Iron Supplementation for fatigue in nonanemic women

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Iron Supplementation for fatigue in non-anemic
women

• Gerardo Moreno, MD
• July 21, 200

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Introduction Fatigue

• Fatigue is common in general population
• Prevalence rates of 14 to 27 reported in
  primary care setting
• Women more than 3 times likely than men to
  mention fatigue in primary care setting
• Unexplained fatigue is common in young women

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Iron Deficiency

• Iron deficiency is highly prevalent among women
  of childbearing age.
• Data from Continuous Survey of Food Intake By
  Individuals (CSFII) suggest that only one fourth
  of adolescent girls and women of childbearing age
  (1249 years) meet the recommended dietary
  allowance for iron through diet.

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Iron deficiency in United States

• Prevalence of iron deficiency in United States
  (CDC 1997)
• 24,894 persons examined in third National Health
  and Nutrition Examination Survey (1994-1998)
• 9-11 of adolescent girls and women of
  childbearing age were iron deficient
• 2-5 were found to have iron deficient anemia
• Iron deficiency anemia more likely in those who
  are minority, low income, and multiparous

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Prevalence of Iron Deficiency
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Causes of Iron Deficiency

• Increased iron requirements
• Blood loss
• Menstruation
• Gastrointestinal tract
• Food sensitivity
• Hookworms Genitourinary tract
• Respiratory tract
• Blood donation
• Growth
• Pregnancy
• Inadequate iron absorption
• Diet low in bioavailable iron
• Impaired absorption
• Gastric surgery
• Intestinal malabsorption
• Hypochlorhydria

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Iron Therapy

• Preferred therapy is oral ferrous sulfate 325mg
  BID-QID (32565mg elemental iron)
• The percentage of iron absorbed (i.e., iron
  bioavailability) can vary from lt1 to gt50. The
  main factor controlling absorption is the amount
  of iron stored in the body.
• Hct half corrected in 3 weeks and full return to
  baseline in 2 months
• Parenteral Iron
• Indications are intolerance or contraindication
  to oral iron. Risk of anaphylactic reaction.
• Red Cell Transfusion

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Serum Ferritin

• Direct relationship exists between ferritin and
  iron stores
• Gold standard for iron deficiency is absence of
  stainable bone marrow
• In the United States, the average ferritin
  concentration is 43ug/l for women (CDC 1998).

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Serum Ferritin

• Acute phase reactant
• Cutoff value of ferritin for iron deficiency is
  12-15ug/l
• Decreased ferritin is the most sensitive and
  specific test and first to reflect iron
  deficiency
• Among women of childbearing age
• A serum ferritin concentration of lt15 ug/L has a
  sensitivity75 and specificity98 for iron
  deficiency
• Similarly, A serum ferritin concentration of lt12
  ug/L has a sensitivity61 and specificity100

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Other Related Research

• Beutler et al. (1960) found that iron therapy in
  35 non-anemic iron deficient women improved
  poorly defined symptoms and lassitude
• Randomized study of cognitive effects of iron
  supplementation in non-anemic iron-deficient
  adolescent girls (John Hopkins Dept Peds). Lancet
  1996.
• Oral ferrous sulfate (650mg BID) vs placebo for 8
  weeks
• Outcomes were assessed by questionnaire and
  hematological and cognitive tests.
• Showed that girls who received iron performed
  better on a test of verbal learning and memory
  than girls in the control group.
• Peterson et al. (2001) showed that that both iron
  therapy and iron rich diet increased the quality
  of life

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Article

• Iron supplementation for unexplained fatigue in
  non-anemic women double blind randomized placebo
  controlled trial
• F Verdon et al.
• BMJ 2003 May 243261124-6.

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Goals of Study

• To determine the subjective response to iron
  therapy in non-anemic women with unexplained
  fatigue.

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Methods

• Randomized double blinded placebo controlled
  trial
• 144 patients included in study
• Conducted in primary care setting
• One academic center (57 patients)
• Eight private general practices (87 patients)
• Women age 18 55 included if main reason for
  consulting was fatigue

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Methods

• Participants received (for 4 weeks) either
• 80 mg/day oral long acting ferrous sulfate or
• placebo
• Iron and placebo were identical in taste and
  appearance
• CBC and ferritin checked at baseline
• Ferritin measured after 1 month only if initial
  value lt20ug/l
• Clinicians could order other tests to rule out
  any disorder to explain fatigue

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Exclusion Criteria

• Women with anemia (hemoglobin lt11.7g/dl)
• Other obvious physical or psychiatric causes of
  fatigue
• Chronic fatigue syndrome
• Predetermined reasons for exclusion during trial
• new pregnancy
• hemochromatosis
• physical or mental disorder after inclusion
• vitamin or iron supplements taken during study

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Outcomes

• Primary outcome was level of fatigue
• Assessed at baseline and after one month
• 10 point visual analogue scale
• 24 item self administered questionnaire
• 8 items for fatigue, anxiety, depression
• Depression and anxiety were secondary outcomes

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Patient Characteristics
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Patient Characteristics
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Patient Flow Through Study
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Patient flow through study

