BMJ 2018;361:k1950 doi: 10.1136/bmj.

k1950 (Published 24 May 2018) Page 1 of 6

Practice

PRACTICE

PRACTICE POINTER

Important considerations for interpreting biochemical

tests in children
1 2 1 2
Khosrow Adeli head and professor, clinical biochemistry , Victoria Higgins PhD candidate , Karin
2
Trajcevski clinical research project coordinator, CALIPER Project , Mark R Palmert associate chair
3
of paediatrics and head of endocrinology
1
CALIPER Program, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada; 2Department of Laboratory Medicine and
Pathobiology, University of Toronto, Toronto, Canada; 3Division of Endocrinology, The Hospital for Sick Children; Departments of Paediatrics and
Physiology, University of Toronto, Toronto, Canada

What you need to know Box 1: Considerations for requesting blood tests in children

• Clinical laboratories often use thresholds to flag abnormal results but • Laboratory medicine is integral to health assessment in the paediatric
these may not be accurate population, but important considerations for laboratory testing in this population
can often be overlooked.
• Appropriate age and sex specific thresholds are sometimes needed
• Pre-analytical factors can differ compared with an adult population. For
• Dynamic physiology of children can alter biochemistry, particularly under example, automated laboratory equipment may not be able to handle small
one year of age and during puberty volume specimens, requiring manual processing, leading to difficulties in
standardising specimen processing. Small sample volume might also pose
• Factors such as capillary blood and small volume samples can alter
challenges to repeat testing to confirm abnormal results.
the result
• Skin puncture specimens (capillary) are more common in the paediatric than
• Creatinine and alkaline phosphatase are examples of tests that are adult population, and results can deviate from results obtained from arterial
known to vary or venous samples.
• Intra-individual biological variation can differ in children compared with adults,
particularly during the first year of life, because of differences in organ
Rapid growth and development during childhood and development and maturity between individuals.2
adolescence pose challenges to paediatric healthcare, including • When deciding when to order a blood test, which blood test to order, and
blood test interpretation.1 Physicians may order blood tests in which decision limits to use to interpret blood tests, the most recent paediatric
guidelines, if available, should be used for the disease of interest. Please refer
children and adolescents with signs and symptoms suggestive to box 2 “What support is available to clinicians?” for specific resources.
of a health condition.
Blood tests can be used for screening, risk assessment, disease
diagnosis or prognosis, and treatment initiation or monitoring
(box 1). For example, newborns are commonly screened for
metabolic disorders and genetic diseases, including
phenylketonuria and congenital heart disease,9 and abnormal
results are later confirmed by diagnostic testing.10 Additionally,
measurement of bilirubin to test for jaundice is common in
newborns. Reference intervals or clinical decision limits are
widely used by clinical laboratories to flag results, thereby
notifying physicians to potentially follow up with additional
medical tests or specialist referral. Depending on an individual’s
risk, children and adolescents might also be screened for
common conditions including type 2 diabetes, dyslipidaemia,
and iron deficiency anaemia, which have all become more
common with increased rates of obesity.11-13

