dose intravenous immunoglobulin can be used to treat haemolytic diseases of the

newborn, especially the most frequent causes of severe hyperbilirubinemia: rhesus and AB0

blood group incompatibility. (4,9,37) In addition, there are studies that implicate that

metalloporphyrins may reduce high levels of unconjugated bilirubin in jaundiced neonates or

can even prevent the formation of bilirubin. However, more research is needed in this field.

(4,9,38)

1.6 Aim of this study As previously stated in section 1.4, a large number of unnecessary painful heel pricks is

performed to ascertain hyperbilirubinemia. This study aims to improve quality and cost

effectiveness in care of jaundiced newborns by implementing the use of a transcutaneous

bilirubinometer at the children’s ward. A convenient, accurate and non-invasive method

would benefit the neonates and their families, but also the doctors. (30)

This study focuses on the question whether the use of a transcutaneous bilirubinometer in

hospitalized jaundiced neonates leads to reduced number of blood tests, reduced

complications, shorter duration of treatment and hospitalization and reduction of costs.

Compared to the present-day situation relying on visual assessment.

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2. Methods

2.1 Setting This randomised controlled trial was carried out between February 2014 and June 2015 in

Isala hospital, a large general teaching hospital which is situated in Zwolle, The Netherlands.

This hospital region has a predominantly Caucasian population. Annually, there are over 520

newborns admitted to the medium care and high care unit of the paediatric ward. In 2010,

71% of these 520 newborns had at least one blood sample taken for bilirubin determination,

while in only 16% an intervention for hyperbilirubinemia was instituted. (27)

2.2 Patient population All admitted newborns with gestational age ≥ 32 weeks, older than 24 hours but younger than

≤ 7 days with a clinically, observable jaundiced skin were eligible for this study. Newborns

were excluded when jaundice appeared in the first 24 hours after birth or after one week.

Other reasons for exclusion were: haemolytic diseases of the newborn, clinical kernicterus,

congenital anomaly on the sternum, earlier treatment with phototherapy or if there was

already a blood sample taken for serum bilirubin.

2.3 Transcutaneous bilirubinometry Dräger Konica Minolta Air-Shields Jaundice Meter model 103 (JM-103) was used to obtain

transcutaneous bilirubin measurements, figures 2.1 and 2.2. This device is a validated

measurement instrument. (30,39) It was used by the prescriptions of Dräger and a non-

published validation research at Isala hospital. (27) It is calibrated daily on a measuring

station and its acquisition price was € 5900,00.

Figure 2.1 Figure 2.2

2.4 Study protocol A randomized controlled trial was performed. After written informed consent of the parents

was obtained, eligible neonates were randomised to the intervention group or control group,

as shown in figure 2.3. The intervention existed of transcutaneous measurement of bilirubin,

whereas in the control group neonates received our standard of care, meaning that the

attending physician decided whether serum bilirubin measurement in blood was ordered after

visual assessment. Blood samples were obtained by a peripheral venous heel puncture by the

laboratory staff. The transcutaneous measurement of bilirubin (TcB) was performed by

placing the JM-103 on the sternum to obtain a single TcB measurement, as can be seen in

figure 2.2. International thresholds for phototherapy or exchange therapy were used as

9

Jaundic

ed n

eonate

Randomisation

Intervention

TcB ≤ 50µmol/L below treshold

Serum bilirubin

Treatment

No treatment TcB > 50µmol/L above treshold

Clinical observation

Control

Serum bilirubin

Treatment

No treatment

No serum bilirubin

Clinical observation

Informed consent Yes/No

follows: in every neonate with a TcB value less than 50 µmol/L under the applicable

threshold for phototherapy, a blood sample was taken for serum bilirubin measurement. (4)

(Appendix A) The decision to start phototherapy was based on the serum bilirubin value

according to the international threshold. The 50 µmol/L margin was applied because of a

known unreliability of TcB compared to serum bilirubin. (16,27,30,34) When TcB was higher

than 50 µmol/L above “obtain an SB threshold,” the neonate would receive clinical

observational care. When it was less than 50 µmol/L below treatment threshold, a serum

bilirubin sample was taken.

