Detection of iron deficiency (ID) in children is critical when working to optimize their brain development. ID is the number one most common nutritional deficiency experienced worldwide by children. Given that fact, you would expect that all physicians would be well-versed in the signs, symptoms and management of ID. Unfortunately, this is not the case. ID affects 2.4 million U.S. children and 273 million children worldwide (Bartonek, et al. 2007) and is under-diagnosed. This is especially the case in children with genetic conditions or learning challenges whose symptoms of ID are often dismissed as simply part of their primary diagnosis.
Any discussion of ID would be incomplete without discussing the role the gut plays in iron absorption. It's a tightly controlled process that is influenced by many factors. I'll review key factors of gut function that influence iron levels within the body as well as several other factors that impact iron absorption.
- Oxygenation - Iron is best known for its role in hemoglobin synthesis. Hemoglobin is the protein within red blood cells that carries oxygen. Without sufficient amounts of iron the body struggles to make hemoglobin which results in a low oxygen carry capacity of red blood cells. Image 1 shows the heme component of hemoglobin that contains iron which is the actual binding site of oxygen within hemoglobin. All tissues of the body require oxygen to function properly, but the brain is especially sensitive to a decrease in supply of oxygen.
- Energy Production - Many enzymes within the body rely on iron as a cofactor to function properly including enzymes within the Citric Acid Cycle. This is a process within mitochondria that our body uses to convert food to energy. Iron is also a cofactor for succinate dehydrogenase, an enzyme within the electron transport chain, another essential step of energy production found within the mitochondria. For more information about supporting mitochondrial function you can read Mitochondria - Why They're Important and What They Need to Function
- Immune System - Both the adaptive and the innate immune system are dependent on iron. While the mechanism behind this function of iron isn't totally understood some aspects have been studied and reported. Iron is important for T cell function and development, which is an energy dependent process. (Cronin, et al. 2019). In addition, ID has been shown to significantly impair cell mediated immunity in children. (Das, et al. 2014)
- Cognitive Function - The most energy dependent organ of the body is the brain. For that reason alone, ID can contribute to long term, irreversible, cognitive impairment in children. (Lozoff, et al. 2006). In addition to energy production, iron is critical for myelination of neurons. Myelination is the process of creating the fatty sheath surrounding neuronal processes and fibers that increases the efficiency of neve impulse transmission. Impaired myelination results in slower auditory and visual processing within the brain. (Algarín, et al. 2003) Lastly, ID has been shown to ultimately result in lower IQ in children. A study from 2007 showed treatment with iron did increase IQ points by 4.8 in a 30 children, but these points did not bring IQ up to the same level as that of children without ID.(Agoaglu, et al 2007) Lastly, iron plays a role in the metabolism of monoamines, which includes dopamine, norepinephrine and serotonin. The effect of ID on monoamine neurotransmitters appears to impact boys more than girls. (Burhans, 2005)
ID can have long term cognitive and social-emotional impact on children, especially when experienced in infancy. Due to it's role in oxygenation, energy production, myelination and neurotransmitter function. ID during early brain development can impact white matter formation, monamine metabolism and functioning of the hippocampus. (Beard 2008) The hippocampus plays a major role in learning and memory. The brain changes seen in ID can lead to altered brain function that lasts into adulthood. (Georgieff 2011)
Myelination of neurons within the brain begins around the seventh month of gestation. After birth the brain rapidly develops over the following two years. This is also the most common stage of development when ID can occur. For these reasons physicians, midwives and other healthcare practitioners working with pregnant women, newborns and infants must be aware of risk factors that can lead to ID.
Multiple studies and published review articles exist that link ID to sleep issues in infants and children.(Leung, et al. 2020) Given the importance of sleep to childhood development, growth and overall health one can see that this is yet another means by which ID can greatly impact the health of children. Sleep disturbance in children can be one of the biggest challenges to parenting that can impact the well-being of the entire family.