Correspondence to K Adeli khosrow.adeli@sickkids.ca

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BMJ 2018;361:k1950 doi: 10.1136/bmj.k1950 (Published 24 May 2018)
Box 2: What support is available to clinicians?
- Consult hospital or local laboratory specialists (eg, clinical/medical biochemist,
haematologist, pathologist, or microbiologist) if uncertain about a paediatric
blood test result
- Initiatives such as www.choosingwisely.org provide guidance on appropriate
testing in children, with a focus on appropriate utilisation of testing.
- Clinicians can keep up-to-date laboratory guidelines, including the most
recent evidence-based reference intervals and decision limits (see below:
KiGGS, CHILDx, AHRIP, CALIPER)
- The European Federation of Clinical Chemistry and Laboratory Medicine
(EFLM; www.eflm.eu), the International Federation of Clinical Chemistry and
Laboratory Medicine (IFCC; www.ifcc.org), and the American Association of
Clinical Chemistry (AACC; www.aacc.org) all provide educational material,
resources, and contacts to improve knowledge of paediatric laboratory test
interpretation.
- Lab Tests Online (www.labtestsonline.org) is an invaluable web resource
for information on laboratory test ordering and interpretation produced by the
AACC.
- Resources for paediatric reference intervals include data from the KiGGS
study in Germany,3 the CHILDx study in the United States,4 Australian
Harmonised Reference Intervals for Paediatrics (AHRIP),5 the Nordic paediatric
reference interval study,6 the Tietz textbook,7 and the CALIPER study in
Canada.8
- The CALIPER database is freely available at http://www.sickkids.ca/
Caliperproject/index.html and on a mobile app (CALIPER Reference App on
both iTunes and Google Play).
Interpretation of many blood tests relies on reference intervals
(normal ranges) to determine if results are within the healthy
range, potentially require follow-up investigations, or exceed
decision limits used to diagnose a condition or initiate treatment.
Unfortunately, many paediatric reference intervals currently
used are inaccurate, for example because they were developed
based on inpatient results, out-of-date methodologies, are not
specific for age and sex, or are specific to the adult population.
This could lead to missed diagnosis, misdiagnosis, or
unnecessary follow-up.14 Several initiatives have begun to
establish accurate paediatric reference intervals,3 4 6 8 14 15
providing important lessons for practising clinicians on
interpreting blood tests. The authors have worked on a
nationwide paediatric reference interval project, the Canadian
Laboratory Initiative on Paediatric Reference Intervals
(CALIPER), which highlights the requirement of several age-
and sex-specific reference interval partitions.8
This Practice Pointer article provides physicians with practical
considerations for ordering blood tests, including pointers on
seeking additional information and communicating with the
clinical laboratory.
Why are accurate paediatric-specific
reference intervals important?
Some tests, such as newborn screening and neonatal bilirubin
levels, have well defined clinical cutoffs. However, many tests
are interpreted using reference intervals, defined as the central
95% of test results expected in a healthy population.16 Results
falling inside a reference interval are considered healthy, while
those falling outside are flagged for further inspection and
possible follow-up testing. Unique growth, development,
nutrition, and diseases in the paediatric population all necessitate
paediatric-specific reference intervals.1 The dynamic physiology
of growing and developing children makes it difficult to assess
pathophysiological changes in this population, as their reference
intervals are a moving target.17 This is particularly evident during
the first year of life and during puberty, because of profound
bodily growth and maturation during child development, as well
as potential maternal transfer of biomarkers to neonates. In
addition to age, many laboratory markers exhibit sex differences,
particularly during puberty, resulting in requirement for both
age and sex partitions for proper interpretation.8
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Page 2 of 6
PRACTICE
Creatinine and alkaline phosphatase
illustrates how a biochemical marker can
change during childhood
Creatinine requires both age and sex partitioning, and highlights
the need for age- and sex-specific reference intervals and the
highly dynamic concentration trend throughout paediatric age.
It is also a commonly requested test in paediatrics for renal
function.