To safeguard against missing a neonate with significant jaundice, the attending physician

could always have a blood sample for serum bilirubin ordered, despite normal values of TcB.

These ‘escape decisions’ and their outcome were recorded.

Figure 2.3 Study protocol Jaundiced neonate. TcB= transcutaneous bilirubin

2.5 Randomisation, allocation and blinding Randomisation was stratified in three groups according to gestational age: preterm ≥ 32 weeks

and <34 weeks; late preterm ≥ 34 weeks and < 38weeks; full-term ≥ 38 weeks.

Randomisation occurred by computer, using the program Research Manager for Windows. In

this way concealment of allocation was secured.

Given the nature of the intervention, blinding of the intervention was not possible.

2.6 Study approval Written informed consent to participate in the study was obtained from the parents of the

neonates. The trial protocol and consent forms were approved by the ethics committee of Isala

hospital, METC number NL40354.075.12 (via ccmo.nl) Trial registration number:

NCT01622699 (via ClinicalTrials.gov)

2.7 Measurements of outcome The primary outcome variable of this study is the number of blood samples taken before

eventual treatment, depicted by the number of patients having at least one blood sample taken

for bilirubin measurement and the number of serum bilirubin samples per neonate.

Secondary outcomes are: the highest measured serum bilirubin value and the duration of

phototherapy treatment in hours.

Additional outcome variables are the amount of serum bilirubin values above exchange

transfusion threshold, the number of neonates with clinical kernicterus and the cost evaluation

regarding blood sampling, JM-103 use and hospitalization. Also, the resemblance between

TcB measurement outcome and SB outcome, with neonates for which the ‘escape decision’

of the medical team is used.

10

Finally, agreement between TcB and serum bilirubin values was assessed in a subgroup of

neonates in the intervention group who had TcB ≤ 50µmol/L below the treatment threshold.

2.8 Data collection The general characteristics recorded were: sex, birth weight and whether birth weight was

normal for gestational age or more than ± 2 standard deviation (SD), date and time of birth,

ethnicity limited to Caucasian or Non-Caucasian, and risk factors for hyperbilirubinemia such

as prematurity, (gestational age below 38 weeks), asphyxia (5 minute APGAR below 5 or

umbilical cord pH below 7.0), blood group incompatibility and clinical suspicion for sepsis or

meningitis. Furthermore, any hematomas or a cephalohematoma were registered. The

following suspected causes of hyperbilirubinemia were recorded: prematurity, feeding

problems (exclusive breastfeeding malnutrition), sepsis/infection, haemolysis because of

hematomas or blood group incompatibility, physiological jaundice or other. In addition, the

kind of feeding given until jaundice appeared was recorded: exclusive breastfeeding,

breastfeeding in combination with formula or exclusive formula. Finally, the lowest weight

after birth was registered to determine the total weight loss during hospitalization. If the

weight loss was more than 7%, the cause was administered as feeding problems, while a loss

of or less than 7% was administered as physiological jaundice; if no other obvious cause.

When gestational age was less than 35 weeks the cause of jaundice was registered as

prematurity. It was also registered whether a single sided light therapy by two lamps or

double sided therapy by two lamps and a blanket was used in case of phototherapy treatment.

Finally, the hospital stay was registered in days.

2.9 Sample size and statistical analysis A total sample size of 164 jaundiced neonates is necessary for demonstrating a minimum of

30% reduction in blood sampling, based upon previous research by Mishra et al. and Maisels

et al. (12,15) On the basis of two-sided significance of 5% and a power of 80%, there are 82

neonates needed in each group.

Data were analysed using IBM SPSS Statistics version 23 for Windows. Continuous variables

with normal distributions were analysed with the Student’ t-test. When a non-normal

distribution was found, the Mann-Whitney U test was used. For the dichotomous outcome

measures, the Chi-square test was used and in case of small numbers the Fisher’s Exact test.

