MBS Reviews
FOLATE TESTING
REPORT
February 2014
February 2014
TABLE OF CONTENTS
Section
Page
TABLE OF CONTENTS .................................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................................ 4
EXECUTIVE SUMMARY ................................................................................................................ 5
PURPOSE OF THE REVIEW ......................................................................................................................................... 5
FOLATE TESTING ...................................................................................................................................................... 5
CONCERNS ABOUT FOLATE TESTING......................................................................................................................... 5
REVIEW METHODOLOGY .......................................................................................................................................... 5
STAKEHOLDER CONSULTATION ................................................................................................................................ 6
SUMMARY OF FINDINGS ........................................................................................................................................... 6
APPROPRIATE CLINICAL INDICATIONS FOR FOLATE TESTING .................................................................................... 7
CONCLUSIONS .......................................................................................................................................................... 8
1 BACKGROUND ON FOLATE TESTING................................................................................. 9
1.1
DESCRIPTION OF CURRENT SERVICES .......................................................................................................... 9
1.2
THE CLINICAL FLOWCHARTS ..................................................................................................................... 13
2 REVIEW METHODOLOGY ..................................................................................................... 15
2.1
SECONDARY DATA ANALYSIS .................................................................................................................... 15
2.2
GUIDELINE CONCORDANCE ....................................................................................................................... 15
2.3
SYSTEMATIC LITERATURE REVIEW FOR CLINICAL EVIDENCE..................................................................... 16
2.4
SYSTEMATIC LITERATURE REVIEW FOR ECONOMIC EVIDENCE .................................................................. 18
3 SECONDARY DATA ANALYSIS ............................................................................................. 20
3.1
MBS ITEM NUMBER USAGE AND EXPENDITURE ......................................................................................... 20
3.2
AGE AND GENDER PROFILE OF PATIENTS ................................................................................................... 23
3.3
FREQUENCY OF TESTING BY PATIENT ........................................................................................................ 24
3.4
PROFILE OF PROVIDERS REQUESTING FOLATE/VITAMIN B12 TESTING SERVICES ....................................... 25
3.5
FREQUENCY OF REQUESTS FOR TESTING BY PROVIDER .............................................................................. 26
4 REVIEW OF GUIDELINES RELEVANT TO FOLATE TESTING .................................. 28
4.1
AUSTRALIAN GUIDELINES ......................................................................................................................... 28
4.2
INTERNATIONAL GUIDELINES .................................................................................................................... 28
4.3
OTHER REPORTS ........................................................................................................................................ 29
5 REVIEW OF THE CLINICAL EVIDENCE FOR FOLATE TESTING ............................ 31
5.1
EVIDENCE BASE ........................................................................................................................................ 31
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February 2014
5.2
APPROPRIATE CLINICAL INDICATIONS FOR FOLATE TESTING ..................................................................... 31
5.3
EVIDENCE THAT TESTING FOLATE LEVELS IMPROVES HEALTH OUTCOMES ................................................ 31
5.4
RISKS/HARMS ASSOCIATED WITH FOLATE TESTING ................................................................................... 32
5.5
QUALITY OF TESTING ................................................................................................................................ 32
6 REVIEW OF THE ECONOMIC EVIDENCE FOR FOLATE TESTING ......................... 33
6.1
COSTING STUDIES OR ECONOMIC ANALYSES RELEVANT TO FOLATE TESTING ............................................ 33
7 FINDINGS AND CONCLUSIONS ............................................................................................ 34
7.1
CURRENT USAGE OF FOLATE AND/OR VITAMIN B12 TESTING SERVICES IN AUSTRALIA ............................. 34
7.2
CLINICAL GUIDANCE ON FOLATE TESTING................................................................................................. 35
7.3
RELATIONSHIP BETWEEN TESTING FOR FOLATE LEVELS AND HEALTH OUTCOMES .................................... 35
7.4
HARMS ASSOCIATED WITH FOLATE TESTING ............................................................................................. 36
7.5
QUALITY OF FOLATE TESTING ................................................................................................................... 36
7.6
COST IMPLICATIONS OF FOLATE TESTING .................................................................................................. 36
7.7
CONCLUSIONS ........................................................................................................................................... 36
APPENDIX 1 – REFERENCES............................................................................................................ 38
APPENDIX 2 – REVIEW CONSULTATION COMMITTEE MEMBERS ............................................... 42
APPENDIX 3 – MBS INFORMATION................................................................................................ 43
APPENDIX 4 – SEARCH TERM STRATEGY ...................................................................................... 44
APPENDIX 5 – TOOLS FOR ASSESSING THE EVIDENCE IN THE SYSTEMATIC REVIEW ................ 49
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LIST OF ABBREVIATIONS
AIHW
Australian Institute of Health and Welfare
ANZFSC
Australian and New Zealand Food Standards Code
CMFM
Comprehensive Management Framework for the MBS
CVD
Cardiovascular disease
FDA
Food and Drug Administration
HTA
Health technology assessment
MBS
Medicare Benefits Schedule
MMA
Methylmalonic acid
MSAC
Medical Services Advisory Committee
NHMRC
National Health and Medical Research Council
NTD
Neural tube defects
PASC
Protocol Advisory Sub-Committee (of MSAC)
PBS
Pharmaceutical Benefits Scheme
PICO
Population, Intervention, Comparator, Outcomes
RBC
Red blood cells
RCC
Review Consultation Committee
RCT
Randomised controlled trials
RDA
Recommended dietary allowance
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EXECUTIVE SUMMARY
In the 2011-12 Budget, the Australian Government announced a further commitment to the
Comprehensive Management Framework for the Medicare Benefits Schedule [MBS]
(CMFM), to continue the systematic review of MBS items to ensure that they reflect
contemporary evidence, improve health outcomes for patients and represent value for money.
MBS Reviews aim to ensure the clinical and financial sustainability of the MBS. Reviews
assess specific MBS services (i.e. MBS items) and associated policy issues in a focussed, fitfor-purpose, evidence-based process. Findings recognise that the MBS funding should align
with contemporary evidence, reflecting appropriate patient groups and best clinical practice.
The Reviews have a primary focus on improving health outcomes and the financial
sustainability of the MBS, through the following criteria:




assess patient safety risk;
identify services that have limited health benefit and/or are used inappropriately;
be evidence-based and fit-for-purpose;
be conducted in consultation with key stakeholders including, but not limited to, the
medical profession and consumers;
 include opportunities for public submission; and
 use Government resources efficiently.
Purpose of the review
This Review Report outlines the rationale behind conducting the review of the MBS items
relevant to folate testing services (refer to Appendix 3 for MBS item descriptor) and the
process undertaken to identify and appraise the available information on the MBS item to
ensure that it reflects contemporary evidence, improves health outcomes for patients, and
represents value for money.
Folate testing
Folate is a water soluble B vitamin (also known as vitamin B9) that occurs naturally in food.
Folate deficiency can be the result of nutritional deficiency, increased requirements, impaired
absorption, or other gastrointestinal causes. Deficiency is associated with a wide spectrum of
haematologic, neurologic and psychiatric disorders. The diagnosis of folate deficiency has
traditionally been based on measuring serum or red blood cell folate.
Concerns about folate testing
Concerns raised with folate testing relate to the increase in the number of claims and benefits
paid for MBS item numbers 66599 and 66602, both of which relate to testing vitamin B12 or
folate levels. Given the widespread testing of folate/vitamin B12 by general practitioners, this
review is focused on identifying appropriate clinical indications for medically necessary folate
testing, and determining whether testing should be limited to certain high risk groups.
Review methodology
The review methodology comprised of consulting with key stakeholders; developing a review
protocol, which outlined the detailed review methodology (including specifying the key
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clinical/research questions for the systematic review, preparing the clinical flowcharts, and
documenting the economic analysis strategy); analysing secondary data sources (Medicare
Australia); conducting an evidence-based systematic literature review on folate; and
undertaking an assessment and analysis of the evidence to draw conclusions in relation to the
clinical/research questions.
Stakeholder consultation
Stakeholder engagement is a pivotal part of the MBS Reviews process, particularly as
feedback helps inform Review Reports. During the review process, stakeholders were
informed of the progress of the MBS items being considered. This included ensuring that
relevant documents were released for public consultation at the appropriate time and that
comments were incorporated into the review process.
As part of the MBS Review process, the Department established a Review Consultation
Committee (RCC). The RCC is a time-limited committee of nominated representatives,
established to provide advice to the Department. A list of RCC members is found at
Appendix 2.
Summary of findings
Current usage of folate and/or vitamin B12 testing services in Australia
Over the past 10 years, the number of claims for MBS item 66599 has more than doubled
(+119%) from 282,531 in 2003/04 to 618,744 in 2012/13. Over the same timeframe the
number of claims for MBS item 66602 has had an even greater increase (+307%) from
522,980 to 2,129,051. The increase in benefits paid for both items reflects the increase in
claims (+120% for item 66599 and +309% for item 66602). While total benefits increased
significantly, the proportion of benefits paid to each state and territory remained relatively
constant over the ten-year period. The highest proportion of benefits paid over the past ten
years was in New South Wales (34% and 38% of total benefits for 66599 and 66602,
respectively), followed by Victoria (30% for 66599 and 28% for 66602).
An analysis was conducted of the number of services per capita (i.e. per 100,000 population).
Across Australia, there were 2,666 claims for item 66599 per 100,000 people enrolled in
Medicare in 2012/13 and 9,172 claims per 100,000 for item 66602. South Australia had the
highest per capita rate of claiming for item 66599, while the Northern Territory had the
lowest. For item 66602, the highest number of claims per capita was for NSW and Victoria,
while Tasmania had the lowest.
MBS item numbers 66599 and 66602 are claimed by both males and females; however,
females had a higher number of tests at all ages, except in the youngest age category (< 5
years). Females also had a steeper increase in testing volume than males, with the largest
difference between genders in the 15-24 and 25-34 year age groups. For item 66599, the
number of tests being performed in people aged 45 years and over was 76% for males and
64% for females. For item 66602, 71% of claims for males were aged 45 years and over
versus 60% for females.
For both MBS items, there was an increase in the overall number of patients tested between
2008/09 and 2012/13. However, there was very little change in the proportion of patients
receiving either one test per year (approximately 91%), two tests per year (approximately
8%), or three or more tests per year (approximately 1%). These data suggest that the majority
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of folate/vitamin B12 testing services are being undertaken for the purposes of
screening/testing rather than monitoring.
Over the five-year time period from 2008/09 to 2012/13, there were no material changes in
the pattern of requesting providers. General practitioners and other medical practitioners
accounted for approximately 71% and 67% of all providers requesting item 66599 and item
66602, respectively. Approximately 14% of providers requesting folate/vitamin B12 testing
were internal medicine consultant physicians. There was a large variety of other providers
requesting services, but they each accounted for less than 4% of provider counts.
For both items, there was an increase over the period 2008/09 to 2012/13 in the overall
number of providers requesting folate/vitamin B12 testing. The majority of providers (97%
and 88% for item 66599 and 66602, respectively) requested 100 or fewer tests per year.
There were a small number of providers that requested more than 400 tests per year (601
providers in 2012/13).
Appropriate clinical indications for folate testing
Although there are a large number of clinical practice guidelines that recommend folate
supplementation, particularly in pregnant women, they do not specifically mention folate
testing, which implies that testing may not be necessary in these populations. Guidelines that
mention folate testing apply to particular populations. For example, NICE guidance on
dementia recommends that measurement of serum folate levels are included in a basic
dementia screen, performed at the time of presentation. Guidance on the diagnosis and
management of chronic fatigue syndrome/myalgic encephalomyelitis from the Royal College
of General Practitioners advises that folate levels should not be carried out unless a full blood
count and mean cell volume show a macrocytosis.
A July 2013 report from Health Quality Canada used expert consultation to identify health
conditions where folate deficiency may be of concern and where folate testing may be
appropriate. Based on the expert consultation, the Ontario Health Technology Advisory
Committee (OHTAC) recommended that red blood cell folate testing be restricted to
individuals with:


low haemoglobin levels and a high mean corpuscular volume;
suspected gastrointestinal disorders causing malabsorption or suspected malnutrition of
any cause.
Evidence that testing folate levels improves health outcomes
The main function of folate is to help form RBCs and produce DNA. Folate also prevents
NTD during fetal development. A deficiency in folic acid can lead to increased homocysteine
levels in plasma since folate is necessary for the conversion of homocysteine to methionine.
In addition, deficiency can result in perturbation of the metabolic pathway of conversion of
homocysteine to methionine with consequent disruption of DNA synthesis caused by
thymidine lack resulting in megaloblastic anaemia, as well as other adverse effects on the
nervous system and other organs. However, folate deficiency is much less common since the
introduction of mandatory fortification with folate of wheat flour in Australia in September
2009. A retrospective study to determine the impact of the fortification program on blood
folate levels reported that the prevalence of low serum folate levels has decreased from 9.3%
in 2007 to 2.1% in 2010 and the prevalence of low RBC folate levels decreased from 3.4% to
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0.5%. Due to the low prevalence of folate deficiency, the clinical utility of folate testing is
questionable.