Prominent physiological changes during the neonatal period
and puberty8 18 are reflected in paediatric creatinine
concentrations (fig 1). Creatinine reference intervals established
by CALIPER required several age- and sex-specific partitions.8
Creatinine is elevated during the first few weeks of life, even
more so in preterm infants.8 19 Elevated creatinine levels in
neonates might be attributed to creatinine reabsorption across
leaky immature tubules and vasculature.19 Once the kidneys
mature, creatinine concentrations decline and are primarily
affected by muscle mass, glomerular filtration rate, and tubular
secretion. Creatinine concentrations gradually increase
throughout childhood and are substantially higher in pubertal
boys than in girls, possibly because of increased muscle mass.8
Paediatric alkaline phosphatase (ALP) concentrations (fig 2)
are another example of profound age related concentration
changes. ALP levels, which mirror fluctuations in bone growth,
are highly variable in the first year of life, increase throughout
childhood, and are highest at ages of peak growth velocity.8
Although ALP values are higher in pubertal boys, values peak
earlier in girls, as girls generally enter puberty and attain peak
height velocity earlier than boys.8 Dynamic ALP concentration
in paediatrics exemplifies the need for age- and sex- specific
reference intervals for accurate interpretation. For example, an
ALP result of 250 U/L in a six month old boy would be
considered healthy based on an appropriate age- and sex-specific
reference interval (eg, 134-518 U/L).8 However, if an adult
reference interval were used (eg, 50-116 U/L)20 this result would
be flagged as abnormally high, potentially leading to further
testing to assess the potential presence of a liver or bone
condition (eg, hepatitis, Paget’s disease). Conversely, an
abnormally low result in this patient would be missed if the
adult reference interval were used.
Several other biochemical, endocrine, and haematological blood
tests differ considerably between paediatric and adult
populations, as highlighted by the Canadian Health Measures
Survey (CHMS) data.20-22 CHMS, a programme of Statistics
Canada, obtained health information and blood samples from
Canadians aged 3 to 80 years. Table 1 provides a non-exhaustive
list of examples of commonly ordered blood tests which differ
between paediatric and adult populations based on CHMS and
several other studies.
When should clinicians use reference
intervals to interpret blood test results?
Reference intervals are used to flag abnormal blood test results
and inform clinicians to follow up with further investigation, if
necessary. A flagged blood test result does not indicate the
presence or risk of disease, but simply identifies a value outside
the expected healthy range. Physicians should interpret blood
test results in accordance with the purpose of the test. For
example, although a blood test result is flagged, the action
required differs depending on whether it was ordered for
screening, diagnosing, or monitoring purposes. Refer to the
most recent guidelines for assessing certain disease conditions
for actionable decision limits. Decision limits are determined
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BMJ 2018;361:k1950 doi: 10.1136/bmj.k1950 (Published 24 May 2018)
from clinical outcome studies or consensus statements to provide
cutoff values specific for disease, such as interpreting the lipid
profile to assess cardiovascular disease risk.32 Blood test results
should be interpreted while considering the clinical scenario,
the patient’s previous blood test results to assess trends over
time, and in relation to other related biomarkers. Both accurate
paediatric reference intervals and paediatric-based decision
limits are integral to blood test result interpretation.
What initiatives are under way to improve
paediatric blood test interpretation?
Despite their critical importance, accurate paediatric reference
intervals have been severely lacking.14 Research in this field
faces challenges such as the larger number of samples required
for multiple age and/or sex partitions, small sample volume,
and parental consent.14 National initiatives have begun to
establish up-to-date paediatric reference intervals for clinicians,
including projects in Germany,3 Australia,15 Nordic Countries,6
the United States,4 and Canada.8 14 Most recently, the CALIPER
study in Canada has provided comprehensive paediatric
reference intervals specific for age, sex, and analytical platforms
for 178 blood tests.8 33
What gaps remain in interpreting