P-value <0.05 was considered significant. A Bland-Altman plot was made for agreement

between measurements of the JM-103 TcB values and the serum bilirubin values. (40)

11

3. Results

3.1 Patients In this study, 176 jaundiced newborns were included from the neonatal medium care and high

care unit of the paediatric ward. As shown in figure 3.1 below, a total number of 241 neonates

were assessed for eligibility, of which 65 were excluded for various reasons: declined to

participate (n=9), not meeting inclusion criteria (n=27) and 29* had other reasons; of which

eleven could not be randomized due to logistic difficulties (weekends, holidays), nine reasons

were unknown, four were not randomized during a period with the JM-103 being out of order,

three were not included because the attending physician did not want to bother parents of very

ill neonates and two because of a language barrier and parents did not understand the purpose

of the study. One neonate was allocated to the intervention group, but a serum bilirubin

sample was taken instead of a TcB measurement, because of a defect JM-103. This neonate

was analysed in the intervention group according to the intention to treat principle.

Figure 3.1 CONSORT Flow Chart for the implementation of a transcutaneous bilirubinometer.

* Main reasons: could not be randomized due to logistic issues (weekends, holidays) (n=11), unknown (n=9) and the JM-103 being out of

order (n=4) ** Was allocated to intervention group, but no transcutaneous bilirubinometer was used: an SB was obtained.

12

3.2 Characteristics Table 3.1 shows the baseline characteristics that were collected per neonate. Both groups are

equal in baseline characteristics which confirms an adequate randomisation.

Characteristics Intervention

(n = 86)

Control

(n = 90)

Age mother (years) 30±5 30±5

Male gender 49 (57) 50 (55.6)

Gestational age (weeks+days

) 35+3

±2 35+3

±2

<34

≥34 - <38

≥38

19 (22.1)

60 (69.8)

7 (8.1)

19 (21.1)

61 (67.8)

10 (11.1)

Birth weight (grams) 2491±664 2434±499

SGA (<2SD)

AGA

LGA (>2SD)

2 (2.3)

80 (93.0)

4 (4.7)

5 (5.6)

85 (94.4)

0 (0)

Risk factors 82 (95.3) 81 (90)

G.A. <38

Asphyxia

Blood group

incompatibility

Sepsis/meningitis

79 (91.9)

2 (2.3)

0 (0)

5 (5.8)

80 (88.9)

0 (0)

0 (0)

2 (2.2)

Ethnicity

Caucasian

Non-Caucasian

Unknown

77 (89.5)

4 (4.7)

5 (5.8)

78 (86.7)

6 (6.7)

6 (6.7)

Feeding

Only breastfeeding

Only formula

Combination

3 (3.5)

19 (22.1)

64 (74.4)

6 (6.7)

20 (22.2)

64 (71.1)

Weight loss (grams) 4.8±2.7 5.2±3.0

<7%

≥7%

71 (82.6)

15 (17.4)

67 (74.4)

23 (25.6)

Haematomas 11 (12.8) 7 (7.8)

Diagnose

G.A. <35

Feeding problems

Sepsis/infection

Haemolysis

Physiologic

Other

30 (34.9)

13 (15.1)

5 (5.8)

4 (4.7)

34 (39.5)

31 (34.4)

20 (22.2)

0 (0)

1 (1.1)

37 (41.1)

1 (1.1)*

Table 3.1 Data expressed as number (%) or mean ± standard deviation (SD). SGA=small for gestational age, AGA=appropriate for

gestational age, LGA=large for gestational age. G.A.=gestational age in weeks. *Was diagnosed with midgut volvulus.

3.3 Primary outcome variable A total number of 180 TcB measurements (mean 2.1±1.1SD per neonate) was recorded in the

intervention group (n=86). There were two medical charts without the measured TcB values

recorded, however these two neonates had no SB samples taken nor phototherapy treatment

registered; assuming that these TcB measurements were in order. Following these 180 TcB

measurements, 116 SB samples (64.4%) were obtained in conformity with the study protocol.

Twenty-six neonates (30.2%) however, did not need an SB sample taken at all, after the TcB

measurement.

13

In the control group (n=90), 87 neonates (96.7%) had at least one SB sample taken after

visual assessment. A total number of 167 SB samples was taken before potential treatment,

shown in table 3.2.

The number of SB measurements before treatment in the intervention group was significantly

lower compared to the control group with a difference of -0.51 in the number of blood

samples per neonate (95%CI -0.84 - -0.17). With a mean of 1.86 SB measurements in the

control group and a difference of -0.51, there is a significant reduction of 27.4% (95%CI 11.7

- 42.0) in the need for invasive blood sampling in the intervention group.