No definitive conclusions can be drawn about the effectiveness of folate testing since no
prospective trials have been conducted to directly assess the impact of testing on health
outcomes in healthy populations or in patients with chronic disease associated with folate
deficiency. Although retrospective studies do not meet the inclusion criteria for this review,
several retrospective studies (low level evidence) were identified that examined the clinical
utility of folate testing in the United States. Given the low rates of serum folate deficiency
and the lack of change in management based on deficient results, the authors of the studies
concluded that in folic acid fortified countries, serum folate testing has low utility for
inpatients and emergency department patients or routine testing in clinical practice for
patients with anaemia or dementia.
No trials designed to directly measure the risks or harms associated with folate testing were
identified. However, folate testing relies on a blood draw, which is a safe procedure. It is
likely that the consequences of inaccurate or inappropriately interpreted folate test results,
such as a false positive, are relatively small. Folate supplements are generally considered safe
when taken in amounts that are not higher than the recommended dietary allowance.
A poor quality systematic review sought to compare the effectiveness of serum versus red cell
folate. The review found that serum folate appeared to be a superior marker of folate status in
vitamin B12 deficiency and may have more sensitivity in responding to changes in folate
intake (supplements or fortification) than red cell folate. Both tests appeared to predict NTD
risk equally. Serum folate also has the advantage of being influenced by fewer analytical
variables. In an evaluation of serum and red cell folate versus homocysteine, there was no
evidence for the better performance of red cell folate and, of the two, serum folate appeared
superior. Studies also demonstrated that very few patients would have their clinical outcome
altered by the measurement of red cell folate in addition to serum folate. The authors
concluded that overall, as a routine test of folate status, serum folate appears to offer the best
combination of test cost and clinical information.
There was very limited and poor quality evidence relating to the cost of folate testing. In one
retrospective study from the United States, the authors concluded that the exceptionally low
utility of serum folate testing makes the costs associated with these tests excessive.
Conclusions
There has been a substantial increase in the number of claims for folate/vitamin B12 testing
over the past ten years. Analysis of MBS data indicates that the majority of vitamin B12
testing services are requested by GPs and OMPs for the purposes of screening or testing,
rather than follow-up monitoring. There are no Australian clinical practice guidelines that
either advocate or recommend against routine testing for folate in any patient population.
However, there is guidance from the UK recommending measurement of serum folate levels
in a basic dementia screen. There is also guidance from the UK that folate levels should not
be carried out in patients with chronic fatigue syndrome/myalgic encephalomyelitis unless a
full blood count and mean cell volume show a macrocytosis. There are no recommendations
on the frequency of folate testing and there is no prospective evidence regarding the clinical
utility of folate testing in any population. However, low level evidence from retrospective
studies suggests that serum folate testing has low utility in folic acid fortified countries.
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1
BACKGROUND ON FOLATE TESTING
1.1
Description of current services
This section describes folate and folate testing, recommended folate status, and the population
groups and clinical conditions/risk factors in which folate testing is recommended.
1.1.1 Description and function of folate
Folate is a water soluble B vitamin (also known as vitamin B9) that occurs naturally in food.
Folate also refers to folic acid otherwise known as pteroyl glutamic acid (PGA). In the body,
folate is typically in the reduced form tetrahydrofolate (THF). Food folates are hydrolysed to
monglutamate forms in the gut to allow absorption in the intestine.(1) Absorbed folate is
transported to the liver, which contains about half the bodies stores of folate(2), while the rest
is transported via the systemic circulation to body tissues.
1.1.2 The functions of folate in the human body
Folate is a substrate (and vitamin B12 a co-enzyme) for the conversion of homocysteine (a
homologue of the amino acids cysteine and methionine) to methionine (an amino acid and one
of the 20 building blocks of proteins) by the enzyme methionine synthase (Figure 1.1).(3, 4)
More importantly, this pathway is closely linked to the generation of thymidine which is vital
for deoxyribonucleic acid (DNA, i.e. the building block of the human body which carries
genetic information) synthesis.
Figure 1.1: The metabolic reactions that require vitamin B12 and folate (folic acid)(5)
1.1.3 Folate requirements
Folate requirements can vary according to lifestyle behaviours (e.g. smoking and alcohol
intake), genetic variations (e.g. C667T polymorphism of methylenetetrahydrofolate), use of
certain medications (e.g. antiepileptic drugs) and pregnancy. The bioavailability of folate in
foods ranges from 50-60%, whilst that of folic acid used to fortify foods (or as a supplement)
is about 85%.(6, 7) In adults in Australia the recommended daily intake for folate is 400
µg/day. For women during pregnancy this increases to 600 µg/day and during lactation to
500 µg/day.(8)
1.1.4 Causes of folate deficiencies
Folate deficiency may occur due to inadequate nutritional intake, increased requirements (e.g.
in pregnancy) or impaired absorption (see Table 1.1). In general, folate deficiency is most
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often the result of decreased intake and is more common in developing and socioeconomically
distressed countries. Situations in which inadequate intake is further compounded occur when
there is an increased folate requirement arising due to pregnancy, lactation, and prematurity.
Other conditions associated with increased cell turnover, such as leukaemia’s, aggressive
lymphomas and other tumours associated with a high proliferative rate, can also cause
increased folate demand.(9)
Table 1.1: Causes of folate deficiency
Nutritional deficiency
 Alcoholism(10, 11)
 Malnutrition(12) and
avoidance of fortified
bread due to coeliac
disease(13, 14)
Increased requirements
 Due to pregnancy and
lactation(15-18)
Impaired absorption or
metabolism
 Gastrectomy(19) or any
intestinal surgery
which involves gastric
resection, sleeve or
banding surgery(20)
 Prolonged use of acidsuppression therapy or
drugs(21)
 Alcoholism(22)
 MTHFR C677T
polymorphism(23)
Other gastrointestinal
causes
 Chronic
gastrointestinal
symptoms e.g.
dyspepsia, recurrent
peptic ulcer,
diarrhoea(3)
 Coeliac disease(24)
 Crohn’s disease(25)
 Tapeworms and other
intestinal parasites(19)
1.1.5 Diseases caused by folate deficiency
The main function of folate is to help form red blood cells (RBCs) and produce DNA. Folate
also prevents neural tube defects (NTD) during fetal development.(26) A deficiency in folic
acid can lead to increased homocysteine levels in plasma since folate is necessary for the
conversion of homocysteine to methionine (see Figure 1.1).(3) In addition, deficiency can
result in perturbation of the metabolic pathway of conversion of homocysteine to methionine
with consequent disruption of DNA synthesis caused by thymidine lack, resulting in
megaloblastic anaemia, as well as other adverse effects on the nervous system and other
organs.(3)
Table 1.2: Clinical manifestations of folate deficiency
Haematologic (3)
 Megaloblastic anaemia
 Panycytopenia (Leukopenia,
thrombocytopenia)
 Pernicious anaemia (i.e. large
immature RBCs)
Neurologic(27)
 Paresthesias (i.e. a skin
sensation such as burning or
itching with no apparent
physical cause)
 Peripheral neuropathy
 Combined systems disease
(demyelination of peripheral
nerves, spinal cord, cranial
nerves and the brain)
Psychiatric(27-30)
 Irritability, personality change
 Mild memory impairment,
dementia
 Depression
 Psychosis
 Alzheimer’s Disease(30)
1.1.6 Dietary sources of folate
Folate is present in a variety of foods including leafy green vegetables, fruits and dried beans
and peas. Examples of some of the dietary food sources and their folate content are also
shown in Table 1.3.
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Table 1.3: Examples of dietary sources of folate(31, 32)
Type of food
Lentils (1/2 cup cooked)
Spinach (1/2 cup cooked)
Tomato juice (1 cup)
Orange juice (1 cup)
Green peas (1/2 cup cooked)
Strawberries
Baked beans (1 cup)
Banana (1 medium)
Estimated folate content
(micrograms)
179
115
49
47
47
40
30
24
Food fortification is the process of adding micronutrients (such as vitamins and minerals) to
food as permitted by the Australian and New Zealand Food Standards Code (ANZFSC).(33)
Regulations regarding the fortification of foods with folate vary between countries. The
voluntary addition of folic acid to certain foods has been permitted in Australia since 1996.(34)
Since then, a variety of products have been fortified with folic acid. However, the mandatory
fortification of folate in Australia was initiated in September 2009 under Clause 4 (2) of
Standard 2.1.1 of the ANZFSC. This ANZFSC states that folic acid (folic acid is the
synthetic form of folate)(35) is added within the prescribed range of 200–300 μg per 100 grams
of wheat flour used for bread-making.(36) This level of folic acid fortification was expected to
prevent between 14 and 49 cases of NTD per year in Australia.(36)
1.1.7 Prevalence of folate deficiency in Australia
The prevalence of folic acid deficiency in the general Australian population is unknown. A
report published by the Australian Institute for Health and Welfare (AIHW) in 2011 found
that the mean folic acid intake for women aged 16–44 years (the target population) in
Australia before the introduction of the mandatory folic acid fortification program was 108
μg/day, which is well below the recommended 400 μg/day.(37) In addition, there were 149
pregnancies affected by NTD in 2005 in Australia (rate of 13.3 per 10,000 births) in the three
states that provide the most accurate baseline of NTD incidence (South Australia, Western
Australia and Victoria).(37)
A retrospective study was conducted between April 2007 and April 2010 to determine the
impact of the mandatory folic acid fortification program on the blood folate levels of an
Australian population since its introduction in 2009.(38) This study reported that the
prevalence of low serum folate levels decreased by 77% (from 9.3% to 2.1%) in all samples
tested (the samples constituted 20,592 blood samples collected from a wide variety of patients
and analysed in a public hospital diagnostic pathology laboratory). The prevalence of low
RBC folate levels also decreased by 85% (from 3.4% to 0.5%).(38) The prevalence of low
RBC folate levels for females of childbearing age was 0.16% of all samples. However, there
were no data on the incidence of NTDs in newborn babies. A 31% increase in mean serum
folate levels (from 881 nmol/L to 1071 nmol/L) was reported. The authors of this study
concluded that the introduction of the mandatory fortification with folic acid has significantly
reduced the prevalence of folate deficiency in Australia, including women of childbearing
age.(38)
1.1.8
Folate testing
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The following tests are commonly used for the detection of folate:(39)

Serum folate: This is the usual first test for folate deficiency. Serum folate depends on
recent dietary intake, therefore this test does not reflect the long-term folate status in the
body. The normal reference range for serum folate is 7-45 nmol/L (3-20 ng/ml) (40).

Red blood cell folate: This test measures the amount of folate in RBCs and is reflective
of the long-term folate status in the body (i.e. stores in the liver).(41) However, this test is
more complex to perform than the serum folate assay and requires more steps in sample
handling before analysis, which may be one of the reasons why the precision of the red
cell folate assay is less than that of the serum folate assay.(42) In addition, red cell folate
concentrations are often low in patients with B12 deficiency(41) and are inversely
associated with haemoglobin concentrations.(43) The reference interval for red cell folate
is highly method dependent. An approximate normal range for red cell folate is 317-1422
nmol/L RBC (140-602 ng/ml RBC).(40) Levels less than 140 ng/mL are indicative of
folate deficiency.

Plasma homocysteine: This test is reflective of low or deficient folate status and is
therefore considered an indicator of folate or vitamin B12 adequacy. However, plasma
homocysteine levels are elevated in patients with renal failure(44) and with ageing(45, 46).
Special care (and collection tubes) should be taken when collecting blood samples for
testing using this method as homocysteine concentration can rise after blood collection in
certain tubes due to ongoing release of homocysteine by the RBCs in vitro.(47)
There is a lack of strong evidence in the literature to support the clinical practice of
performing serum folate as well as RBC folate measurements in an individual to detect folate
deficiency. The evidence that suggests that red cell folate is a better indicator of folate status
than serum folate is old(48) and the methodology used is less reliable than modern-day assays
used for the assessment of serum folate. A more recent study that analysed the use of the two
methodologies in determining folate deficiency in individuals reported that serum folate
measurements provide equivalent information to RBC folate measurements.(49)
The alternative approach for assessment of folate status involves measurement of the
metabolite homocysteine, which is known to increase in folate deficiency and provides certain
advantages over direct measurement of serum folate concentrations.(4, 50) However,
homocysteine requires both folate and vitamin B12 for its conversion to methionine (refer to
Figure 1.1). Consequently, plasma homocysteine concentrations rise in both folate and
vitamin B12 deficiencies. Therefore, the only way to distinguish whether an individual is
deficient in either of these vitamins is to measure serum MMA. Increased serum levels of
MMA are solely attributed to vitamin B12 deficiency. It is important to note that the
correction of folate deficiency through the use of supplementation and/or fortification may
mask an occult vitamin B12 deficiency and further exacerbate or initiate neurologic disease.