paediatric blood test results?
Accurate neonatal/infantile reference intervals that reflect
dynamic changes during the first few days, weeks, and months
of life, are still lacking because of recruitment difficulties and
small blood sample volume. Some blood tests still vary
substantially between laboratory instruments, necessitating
instrument-specific reference intervals.
Interpretation can be complicated by large variation in reference
intervals reported by clinical laboratories, even those using the
same instruments/reagents and within the same geographical
area.34 35
Physicians should be aware of this limitation when interpreting
results obtained from multiple laboratories. Using assays
calibrated against an international reference material is
encouraged, as standardised blood tests will help facilitate the
harmonised blood test results and reference intervals. To help
address these issues, the Australasian Harmonised Reference
Intervals for Paediatrics,5 and the new Harmonised Reference
Interval Working Group in Canada34 are working towards
harmonising reference intervals to improve the consistency of
test result interpretation to improve patient care.
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Page 3 of 6
PRACTICE
Community participation
Participation of healthy children and their families was critical to development
of the CALIPER database of paediatric reference intervals for laboratory
markers. Despite considerable challenges in recruiting healthy children into
such a study, CALIPER has been successful in recruiting more than 9800
healthy children and adolescents who agreed to complete a health
questionnaire, to allow anthropometric measurements, and to donate a blood
sample. The key message that resonated with families was that their
participation in the study directly contributed to improved laboratory test
interpretation in sick children with various medical concerns. These families
also appreciated the fact that if they ever needed health assessment for their
own children in the future, they would directly benefit from the laboratory
reference data generated by CALIPER.
One community member and parent, Ralph Pot, who has been involved with
CALIPER, views the project from a few different perspectives. “As a school
principal, the CALIPER Project was a fantastic way for our students to
contribute in a tangible way to important medical research. As a father, it was
good to see my children volunteer for this opportunity, not only because they
learned more about medical research, but also because of the positive way
that they were challenged to do something tangible for the good of others. As
our family also includes two children who have spent considerable time at
The Hospital for Sick Children and McMaster Children's Hospital over the
years, my typically developing, healthy children were eager to participate.”
Education into practice
Think about the last time you used the reference interval provided on your
patient’s blood test report to interpret their test result. Or tests which you
commonly order for children. How does this article make you reflect on those
orders differently? How does it offer ideas on how to improve your performance
interpreting?
What did you know about how reference ranges are constructed before
reading this?
Is there anything you can take to share with colleagues from this?
How this article was made
To prepare this update on paediatric reference intervals of laboratory markers,
we largely used a personal archive of references. Khosrow Adeli is the principal
investigator and Victoria Higgins and Karin Trajcevski are trainees/co-ordinators
involved with the CALIPER project. In addition to CALIPER publications,
several other national paediatric reference interval studies were discussed.
Mark Palmert and Khosrow Adeli offered their experience to identify illustrative
examples regarding the practical use of reference intervals. All authors
participated in writing and revising the manuscript.
All authors have read and understood the BMJ policy on declaration of interests
and have nothing to declare.
Statement on Contributorship: All listed authors meet the four ICMJE authorship
criteria. Khosrow Adeli substantially contributed to the conception and design of
the work, critically revised the work for important intellectual content, had final
approval of the version to be published and agrees to be accountable for all aspects
of the work in ensuring that questions related to the accuracy or integrity of any
part of the work are appropriately investigated and resolved. Victoria Higgins