Intervention

(n=86)

Control

(n=90)

Difference (95% CI) p-Value

Number of SB before phototherapy 116 167 - -

Neonates with minimal one SB sample 60 (69.8) 87 (96.7) 26.9 (11.7 - 42.0) <0.001*

SB samples before phototherapy 1.3±1.3 1.9±1.0 -0.51 (-0.84 - -0.17) 0.003*

Table 3.2 Data expressed as number(%), mean ±SD, CI= confidence interval. *Significant

Figure 3.2 below shows an overview of the number of SB measurements per neonate. As can

be seen, there was also a single neonate that required six SB samples following the study

protocol. This figure clearly illustrates the higher number of SB samples taken in the control

group.

Figure 3.2 Number of SB measurements per neonate. SB=serum bilirubin

14

3.4 Secondary outcome variables 3.4.1 Highest serum bilirubin

The mean highest serum bilirubin in the intervention group was significantly higher with

232.3µmol/L±SD53.3µmol/L, compared to 208.7µmol/L±SD59.9µmol/L in the control

group, with a difference of 23.6µmol/L (95% CI 4.72 - 42.55; p=0.015) as can be seen in table

3.3. There is no obvious reason that could explain why the serum bilirubin was higher in the

intervention group. More importantly this difference is very small and does not seem to be

clinically relevant.

Intervention

(n=86)

Control

(n=90)

Difference (95% CI) p-Value

Highest SB (µmol/L) 232.3±53.3 208.7±59.9 23.6 (4.72 - 42.55) 0.015*

Table 3.3 Data expressed as mean ±SD , CI=confidence interval.*Significant

3.4.2 Phototherapy

Overall, 56 neonates (31.8%) required phototherapy (31/86, 36% in the intervention group

versus 25/90, 27.8% in the control group (difference 8.3; 95% CI 22 - -5.45; p=0.239), see

table 3.4. Most of these treatments were single sided therapy, 74.2% in the intervention group

versus 76% in the control group. The mean age at the start of phototherapy was approximately

3.5 days, while the first measurement, because of visible jaundice, was taken after

approximately 2.5 days. The duration of phototherapy was almost equal in both groups. There

was no difference between the amount of SB samples taken after phototherapy (p=0.362), see

table 3.5. Almost all neonates had at least two SB measurements taken after treatment was

finished, which is usually done to monitor the effect of treatment, the tendency of bilirubin

and to detect rebound hyperbilirubinemia. There was one neonate in both groups without

recorded SB samples after treatment, because of relocation to another hospital during

phototherapy treatment for logistic reasons and no discharge letter with medical information

was send back.

Intervention

(n=86)

Control

(n=90)

Difference (95% CI) p-Value

Phototherapy 31 (36) 25 (27.8) 8.3% (22 - -5.45) 0.239

Age (h) at first measurement 59±20 64±21 4.50 (-10.74 - 1.75) 0.157

Age (h) at the start of phototherapy 83±22 87±26 4 (-16.73 - 8.8) 0.536

Duration of phototherapy (h) 24 [20-44] 24 [22-45] - 0.924

Table 3.4 Data expressed as number (%) , mean ± SD or median and interquartile range [], h=hours, CI=confidence interval.

Intervention

(n=30)

Control

(n=24)

Difference (95% CI) p-Value

Number of SB after phototherapy 2.2±1.7 2.6±1.5 -0.40 (-1.27 - 0.47) 0.362

Table 3.5 Data expressed as mean ±SD, CI=confidence interval.

3.4.3 Additional outcome variables

Table 3.6 below shows an overview of additional outcome variables. Three neonates (3.5%)

had SB values above the exchange transfusion threshold, all in the intervention group. These

neonates were very premature, 32 and 33 weeks of gestational age. Their development

appears to be normal and clinical follow up has been terminated. None of the neonates in both

groups underwent exchange transfusion, because serum bilirubin was below transfusion

threshold after initiating phototherapy before the exchange blood was available. None of all

participating neonates developed a clinical kernicterus or had indicating symptoms. The

15

duration of hospital admission was comparable in both groups. No additional complications

were registered in the medical charts of any of the participating neonates.