Sleep spindles are EEG waves seen during NREM (non-rapid eye movement) sleep. They represent brain activity that's necessary for memory formation, development of the cerebral cortex and regulation of motor activity. (Andrillon, et al. 2011) ID in 6 month old infants was shown to result in altered sleep spindle patterns. (Peirano, et al. 2007) Alterations in sleep can be long-lasting despite reversal of ID. A group of researchers in Chile found 4 year old children who experienced ID as infants had persistent alterations to their sleep organization (Peirano, et al. 2013)
Due to the brain changes seen in regulation of motor activity in infants with ID, it's no wonder that restless sleep in children is often a result of ID. (Dosman, et al. 2012) Other causes of restless sleep in children exist, but some sleep specialists recommend supplementing with iron in children with restless sleep who also have a ferritin of <50 ug/L. Researchers in 2013 reported, "The most striking single symptom (of ID) was awakening after 1-3 h of sleep followed by screaming, crying, kicking or hitting the legs." (Tilma, et al. 2013)
Gross motor skills:
Researchers at the Center for Human Growth and Development at the University of Michigan in 2006 reported on the effects of ID on gross motor development in children in Costa Rica. Not only are gross motor skills of infants with ID delayed, but "there was no evidence of catch-up in motor development, despite iron therapy in infancy that corrected ID anemia in all cases." (Shafir, et al. 2006) Their findings confirmed that of many others: "Children who have iron-deficiency anemia in infancy are at risk for long-lasting developmental disadvantage as compared with their peers with better iron status." (Lozoff, et al. 1991) These "development disadvantages" extend beyond cognition and include gross motor skills. Shafir, et al later mentioned the dilemma of ID detection without anemia as this is less often detected by practitioners who only use hemoglobin levels to screen for ID. (Shafir, et al. 2008)
Last, but not least, is the long-term social-emotional issues that can result from ID. Infants and toddlers who experience ID have been found by "virtually every case-controlled study" to be "more wary, hesitant, solemn, unhappy, kept closer to their mothers" (Lozoff, et al. 2006) Once again, these effects were are not necessarily reversible once ID is treated. These effects can be long-term. Parents and teachers had reported more social problems, anxiety/depression and attention problems in children who previously experienced ID.(Lozoff, et al. 2006) Attention problems are also common among children and young adults who were iron deficient as infants. Researchers from Department of Psychology and Social Behavior, University of California, Irvine stated, "Participants with chronic, severe ID in infancy performed less well on frontostriatal-mediated executive functions, including inhibitory control, set-shifting, and planning." (Lukowski, et al. 2010) These and results from other studies show that executive function, impulsivity and decision-making in adolescents and young adults can be impacted by previous ID in infancy. Experts from Division of Child Development and Community Health at the Universty of California in San Diego went so far as to say, "Youth with a known history of IDA would benefit from monitoring for emotional volatility and inattention, both during childhood and at adolescence, as they become more independent and have the potential to engage in serious risk behaviors." (East, et al. 2018)
The most common symptom of ID in children is fatigue. However, fatigue can manifest very differently in children than it does in adults. Children who are tired can actually present as hyperactive as they continuously move in order to avoid falling asleep during the day. It's commonly referred to as "tired-wired". Fatigue can also present as behavioral issues that include lack of focus, irritability and even aggression. Fatigue from ID is due not only to the low oxygen carrying capacity of red blood cells but also to low activity of the enzymes mentioned above needed for energy production within mitochondria.
Gut factors that impact iron absorption:
- stomach acidity (pH)
Iron can be found within the body in two states: Fe2+ and Fe3+. The form that's absorbable by the body is Fe2+. Iron takes this form in a low pH (acidic) environment. This low pH is created by gastric acid production within the stomach. Without gastric acid or when gastric acid production is blocked by an acid blocker like Omeprazole (Prilosec) or Ranitadine (Zantac) iron absorption will also be blocked. Taking supplemental iron may be helpful but if the pH environment within the GI tract is not remedied then the supplemental iron will not be absorbed. Iron that is not absorbed causes GI irritation, upset tummies and constipation.
Another factor impacting absorption is the microbiome within the gut lumen. Commensal bacteria are those that are part of the normal flora of the gut. They exist in varying amounts in different areas of the gut. The upper gastrointestinal tract has the lowest concentration of bacteria (cfu/mL) while the lower gastrointestinal tract has a very high level of bacteria. Too much bacteria in the small intestine (small intestinal bacterial overgrowth, aka SIBO) can interfere with iron absorption. (Losurdo, et al. 2020)
Another factor within the gut that can impact iron absorption is biofilm. Biofilm is a complex polymer made of polysaccharides, proteins, lipids, and extracellular DNA. It's an extracellular matrix that yeast and bacteria secrete to help them cling to surfaces and in some cases medical devices inside the body. It helps them form colonies, communicate with one another and protects them from antimicrobials. Some common forms of biofilm are plaque on teeth and the slime at the bottom of a bottle of kombucha. Biofilms on surfaces are difficult to remove without the use of mechanical scrubbing or enzymes. They're a significant cause of chronic infections and antibiotic resistant infections.