substantially contributed to the conception and design of the work, drafted the
work, had final approval of the version to be published and agrees to be accountable
for all aspects of the work in ensuring that questions related to the accuracy or
integrity of any part of the work are appropriately investigated and resolved. Karin
Trajcevski substantially contributed to the conception and design of the work,
drafted the work, had final approval of the version to be published and agrees to
be accountable for all aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately investigated and
resolved. Mark Palmert substantially contributed to the conception and design of
the work, critically revised the work for important intellectual content, had final
approval of the version to be published and agrees to be accountable for all aspects
of the work in ensuring that questions related to the accuracy or integrity of any
part of the work are appropriately investigated and resolved.
Provenance and peer review: commissioned; externally peer reviewed.
1 Coffin CM, Hamilton MS, Pysher TJ, etal . Pediatric laboratory medicine: current challenges
and future opportunities. Am J Clin Pathol 2002;117:683-90.
10.1309/C52D-BY0U-VXXU-R360 12090415
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BMJ 2018;361:k1950 doi: 10.1136/bmj.k1950 (Published 24 May 2018)
2 Bailey D, Bevilacqua V, Colantonio DA, etal . Pediatric within-day biological variation and
quality specifications for 38 biochemical markers in the CALIPER cohort. Clin Chem
2014;60:518-29. 10.1373/clinchem.2013.214312 24366727
3 Kohse KP. KiGGS - the German survey on children’s health as data base for reference
intervals and beyond. Clin Biochem 2014;47:742-3.
10.1016/j.clinbiochem.2014.05.039 24854685
4 Clifford SM, Bunker AM, Jacobsen JR, Roberts WL. Age and gender specific pediatric
reference intervals for aldolase, amylase, ceruloplasmin, creatine kinase, pancreatic
amylase, prealbumin, and uric acid. Clin Chim Acta 2011;412:788-90.
10.1016/j.cca.2011.01.011 21238443
5 Tate JR, Sikaris KA, Jones GR, etal . Harmonising adult and paediatric reference intervals
in australia and new zealand: an evidence-based approach for establishing a first panel
of chemistry analytes. Clin Biochem Rev 2014;35:213-35.25678727
6 Hilsted L, Rustad P, Aksglæde L, Sørensen K, Juul A. Recommended Nordic paediatric
reference intervals for 21 common biochemical properties. Scand J Clin Lab Invest
2013;73:1-9. 10.3109/00365513.2012.721519 23013046
7 Reference information for the clinical laboratory (Adeli, Ceriotti, Nieuwesteeg). In: Tietz
Textbook of Clinical Chemistry and Molecular Diagnostics . 6th ed. Elsevier; 2018.
8 Colantonio DA, Kyriakopoulou L, Chan MK, etal . Closing the gaps in pediatric laboratory
reference intervals: a CALIPER database of 40 biochemical markers in a healthy and
multiethnic population of children. Clin Chem 2012;58:854-68.
10.1373/clinchem.2011.177741 22371482
9 Therrell BL, Padilla CD, Loeber JG, etal . Current status of newborn screening worldwide:
2015. Semin Perinatol 2015;39:171-87. 10.1053/j.semperi.2015.03.002 25979780
10 Laboratory Medicine Practice Guidelines. Follow-up Testing for Metabolic Diseases
Identified by Expanded Newborn Screening Using Tandem Mass Spectrometry. American
Association for Clinical Chemistry; 2009. www.aacc.org.
11 Cepeda-Lopez AC, Aeberli I, Zimmermann MB. Does obesity increase risk for iron
deficiency? A review of the literature and the potential mechanisms. Int J Vitam Nutr Res
2010;80:263-70. 10.1024/0300-9831/a000033 21462109
12 Daniels SR, Greer FRCommittee on Nutrition. Lipid screening and cardiovascular health
in childhood. Pediatrics 2008;122:198-208. 10.1542/peds.2008-1349 18596007
13 Pulgaron ER, Delamater AM. Obesity and type 2 diabetes in children: epidemiology and
treatment. Curr Diab Rep 2014;14:508. 10.1007/s11892-014-0508-y 24919749
14 Shaw JLV, Binesh Marvasti T, Colantonio D, Adeli K. Pediatric reference intervals:
challenges and recent initiatives. Crit Rev Clin Lab Sci 2013;50:37-50.
10.3109/10408363.2013.786673 23656169
15 Southcott EK, Kerrigan JL, Potter JM, etal . Establishment of pediatric reference intervals
on a large cohort of healthy children. Clin Chim Acta 2010;411:1421-7.
10.1016/j.cca.2010.06.018 20598674
16 Clinical and Laboratory Standards Institute (CLSI)EP28-A3c: Defining, establishing, and
verifying reference intervals in the clinical laboratory , 3rd ed.; 2010.
17 Ceriotti F. Establishing pediatric reference intervals: a challenging task. Clin Chem
2012;58:808-10. 10.1373/clinchem.2012.183483 22377530
18 Konforte D, Shea JL, Kyriakopoulou L, etal . Complex biological pattern of fertility hormones