Intervention

(n=86)

Control

(n=90)

SB value above transfusion threshold 3 (3.5) 0 (0)

Exchange transfusion 0 (0) 0 (0)

Kernicterus 0 (0) 0 (0)

Duration of hospital admission (days) 13 [6-18] 12 [7-17] Table 3.6 Data expressed as number (%) or median and interquartile range []

3.4.4 Costs

The single costs for an SB sample determination by the laboratory staff is € 8.00. As shown in

figure 3.1 above, 241 neonates were visibly jaundiced during the 17 month study period, of

which 61% had their blood taken at least once. So annually, there are at least 170 jaundiced

neonates at the children’s ward. With a mean of 1.86 SB samples per neonate (table 3.2) there

are annually 316 SB measurements performed. The transcutaneous bilirubinometer reduces

the need for blood sampling by 27.4%. This means that the annual cost reduction, after

implementing the JM-103, will be a minimal of € 693.11. With the JM-103 purchasing price

of € 5,900.00, it will take a maximum of 8.5 years to have a cost recovery. With a functional

depreciation of 10 years for medical devices in the Isala hospital, the JM-103 has its own cost

recovery. (41)

3.4.5 Escape decision

The escape decision was the opportunity for the attending physician to overrule an obtained

TcB value and determine an SB. With two neonates (2.3%) the escape decision was made by

the attending physician. One time this was done because the JM-103 was out of order, so only

an SB sample was measured and no comparison could be made, see figure 3.1; the other time

the reason for obtaining an SB after a normal TcB was not registered in the medical chart.

This latter escape decision had a TcB value of 188 µmol/L and an SB value of 213 µmol/L,

with a difference of 25 µmol/L. These values were below phototherapy threshold, so there

were no clinical consequences in this case and the SB measurement appeared to be

unnecessary. The next day, only the JM-103 was used with this neonate, with no blood

sampling or treatment as a consequence.

3.4.6 Agreement between TcB and serum bilirubin

A Bland-Altman plot, figure 3.3 below, was used for the evaluation of the agreement between

TcB values and SB values recorded with neonates whose SB sample was taken following

study protocol; when the TcB value was less than 50 µmol/L below the phototherapy

threshold. This Bland-Altman plot shows no agreement (p<0.001) between the limits of

agreement with a mean bias of 10.56 µmol/L, with the upper limit of agreement of 72.56

µmol/L and a lower limit of agreement of -51.44 µmol/L. With the lower limit being almost

equal to the clinical margin set at 50 µmol/L.

The total number of combined measurements to compare was 110, while 116 SB samples

were taken. It appeared that in the first phase of the study sometimes, for the second

assessment an SB was taken right away, instead of taking a TcB measurement first. Of these

110 combined measurements, 14 (12.7%) had more than the previously mentioned 50 µmol/L

margin difference between the JM-103 TcB value and SB value, higher or lower. In 11 (10%)

of these 14, the TcB was more than 50 µmol/L higher than the actual SB value, in retrospect

one can judge that blood samples were taken unnecessarily. In the other three samples (2.7%)

the TcB was more than 50 µmol/L lower that the actual SB value, meaning that these

16

neonates in theory could have been missed using only the JM-103. In this study, these three

neonates did get an SB sample, because their TcB value was still in range of the 50 µmol/L

margin. These neonates were all Caucasian, preterm, had feeding problems and had ≥ 7%

weight loss; one was later diagnosed with pyloric hypertrophy. Because their SB value was

above the phototherapy threshold, they all received appropriate treatment and there were no

complications.

Figure 3.3 Bland-Altman plot for the total amount of combined measurements (n=110).

SB= serum bilirubin, JM-103= jaundice meter-103

The JM-103 TcB values in this study were generally more overestimating and in the higher

regions of serum bilirubin values the JM-103 underestimates. There are no factors found to

explain this over- and underestimating.

The mean delay in time between the TcB measurement and the following SB measurement

was 138 minutes±142SD. The time interval between the 14 measurements that differed more

than 50 µmol/L from each other, was not significantly different.

