The Interconnectedness of Non-Anemic Iron Deficiency, Iron Deficiency Anemia, and Heavy Menstrual Bleeding

Although there are several definitions of heavy menstrual bleeding (HMB), the earliest (published in 1966) characterizes HMB as greater than 80 mL of menstrual blood loss per cycle.⁶  This definition developed from early population-based studies that defined the upper limit of normal menstrual blood loss based on a greater prevalence of iron deficiency.^4,7  While tools such as the pictorial blood loss assessment chart (PBAC) are available to quantify vaginal blood loss, they remain underused.^8,9  In fact, only 21% of medical residents at a large Canadian university from a variety of specialties (including obstetrics and gynecology) have heard of the PBAC.⁹  Accordingly, in day-to-day practice, the definition of HMB continues to be poorly understood and challenging to operationalize, which renders it difficult for many clinicians to diagnose.⁴  In the absence of a diagnosis, you cannot provide treatment, and as Mahatma Gandhi famously said, “A correct diagnosis is three-fourths the remedy.”

To address the challenge in diagnosing HMB, the American College of Obstetricians and Gynecologists (ACOG) developed an updated definition marked by presence of any of the following: 1) bleeding that lasts more than seven days; 2) bleeding that soaks through one or more tampons or pads every hour for several hours in a row; 3) needing to wear more than one pad at a time to control menstrual flow; 4) needing to change pads or tampons during the night; and/or 5) menstrual flow with blood clots that are as big as a quarter or larger.¹⁰  While this definition is an improvement and contextualizes blood loss using tampons or sanitary pads as a unit of measure, it requires patients to have access to menstrual blood products.¹  Unfortunately, it is estimated that 16.9 million women in the U.S. currently experience “period poverty,” or inadequate access to menstrual products and hygiene facilities.¹¹  This lack of access not only obstructs the ability to measure blood loss, but also contributes to the broader issue of delayed diagnosis.

Moreover, ACOG’s definition does not include consideration of the level of absorbency of pads and tampons, which has a marked influence on the amount of blood lost. Thus, reliance on the number of pads or tampons used contributes to underdiagnosis of HMB.¹²  In addition, women who experience HMB may normalize their symptoms, based on their length and on the experiences of their family members, blocking off discussion with clinicians.^4,13  Race and ethnicity also influence the prevalence of HMB, with studies finding that the condition is more prevalent among Black women.^14,15  Further complicating matters is a growing body of evidence that clinicians do not believe women who report heavy vaginal blood loss and serially disregard their symptoms, resulting in health care-related trauma that further blocks the opportunity for diagnosis and treatment.¹⁶  Ultimately, a timely diagnosis of HMB is dependent on the patient’s awareness of heavy periods; clinicians believing their symptoms; patient trust in their health care provider and system; and clinicians being adept at diagnosing HMB.

Negative iron balance is exceedingly common in women. When iron losses from HMB, or iron demands from pregnancy, exceed iron intake, iron deficiency with or without anemia develops.¹⁷  In fact, recent data from a U.S. study indicates an approximate 40% prevalence of NAID.²  Two Canadian studies using outpatient community laboratory data found that 38.3% of non-pregnant females were iron deficient, with 52.8% of pregnant women experiencing iron deficiency at least once during pregnancy.^18,19  Few conditions in medicine are as prevalent, and it is clear that prevalence estimates depend on the definition of iron deficiency used.²⁰  While there is abundant evidence since the early 1990s that serum ferritin levels below 30 μg/L are accurately predictive of iron deficiency in adults,¹  evolving evidence suggests that serum ferritin levels below 50 μg/L may, in fact, indicate iron deficiency in adult patients. Thus, the diagnosis and true prevalence estimate of iron deficiency is entirely dependent on which diagnostic laboratory reference interval lower limit of normal (LLN) is used.²¹ 

Unfortunately, the serum ferritin threshold by which clinicians diagnose iron deficiency is inconsistent between community and hospital laboratories and is often far below 30 μg/L. A recent systematic review of 62 studies reported numerous serum ferritin assays having an LLN well below 30 μg/L, with a median of 8 μg/L in females and 25 μg/L in males.²²  Notably, the authors reported a high risk of bias in the existing data given the lack of exclusion of individuals at risk for iron deficiency (e.g., based on diet, bleeding history) and lack of adherence to Clinical and Laboratory Standards Institute recommendations for establishing reference intervals in the presumed “normal” reference sample.²²  The discrepancy between a clinically relevant decision limit (<30 μg/L) and LLN (<8 μg/L) for serum ferritin levels leaves a large proportion of the population undiagnosed and thus untreated, particularly women of reproductive age, who are at the greatest risk.¹ 

NAID and IDA are increasingly recognized as issues rooted in structural sexism, defined as “beliefs, policies, and practices at any level of society or organization that [are] derived on the basis of sex and gender, leading to inequity.”^1,23,24  To effectively address systemic barriers to care, such as inappropriately low laboratory serum ferritin thresholds to flag the diagnosis of iron deficiency, clinicians need multi-sectoral, collaborative interventions coupled with knowledge translation strategies and rigorous post-intervention evaluation.²⁵  Structural problems require structural solutions, with investment and commitment from clinician leaders, jurisdictional health authorities, and patient advocates.

In Ontario, the most populous Canadian province, an ongoing initiative called Raise the Bar has changed the LLN of laboratory serum ferritin to a clinical decision limit of <30 μg/L for adults and <20 μg/L for children across the largest community laboratories and numerous hospital labs. Coupled with this change, a comment flagging the diagnosis of iron deficiency is provided with additional education resources for clinicians (hemequity.com/raise-the-bar-home). Future work will evaluate for changes over time both pre-and post-implementation. We hypothesize that the downstream effects of this initiative will also highlight NAID and IDA in women of reproductive age, prompting an earlier diagnosis of NAID in women with HMB and in pregnant women, allowing for earlier treatment. The ultimate goal is to minimize the negative effects of NAID and IDA for individuals and generations to come.

Ms. Tang indicated no relevant conflicts of interest. Dr. Selby is the co-chair of the Test Review and Utilization Committee (TRUC) that advises the Laboratories and Diagnostics Branch of the Ministry of Health of Ontario, as well as provincial medical director of the Ontario Laboratory Medicine Program. Dr. Sholzberg reports unrestricted research funding and honoraria for speaking engagements and advisory boards from Octapharma and Pfizer, and she is also a Hematology committee member of the Ontario Laboratory Medicine Program.