The Pathogenesis and Impact of Iron Deficiency and Iron Deficiency Anemia

Anemia is a condition characterized by a low hemoglobin concentration, defined by the World Health Organization (WHO) as being below 12 g/dL in non pregnant, reproductive-aged women.  The prevalence of anemia is extremely high affecting almost 30 percent of the world’s population. Disproportionally affected by anemia are reproductive-aged girls and women.  Approximately 75% of all anemia cases worldwide are secondary to iron deficiency (ID) recognized by the WHO as the world's most common micronutrient deficiency.

Iron has a major role in human physiology, well beyond the creation of heme being necessary for many organismal processes including mitochondrial energy metabolism and a variety of critical enzymatic processes in a spectrum of organs and tissues. For example, iron is essential for normal myocardial and skeletal muscle function, and for the production of neurotransmitters, DNA repair, and the integrity of the immune system. There is no mechanism for active iron excretion. Consequently, in reproductive aged women ID is largely a consequence of one or a combination of two principal mechanisms: Insufficient iron intake and iron loss secondary to  HMB, previous pregnancy, or other sources of chronic bleeding most commonly from the gastrointestinal tract.

In ID's initial stages, iron is mobilized from its stored form, ferritin that is largely, but not totally, located in the liver. When these iron stores are depleted, the body prioritizes e erythropoiesis, depleting iron from  the dependent enzymes necessary for the physiological processes mentioned above. Because heme synthesis is preserved at the expense these iron-dependent enzymatic processes,  symptoms are typically experienced long before the appearance of anemia. Such symptoms include fatigue and exhaustion, ' brain fog’, muscle weakness, shortness of breath, dizziness, pica, insomnia, restless legs, and hair loss.  Iron deficiency alone has been demonstrated to be associated with both physical(22) and cognitive impairment(23, 24).

The symptom of heavy menstrual bleeding (HMB), experienced by as many as 50% of non-pregnant women in the reproductive years, is the major contributor to the development of ID in this age group (28) and is the most common cause or contributor to IDA(12).  Some investigators have estimated that two-thirds of women with the symptom of HMB are anemic(30, 31). The prevalence of ID and IDA  is even higher in low-and-middle-income-countries (LMICs) and other settings where nutritional insecurity is common as the cumulative iron depletion caused by HMB adds to the negative iron balance and IDA, as reflected in available data compiled by the WHO(32).

The Combined Impact of HMB, ID, and IDA

The symptom of HMB and resulting presence of ID can combine to result in insidious adverse clinical and economic impacts on women, children, employers, health care systems, and society at large.  By its very definition, the symptom of HMB intermittently and directly interferes with a woman’s physical, social, emotional, and/or material quality of life (QoL) and affected women score significantly lower in studies using the widely validated SF-36 (Short Form 36) instrument. While the symptom of HMB manifests on an intermittent basis, ID erodes QoL every day, even in the absence of IDA. The economic burden of HMB alone has been associated with work absenteeism in almost 14% and presenteeism, where the symptom affects work quality, in more than 80% of affected women.  A number of studies in the early 2000s showed that the annual economic impact of HMB was estimated to be more than $2,000 per family, mainly due to the cost of menstrual products and the impact of work absence and presenteeism.

Unknown to many is the potential impact of ID and IDA on pregnancy and the fetus. Among the adverse pregnancy outcomes associated with IDA are growth restriction, preterm labor and birth, and placental abruption and postpartum hemorrhage, all proportional to the severity of anemia starting in the second trimester. However, there is evidence that periconceptual ID and IDA is a potential cause of irreversible adverse effects on fetal neurologic development linked to meaningful increases in the risk of autism spectrum,  intellectual disability, attention deficit disorders and other adverse neuropsychiatric outcomes that extend well into adulthood. All of this argues for proactive normalization of iron status in all reproductive aged women, a circumstance that requires recognition of women with HMB and appropriate repletion of iron and iron stores.