There was also a Bland and Altman comparison made (not shown) between the TcB and SB

measurements of the non-Caucasian neonates and these combined with the neonates whose

ethnicity remained unknown; in case they were all non-Caucasian. As can be seen in table 3.1

above, there are only four neonates who are non-Caucasian in the intervention group. These

neonates together had only five TcB values and SB values to compare. These five had a

significance of p=0.454 which means that there is an agreement between the measurements.

Combined with the neonates whose ethnicity remained unknown, there were ten

measurements to compare of nine neonates. Also, all these measurements were between the

limits of agreement.

17

4. Discussion

4.1 Main findings This study showed a useful way of diminishing unnecessary blood sampling in jaundiced

newborns by using a transcutaneous bilirubinometer compared to the visual assessment of

jaundiced neonates admitted to the neonatal ward. We safely achieved a reduction of 27% in

number of blood tests. The costs for purchasing the bilirubinometer (JM-103) were

compensated by the reduction in costs due to less blood tests. Obtaining a TcB is quick and

easy, and it can be used as many times as desired. One must however always be critical after a

TcB measurement and clinical assessment remains most important.

4.2 Comparison with existing literature Mishra et al. found a reduction of 34% in need for blood sampling, compatible with the 40%

Maisels et al. found, which is slightly more than the 27.4% in this study. (12,15) Although

they only included healthy newborns with gestational age ≥ 35 weeks and we included more

preterm neonates.

Mishra et al. showed a basal rate of 26.4% of SB samples taken after visual assessment, which

is much lower than the 96.7% found in our study. They had the visual assessment done only

by a paediatrician who had a minimum of five years of clinical experience and was trained to

do so following their study protocol related to Kramer’s rule. In our study period, there were

different doctors on the ward, varying from a paediatrician, a resident and a junior resident to

interns. They all rely on their own experience and knowledge, resulting in different ratings of

SB samples taken; which is more reliable to clinical practice. Moreover our study population

yielded hospitalized, sick neonates, in whom the threshold for obtaining an SB on our ward

has been low, for reasons of not wanting to miss a high bilirubin in this vulnerable population.

Our study showed that after the initial assessment of hyperbilirubinemia by transcutaneous

bilirubinometry in 64.4% serum bilirubin was obtained, because the TcB was < 50 µmol/L

below phototherapy threshold. Mishra et al. found only 17.5% in their Indian population

needing an SB after the initial TcB. They used the same margin of 50 µmol/L, but it is not

known if they used the AAP thresholds. However, they included only healthy newborns with

gestational age of ≥ 35 week, whereas we included all neonates ≥32 weeks. It is known that

prematurity is a major risk factor for hyperbilirubinemia. Moreover, the thresholds for

phototherapy in preterm neonates are much lower than in term neonates, due to increased

neurological vulnerability and susceptibility for bilirubin toxicity. Also, they visually

evaluated jaundice every 8 hours, with a TcB measurement followed immediately and

obtained many more TcB measurements this way. In our study a TcB was obtained, only

when visible jaundice occurred. This will have resulted in less SB measurements compared to

TcB, as repeated TcB measurements were only necessary in jaundiced neonates not needing

phototherapy.

While in our study 32% of the neonates underwent phototherapy compared to 7.1% Mishra et

al. found. This may explain the higher rate of SB measurements obtained in our study

population. The 32% found in our study is much higher than the general estimate of the NVK

of 2% - 5% in the Netherlands. (9) This is probably caused by our study population with a

high number of preterm neonates, which are more at risk of developing hyperbilirubinemia. A

few more neonates in the intervention group needed phototherapy however, this fact may

partially account for the higher serum bilirubin that was found in the intervention group. In

both groups the physiology of jaundice appeared to develop normally: almost all neonates

became jaundiced after 48 hours and the peak serum bilirubin appeared to be around the third

day of life, which in 32% led to phototherapy.