in children and adolescents: a study of healthy children from the CALIPER cohort and
establishment of pediatric reference intervals. Clin Chem 2013;59:1215-27.
10.1373/clinchem.2013.204123 23637248
19 Guignard JP, Drukker A. Why do newborn infants have a high plasma creatinine?Pediatrics
1999;103:e49. 10.1542/peds.103.4.e49 10103341
20 Adeli K, Higgins V, Nieuwesteeg M, etal . Biochemical marker reference values across
pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference
intervals on the basis of the Canadian Health Measures Survey. Clin Chem
2015;61:1049-62. 10.1373/clinchem.2015.240515 26044506
21 Adeli K, Higgins V, Nieuwesteeg M, etal . Complex reference values for endocrine and
special chemistry biomarkers across pediatric, adult, and geriatric ages: establishment
For personal use only: See rights and reprints http://www.bmj.com/permissions
Page 4 of 6
PRACTICE
of robust pediatric and adult reference intervals on the basis of the Canadian Health
Measures Survey. Clin Chem 2015;61:1063-74. 10.1373/clinchem.2015.240523 26044507
22 Adeli K, Raizman JE, Chen Y, etal . Complex biological profile of hematologic markers
across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult
reference intervals on the basis of the Canadian Health Measures Survey. Clin Chem
2015;61:1075-86. 10.1373/clinchem.2015.240531 26044509
23 Bidlingmaier M, Friedrich N, Emeny RT, etal . Reference intervals for insulin-like growth
factor-1 (igf-i) from birth to senescence: results from a multicenter study using a new
automated chemiluminescence IGF-I immunoassay conforming to recent international
recommendations. J Clin Endocrinol Metab 2014;99:1712-21.
10.1210/jc.2013-3059 24606072
24 Broughton Pipkin F, Smales OR, O’Callaghan M. Renin and angiotensin levels in children.
Arch Dis Child 1981;56:298-302. 10.1136/adc.56.4.298 7018406
25 Candito M, Albertini M, Politano S, Deville A, Mariani R, Chambon P. Plasma
catecholamine levels in children. J Chromatogr 1993;617:304-7.
10.1016/0378-4347(93)80503-V 8408397
26 Eliot RJ, Lam R, Leake RD, Hobel CJ, Fisher DA. Plasma catecholamine concentrations
in infants at birth and during the first 48 hours of life. J Pediatr 1980;96:311-5.
10.1016/S0022-3476(80)80836-5 7351604
27 Behrman R. Nelson textbook of pediatrics. 14th ed. WB Saunders Company, 1992.
28 Kahlmann V, Roodbol J, van Leeuwen N, etal . Validated age-specific reference values
for CSF total protein levels in children. Eur J Paediatr Neurol 2017;21:654-60.
10.1016/j.ejpn.2017.03.006 28461111
29 McCudden CR, Brooks J, Figurado P, Bourque PR. Cerebrospinal fluid total protein
reference intervals derived from 20 years of patient data. Clin Chem 2017;63:1856-65.
10.1373/clinchem.2017.278267 29021324
30 Kyriakopoulou L, Yazdanpanah M, Colantonio DA, Chan MK, Daly CH, Adeli K. A sensitive
and rapid mass spectrometric method for the simultaneous measurement of eight steroid
hormones and CALIPER pediatric reference intervals. Clin Biochem 2013;46:642-51.
10.1016/j.clinbiochem.2013.01.002 23337690
31 Soldin OP, Sharma H, Husted L, Soldin SJ. Pediatric reference intervals for aldosterone,
17alpha-hydroxyprogesterone, dehydroepiandrosterone, testosterone and 25-hydroxy
vitamin D3 using tandem mass spectrometry. Clin Biochem 2009;42:823-7.
10.1016/j.clinbiochem.2009.01.015 19318024
32 Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in
Children and AdolescentsNational Heart, Lung, and Blood Institute. Expert panel on
integrated guidelines for cardiovascular health and risk reduction in children and
adolescents: summary report. Pediatrics 2011;128(Suppl 5):S213-56.
10.1542/peds.2009-2107C 22084329
33 Estey MP, Cohen AH, Colantonio DA, etal . CLSI-based transference of the CALIPER
database of pediatric reference intervals from Abbott to Beckman, Ortho, Roche and
Siemens Clinical Chemistry Assays: direct validation using reference samples from the
CALIPER cohort. Clin Biochem 2013;46:1197-219.
10.1016/j.clinbiochem.2013.04.001 23578738
34 Adeli K, Higgins V, Seccombe D, etal. CSCC Reference Interval Harmonization (hRI)
Working Group. National survey of adult and pediatric reference intervals in clinical
laboratories across Canada: a report of the CSCC Working Group on Reference Interval
Harmonization. Clin Biochem 2017;50:925-35.
10.1016/j.clinbiochem.2017.06.006 28647526
35 Jones GR, Koetsier SD. RCPAQAP First Combined Measurement and Reference Interval
Survey. Clin Biochem Rev 2014;35:243-50.25678729
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BMJ 2018;361:k1950 doi: 10.1136/bmj.k1950 (Published 24 May 2018) Page 5 of 6