Therefore, it has been recommended that clinicians consider ruling out vitamin B12
deficiency before initiating folic acid therapy.(51)
1.1.9 Folate reference ranges
The cut-off value for folate deficiency varies markedly between laboratories worldwide.
Table 1.4 presents the ‘usual or approximate’ reference intervals for folate deficiency.
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Table 1.4: Folate (40) reference intervals
Status
Normal range
Deficient
Serum folate (nmol/L)
7-40
<7
RBC folate (nmol/L)
360-1400
< 360
1.1.10 MBS item for folate testing
The MBS item numbers for folate testing in scope of this review include 66599 and 66602
(see Appendix 3). Both of the items relate to testing serum vitamin B12 or testing red cell (or
serum) folate. Both of the items are subject to Rule 21 (i.e. no more than three of any
combination of these tests are eligible for Medicare subsidy per patient per year). There is no
MBS item for folate testing on its own.
1.1.11 Service providers claiming MBS benefits for folate testing
Most pathology in Australia is provided in comprehensive laboratories that provide a wide
range of testing services at a single location. Only approved pathology practitioners are
eligible to claim folate testing.
1.2
The clinical flowcharts
The clinical decision pathway that determines whether folate testing should be undertaken is
provided in Figure 1.2.
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Figure 1.2: Clinical flow chart for folate testing
Patient presents to clinician (e.g. General Practitioner,
Obstetrician etc)
Does the patient have any of the following
clinical symptoms of folate deficiency?
Neuropsychiatric symptoms (mild) including:
• dementia; and/or
• depression; and/or
• Psychosis; and/or
• personality changes.
Does the patient have any of the following
haematological symptoms of folate deficiency?
Does the patient have any of the following risk
factors associated with folate deficiency?
•
•
•
•
•
• anaemia; and/or
• macrocytosis.
No Yes
Patient ineligible to claim
benefits under MBS item
numbers 66599 or 66602
Is Vitamin B12/folate
testing clinically
relevant?
No
MBS Reviews – Folate Review Report
patients with coeliac disease; and/or
pregnancy; and/or
dietary deficiency; and/or
alcoholism; and/or
malignancy (e.g. leukaemia).
Page 14
Yes
Measure Vitamin B12
and/or folate and claim
MBS item 66602 or 66599
February 2014
2
REVIEW METHODOLOGY
The review methodology comprises an analysis of secondary data (MBS claims), a guideline
concordance analysis, and a systematic literature review for clinical and economic evidence.
This Chapter presents clinical research questions and the methodology used for each of these
review components.
2.1
Secondary data analysis
Data from Medicare Australia were analysed to determine whether the existing MBS item
numbers for folate testing (66599 and 66602) are appropriate.
2.1.1 The research questions for the MBS analysis
The MBS data were examined to determine:
(1) Whether the existing MBS items for service (66599 and 66602), including the associated
explanatory notes, are appropriate
a. How frequent are the MBS item numbers under review claimed?
b. Are there any age, sex, temporal or geographic trends associated with usage of these
item numbers?
c. Are the Medicare claims data consistent with trends in the incidence/prevalence of the
conditions/diseases being addressed by the services?
d. What is the frequency of folate testing per patient?
e. What is the frequency of folate testing by referring clinician?
f. What is the profile of referring clinician for folate testing?
2.1.2 Methods for analysis of MBS data
MBS data relates to private medical services (provided in- or out-of-hospital), where the
services are provided to patients regardless of whether or not they have private health cover.
MBS in-hospital services are mainly provided in private hospitals and day surgery clinics, but
patients can elect to be treated as a private patient in a public hospital.
MBS data were analysed by patient gender, age group, and discipline of provider requesting
the service.
Results of the analysis of the MBS data is presented in Chapter 3.
2.2
Guideline concordance
2.2.1 The research questions for the guideline concordance analysis
The research question addressed as part of the Review using guideline concordance analysis
are:
(1) Are the existing MBS items for service consistent with evidence-based (or in the absence
of evidence, consensus-based) recommendations provided in relevant clinical practice
guidelines?
(2) What are the appropriate clinical indications for folate testing?
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February 2014
(3) How frequently should folate levels be tested?
a. in apparently healthy populations (including pregnant women, elderly, vegetarians)?
b. in patients with chronic disease linked to folate deficiency (e.g. infants with metabolic
disease; patients with anaemia or haematologic , neurologic, psychiatric,
gastrointestinal and malabsorption disorders)?
2.2.2 Methods for guideline concordance analysis
Searches of guidelines databases1 and relevant discipline websites were undertaken to locate
any existing guidelines relevant to folate testing. Analysis of MBS item numbers 66599 and
66602 was undertaken relative to ‘best practice’, as recommended in relevant Australian
clinical practice guidelines. Where Australian clinical practice guidelines do not exist, other
guidelines in operation in comparable health systems overseas were included. Where
guidelines existed, they were assessed for quality using the AGREE II instrument(52).
Differences in the purpose and intended audience of any such guidelines were considered,
documented and acknowledged.
See Chapter 4 for results of the concordance analysis for folate testing.
2.3
Systematic literature review for clinical evidence
2.3.1 The clinical/research questions for the systematic literature review
The clinical/research questions that were the focus of the literature review are:
(1) What are the appropriate clinical indications for folate testing?
(2) Is there evidence that testing for folate levels improves health outcomes?
a. in apparently healthy populations (including pregnant women, elderly, vegetarians)?
b. in patients with chronic disease linked to folate deficiency?
(3) Are there risks/harms associated with folate testing?
(4) Does quality of testing vary according to testing platform?
2.3.2 Search strategy
A comprehensive search of peer-reviewed scientific literature was conducted to identify
relevant studies addressing the key questions. Electronic databases were searched for original
research papers including systematic reviews as shown in Table 2.1. Searches were restricted
to studies published in the English language between January 2002 and July 2013. Databases
maintained by Health Technology Assessment (HTA) agencies were searched to identify
existing assessments of folate testing.
1
The search included: Guidelines International Network (G-I-N) at www.g-i-n.net/library/internationalguidelines-library/; National Guidelines Clearinghouse at www.guidelines.gov; National Health and Medical
Research Council (NHMRC) at http://www.nhmrc.gov.au/guidelines-publications
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February 2014
Table 2.1: Databases searched
Database
MEDLINE
PubMed
The Cochrane Library (includes Cochrane Database of Systematic
Reviews, Database of Abstracts of Reviews of Effects, Cochrane
Central Register of Controlled Trials, NHS Economic Evaluation
Database, Health Technology Assessment, Cochrane Methodology
Register)
Relevant HTA websites and databases2
Search period
2002 – September 2013
2002 – September 2013
2002 – September 2013
Up to September 2013
Reference lists of systematic, semi-systematic and selected narrative reviews were also
reviewed. In addition, during the consultation process clinicians were asked if they were
aware of any relevant clinical guidelines, unpublished studies or reviews relevant to this
review of folate testing.
2.3.3 Eligibility criteria for studies
The PICO (Population, Intervention, Comparator, Outcomes) criteria(53) was used to develop
well-defined questions for the search of published literature. This involved focusing the
question on four elements:




the target population for the intervention;
the intervention being considered;
the comparator for the existing MBS service (where relevant); and
the clinical outcomes that are most relevant to assess safety and effectiveness.
The PICO criteria were determined on the basis of information provided in the literature, as
well as clinical advice. The PICO criteria for the review of folate testing is shown in Table
2.2.
Table 2.2: PICO criteria for the folate testing items under review
Population
Intervention
Comparator
Outcomes
Patients at risk of folate deficiency,
Effectiveness
including (but not limited to):
 Physical health outcomes
(1) Pregnant women
as a consequence of folate
(2) Elderly
testing
(3) Alcoholics
Supplementation Safety
(4) Patients with gastrointestinal
Folate testing
without testing  Complications associated
and malabsorption disorders
with folate testing (e.g.
(5) Patients with anaemia and
infection, needle injuries)
haematologic diseases
The detailed search strategy and terms used is presented in Appendix 4.
2
The following HTA websites were searched: Agency for Healthcare Research and Quality (AHRQ) at
www.ahrq.gov; Canadian Agency for Drugs and Technologies in Health (CADTH) at http://www.cadth.ca/en;
National Institute for Health and Care Excellence (NICE) at www.nice.org.uk; Australasian College of Surgeons
(ASERNIP-S) at http://www.surgeons.org/for-health-professionals/audits-and-surgical-research/asernip-s/
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February 2014
Studies were excluded on the basis of citation information and/or abstract, where it was
obvious that they did not meet the inclusion criteria. Where there was any doubt about any
reference based on the title and/or abstract, the full paper was retrieved and evaluated. Table
2.3 lists the pre-specified inclusion and exclusion criteria.
Table 2.3: Inclusion/exclusion criteria for identification of relevant studies
Characteristic Criteria
Search period 2002 – 2013
Should there be limited data available during this period, the search will be extended
back in five year increments until sufficient data are sourced.
Clinical studies included. Non-systematic reviews, letters, editorials, animal, in vitro
Publication
and laboratory studies excluded.
type
Systematic reviews
Systematic reviews that have been superseded were excluded
Primary studies
Primary studies published during the search period of included systematic reviews
were excluded
Effectiveness studies included if:
 prospective, comparative trial
 >20 patients
Safety studies included if:
 >50 patients
Intervention Folate testing
Comparator Supplementation without folate testing
Studies must report on at least one of the following outcomes:
Outcome
 Patient outcomes: morbidity, mortality, quality of life
 Safety: adverse physical health outcomes or complications associated with testing
Non-English language articles excluded
Language
2.3.4 Process for classifying the evidence
All eligible studies were assessed according to the National Health and Medical Research
Council (NHMRC) Dimensions of Evidence (refer to Appendix 5). There are three main
domains: strength of the evidence, size of the effect, and relevance of the evidence. One
aspect of the ‘strength of the evidence’ domain is the level of evidence, which is assigned
using the NHMRC Levels of Evidence (Appendix 5). For any eligible publications, study
quality was evaluated and reported using the NHMRC Quality Criteria (Appendix 5) for
randomised controlled trials (RCTs), cohort studies, case-control studies and systematic
reviews.
The results of the review of clinical evidence for folate testing are presented in Chapter 5.
2.4
Systematic literature review for economic evidence
The research question for the review of economic literature is:
(1) What is the evidence regarding the cost implications associated with folate testing
compared with not testing
Consistent with the terms of reference, a formal modelled economic evaluation of folate
testing was not in scope. The review relied on published costing studies and economic
MBS Reviews – Folate Review Report
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February 2014
analyses identified through a systematic literature search of the databases shown in Table 2.1.
The detailed search strategy and terms used is presented in Appendix 4. Citations were
reviewed to identify acceptable evidence including: trial-based costing studies, cost analyses
and economic modelling studies. Acceptable outcomes were limited to: cost, incremental
cost-effectiveness ratio (e.g. cost per event avoided, cost per life year gained, cost per quality
adjusted life year or disability adjusted life year).
The results of the search for economic evaluations of folate testing are presented in Chapter 6.
MBS Reviews – Folate Review Report
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February 2014
3
SECONDARY DATA ANALYSIS
This Chapter presents an analysis of the available secondary data (including MBS data) that
describes the use of folate testing in Australia. When interpreting the data, it is important to
keep in mind that the MBS item numbers within scope are for both folate and vitamin B12
testing. It is not possible to separate the data that specifically relates to folate testing alone.
3.1
MBS item number usage and expenditure
Figure 3.1 shows the number of claims for each of the MBS folate/vitamin B12 testing items
over the past 10 years. The number of claims for MBS item 66599 has more than doubled
(+119%) from 282,531 in 2003/04 to 618,744 in 2012/13. Over the same timeframe the
number of claims for MBS item 66602 has had an even greater increase (+307%) from
522,980 to 2,129,051. The total number of claims for both items has increased over the past
ten years from 0.98m to 2.7m.
Figure 3.1: Number of claims for MBS items 66599 and 66602, 2003/04 to 2012/13
Number of MBS item claims
2,500,000
2,000,000
1,500,000
1,000,000
500,000
0
66602
66599
Source: Department of Human Services – Medicare Australia
Figure 3.2 shows the benefits paid for MBS items 66602 and 66599 over the past ten years by
state. The increase in benefits paid for both items reflects the increase in claims. Benefits
paid for MBS item 66599 increased from $5.7m to $12.5m (+120%) whilst benefits for MBS
item 66602 increased from $19.2m to $78.5m (+309%). Whilst total benefits increased
significantly, the proportion of benefits paid to each state and territory remained relatively
constant over the ten-year period.