18

Results show that after a neonate has had phototherapy, at least two SB measurements

followed. Sometimes when a neonate reaches or exceeds the exchange transfusion threshold,

an SB value is obtained a couple of hours after starting treatment to evaluate the tendency, but

this is also done to make sure a rebound hyperbilirubinemia does not occur after discontinuing

phototherapy. (4,9) However, Yetman et al. and Maisels et al. show that a rebound

hyperbilirubinemia after discontinuing phototherapy is rare in healthy newborns. (42,43)

Highest serum bilirubin

A statistically significant difference of 23.6 µmol/L was found between the mean highest

serum bilirubin in the intervention group and the control group, with a higher serum bilirubin

in the intervention group. These results are contrary to the results of Hartshorn&Buckmaster,

who also recorded the mean highest SB in their study but found no difference. (10) No cause

could be indicated for the difference found in this study. After randomisation, the baseline

characteristics concerning gestational age of feeding problems were not different between the

intervention group and the control group. There were slightly more neonates with hematomas

and asphyxia in the intervention group, with possibly higher serum bilirubin as a

consequence. Another cause that may have affected the serum bilirubin is the fact that there

were more neonates with an infection/sepsis in the intervention group. More importantly, the

difference that was found between the groups’ mean serum bilirubin was only 23.6 µmol/L

therefore, it does not seem to be of major clinical relevance.

Costs

Although decreasing costs was not the main purpose of this study, it is pleasant when a new

intervention in medical care comes with lowering costs instead of increasing them. Our study

showed an annual cost reduction of € 693.11 and a JM-103 cost recovery of 8.5 years.

Hartshorn&Buckmaster however, showed an annual cost reduction of almost $ 7,000, with a

JM-103 cost recovery every 14 months. (10) They perform 1020 SB measurements annually

though, compared to only around 300 SB measurements in the Isala hospital. Maisels et al.

showed back in 1997 a more reliable and comparable cost reduction of $1,625, as they also

took into account the SB measurements that will follow upon a TcB measurement based on

the protocol margin. (12) Currently, our costs for an SB measurement by the laboratory staff

are lower than when the study protocol was incorporated. This may explain why the estimated

time of 8.5 years of cost recovery is higher than assumed in first instance.

After implementing the JM-103, it will no longer be necessary to obtain an SB after every

TcB measurement within the clinical margin, like the six times with the neonate in figure 3.2;

since a neonate follows its own tendency with regard to their own treatment threshold.

Generalizability of the effects on costs are merely dependent on costs for blood sampling and

SB measurement, which may vary largely between different countries and even between

hospitals in the same country.

Agreement between measurements

The agreement between the laboratory measurement and the transcutaneous bilirubinometry

was not optimal, with the limits of agreement being wider than the predetermined clinical

relevant margin set at 50 µmol/L. The mean difference between measurements was a small

bias and the disagreement was merely caused by the TcB being higher than SB measurements.

This implies that we did not miss possible treatment thresholds, but have over-treated some

neonates. Most published Bland-Altman plots show a comparable negligible bias with the JM-

103 values compared to the SB when used at the sternum. (44)

With 10% of the compared measurements, the TcB was more than 50 µmol/L above SB

value, of which the majority of this 10% was still between the limits of agreement. This

19

means that the JM-103 rather overestimates, as already described by Szabo et al. (11)

Although Szabo’s study concerns the previous model of the JM-103, Maisels et al. also

showed an overestimation with the JM-103. (30) It has also been described that the JM-103

overestimates values in the higher range (>250µmol/L), but the data in our study show an

underestimation of 2.7% near the 300µmol/L. This is comparable with the underestimation of

2.2% which Taylor et al. found. (45) Other authors suggest obtaining an SB with TcB values

higher than 250 µmol/L. (7) The TcB values of these neonates in our study however, were

within the 50 µmol/L margin so they did get an SB sample taken and received necessary

treatment.

What stands out in our study was the long time of two hours passed between the JM-103

measurement and the following SB sample taken. In most other studies, the time between

measurements was at most 60 minutes and often measurements were taken approximately at

the same time. (44) Although, the comparison between methods was not the aim of this study

though, this study reveals the actual clinical practice and it shows that a lot of time passes

between measurements in clinical practice. As a consequence, one could expect our SB values

turn out to be much higher than the TcB values, but this did not occur. This means that the

two hour interval found in this study may be accepted in clinical practice, but is not desirable.

The population of Isala hospital appears to be predominantly Caucasian. The Bland and

Altman comparison that was made between the non-Caucasian newborns however, could not

have been fully interpreted, because of the low number of measurements to compare.