• 366 women presented with fatigue
• 222 excluded
• 100 women with psychiatric disorders
• 61 women with physical disorders
• 16 women refused to participate
• 35 women with other reasons
• 144 patients enrolled in study
• 7 lost to follow-up
• Stopped up due to side effects (in placebo arm)
• 136 completed study (94)

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ResultsLevels of fatigue after one month

• P value 0.004
• Difference0.97 (95 CI 0.31 to 1.62)

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Results

• Low serum ferritin was common
• 50 ug/l in 115 (85) patients
• 20 ug/l in 69 (51) patients
• Significant response to therapy only in patients
  with baseline serum ferritin concentration 50
  ug/l
• No significant response in group with ferritin
  gt50 ug/l

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Results

• The difference for depression was not
  statistically different between groups
• -2.1 vs -1.0 points, p0.31
• Larger decrease in anxiety in iron group
• -1.7 vs 1.3, p0.003
• Younger age associated with larger decrease in
  fatigue (but results not reported)

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Results

• In multivariate analysis, iron group baseline
  depression and anxiety level, age, ferritin, and
  hemoglobin were not predictive of the mean
  decrease in overall intensity of fatigue
• Compliance and drop-out rates were similar in
  both groups
• Post-intervention ferritin levels were highest in
  iron group
• 21.0 vs 13.7, p0.001

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Conclusions

• Investigators concluded that women aged 18-55
  with unexplained fatigue may benefit from iron
  therapy in absence of anemia
• Furthermore, effect may be restricted to women
  with low or borderline serum ferritin
  concentrations
• Iron deficiency may be under-recognized cause of
  fatigue in women of childbearing age
• Suggest iron deficiency could be present even
  with a normal ferritin level

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Disclosures

• Investigators received financial support from
  Robapharm
• Robapharm is maker of ferrous sulfate
  (Tardyferon) preparation used in this clinical
  trail

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Validity

• Well organized, double blinded, randomized
  placebo controlled trial
• All patients accounted for at conclusion
• Both groups very similar at start of trial
• Few subject dropouts

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Limitations

• Double blinded study but could not correct for
  iron side effects
• Low dose iron used
• Both groups told their drug could change color of
  stool
• Primary outcome was fatigue, a patient centered
  subjective measure
• No incidence of side effects reported

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Limitations

• How to interpret the magnitude of the effect?
  What does -1 point change mean?
• Did not report measured post-therapy ferritin
  levels for 51 (69/136) of subjects
• Did not measure hemoglobin concentration after
  iron therapy

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Relevance to Clinical Practice

• Women with fatigue are commonly encountered in
  primary care practice
• May avoid inappropriate attribution of symptoms
  to emotional causes or life stressors
• Instituting iron therapy early may improve
  quality of life
• Iron therapy is inexpensive

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Discussion

• Was decrease in fatigue associated with an
  increase in ferritin level within the treatment
  group?
• Should ferritin be part of work up for non-anemic
  women with unexplained fatigue? Or should we
  treat empirically?
• Was decrease in fatigue due to increase in
  hemoglobin in patients with low-normal values?

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Discussion

• Authors stated that improvement in fatigue was
  greater in younger women, but gave no data.
• What do they mean by younger age?
• Multivariate analysis revealed that age was not
  predictive of decrease in fatigue

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Discussion

• Could iron deficiency be present even with a
  normal concentration of serum ferritin?
• Should reference limits for hemoglobin and
  ferritin concentrations be raised for women
  (e.g., to same as limits for men)?
• Can a similar benefit be obtained by increasing
  dietary iron?

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Discussion

• What is the appropriate formulation and amount of
  iron supplementation to give?
• Should we check ferritin level to screen for
  hemochromatosis before giving iron supplements?

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Areas of Further Research

• Results need to be duplicated with larger patient
  population?
• Longer follow-up needs to be addressed?
• Is there an age-related response to iron therapy?
• Comparison between iron deficient and iron
  deficient anemic women
• What is the relationship between decrease in
  fatigue and ferritin levels

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References

• Brunner AB, et al. Randomized study of cognitive
  effects of iron supplementation in non-anemic
  iron-deficient adolescent girls. Lancet 1996
  348 992-6.
• Looker AC, Dallman PR, Caroll MD, Gunter EW,
  Johnson CL. Prevalence of iron deficiency in the
  United States. JAMA 1997 277 973-6.
• U.S. Department of Agriculture, Agricultural
  Research Service. Survey of Food Intakes by
  Individuals and 199496 Diet and Health Knowledge
  Survey. Riverdale, MD U.S. Department of
  Agriculture, Agricultural Research Service,
  Beltsville Human Nutrition Research Center,
  December 1998.
• Hallberg L, Bengtsson C, Lapidus L, Lindstedt G,
  Lundberg P-A, Hultén L. Screening for iron
  deficiency an analysis based on bone-marrow
  examinations and serum ferritin determinations in
  a population sample of women. Br J Haematol
  19938578798.

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Acknowledgements

• David Thom, MD, PhD
• Julie Haugen, MILS