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February 2014
Figure 3.2: Benefits paid for MBS items 66599 and 66602 by state and territory, 2003/04 to
2012/13
Medicare benefits paid
Item 66599
$12,000,000
$10,000,000
$8,000,000
$6,000,000
$4,000,000
$2,000,000
$0
2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012
NSW
VIC
SA
QLD
WA
TAS
ACT
NT
Item 66602
Medicare benefits paid
$90,000,000
$80,000,000
$70,000,000
$60,000,000
$50,000,000
$40,000,000
$30,000,000
$20,000,000
$10,000,000
$0
2003/2004 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013
NSW
VIC
QLD
SA
WA
TAS
ACT
NT
Source: Department of Human Services – Medicare Australia
Figure 3.3 shows that the highest proportion of benefits paid over the past ten years was in
New South Wales (NSW) (34% for 66599 and 38% of total for 66602). This was followed by
Victoria (30% of total for 66599 and 28% of total for 66602). For MBS item 66602,
Queensland had the third highest proportion of claims (19%) followed by Western Australia
(8%) and South Australia (5%). This pattern was slightly different for MBS item 66599, with
South Australia having the third highest proportion of claims (13%) followed by Queensland
(11%) and Western Australia (8%).
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February 2014
Figure 3.3: Proportion of total benefits paid for MBS items 66599 and 66602 by state and
territory, July 2003 to June 2013
Percent of benefits paid
40%
35%
30%
25%
20%
15%
10%
5%
0%
NSW
VIC
QLD
SA
66602
WA
TAS
ACT
NT
66599
Source: Department of Human Services – Medicare Australia
To further explore geographical trends in testing, an analysis was conducted of the number of
services per capita (i.e. per 100,000 population), according to the address at the time of
claiming of the patient to whom the service was rendered. In 2012/13, there were 2,666
claims per 100,000 people enrolled in Medicare across Australia for item 66599 and 9,172
claims per 100,000 people for item 66602 (Table 3.1). South Australia had the highest rate of
claiming for item 66599 per capita (3,635 claims per 100,000 population), followed by the
Australian Capital Territory (ACT) and NSW. The lowest per capita rate of claims for item
66599 was in the Northern Territory (762 claims per 100,000 population). For item 66602,
the highest number of claims per capita in 2012/13 was for NSW and Victoria (over 10,000
claims per 100,000 population in both states), while Tasmania had the lowest (less than 4,000
claims per 100,000 population).
Table 3.1: Claims for MBS items 66599 and 66602 per capita (100,000 population)*, 2008/09 to
2012/13
State/
territory
NSW
VIC
QLD
SA
WA
TAS
ACT
NT
Total
2008/09
1,922
1,928
1,013
3,034
1,525
1,910
2,163
420
1,773
Item
2009/10
2,065
2,052
961
3,172
1,165
2,204
2,285
555
1,822
66599
2010/11
2,343
2,155
1,195
3,094
1,329
2,435
2,310
676
2,002
2011/12
2,635
2,472
1,608
3,327
1,387
2,522
2,602
703
2,286
2012/13
3,021
2,918
2,050
3,635
1,599
2,732
3,046
762
2,666
2008/09
7,774
7,860
6,174
4,895
5,025
3,796
8,831
1,698
6,849
Item
2009/10
8,299
8,454
6,157
5,015
5,778
3,630
8,658
1,962
7,243
66602
2010/11
8,561
8,435
6,787
4,994
5,987
3,462
8,191
2,329
7,462
2011/12
9,134
8,985
7,589
5,570
6,021
3,546
8,256
2,796
7,998
2012/13
10,401
10,261
8,822
6,483
6,887
3,947
9,265
4,639
9,172
Source: Department of Human Services – Medicare Australia
* Services per capita (i.e. per 100,000 population) is calculated by dividing the number of services processed in a month by the number of
people enrolled in Medicare at the end of that month.
Data relating to the average fee per service and average benefit per service from 2008/09 to
2012/13 are summarised in Table 3.2. The proportion of services bulk billed was high (more
than 94% of services) from 2008/09 to 2012/13, which is consistent with the high proportion
of out-of-hospital services (approximately 97%).
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February 2014
Table 3.2: Fees charged and benefits paid for MBS items 66599 and 66602, 2008/09 to 2012/13
Total number of
services
Total fees
charged
Average fee per
service
Total benefits
paid
Average benefit
per service
Out-of-hospital
services
Services
bulkbilled
Average OOP
cost*
Item
66599
66602
66599
66602
66599
66602
66599
66602
66599
66602
66599
66602
66599
66602
66599
66602
2008/09
382,241
1,476,465
$7,995,258
$56,002,248
$20.91
$37.93
$7,843,976
$55,208,644
$20.52
$37.39
96.8%
97.5%
94.2%
95.3%
$9.14
$16.65
2009/10
399,282
1,586,968
$8,310,784
$60,132,026
$20.81
$37.89
$8,102,717
$58,728,189
$20.29
$37.00
97.3%
97.4%
94.3%
93.8%
$12.33
$18.17
2010/11
447,211
1,667,155
$9,225,951
$62,715,325
$20.63
$37.62
$9,061,322
$61,669,203
$20.26
$36.99
97.3%
97.0%
95.8%
95.4%
$13.00
$20.44
2011/12
520,688
1,821,490
$10,698,027
$68,264,085
$20.54
$37.48
$10,545,169
$67,358,102
$20.25
$36.97
97.4%
97.2%
96.0%
95.7%
$9.92
$15.54
2012/13
618,744
2,129,051
$12,665,119
$79,337,023
$20.46
$37.26
$12,484,776
$78,506,111
$20.17
$36.87
97.1%
97.4%
96.2%
96.3%
$10.26
$14.34
Total
2,368,166
8,681,129
$48,895,138
$326,450,707
$20.64
$37.60
$48,037,960
$321,470,248
$20.28
$37.03
97.2%
97.3%
95.4%
95.4%
$10.96
$17.29
Source: Department of Human Services – Medicare Australia
*Average out-of-pocket cost is equal to ‘fees charged for patient-billed out-of-hospital services’ minus ‘benefits paid for patient-billed outof-hospital services’ divided by ‘number of patient-billed out-of-hospital services’
3.2
Age and gender profile of patients
The pattern of use by age and gender for item numbers 66599 and 66602 is shown in Figure
3.4. Folate/vitamin B12 testing claimed under MBS item numbers 66599 and 66602 is
performed for both males and females; however, on average (across all age groups), the test is
undertaken more frequently in females than males (1.8 times more frequently for MBS item
66599 and 1.9 times more frequently for MBS item 66602). For both MBS items, this
difference is greatest in the 15-24 and 25-34 year age groups where females are over 3 times
more likely to have a folate/vitamin B12 test.
For both males and females, the number of tests being performed is higher in older age
groups, particularly for MBS item 66599. This trend was slightly greater for males, with 76%
of claims for MBS item 66599 being for those aged 45 years and over versus 64% for
females. Similarly, for MBS item 66602, 71% of claims for males were aged 45 years and
over versus 60% for females.
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February 2014
Figure 3.4: Use of the MBS items for B12/folate testing by age and gender (2008/09 to 2012/13)
300,000
Number of services for MBS item 66599
Number of services for MBS item 66602
1,000,000
900,000
800,000
700,000
600,000
500,000
400,000
300,000
200,000
100,000
0
250,000
200,000
150,000
100,000
50,000
0
Female
Male
Female
Male
Source: Department of Human Services – Medicare Australia
3.3
Frequency of testing by patient
An analysis of folate/vitamin B12 testing frequency per patient was conducted. For item
66599, there was an increase3 in the overall number of patients tested for folate/vitamin B12,
from 350,954 patients in 2008/09 to 502,547 patients in 2012/13 (+43%). As can be clearly
seen from Figure 3.5, over the period 2008/09 to 2012/13 there has been very little change in
the proportion of patients receiving either one test per year (92%), two tests per year (7.5%),
or three or more tests per year (0.8%).
For item 66602, there was an increase in the overall number of patients tested for
folate/vitamin B12, from 1,324,646 in 2008/09 to 1,706,258 in 2012/13 (+29%). The
proportion of patients receiving only one test within a year was stable over the five-year
timeframe (90%). Approximately 9% of patients received two tests per year and
approximately 1% received three or more tests per year.
These data suggest that the majority of folate/vitamin B12 testing services are being
undertaken for the purposes of screening/testing rather than monitoring.
3
Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.
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February 2014
Figure 3.5: Frequency of claiming MBS items 66599 and 66602 per year by patient, 2008/09 to
2012/13*
Percentage of patients
Item 66602
100.0%
80.0%
60.0%
40.0%
20.0%
0.0%
2008/09
2009/10
1 test
2010/11
2 tests
2011/12
2012/13
2011/12
2012/13
3+ tests
Percentage of patients
Item 66599
100.0%
80.0%
60.0%
40.0%
20.0%
0.0%
2008/09
2009/10
1 test
2010/11
2 tests
3+ tests
Source: Department of Human Services – Medicare Australia
* Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.
3.4
Profile of providers requesting folate/vitamin B12 testing
services
The profile of providers requesting folate/vitamin B12 services was examined over time from
2008/09 to 2012/13 (Table 3.3). Over the five-year time period, there were no material
changes in the pattern of requesting providers. General practitioners (GPs) and other medical
practitioners (OMPs) accounted for approximately 71% of all providers requesting
folate/vitamin B12 testing services for item 66599. Internal medicine consultant physicians
accounted for approximately 14% of all provider counts over the five-year time period,
followed by general surgeons (specialist – subspecialties) and interns. There was a large
variety of other providers requesting services, but they each accounted for less than 2% of
provider counts.
The profile of providers requesting item 66602 was similar to that of item 66599. GPs and
OMPs accounted for 67% of all providers requesting item 66602, followed by internal
medicine consultant physicians (approximately 14%), psychiatrists, general surgeons
(specialist – subspecialties) and interns.
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February 2014
Table 3.3: Number of providers requesting MBS items 66599 and 66602, 2008/09 to 2012/13
Providers requesting
folate/vitamin B12 testing
services
Item 66599
GPs and OMPs
Consultant physician - internal
medicine
General Surgeon - Specialist subspecialties
Intern
Psychiatrist
Obstetrics & Gynaecology
(Specialist & Non-Specialist)
General Surgeon - Specialist
Other Temporary Resident Doctors
All other provider groups#
Item 66602
GPs and OMPs
Consultant physician - internal
medicine
Psychiatrist
General Surgeon - Specialist subspecialties
Intern
General Surgeon - Specialist
Obstetrics & Gynaecology
(Specialist & Non-Specialist)
Other Temporary Resident Doctors
All other provider groups#
2008/09€
2009/10€
Provider
2010/11
count
2011/12
2012/13*
% of all
providers
July 2008
to May
2013
19,882
3,859
20,363
3,955
21,533
4,283
23,263
4,884
24,019
5,135
70.9%
14.4%
648
600
677
819
759
2.3%
491
494
488
574
493
495
529
567
550
873
705
635
885
703
643
2.2%
1.9%
1.8%
414
211
1,016
427
228
1,042
454
243
1,172
525
439
1,428
527
476
1,490
1.5%
1.0%
4.0%
23,424
4,723
24,403
5,184
25,554
5,454
26,802
5,744
27,843
5,834
67.3%
14.2%
1,090
1,075
1,169
1,193
1,272
1,251
1,371
1,307
1,374
1,305
3.3%
3.2%
790
625
586
904
666
592
938
689
612
1,056
711
662
918
720
643
2.4%
1.8%
1.6%
398
1,649
452
1,769
493
1,953
503
2,076
426
2,102
1.2%
5.0%
Source: Department of Human Services – Medicare Australia
€
Data are incomplete for 2008/09 and 2009/10 because small provider counts were suppressed.
* Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.
#
Other includes the following peer groups, which each accounted for <1% of the provider count: Dermatologist – specialist; Surgeon – nonspecialist; Other medical specialist; IVF; Unclassified-miscellaneous-non-specialist; Anaesthetics – specialist; Dentist/orthodontist;
Therapeutic radiologist/therapeutic nuclear medicine – specialist; Pathologist; Anaesthetics – non-specialist; Specialist physician – internal
medicine; Diagnostic imagist – specialist; Diagnostic imagist – non-specialist; Acupuncture; Other, other allied health, abortion/fertility
control; Unclassified-miscellaneous-specialist.
3.5
Frequency of requests for testing by provider
An analysis was conducted of requests for item 66599 and 66602 by frequency from any one
provider. For both items, there was an increase over the period 2008/09 to 2012/13 in the
overall number of providers requesting folate/vitamin B12 testing. For item 66599, the
majority of providers (97%) requested 100 or fewer tests per year. Approximately 2% of
providers requested 101 to 200 tests, and the remaining providers requested more than 200
tests per year (Table 3.4). There were a small number of providers (ranging from 36 to 62 per
year) that requested more than 400 tests per year.
From 2008/09 to 2012/13, approximately 88% of the providers requesting item 66602
requested 100 or fewer tests per year (Table 3.4). Approximately 7% of providers requested
between 101 and 200 tests per year and 2.5% requested 201 to 300 tests per year. Between
2010/11 and 2012/13, over 500 providers requested more than 400 tests per year.