However, the overestimation of TcB in non-Caucasian neonates that was described by

Maisels et al. was not found. (30) Our study is consistent with the findings of Afanetti et al.

that skin colour does not influence the transcutaneous bilirubinometer. (33)

Escape decision

In our study, one neonate (1.2%) had an SB sample taken after a TcB measurement that did

not commend to obtain an SB and without reason registered in the medical chart. There were

also no clinical consequences because of this SB value. It appears that the medical staff felt

confident to rely on the obtained values of TcB measurements. Beforehand, a higher number

of times that the escape decision may have been made was anticipated, compatible with the

study of Hartshorn&Buckmaster where in 22 cases (1.8%) the escape decision was made. (10)

This is approximately identical to the 1.6% that Mishra et al. found. (15)

4.3 Study limitations and strengths A major strength of this study is the fact that to the best of our knowledge this is the first

randomized controlled trial in the Netherlands for implementing a transcutaneous

bilirubinometer for use at the children’s ward, that includes full-term and preterm neonates.

Our study design was rigorous and we used a large enough sample size for the results to be

conclusive for our study population.

A limitation might be that we found that a lot of different doctors during the study made the

decision whether to obtain an SB in the control group, while in other studies only a

paediatrician or a trained ward nurse performed visual assessment.

Another limitation might be that in the intervention group there was no option to do a visual

assessment only and to decide not to obtain a TcB value on the basis thereof. Instead, with

every jaundiced newborn in the intervention group the JM-103 was used, while in practice not

every jaundiced newborn needs an actual value of bilirubin, whether transcutaneous or

through blood sample.

20

4.4 Future research and recommendations In the search for diminishing invasive blood sampling methods with a very vulnerable patient

population, research of extended use of a transcutaneous bilirubinometer should continue.

Decreasing the number of blood samples before phototherapy raises the question of whether it

is also possible to use a transcutaneous bilirubinometer during and after phototherapy. Several

positive studies have been published in this regard (46-48) and there is an ongoing debate

about the best TcB measuring place for very preterm neonates. (49) Also, we think that with

improving accuracy of the bilirubinometer, or by accepting a lower margin from the treatment

threshold, we can further lower the number of infants needing a heel puncture, without

compromising safety. Next to this it would be interesting to research the use of a

transcutaneous bilirubinometer with other populations, as NICU departments, well-born units,

out hospital patients and more non-Caucasian newborns. These questions may all be

answered, but all need additional research.

TcB measurements work well in hospitalized newborns and are better than visual estimation

of SB, notwithstanding that one must keep in mind that the JM-103 gives a transcutaneous

value and not a serum value of bilirubin. This means: with the NVK guidelines and AAP

thresholds with a margin of 50 µmol/L a reliable nomogram for the Isala hospital is obtained

and the use of the JM-103 is recommended. (4,44)

5. Conclusion

The aim of this study was to find out whether the use of a transcutaneous bilirubinometer in

hospitalized jaundiced neonates would lead to a reduction of blood tests. This study shows

that the implementation of the JM-103 in the Isala hospital significantly reduces the number

of painful and invasive blood tests with 27% compared to the present-day situation of relying

on visual assessment; without increasing the risk of missing neonates who are at risk of

kernicterus. Furthermore, this study showed no difference in duration of treatment nor

hospitalization length. As for the costs of implementing the JM-103, the true value of the JM-

103 is not related to the purchasing price: it pays itself back in higher quality of patient care,

lower risks and less inconvenience for newborns and their families in the Isala hospital.

The JM-103 is a useful screening tool for obtaining a bilirubin value and with the 50 µmol/L

margin on the nomograms of the AAP, it is a safe manner to reduce blood sampling.

However, while taking into account a TcB value, clinical assessment remains most important.

We advise the use of a transcutaneous bilirubinometer in hospitalised jaundiced newborns.

21

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25

7. Appendix A

The curves below are the ones that were used during the study period. Based upon the

treatment thresholds from the AAP and NVK guidelines with a 50 µmol/L margin. (4,9,27)

Bilirubin curves of ≥ 35 weeks of gestational age with normal birth weight.

26

Bilirubin curve of < 35 weeks of gestational age with birth weight > 2000 grams.

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