PRACTICE

Table

Table 1| Examples of commonly ordered blood tests that differ between paediatric and adult populations

Analyte Differences between paediatric and adult reference values

7
Alpha-fetoprotein (AFP) Extremely elevated in neonates, continuously and rapidly declining throughout the first year of life. By age 3, levels are
consistently low and remain low throughout childhood and adulthood
Insulin-like growth factor (IGF)-1723 Concentration is lower during the first year of life, subsequently increasing until a pubertal peak (slightly higher in boys),
then subsequently declining and plateauing throughout adulthood
Prolactin7 Elevated and variable in neonates, subsequently decreasing throughout the first year of life. Levels are low and constant
throughout childhood. At the onset of puberty, levels decrease in boys and increase in girls, remaining constant throughout
adulthood
Cystatin C7 Elevated in neonates, subsequently decreasing throughout the first year of life and remaining relatively constant through
childhood and adulthood. Levels are slightly higher in boys after puberty
Aldosterone7 Elevated and variable in neonates, subsequently decreasing throughout the first year of life. Levels are relatively constant
throughout childhood, decreasing at the onset of puberty, and remaining stable throughout adulthood
Renin24 Higher in neonates, gradually decreasing throughout childhood and adolescence to levels which plateau in adulthood
Catecholamines2526 Elevated immediately after birth, rapidly declining during initial 48 hours. Levels begin increasing again at 3 months,
then decrease again at 2 years, plateauing through childhood, adolescence, and adulthood
Base excess27 More variable and negative in newborns. Levels increase and approach zero as a median value throughout childhood
and plateau in adulthood
Gamma-glutamyl transferase (GGT)20 Lower and less variable in infants/children. Higher and more variable at 20 years
20
Lactate dehydrogenase (LDH) Higher in children, begins declining at 11 years, plateaus at 16 years
Phosphate20 Higher in children, begins declining at 6 years, plateaus at 16 years
Cerebrospinal Fluid (CSF) – Protein2829 Elevated during the first week of life, subsequently decreasing until 6 months, at which time levels remain constant
throughout childhood and adolescence. Levels then increase into adulthood
17-α-hydroxyprogesterone3031 Elevated and variable in neonates, subsequently rapidly decreasing and remaining stable throughout childhood. Levels
increase again at the onset of puberty, plateauing throughout adulthood. Values also differ substantially throughout the
menstrual cycle in females

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Figures

Fig 1 Physiological changes in serum concentrations of creatinine across the paediatric age (0 to <19 years). Data from
the Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) project8

Fig 2 Physiological changes in serum concentrations of alkaline phosphatase (ALP) across the paediatric age (0 to <19
years). Data from the Canadian Laboratory Initiative on Paediatric Reference Intervals (CALIPER) project8

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