Signs and symptoms of a riboflavin deficiency include:
- glossitis (red, swollen tongue)
- angular cheilitis (rash or cracks in the corners of the mouth)
- cracked, dry lips
- irritated mucosal membrane of the mouth
- sore throat
- moist, scaly skin inflammation
- hearing loss
- choking, swallowing, feeding issues
- tongue and/or facial weakness
- sensory gait ataxia (clumsy, staggering walk)
- dysphonia – inability to produce sound due to laryngeal weakness
For more information about riboflavin deficiency I recommend reading Riboflavin (vitamin B-2) and health.
It's important to assess for gastrointestinal issues when other causes of ID are not readily evident. This is best done through a comprehensive stool analysis that can be ordered and interpreted by a trained functional medical or Naturopathic physician. These stool tests are able to detect pathogenic and commensal bacteria in the gut that can impact iron absorption. You can read more about stool analysis options on this page of our website: Stool Test Options.
Choosing the right form of iron to give as a supplement is important as well. Iron that is not absorbed causes GI irritation and constipation. Dark or black stools that are seen after the start of iron supplementation is a sign of poor iron absorption. Non-heme iron supplements are the standard for iron supplementation, but come in many forms. Many standard iron supplements come as iron sulfate which is not easily absorbed and subsequently is more likely to cause gastrointestinal side effects. Iron bisglycinate is a form of iron that is bound to glycine which makes it more absorbable and less likely to cause gastrointestinal issues. The taste of both of these forms of iron can be a problem for most children who cannot swallow capsules.
Micronised microencapsulated iron pyrophosphate is a form of liquid iron that solves both issues of absorption and taste. Micronisation is the process of reducing particles to a smaller size often with the goal of increasing absorption. Microencapsulation is the process of coating small particles with a substance that will either protect it from being broken down in digestion or increase its absorption. Using a phospholipid bilayer or liposome as the protective layer increases absorption of iron pyrophosphate and blocks the iron from coming into contact with taste buds in the mouth, masking the iron flavor. "Micronised microencapsulated ferric pyrophosphate (MMFP) is a recently developed formulation characterised by a higher intestinal bioavailability due to the small particle size distribution at nanometer level. " (Pappalardo, et al. 2019)
Bovine lactoferrin can be taken as a supplement and has been shown to increase total serum iron, red blood cell count, hemoglobin, and hematocrit of pregnant women experiencing ID anemia. (Rosa, et al. 2017) They were given 100 mg of lactoferrin twice a day. Taking lactoferrin also decreased their IL-6 level, which is a cytokine involved in inflammation. Infants who received bovine lactoferrin added to their formula were shown to have accelerated neurodevelopment by one year old and improved language by 18 months old. (Li, et al. 2019)
Vitamin C (ascorbic acid) is a powerful enhancer or non-heme iron absorption. Taking an iron supplement together with a vitamin C supplement can greatly improve iron absorption. "Ascorbic acid forms a chelate with ferric (Fe3+) iron in the low pH of the stomach which persists and remains soluble in the alkaline environment of the duodenum." (Ems, et al. 2020)
Pure Encapsulations Iron liquid contains SunActive® Fe, a micronized water-soluble form of iron pyrophosphate with high bioavailability. A blend of cranberry and blueberry fruit extracts offers antioxidant protection and additional microvascular support.
Lactoferrin is a purified derivative of whey protein has important iron binding properties in human nutrition. Among the numerous functional properties of Lactoferrin are the promotion of beneficial intestinal flora through naturally occurring microbial action.
This delicious, effervescent, orange-flavored powder easily provides therapeutic dosing of vitamin C. Potassium bicarbonate is included in this formula as a buffering agent and to give it “fizz.“ Also included are quercetin, hesperidin and rutin, which are natural bioflavonoids found in citrus fruits.