Iron Deficiency in Kids: Time for More Spinach

Quick facts!

Iron deficiency is the #1 hematologic condition worldwide. 

Iron is important for many reasons: 

• DNA
• ATP synthesis
• Myelination
• RBCs

Healthy adults have 3-5 grams of total body iron, and only need to take in 1-2 mg per day. Once the brain and bone marrow are done using iron, the remainder gets stored in the liver, macrophages, and muscle. 

• The majority of iron needs are met by efficient iron recycling, which occurs via the breakdown of older red blood cells by macrophages within the reticuloendothelial system. However, in infants and children, 30% of daily iron needs must come from diet because of the rapid growth and increase in body (muscle) mass that occurs during this age range.

Heme iron is the main type of iron absorbed, found in meat. Non-heme iron is absorbed to a much smaller degree, aided by vitamin C. The gut is the main site of regulation of absorption. 

Case

A 21-month-old child presents for a same-day visit with pallor, which has been present for a few weeks. The child took formula during the first year of life, but now drinks four or five 8oz bottles of cow’s milk per day. The family has noticed that the child often chews on cardboard books. Per chart review, the child had a normal CBC at 12 months of age. 

Background

Definitions:

• Anemia = Hgb that is 2 SD less than the mean (age / sex)
• Iron deficiency = A state in which there is insufficient iron to maintain normal physiologic functions
• Iron-deficiency anemia = An anemia (as defined above) that results from iron deficiency

Is prevalence changing over time?

• Between 1976 and 2002, there was no statistically significant change in iron deficiency prevalence in US children aged 1 to 3 years old. The prevalence of iron deficiency was 10% and 8% in NHANES II and NHANES IV, respectively. Among 1-year-old children, iron deficiency prevalence decreased from 23% in 1976-1980 to 12% in 1999-2002 (P = .02). In 2- and 3-year-old children, however, there was no change in iron deficiency prevalence. The significant difference in iron deficiency prevalence between 1- and 2- to 3-year-old children in 1976-1980 diminished by 1988-1994 and then disappeared in 1999-2002

Why are we still using race-based cutoffs?

Unfortunately, race-based cut-offs for Hgb are commonly used today. 

• Arguments for separate cutoffs rely on US-based NHANES data that only has 3 categories for race: white, black, and other
• WHO global cutoffs originate from white adults
• Very few large-scale non-NHANES studies to establish reference values
• Global region-specific studies “validating” WHO global cutoffs

One recent 2021 study found that current WHO cutoffs to define anemia are higher than the pooled 5th percentile of Hgb among persons who are outwardly healthy and from nearly all survey-specific estimates.

What about sex-based Hgb cutoffs?

• Androgens stimulate bone marrow whereas estrogens inhibit bone marrow
• EPO is not higher in individuals with low androgen. 
  • Possible hormonally regulated mechanism in kidney microvasculature
• Hormone therapy alters baseline Hgb
  • Evident after 3 months of affirming treatment
  • At 6 months, Hgb is in the reference range of affirmed gender
    • As such, once individuals have commenced gender-affirming hormone therapy, the reference range of the affirmed gender should be used. 

Screening (not just a CBC!)

Initial screening with risk assessment and CBC should be performed at 9-12 months of age. In the presence of low Hgb or risk factors, the AAP recommends labs specific to iron deficiency: ferritin, CRP, CHr. Alternatively, if anemia is mild, empirically treat and assess response. 

Risk factors for iron deficiency: 

• Prematurity
  • Most maternal transfer of iron occurs in the 3rd trimester. As such, healthy term newborns have adequate iron stores for 4-6 months. 
• Dietary factors
  • Exclusive breast/chestfeeding without supplementation
  • Weaning to whole milk
  • Complementary foods lacking iron fortification (e.g., non-iron fortified cereal, baby food with heme- or non-heme iron and vitamin C, certain table foods)
  • Feeding problems / inadequate nutrition
  • Prolonged bottle feeding
• GI pathology
• Socioeconomic disparities

In the presence of risk factors, screening should be repeated at 15-18mo of age. 

In adolescents, additional factors should be considered: 

• Blood loss (e.g., GI, menstrual)
  • Alarm symptoms for abnormal uterine bleeding: duration >7 days, >5 pads/day, gushing, family history, other mucosal bleeding
• Family history of bleeding disorders
• Dietary factors
  • ex: vegetarianism/veganism, excessive junk food, low protein/veggie mains, skipping meals
• Athletic activity

Iron Absorption & Supplementation

“Adequate” iron absorption varies by age: 

• Preterm infant (0-12 months): 2 mg/kg/day
• Term newborn (0-6 months): 0.27 mg/day (!)
• Term infant (6-12 months): 11 mg/day
• 1-3 years-old: 7 mg/day
• Adult: 1-2 mg/day

Iron supplementation varies by age and feeding: 

• Age <6mo AND >50% breast/chestfed:
  • Term: At 4mo, begin taking 1 mg/kg/day until diet supports requirements
  • Preterm: Within 2wk, begin taking 2-4 mg/kg/day through 1yr
• Age <6mo AND formula-fed OR <50% breast/chestfed:
  • Iron-fortified formula (>6 mg/L)
    • Note that many European brands have <6mg/L
• Age 6mo-5yr
  • Diet, vitamin C, <24oz cow’s milk, consider supplement if insufficient dietary intake

Always confirm treatment success!

• Check a follow-up CBC and retic after 1-3mo of supplementation
  • An increase in Hgb concentration of 1 g/dL after 1 month of therapeutic supplementation has been used to signify the presence of IDA.
• Ensure underlying etiology is treated
  • Only 40% of the cases of anemia identified at 12 months of age will be secondary to IDA
• Can recheck sooner (7-10 days) if initial IDA was severe
• Document the diagnosis, treatment, re-evaluation, and follow-up plan
  • Only 10-15% of patients have documentation of Hgb correction

Back to the Case!

After initiating iron supplementation, the patient returns to clinic after 1 month. The family says that they are giving iron 1-2x/week because of constipation when given more often. 

• Key question: Does this patient or family have barriers to taking PO iron daily two hours before/after a meal with no dairy? If so, consider IV iron!

Symptoms

Key point: Iron deficiency can be symptomatic without anemia!

• Who?
  • AUB
  • GI disorders
  • Chronic inflammation
  • Heart Failure
  • High-endurance athletes
    • Athletes’ anemia results from a combination of plasma volume expansion, trace GI bleeding, and repetitive forceful body strikes that causes red cell lysis in the feet and intravascular hemolysis. Other contributors include insufficient dietary iron intake, losses through sweat, and exercise-induced acute inflammation. Also menstruation and calories.
  • Restricted caloric intake
• Symptoms: 
  • Fatigue
  • Poor concentration
  • Pica
  • Disordered sleep
  • Restless leg syndrome
  • Stereotyped movements
  • POTS

Take-Home Points!

• Iron is important for MANY reasons—not just RBCs!
• The majority of iron needs in adolescents and adults are met by efficient iron recycling, but this process is inadequate in infants and children. 
• Screening for iron deficiency requires a review of risk factors, not just a CBC!
• Iron deficiency can be symptomatic without anemia. 

Blog post based on Med-Peds Forum talk by Anu Goel, PGY1