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February 2014
Table 3.4: Frequency of MBS items 66599 and 66602 requested per year by any provider,
2008/09 to 2012/13*
Provider count per test number category (% of providers)
No. of tests
requested
in the year
Item 66599
1 – 100
101 – 200
201 – 300
301 – 400
401 +
Total
Item 66602
1 – 100
101 – 200
201 – 300
301 – 400
401 +
Total
2012/13*
2008/09
2009/10
2010/11
2011/12
Total
26,884 (97.7%)
458 (1.7%)
120 (0.4%)
24 (0.1%)
42 (0.2%)
27,528 (100%)
27,521 (97.6%)
469 (1.7%)
123 (0.4%)
46 (0.2%)
36 (0.1%)
28,195 (100%)
29,205 (97.3%)
559 (1.9%)
133 (0.4%)
56 (0.2%)
55 (0.2%)
30,008 (100%)
32,600 (97.1%)
678 (2.0%)
172 (0.5%)
59 (0.2%)
62 (0.2%)
33,571 (100%)
33,602 (97.0%) 149,812 (97.2%)
724 (2.1%)
2,888 (1.9%)
185 (0.5%)
733 (0.5%)
66 (0.2%)
251 (0.2%)
60 (0.2%)
255 (0.2%)
34,637 (100%) 153,939 (100%)
30,487 (88.7%)
2,260 (6.6%)
772 (2.2%)
380 (1.1%)
461 (1.3%)
34,360 (100%)
32,203 (88.6%)
2,390 (6.6%)
869 (2.4%)
384 (1.1%)
486 (1.3%)
36,332 (100%)
33,819 (88.5%)
2,527 (6.6%)
912 (2.4%)
438 (1.1%)
520 (1.4%)
38,216 (100%)
35,402 (88.0%)
2,706 (6.7%)
1,032 (2.6%)
510 (1.3%)
582 (1.4%)
40,232 (100%)
35,985 (87.4%) 167,896 (88.2%)
2,917 (7.1%)
12,800 (6.7%)
1,152 (2.8%)
4,737 (2.5%)
570 (1.4%)
2,282 (1.2%)
541 (1.3%)
2,590 (1.4%)
41,165 (100%) 190,305 (100%)
Source: Department of Human Services – Medicare Australia
* Based on data processed to 31 May 2013; 2012/13 is therefore incomplete.
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4
REVIEW OF GUIDELINES RELEVANT TO FOLATE TESTING
This Chapter presents the results of the literature search for clinical practice guidelines and
the guideline concordance analysis conducted for folate testing.
4.1
Australian guidelines
The MBS data (Chapter 3) indicate that the majority of requests for folate/vitamin B12 testing
are initiated by GPs and OMPs. The relevant College proving practice advice is the Royal
Australian College of General Practitioners (RACGP). In 2012 the Royal Australian College
of General Practitioners (RACPG) published guidelines for preventative activities in general
practice.(54) The ‘red book’ has been published since 1989 and is accepted as the main guide
to preventative care in Australian general practice. The intention is to provide a
comprehensive and concise set of recommendations for patients in general practice. The
recommendations in the guidelines are based on current, evidence-based guidelines for
preventative activities relevant to Australian general practice. Where Australian guidelines
are not available or recent, other sources have been used, such as Canadian or United States
preventative guidelines or the results of systematic reviews. Folate supplementation is only
mentioned in one section of the RACGP guidelines. In the section on pre-conception
preventative interventions, folate supplementation is recommended. The guidelines do not
comment on testing for folate levels, which indicates that it is not necessary for this
population.
In March 2013, the Royal Australian and New Zealand College of Obstetricians and
Gynaecologists (RANZCOG) updated their College Statement (C-Obs 25) on vitamin and
mineral supplementation and pregnancy. The statement makes recommendations for folate
supplementation, without any mention of the need for measurement of folate levels. The
College recommends that folic acid should be taken for a minimum of one month before
conception and for the first 12 weeks of pregnancy. The recommended dose of folic acid is
increased where there is an increased risk of NTD (e.g. anticonvulsant medication, prepregnancy diabetes mellitus, previous child or family history of NTD or BMI >30). Women
at increased risk of folate deficiency (e.g. multiple pregnancies, haemolytic anaemia) are
advised to take 5 mg of folic acid throughout the pregnancy.
No Australian clinical practice guidelines were identified that specifically mention folate
testing.
4.2
International guidelines
Although there are a large number of international clinical practice guidelines that
recommend folate supplementation in specific populations, in most cases they do not mention
or make explicit recommendations regarding folate testing. The implication is that
supplementation should commence without measurement of folate levels. The following
guidelines are those that were identified that specifically mention folate testing.
Although somewhat dated, a best practice review was published by Smellie et al. (2005) on
the diagnosis and monitoring of vitamin B12 (and folate) deficiency.(55) The review was
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based on a standardised literature search of national and international guidance notes,
consensus statements, health policy documents, and evidence based medicine reviews,
supplemented by relevant primary research documents. However, the authors state that the
recommendations were mostly ‘consensus rather than evidence based’. Therefore, the
guidance was derived from a small number of reviews, supplemented by extrapolations from
knowledge of the physiology of vitamin B12 and folate. The review recommended that folate
testing (together with vitamin B12 testing) should be performed for the following indications:



macrocytic anaemia;
macrocytosis; and
specific neuropsychiatric abnormalities (including paraesthesia, ataxia, peripheral
neuropathy, and memory loss).
In terms of monitoring in patients who have or are receiving replacement, the authors state
that there is no obvious merit in repeating folate measurements during replacement unless
lack of compliance is suspected or anaemia recurs.
There are several disease-specific guidelines that mention the measurement of folate levels.
The National Institute for Health and Clinical Excellence (NICE) in the United Kingdom
released guidance in November 2006 (modified October 2012) to support people with
dementia and their carers in health and social care.(56) The guideline recommends that
measurement of serum vitamin B12 and folate levels are included in a basic dementia screen,
which is performed at the time of presentation (usually within primary care).
In 2007, the UK Royal College of General Practitioners released guidance on the diagnosis
and management of chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy)
in adults and children.(57) The guidance states that tests for vitamin B12 deficiency and folate
levels should not be carried out unless a full blood count and mean cell volume show a
macrocytosis.
4.3
Other reports
In July 2013, Health Quality Ontario released recommendations on folate testing from the
Appropriateness Working Group of the Ontario Health Technology Advisory Committee
(OHTAC)(58). The objective of their Appropriateness Initiative is to develop a systematic
framework for the ongoing identification, prioritisation, and assessment of health
interventions in Ontario for which there is possible misuse, overuse, or underuse. Seven
health interventions were examined in the first phase: annual health exams, aspartate
aminotransferase testing, ferritin testing, folate testing and vitamin B12 testing. Due to the
very limited evidence base, the analysis of folate testing was undertaken using expert
consultation and consensus rather than rapid reviews or full evidence-based analyses.(59) In
the background section, the document states that the five specialties (in Ontario) that ordered
the most folate testing in the community were family practice/general practice (82%), internal
medicine (4.5%), nurse practitioners (2.4%), neurology (2.4%), and gastroenterology (1.8%).
Folate testing was used in males and females in all age categories; however, greatest use was
in women. The provider profile for folate test requests and patient age and gender pattern was
not dissimilar to Australia.
Expert consultation identified health conditions where folate deficiency may be of concern
and where folate testing may be appropriate. Based on the expert consultation, OHTAC
recommended that red blood cell folate testing be restricted to individuals with:
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

low haemoglobin levels and a high mean corpuscular volume; and
suspected gastrointestinal disorders causing malabsorption or suspected malnutrition of
any cause.
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5
REVIEW OF THE CLINICAL EVIDENCE FOR FOLATE
TESTING
This Chapter presents the results of the systematic literature review on folate testing in
relation to the clinical research questions.
5.1
Evidence base
5.1.1 Search results
A literature search was performed on 23rd September 2013, using OVID MEDLINE,
EMBASE, and the Cochrane Library, for studies published from January 2002 until
September 2013. Abstracts were reviewed and for those studies meeting the eligibility
criteria, full-text articles were obtained. Reference lists were also examined for any additional
relevant studies not identified through the search. The database search yielded 985 citations
(with duplicates removed). Articles were excluded based on information in the title and
abstract and the full texts of potentially relevant articles were obtained for further assessment.
5.1.2 Existing health technology reports and systematic reviews
There were no health technology reports or systematic reviews on the safety and effectiveness
of folate testing. One systematic review of poor quality was identified, which aimed to
compare measurement of serum versus red cell folate.(60)
5.2
Appropriate clinical indications for folate testing
There were no studies meeting the eligibility criteria that evaluated the clinical indications for
folate testing. However, as discussed in Chapter 4, a limited number of clinical practice
guidelines mention measurement of serum folate levels for particular populations.
5.3
Evidence that testing folate levels improves health outcomes
No definitive conclusions can be drawn about the effectiveness of folate testing since no
prospective trials have been conducted to directly assess the impact of testing on health
outcomes in healthy populations or in patients with chronic disease associated with folate
deficiency.
Although retrospective studies do not meet the inclusion criteria for this review, several
retrospective studies (low level evidence) were identified that examined the clinical utility of
folate testing. For example, a retrospective study undertaken in the United States by Ashraf et
al. (2008) examined the utility of folate testing for patients with anemia or dementia. During
the 4-month study period, 1,007 folate tests were performed at their medical centre on 980
patients. Fourteen patients (0.4%) had folate levels that were low or borderline (four patients
had levels < 3.0 ng/mL and ten patients had levels 3-4 ng/mL). All 14 patients were
inpatients. Five patients received folate replacement and six patients had their folate levels
rechecked within 12 months, at which time all levels had returned to normal. The authors
concluded that their study demonstrates the low utility of routine folate testing in clinical
practice; the test should be reserved for patients with macrocytic anaemia and those at high
risk for folate deficiency.(61)
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Another retrospective study from the United States analysed all inpatient and emergency
department serum folate tests at a single institution over a twelve-month period to determine
the indications, comorbidities and change in management based on the test results.(62) A total
of 2,093 serum folate tests were performed in 1,944 patients, with only two patients (0.1%)
having deficient levels (≤ 3.0 ng/mL). The most common indications for testing (based on a
random sample of 250 chart reviews) were anaemia without macrocytosis, anaemia with
macrocytosis, delirium, malnutrition, and peripheral neuropathy. Given the low rate of serum
folate deficiency and the lack of change in management based on deficient results, the authors
concluded that in folic acid fortified countries, serum folate testing has low utility for all
indications in inpatients and emergency department patients.(62) The authors commented that
based on prior studies, and supported by their results, there is no evidence for checking serum
folate levels in delirium, dementia, peripheral neuropathy, malnutrition, or any of the other
indications. In addition, their results demonstrated a low utility even in patients with anaemia
or macrocytic anaemia.
5.4
Risks/harms associated with folate testing
No trials designed to directly measure the risks or harms associated with folate testing were
identified. However, folate testing relies on a blood draw, which is a safe procedure. It is
likely that the consequences of inaccurate or inappropriately interpreted folate test results,
such as a false positive, are relatively small. Folate supplements are generally considered safe
when taken in amounts that are not higher than the recommended dietary allowance.
5.5
Quality of testing
A poor quality systematic review by Farrell et al. (2012) sought to compare the effectiveness
of serum versus red cell folate.(60) The authors undertook a literature search on Medline using
the terms ‘red cell folate’ and ‘serum folate’ and identified 328 papers. A narrative
assessment of the body of evidence was undertaken. The authors declared no conflicts of
interest.
After assessing different aspects of the performance of serum and red cell folate assays, the
review did not find evidence to justify the higher cost of routinely measured red cell folate. In
addition, it was found that serum folate is influenced by fewer analytical variables, for
example C677TT polymorphism of methylenetetrahydrofolate alters the distribution of folate
forms in red cells and may therefore cause analytical variability. In the evaluation of serum
and red cell folate versus homocysteine, there was no evidence for the better performance of
red cell folate and, of the two, serum folate appeared superior. Studies also demonstrated that
very few patients would have their clinical outcome altered by the measurement of red cell
folate in addition to serum folate.
In relation to specific population groups, serum folate appeared to be a superior marker of
folate status in vitamin B12 deficiency.(60) The authors also found that serum folate may have
more sensitivity in responding to changes in folate intake (supplements or fortification) than
red cell folate at both short- and long-term follow-up.(60) When blood was collected during
pregnancy, serum folate appeared to predict NTD risk as well as red cell folate.(60)
The authors concluded that overall, as a routine test of folate status, serum folate appears to
offer the best combination of test cost and clinical information.
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6
REVIEW OF THE ECONOMIC EVIDENCE FOR FOLATE
TESTING
This Chapter presents a preliminary economic evaluation of folate testing, which is limited to
a summary of the findings from the available studies identified through the systematic
literature review. A formal modelled economic evaluation of folate testing was not within the
scope of this review.
6.1
Costing studies or economic analyses relevant to folate testing
A simple costing analysis was undertaken in the retrospective study mentioned in Section 5.3
that analysed inpatient and emergency department serum folate tests at their institution in the
United States.(62) Based on the institution’s charge for serum folate, a total of $US316,043
was charged for the 2,093 folate tests performed. The amount charged per deficient result
(0.1% of tests) was $US158,022. The authors compared their results with that of a 2001 study
(also a retrospective review) in patients with macrocytosis and anaemia, which reported a
charge of $US1,321 per deficient test. The 100-fold difference was attributed to decreased
rate of deficient tests from 2001 to 2013, due to mandatory fortification.
The authors acknowledged that the actual cost to the hospital of a serum folate test was much
lower due to the highly automated process, and was estimated to be <$US2,093. Because no
change was made for the deficient patients in the study, the charge per serum folate deficient
result that changed management approached infinity. The authors concluded that the
exceptionally low utility of serum folate testing makes the costs associated with these tests
excessive.
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7
FINDINGS AND CONCLUSIONS
This Chapter sets out the findings and conclusions of the review of folate testing – as
represented by MBS item numbers 66599 and 66602 – based on the analysis of the available
MBS data; evidence obtained through systematic literature review; and the information
derived from the stakeholder consultations.
7.1
Current usage of folate and/or vitamin B12 testing services in
Australia
Over the past 10 years, the number of claims for MBS item 66599 has more than doubled
(+119%) from 282,531 in 2003/04 to 618,744 in 2012/13. Over the same timeframe the
number of claims for MBS item 66602 has had an even greater increase (+307%) from
522,980 to 2,129,051. The increase in benefits paid for both items reflects the increase in
claims. Benefits paid for MBS item 66599 increased from $5.7m to $12.5m (+120%),
whereas benefits for MBS item 66602 increased from $19.2m to $78.5m (+309%). While
total benefits increased significantly, the proportion of benefits paid to each state and territory
remained relatively constant over the ten-year period. The highest proportion of benefits paid
over the past ten years was in New South Wales (34% of total for 66599 and 38% for 66602),
followed by Victoria (30% of total for 66599 and 28% for 66602).
To further explore geographical trends in testing, an analysis was conducted of the number of
services per capita (i.e. per 100,000 population), according to the address at the time of
claiming of the patient to whom the service was rendered. In 2012/13, there were 2,666
claims per 100,000 people enrolled in Medicare across Australia for item 66599 and 9,172
claims per 100,000 people for item 66602. South Australia had the highest rate of claiming
for item 66599 per capita (3,635 claims per 100,000 population), while the lowest per capita
rate was in the Northern Territory (762 claims per 100,000 population). For item 66602, the
highest number of claims per capita in 2012/13 was for NSW and Victoria (over 10,000
claims per 100,000 population in both states), while Tasmania had the lowest (less than 4,000
claims per 100,000 population).
MBS item numbers 66599 and 66602 are claimed by both males and females; however,
females had a higher number of tests at all ages, except in the youngest age category (< 5
years). Females also had a steeper increase in testing volume than males, with the largest
difference between genders in the 15-24 and 25-34 year age groups. For item 66599, the
number of tests being performed in people aged 45 years and over was 76% for males and
64% for females. For item 66602, 71% of claims for males were aged 45 years and over
versus 60% for females. For females, testing decreased from age 65 years. Similarly, the
number of tests dropped dramatically in elderly men.
For both MBS items, there was an increase in the overall number of patients tested between
2008/09 and 2012/13. However, there was very little change in the proportion of patients
receiving either one test per year (92% and 90% for items 66599 and 66602, respectively),
two tests per year (7.5% and 9% for items 66599 and 66602, respectively), or three or more
tests per year (0.8% for item 66599 and 1.1% for item 66602). These data suggest that the
majority of folate/vitamin B12 testing services are being undertaken for the purposes of
screening/testing rather than monitoring.
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Over the five-year time period from 2008/09 to 2012/13, there were no material changes in
the pattern of requesting providers. General practitioners and other medical practitioners
accounted for approximately 71% and 67% of all providers requesting item 66599 and item
66602, respectively. Approximately 14% of providers requesting folate/vitamin B12 testing
were internal medicine consultant physicians. There was a large variety of other providers
requesting services, but they each accounted for less than 4% of provider counts.
For both items, there was an increase over the period 2008/09 to 2012/13 in the overall
number of providers requesting folate/vitamin B12 testing. For item 66599, the majority of
providers (97%) requested 100 or fewer tests per year. Approximately 2% of providers
requested 101 to 200 tests, and the remaining providers requested more than 200 tests per
year. There were a small number of providers (ranging from 36 to 62 per year) that requested
more than 400 tests per year. Approximately 88% of the providers requesting item 66602
requested 100 or fewer tests per year. Approximately 7% of providers requested between 101
and 200 tests per year and 2.5% requested 201 to 300 tests per year. Between 2010/11 and
2012/13, more than 500 providers requested over 400 tests per year.
7.2
Clinical guidance on folate testing
Although there are a large number of clinical practice guidelines that recommend folate
supplementation, particularly in pregnant women, they do not specifically mention folate
testing, which implies that testing may not be necessary in these populations. Guidelines that
mention folate testing apply to particular populations. For example, NICE guidance on
dementia recommends that measurement of serum folate levels are included in a basic
dementia screen, performed at the time of presentation. Guidance on the diagnosis and
management of chronic fatigue syndrome/myalgic encephalomyelitis from the Royal College
of General Practitioners advises that folate levels should not be carried out unless a full blood
count and mean cell volume show a macrocytosis.
A July 2013 report from Health Quality Canada used expert consultation to identify health
conditions where folate deficiency may be of concern and where folate testing may be
appropriate. Based on the expert consultation, the Ontario Health Technology Advisory
Committee (OHTAC) recommended that red blood cell folate testing be restricted to
individuals with:


low haemoglobin levels and a high mean corpuscular volume;
suspected gastrointestinal disorders causing malabsorption or suspected malnutrition of
any cause.
7.3
Relationship between testing for folate levels and health
outcomes
The main function of folate is to help form RBCs and produce DNA. Folate also prevents
NTD during fetal development. A deficiency in folic acid can lead to increased homocysteine
levels in plasma since folate is necessary for the conversion of homocysteine to methionine.
In addition, deficiency can result in perturbation of the metabolic pathway of conversion of
homocysteine to methionine with consequent disruption of DNA synthesis caused by
thymidine lack resulting in megaloblastic anaemia, as well as other adverse effects on the
nervous system and other organs. However, folate deficiency is much less common since the
introduction of mandatory fortification with folate of wheat flour in Australia in September
2009. A retrospective study to determine the impact of the fortification program on blood
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folate levels reported that the prevalence of low serum folate levels decreased from 9.3% in
2007 to 2.1% in 2010 and the prevalence of low RBC folate levels decreased from 3.4% to
0.5%. Due to the low prevalence of folate deficiency, the clinical utility of folate testing is
questionable.
No definitive conclusions can be drawn about the effectiveness of folate testing since no
prospective trials have been conducted to directly assess the impact of testing on health
outcomes in healthy populations or in patients with chronic disease associated with folate
deficiency.
Although retrospective studies do not meet the inclusion criteria for this review, several
retrospective studies (low level evidence) were identified that examined the clinical utility of
folate testing in the United States. Given the low rates of serum folate deficiency and the lack
of change in management based on deficient results, the authors of the studies concluded that
in folic acid fortified countries, serum folate testing has low utility for inpatients and
emergency department patients or routine testing in clinical practice for patients with anaemia
or dementia.
7.4
Harms associated with folate testing
No trials designed to directly measure the risks or harms associated with folate testing were
identified. However, folate testing relies on a blood draw, which is a safe procedure. It is
likely that the consequences of inaccurate or inappropriately interpreted folate test results,
such as a false positive, are relatively small. Folate supplements are generally considered safe
when taken in amounts that are not higher than the recommended dietary allowance.
7.5
Quality of folate testing
A poor quality systematic review sought to compare the effectiveness of serum versus red cell
folate. The review did not find evidence to justify the higher cost of routinely measured red
cell folate. The review found that serum folate appeared to be a superior marker of folate
status in vitamin B12 deficiency and may have more sensitivity in responding to changes in
folate intake (supplements or fortification) than red cell folate. Both tests appeared to predict
NTD risk equally. Serum folate also has the advantage of being influenced by fewer
analytical variables. In an evaluation of serum and red cell folate versus homocysteine, there
was no evidence for the better performance of red cell folate and, of the two, serum folate
appeared superior. Studies also demonstrated that very few patients would have their clinical
outcome altered by the measurement of red cell folate in addition to serum folate. The
authors concluded that overall, as a routine test of folate status, serum folate appears to offer
the best combination of test cost and clinical information.
7.6
Cost implications of folate testing
There was very limited and poor quality evidence relating to the cost of folate testing. In one
retrospective study from the United States, the authors concluded that the exceptionally low
utility of serum folate testing makes the costs associated with these tests excessive.
7.7
Conclusions
There has been a substantial increase in the number of claims for folate/vitamin B12 testing
over the past ten years. Analysis of MBS data indicates that the majority of vitamin B12
testing services are requested by GPs and OMPs for the purposes of screening or testing,
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rather than follow-up monitoring. There are no Australian clinical practice guidelines that
either advocate or recommend against routine testing for folate in any patient population.
However, there is guidance from the UK recommending measurement of serum folate levels
in a basic dementia screen. There is also guidance from the UK that folate levels should not
be carried out in patients with chronic fatigue syndrome/myalgic encephalomyelitis unless a
full blood count and mean cell volume show a macrocytosis. There are no recommendations
on the frequency of folate testing and there is no prospective evidence regarding the clinical
utility of folate testing in any population. However, low level evidence from retrospective
studies suggests that serum folate testing has low utility in folic acid fortified countries.
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APPENDIX 1 – References
1.
Halsted CH. The intestinal absorption of dietary folates in health and disease. J Am Coll Nutr
1989 Dec;8(6):650-8.
2.
Gregory JF, 3rd, Williamson J, Liao JF, Bailey LB, Toth JP. Kinetic model of folate
metabolism in nonpregnant women consuming [2H2]folic acid: isotopic labeling of urinary
folate and the catabolite para-acetamidobenzoylglutamate indicates slow, intake-dependent,
turnover of folate pools. J Nutr 1998 Nov;128(11):1896-906.
3.
Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician 2003 Mar 1;67(5):979-86.
4.
Green R. Indicators for assessing folate and vitamin B-12 status and for monitoring the
efficacy of intervention strategies. Am J Clin Nutr 2011 Aug;94(2):666S-72S.
5.
Stabler SP. Screening the older population for cobalamin (vitamin B12) deficiency. J Am
Geriatr Soc 1995 Nov;43(11):1290-7.
6.
Gregory Iii JF. Bioavailability of folate. Eur J Clin Nutr 1997;51(SUPPL. 1):S54-S9.
7.
Pfeiffer CM, Rogers LM, Bailey LB, Gregory Iii JF. Absorption of folate from fortified
cereal-grain products and of supplemental folate consumed with or without food determined
by using a dual- label stable-isotope protocol. American Journal of Clinical Nutrition
1997;66(6):1388-97.
8.
Australian Health and Medical Research Council and the New Zealand Ministry of Health.
Nutrient reference values for Australia and New Zealand including recommended daily
intakes. 2006; Available from: http://www.nrv.gov.au/nutrients/folate.htm.
9.
Kaushansky K BE, Seligsohn U, Lichtman MA, Kipps TJ, Prchal JT,. Folate, cobalamin, and
megaloblastic anemias. 8th ed ed. R. G, editor. New York: McGraw-Hill; 2010.
10.
Halsted CH. Folate deficiency in alcoholism. Am J Clin Nutr 1980 Dec;33(12):2736-40.
11.
Lindenbaum J. Folate and vitamin B12 deficiencies in alcoholism. Semin Hematol 1980
Apr;17(2):119-29.
12.
Nkrumah FK, Nathoo KJ, Sanders DM. Iron, folate and vitamin B12 in severe protein-energy
malnutrition. Cent Afr J Med 1988 Mar;34(3):39-43.
13.
Thompson T. Folate, iron, and dietary fiber contents of the gluten-free diet. J Am Diet Assoc
2000 Nov;100(11):1389-96.
14.
Malterre T. Digestive and nutritional considerations in celiac disease: could supplementation
help? Altern Med Rev 2009 Sep;14(3):247-57.
15.
Higgins JR, Quinlivan EP, McPartlin J, Scott JM, Weir DG, Darling MR. The relationship
between increased folate catabolism and the increased requirement for folate in pregnancy.
Bjog 2000 Sep;107(9):1149-54.
16.
Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, Scott JM. Maternal plasma folate and
vitamin B12 are independent risk factors for neural tube defects. Q J Med 1993
Nov;86(11):703-8.
MBS Reviews – Folate Review Report
Page 38
February 2014
17.
Groenen PM, van Rooij IA, Peer PG, Gooskens RH, Zielhuis GA, Steegers-Theunissen RP.
Marginal maternal vitamin B12 status increases the risk of offspring with spina bifida. Am J
Obstet Gynecol 2004 Jul;191(1):11-7.
18.
Suarez L, Hendricks K, Felkner M, Gunter E. Maternal serum B12 levels and risk for neural
tube defects in a Texas-Mexico border population. Ann Epidemiol 2003 Feb;13(2):81-8.
19.
Green R MJ. Handbook of Vitamins. 4th ed. Zempleni J RR, editor. Boca Raton, FL: Taylor
& Francis Group; 2007.
20.
Aarts EO, Janssen IM, Berends FJ. The gastric sleeve: losing weight as fast as micronutrients?
Obes Surg 2011 Feb;21(2):207-11.
21.
Schubert ML. Gastric secretion. Curr Opin Gastroenterol 2007 Nov;23(6):595-601.
22.
Cravo ML, Camilo ME. Hyperhomocysteinemia in chronic alcoholism: Relations to folic acid
and vitamins B6 and B12 status. Nutrition 2000;16(4):296-302.
23.
Shelnutt KP, Kauwell GPA, Chapman CM, Gregory Iii JF, Maneval DR, Browdy AA, et al.
Folate Status Response to Controlled Folate Intake Is Affected by the
Methylenetetrahydrofolate Reductase 677C→T Polymorphism in Young Women. Journal of
Nutrition 2003;133(12):4107-11.
24.
Ponziani FR, Cazzato IA, Danese S, Fagiuoli S, Gionchetti P, Annicchiarico BE, et al. Folate
in gastrointestinal health and disease. Eur Rev Med Pharmacol Sci 2012 Mar;16(3):376-85.
25.
Yakut M, Ustun Y, Kabacam G, Soykan I. Serum vitamin B12 and folate status in patients
with inflammatory bowel diseases. Eur J Intern Med 2010 Aug;21(4):320-3.
26.
Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.
MRC Vitamin Study Research Group. Lancet 1991 Jul 20;338(8760):131-7.
27.
Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, et al.
Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or
macrocytosis. N Engl J Med 1988 Jun 30;318(26):1720-8.
28.
Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM. Vitamin B12,
folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry 2002
Dec;159(12):2099-101.
29.
Ramos MI, Allen LH, Mungas DM, Jagust WJ, Haan MN, Green R, et al. Low folate status is
associated with impaired cognitive function and dementia in the Sacramento Area Latino
Study on Aging. Am J Clin Nutr 2005 Dec;82(6):1346-52.
30.
Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and
folate in relation to the development of Alzheimer's disease. Neurology 2001 May
8;56(9):1188-94.
31.
Medicine Io, Board FaN. Dietary Reference Intakes: Thiamin, riboflavin, niacin, vitamin B6,
folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, DC1998.
32.
US Department of Agriculture ARS. USDA National Nutrient Database for Standard
Reference, Release 24. 2011; Available from: http://www.ars.usda.gov/ba/bhnrc/ndl.
33.
Food Standards ANZ. Adding vitamins and minerals to food. 2012; Available from:
http://www.foodstandards.gov.au/consumerinformation/fortification.cfm.
MBS Reviews – Folate Review Report
Page 39
February 2014
34.
K ABW. Interim evaluation of the voluntary folate fortification policy. Canberra, ACT:
Australian Food and Nutrition Monitoring Unit2001.
35.
1999.
Shils M OJ, Shike M, Ross AC. Folic Acid. V H, editor. Baltimore: Williams & Wilkins;
36.
Standards ANZF. Standard 2.1.1 Clause 4 (2). 2009.
37.
AIHW. Mandatory folic acid and iodine fortification in Australia and New Zealand. Baseline
report for monitoring
Canberra, ACT2011.
38.
Brown RD, Langshaw MR, Uhr EJ, Gibson JN, Joshua DE. The impact of mandatory
fortification of flour with folic acid on the blood folate levels of an Australian population.
Med J Aust 2011 Jan 17;194(2):65-7.
39.
Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary
care physician. Arch Intern Med 1999 Jun 28;159(12):1289-98.
40.
Cook JD, Duh S. Laboratory reference range values. 2005.
41.
Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies. A
publication of the British Committee for Standards in Haematology. BCSH General
Haematology Test Force. Clin Lab Haematol 1994 Jun;16(2):101-15.
42.
NEQAS U. Haematinic assays scheme. Annual report 2001 Sutton, Coldfield2002.
43.
Arsenault JE, Mora-Plazas M, Forero Y, Lopez-Arana S, Baylin A, Villamor E. Hemoglobin
concentration is inversely associated with erythrocyte folate concentrations in Colombian
school-age children, especially among children with low vitamin B12 status. Eur J Clin Nutr
2009 Jul;63(7):842-9.
44.
Wilcken DE, Gupta VJ, Reddy SG. Accumulation of sulphur-containing amino acids
including cysteine-homocysteine in patients on maintenance haemodialysis. Clin Sci (Lond)
1980 May;58(5):427-30.
45.
Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as
primary determinants of homocysteinemia in an elderly population. Jama 1993 Dec
8;270(22):2693-8.
46.
Jacques PF, Rosenberg IH, Rogers G, Selhub J, Bowman BA, Gunter EW, et al. Serum total
homocysteine concentrations in adolescent and adult Americans: results from the third
National Health and Nutrition Examination Survey. Am J Clin Nutr 1999 Mar;69(3):482-9.
47.
Louey W LZ, and Sikaris KA. Which Blood Collection Tube is Better for Homocysteine.
48.
Hoffbrand AV, Newcombe FA, Mollin DL. Method of assay of red cell folate activity and the
value of the assay as a test for folate deficiency. J Clin Pathol 1966 Jan;19(1):17-28.
49.
Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology
Alliance benchmarking review. J Clin Pathol 2003 Dec;56(12):924-6.
50.
Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and
homocysteine. Hematology Am Soc Hematol Educ Program 2003:62-81.
MBS Reviews – Folate Review Report
Page 40
February 2014
51.
Tucker KL, Mahnken B, Wilson PW, Jacques P, Selhub J. Folic acid fortification of the food
supply. Potential benefits and risks for the elderly population. Jama 1996 Dec
18;276(23):1879-85.
52.
AGREE Next Steps Consortium. The AGREE II Instrument 2009; Available from:
http://www.agreetrust.org
53.
Richardson WS, Scott MD WM, et al. The well built clinical question: a key to evidence based
decisions. ACP Journal Club 1995;123:ppA-12. .
54.
Royal Australian College of General Practitioners. Guidelines for preventative activities in
general practice. 8th edition. 2012.
55.
Smellie WSA, Wilson D, McNulty CAM, Galloway MJ, Spickett GA, Finnigan DI. Best
practice in primary care pathology: Review 1 J Clin Pathol 2005;58(10):1016-24.
56.
National Institute for Health and Clinical Excellence. National Clinical Practice Guidelines
Number 42. Dementia: A NICE-SCIE Guideline on supporting people with dementia and their
carers in health and social care. 2012.
57.
Turnbull N, Shaw EJ, Baker R, Dunsdon S, Costin N, Britton G, et al. Chronic fatigue
syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management of
chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy) in adults and
children. London: Royal College of General Practitioners. 2007.
58.
Ontario Health Technology Advisory Committee. Health Quality Ontario. Appropriateness
Phase 1 OHTAC Recommendations: Annual health exams, aspartate aminotransferase
testing, ferritin testing, folate testing and vitamin B12 testing. 2013.
59.
Health Quality Ontario. Folate and folic acid: an expert consultation. . 2013.
60.
Farrell CJL, Kirsch SH, Herrmann M. Red cell or serum folate: What to do in clinical
practice? Clinical Chemistry and Laboratory Medicine 2013;51(3):555-69.
61.
Ashraf MJ, Cook JR, Rothberg MB. Clinical utility of folic acid testing for patients with
anemia or dementia. Journal of General Internal Medicine 2008;23(6):824-6.
62.
Theisen-Toupal J, Horowitz GL, Breu AC. Utility, charge, and cost of inpatient and
emergency department serum folate testing. Journal of Hospital Medicine 2013;8(2):91-5.
63.
NHMRC. NHMRC levels of evidence and grades for recommendations for developers of
guidelines. [Internet]. Canberra, ACT: National Health and Medical Research Council; 2009.
Available
from:
http://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/evidence_statement_form.pdf.
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APPENDIX 2 – Review Consultation Committee members
As part of the MBS Review process, the Department established a Review Consultation
Committee (RCC). The RCC is a time-limited committee of nominated representatives to
provide advice to the Department to inform the review process, such as the development of
review reports, i.e. scope and protocol documents, clinical practice and policy issues.
Name
A/Prof Ken Sikaris
A/Prof Hans Schneider
Dr Zhong Lu
Dr Paul Glendenning
Dr Richard Whiting
Dr Andrew Boyden
Dr Ie-Wen Sim
Dr Peter Harman
Dr Dan McLaughlin
Dr Walid Jammal
Chair and Secretariat
MBS Reviews – Folate Review Report
Representing
Royal College of Pathologists of Australasia
Royal College of Pathologists of Australasia
Royal College of Pathologists of Australasia
Royal College of Pathologists of Australasia
Australian Medical Association
NPS Medicinewise
Endocrine Society of Australia
In-vitro Diagnostic (IVD) Australia
Australian and New Zealand Association of Neurologists
General Practitioner
MSAC Evaluation Sub-Committee (ESC) member
Department of Health
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February 2014
APPENDIX 3 – MBS Information
The MBS item numbers for folate testing in scope of this review include 66599 and 66602
(see Table A3.1). Both of the items relate to testing serum vitamin B12 or testing red cell (or
serum) folate. Both of the items are subject to Rule 21 (i.e. no more than three of any
combination of these tests are eligible for Medicare subsidy per patient per year).
Table A3.1: Description of folate testing funded under the MBS
Item number
66599
66602
MBS item number description
Serum B12 or red cell folate and, if required, serum folate
(Item is subject to Rule 21)
Fee: $23.60
Benefit: 75% = $17.70
85% = $20.10
Serum B12 and red cell folate and, if required, serum folate
(Item is subject to Rule 21)
Fee: $42.95
Benefit: 75% = $32.25
Both of the items are subject to Rule 21:
85% = $36.55
Serum B12 and red cell folate testing
21.(1) For items 66599 and 66602, a medicare benefit is not payable for more than 3 episodes of
services described in item 66599 or 66602, or any combination of those items, in a 12 month period.
21.(2) A medicare benefit is not payable for a service described in item 66599 if the service was
provided as part of the same patient episode as a service described in item 66602.
Source: Department of Human Services – Medicare Australia, accessed September 2013
Table A3.2 shows when the MBS item numbers for folate/vitamin B12 testing were included
on the MBS.
Table A3.2: Item number, descriptor and schedule fee start dates for MBS item numbers
MBS item number
66599
66602
Type of date
Item Start Date
Current Descriptor Start Date
Current Schedule fee start date
Item Start Date
Current Descriptor Start Date
Current Schedule fee start date
Date
01-Nov-1998
01-Mar-1999
01-Jan-2013
01 Nov 1998
01 Mar 1999
01-Jan-2013
Source: Department of Human Services – Medicare Australia, accessed September 2013
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APPENDIX 4 – Search term strategy
The literature search strategies focused on the clinical evidence for folate testing (Table A4.1)
and the cost implications associated with folate testing (Table A4.2).
Table A4.1: Search strategy for clinical evidence
Population
General healthy population
Patients diagnosed with
anaemia
Search Terms
Embase and Medline
Population – ((‘pregnancy’/exp OR ‘pregnancy’) OR (‘infant’/exp OR ‘infant’)
OR (‘human milk’/exp OR ‘human milk’) OR (‘lactation’/exp OR ‘lactation’) OR
(‘vegetarian’/exp OR ‘vegetarian’) OR (‘malnutrition’/exp OR ‘malnutrition’) OR
(‘elderly’/exp OR ‘elderly’) OR (‘aged’/exp OR ‘aged’) OR (‘gluten free diet’/exp
OR ‘gluten free diet’) OR (‘alcoholism’/exp OR ‘alcoholism’))
AND
Intervention – (‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR
‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR
‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red
cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte
folate’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR
‘haematologic test*’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane Library
Population – ((MeSH descriptor Pregnancy explode all trees) OR (MeSH
descriptor Infant explode all trees) OR (MeSH descriptor Human Milk explode all
trees) OR (MeSH descriptor Lactation explode all trees) OR (MeSH descriptor
vegetarian explode all trees) OR (MeSH descriptor Malnutrition explode all trees)
OR (MeSH descriptor Aged explode all trees) OR (MeSH descriptor Alcoholism
explode all trees) OR ((pregnancy) OR (pregnancy):ti,ab,kw) OR ((infant) OR
(infant):ti,ab,kw) OR ((human milk) OR (human milk):ti,ab,kw) OR ((lactation)
OR (lactation):ti,ab,kw) OR ((vegetarian) OR (vegetarian):ti,ab,kw) OR
((malnutrition) OR (malnutrition):ti,ab,kw) OR ((elderly) OR (eldrely):ti,ab,kw)
OR ((aged) OR (aged):ti,ab,kw) OR ((gluten free diet) OR (gluten free
diet):ti,ab,kw) OR ((alcoholism) OR (alcoholism):ti,ab,kw))
AND
Intervention – (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR
(MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR
(MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR
(MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic
acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all
trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum
folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red
cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor
Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) AND
((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH
descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)
AND
Limits [humans]/lim AND [english]/lim
Embase and Medline
Population – ((‘anaemia’/exp OR ‘anaemia’ OR ‘anemia’/exp OR ‘anemia’) OR
(‘macrocyt*’/exp OR ‘macrocyt*)’ OR (‘megaloblastic ’/exp OR ‘megaloblastic’)
OR (‘pernicious’/exp OR ‘pernicious’) OR (‘pancytopenia’/exp OR
‘pancytopenia’)) AND NOT (‘iron deficiency anaemia’/exp OR ‘iron deficiency
anaemia’)
AND
Intervention – (‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR
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Population
Patients with neurologic
disease
Search Terms
‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR
‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red
cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte
folate’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR
‘haematologic test*’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane Library
Population – ((MeSH descriptor Anaemia explode all trees) OR (MeSH descriptor
Megaloblastic explode all trees) OR (MeSH descriptor Pernicious explode all
trees) OR (MeSH descriptor Pancytopenia explode all trees) OR ((anaemia) OR
(anaemia):ti,ab,kw) OR ((megaloblastic) OR (megaloblastic):ti,ab,kw) OR
(macrocyt*) OR ((pernicious) OR (pernicious):ti,ab,kw) OR ((pancytopenia) OR
(pancytopenia):ti,ab,kw) ) AND NOT ((MeSH descriptor Iron deficiency anaemia)
OR (iron deficiency anaemia):ti,ab,kw)
AND
Intervention –((MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR
(MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR
(MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR
(MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic
acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all
trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum
folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red
cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor
Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) AND
((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH
descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)
AND
Limits [humans]/lim AND [english]/lim
Embase and Medline
Population – ((‘paresthesias’/exp OR ‘paresthesias’) OR (‘peripheral
neuropathy’/exp OR ‘peripheral neuropathy’) OR (‘combined system disease’/exp
OR ‘combined systems disease’))
AND
Intervention – ‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR
‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR
‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red
cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte
folate’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR
‘haematologic test*’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane Library
Population – ((MeSH descriptor Paresthesias explode all trees) OR (MeSH
descriptor Peripheral Neuropathy explode all trees) OR (MeSH descriptor
Combined Systems Disease explode all trees) OR ((paresthesias) OR
(paresthesias):ti,ab,kw) OR ((peripheral neuropathy) OR (peripheral
neuropathy):ti,ab,kw) OR ((combined systems disease) OR (combined systems
disease):ti,ab,kw))
AND
Intervention – (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR
(MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR
(MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR
(MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic
acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all
trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum
folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red
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Population
Patients with
gastrointestinal and
malabsoption diseases
Search Terms
cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor
Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) AND
((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH
descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)
AND
Limits [humans]/lim AND [english]/lim
Embase and Medline
Population – ((‘atrophic body gastritis’/exp OR ‘atrophic body gastritis’) OR
(‘gastrectomy’/exp OR ‘gastrectomy’) OR (‘gastric sleeve’/exp OR ‘gastric
sleeve’) OR (‘peptic ulcer’/exp OR ‘peptic ulcer’) OR (‘H. Pylori’/exp OR ‘H.
Pylori’) OR
(‘dyspepsia’/exp OR ‘dyspepsia’) OR (‘diarrhoea’/exp OR
‘diarrhoea’) OR (‘coeliac disease’/exp OR ‘coeliac disease’) OR (‘Crohn’s
disease’/exp OR ‘Crohn’s disease’) OR (‘tapeworms’/exp OR ‘tapeworms’))
AND
Intervention – (‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR
‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR
‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red
cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte
folate’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR
‘haematologic test*’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane Library
Population – ((MeSH descriptor Atrophic Body Gastritis explode all trees) OR
(MeSH descriptor Gastrectomy explode all trees) OR (MeSH descriptor Gastric
Sleeve explode all trees) OR (MeSH descriptor Peptic Ulcer explode all trees) OR
(MeSH descriptor H. pylori explode all trees) OR (MeSH descriptor Dyspepsia
explode all trees) OR (MeSH descriptor Diarrhoea explode all trees) OR (MeSH
descriptor Coeliac Disease explode all trees) OR (MeSH descriptor Crohn’s
Disease explode all trees) OR (MeSH descriptor Tapeworms explode all trees) OR
((atrophic body gastritis) OR (atrophic body gastritis):ti,ab,kw OR (gastrectomy)
OR (gastrectomy):ti,ab,kw OR (gastric sleeve) OR (gastric sleeve):ti,ab,kw OR
(peptic ulcer) OR (peptic ulcer):ti,ab,kw OR (h. pylori) OR (h. pylori):ti,ab,kw OR
(dyspepsia) OR (dyspepsia):ti,ab,kw OR (diarrhoea) OR (diarrhoea):ti,ab,kw OR
(coeliac disease) OR (coeliac disease):ti,ab,kw OR (Crohn’s disease) OR (Crohn’s
disease):ti,ab,kw OR (tapeworms) OR (tapeworms):ti,ab,kw )
AND
Intervention – ((MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw
OR (MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR
(MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR
(MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic
acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all
trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum
folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red
cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor
Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) AND
((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH
descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)
AND
Limits [humans]/lim AND [english]/lim
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Population
Patients with psychiatric
disorders
Search Terms
Embase and Medline
Population – ((‘dementia’/exp OR ‘dementia’) OR (‘depression’/exp OR
‘depression’) OR (‘psychosis’/exp OR ‘psychosis’) OR (‘Alzheimer’s
disease’/exp OR ‘Alzheimer’s disease’))
AND
Intervention – ‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR
‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR
‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red
cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte
folate’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR
‘haematologic test*’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane Library
Population – ((MeSH descriptor Dementia explode all trees) OR (MeSH
descriptor Depression explode all trees) OR (MeSH descriptor Psychosis explode
all trees) OR (MeSH descriptor Alzheimer’s disease explode all trees)
OR((dementia)
OR
(dementia):ti,ab,kw)
OR
((depression)
OR
(depression):ti,ab,kw) OR ((psychosis) OR (psychosis):ti,ab,kw) OR
((Alzheimer’s disease) OR (Alzheimer’s disease):ti,ab,kw))
AND
Intervention –((MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR
(MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR
(MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR
(MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic
acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all
trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum
folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red
cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor
Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) AND
((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH
descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)
AND
Limits [humans]/lim AND [english]/lim
Table A4.2: Search strategy for economic evidence
Population
Search Terms
Patients undertaking folate
testing
Embase and Medline
Intervention – (‘folate’/exp OR ‘folate’ OR ‘folic acid’/exp OR ‘folic acid’ OR
‘vitamin B9’/exp OR ‘vitamin B9’ OR ‘tetrahydrofolic acid’ OR
‘methylenetetrahydrofolic acid’ OR ‘serum folate’/exp OR ‘serum folate’ OR’ red
cell folate’/exp OR ‘red cell folate’ OR ‘erythrocyte folate’/exp OR ‘erythrocyte
folate’) AND (‘testing’/exp OR ‘testing’ OR ‘haematologic test*’/exp OR
‘haematologic test*’)
AND
Economic Terms – (‘economic aspect’/exp OR ‘cost benefit analysis’ OR cost*
OR ‘cost effectiveness’)
AND
Limits – [humans]/lim AND [english]/lim
Cochrane Library
Intervention – (MeSH descriptor Folate explode all trees) OR (folate):ti,ab,kw OR
(MeSH descriptor Folic acid explode all trees) OR (folic acid):ti,ab,kw) ) OR
(MeSH descriptor Vitamin B9 explode all trees) OR (vitamin B9):ti,ab,kw OR
(MeSH descriptor Tetrahydrofolic acid explode all trees) OR (tetrahydrofolic
acid):ti,ab,kw) ) OR (MeSH descriptor Methylenetetrahydrofolic acid explode all
trees) OR (methylenetetrahydrofolic acid):ti,ab,kw OR (MeSH descriptor Serum
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Population
Search Terms
folate explode all trees) OR (serum folate):ti,ab,kw) ) OR (MeSH descriptor Red
cell folate explode all trees) OR (red cell folate):ti,ab,kw OR (MeSH descriptor
Erythrocyte folate explode all trees) OR (erythrocyte folate):ti,ab,kw) ) AND
((MeSH descriptor Testing explode all trees) OR (Testing):ti,ab,kw OR (MeSH
descriptor Haematologic test* explode al trees) OR (Haematologic test*):ti,ab,kw)
AND
Economic Terms – (((economic aspect) OR (economic aspect):kw) OR ((cost
benefit) OR (cost benefit):kw)) OR ((cost effectiveness) OR (cost
effectiveness):kw) OR (MeSH descriptor Cost-Benefit Analysis explode all
trees) OR (MeSH descriptor Costs and Cost Analysis explode all trees))
AND
Limits [humans]/lim AND [english]/lim
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APPENDIX 5 – Tools for assessing the evidence in the systematic review
Table A5.1: NHMRC Dimensions of Evidence(63)
Type of evidence
Strength of the
evidence
 Level


Quality
Statistical
precision
Definition
The study design used, as an indicator of the degree to which bias has been
eliminated by design.
The methods used by investigators to minimise bias within a study design.
The p-value or, alternatively, the precision of the estimate of the effect (as
indicated by the confidence interval). It reflects the degree of certainty
about the existence of a true effect.
Size of effect
The distance of the study estimate from the “null” value and the inclusion
of only clinically important effects in the confidence interval.
Relevance of evidence
The usefulness of the evidence in clinical practice, particularly the
appropriateness of the outcome measures used.
Table A5.2: NHMRC designations of levels of evidence for an intervention (NHMRC)(63)
Level
I
Intervention
A systematic review of level II studies
II
A randomised controlled trial
III-1
A pseudo randomised controlled trial (i.e. alternate allocation or some other
method)
III-2
A comparative study with concurrent controls:
 Non-randomised, experimental trial
 Cohort study
 Case-control study
 Interrupted time series with a control group
A comparative study without concurrent controls:
 Historical control study
 Two or more single arm study
 Interrupted time series without a parallel control group
Case series with either post-test or pre-test/post-test outcomes
III-3
IV
Source: Hierarchies adapted and modified from: NHMRC 1999; Bandolier 1999; Lijmer et al. 1999; Phillips et al. 2001
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February 2014
Table A5.3: NHMRC quality criteria for RCTs, cohort studies, case-control studies and systemic
reviews(63)
Study type
Randomised
controlled trialsa
Cohort studiesb
Case-control studiesb
Systematic reviewsc
Quality criteria
Was the study double blinded?
Was allocation to treatment groups concealed from those responsible for
recruiting the subjects?
Were all randomised participants included in the analysis?
How were subjects selected for the ‘new intervention’?
How were subjects selected for the comparison or control group?
Does the study adequately control for demographic characteristics, clinical
features and other potential confounding variables in the design or analysis?
Was the measurement of outcomes unbiased (i.e. blinded to treatment group
and comparable across groups)?
Was follow-up long enough for outcomes to occur?
Was follow-up complete and were there exclusions from the analysis?
How were cases defined and selected?
How were controls defined and selected?
Does the study adequately control for demographic characteristics and
important potential confounders in the design or analysis?
Was measurement of exposure to the factor of interest (e.g. the new
intervention) adequate and kept blinded to case/control status?
Were all selected subjects included in the analysis?
Was an adequate search strategy used?
Were the inclusion criteria appropriate and applied in an unbiased way?
Was a quality assessment of included studies undertaken?
Were the characteristics and results of the individual studies appropriately
summarised?
Were the methods for pooling the data appropriate?
Were sources of heterogeneity explored?
Source: National Health and Medical Research Council (NHMRC), 2000. How to review the evidence: systematic identification and review
of the scientific literature, NHMRC, Commonwealth of Australia, Canberra.
a
Based on work of Schulz et al (1995) and Jadad et al (1996)
b
Based on quality assessment instruments developed and being tested in Australia and Canada
c
Based on articles by Greenhalgh (1997) and Hunt and McKibbon (1997).
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