Patients who were younger at the time of presentation with heavy menstrual bleeding were screened more often than older patients (risk difference for screening percentage of young [10–13 years old (13.9%) vs 14–17 years old (6.4%)] 7.5%, 95% CI 6.5–8.5%, P<.001). Patients admitted for heavy menstrual bleeding, those with a diagnosis of iron deficiency anemia, and those who underwent testing for iron deficiency anemia were screened more often for von Willebrand disease (risk difference screening percentage, respectively, 7.0%, 95% CI 3.0–11.0%, P<.001; 8.5%, 95% CI 6.0–11.0%, P<.001; 15.6%, 95% CI 14.7–16.4%, P<.001) (Table 3). Having a blood transfusion was not significantly associated with von Willebrand disease screening.
Logistic regression analysis showed that girls and adolescents meeting our criteria for severe heavy menstrual bleeding had a significantly increased likelihood of undergoing von Willebrand disease screening (16.2% vs 7.8%, OR 1.58, 95% CI 1.31–1.91) when compared with females who did not meet our criteria for severe heavy menstrual bleeding. Patients who underwent testing for iron deficiency anemia had the highest likelihood of being screened for von Willebrand disease (18.3% vs 2.8%, OR 7.08, 95% CI 6.32–7.93) (Table 4).
There were 17,095 females with private insurance, of whom more than 80% lived within a metropolitan statistical area. We had metropolitan statistical area data for 16,654 patients (only 2.6%, 441 had missing codes). Metropolitan statistical area data were not available for Medicaid patients. Privately insured patients were screened more often than Medicaid patients (risk difference screening percentage 2.3%, 95% CI 1.6–3.0%, P<.001). Logistic regression analysis showed that privately insured patients were significantly more likely to be screened for von Willebrand disease than Medicaid patients (8.8% vs 6.5%, OR 1.66, 95% CI 1.47–1.87). Among those who were privately insured, adolescents living within a metropolitan statistical area were more likely to be screened than those living outside a metropolitan statistical area (9.5% vs 5.5%, OR 1.64, 95% CI 1.38–1.95).
When looking at health care provider type, we found that patients seeing family practice providers at the time of initial diagnosis of heavy menstrual bleeding were less likely to undergo von Willebrand disease screening when compared with patients seeing obstetric–gynecologic providers (3.2% vs 6.0%, OR 0.43, 95% CI 0.34–0.54). Patients seeing acute care providers (10.4% vs 6.0%, OR 1.22, 95% CI 1.03–1.44) and pediatricians (12.0% vs 6.0%, OR 1.21, 95% CI 1.02–1.42) at the time of initial diagnosis were modestly more likely to undergo screening when compared with patients seeing obstetric–gynecologic providers (Table 4). There were 6,310 patients in whom the health care provider type at initial diagnosis of heavy menstrual bleeding was “other” or “missing.” Other health care provider types included other subspecialty surgeons such as otolaryngologists. A missing health care provider type indicates that the diagnosis code was associated with a laboratory encounter that could not be linked back to a specific health care provider.
We calculated the approximate travel time to the nearest hemophilia treatment center in all patients who lived within a metropolitan statistical area (n=13,475). Of these, more than one third (36%) had to travel longer than 1 hour to get to the nearest hemophilia treatment center (Table 2). Patients living in a metropolitan statistical area who were less than 1 hour to the nearest hemophilia treatment center were more likely to undergo von Willebrand disease screening than patients living further from a hemophilia treatment center (10.7% vs 7.6%, OR 1.37, 95% CI 1.19–1.56) (Table 4).
In 2001, ACOG recommended screening adolescents with heavy menstrual bleeding since menarche for von Willebrand disease. The refined recommendations, published in 2013, better defined what a diagnosis of heavy menstrual bleeding entails and included recommendations for screening in adolescents reporting heavy menstrual bleeding and any of the following: 1) menses lasting more than 7 days or bleeding through a pad or tampon in 2 hours, 2) a personal history of anemia, 3) a family history of a bleeding disorder, or 4) a personal history of abnormal bleeding after a hemostatic challenge. In this study of a national claims database, we found that of 27,888 postpubertal girls and adolescent girls (10–17 years) with a diagnosis of heavy menstrual bleeding, 8% were screened for von Willebrand disease. Because ACOG's recommendations do not provide a definition for severe heavy menstrual bleeding and given the limitations of using an administrative database, we elected to use the following criteria to define severe heavy menstrual bleeding: a diagnosis of heavy menstrual bleeding plus a hospital admission for menstrual bleeding, a diagnosis of iron deficiency anemia, or evidence of a blood transfusion. Among those patients who met our criteria for severe heavy menstrual bleeding, the screening rate was modestly better (16% were screened for von Willebrand disease). Our study demonstrated that despite published recommendations, von Willebrand disease screening was rarely performed as part of the evaluation of postpubertal girls and adolescents with heavy menstrual bleeding in the United States. The following patient characteristics were significantly associated with a higher frequency of von Willebrand disease screening: inpatient admission for heavy menstrual bleeding, diagnosis of iron deficiency anemia, testing for iron deficiency anemia, younger age at presentation with heavy menstrual bleeding, commercial insurance, an obstetrician–gynecologist as opposed to a family practice provider at the initial encounter for heavy menstrual bleeding, geographic location within a metropolitan statistical area, and travel time less than 1 hour to the nearest hemophilia treatment center. Additionally, patients who underwent testing for iron deficiency anemia, regardless of having a subsequent diagnosis of iron deficiency anemia, had a significantly increased likelihood of undergoing von Willebrand disease screening. Even among patients living within a metropolitan statistical area, the distance to the nearest hemophilia treatment center remained modestly predictive of their likelihood to be screened for von Willebrand disease.
There are important limitations of our study design to consider. We were not able to account for ethnicity, family history of bleeding disorders, medical history, and medications because these data were not available in Truven Databases. Additionally, if ICD-9 diagnosis codes for heavy menstrual bleeding were recorded incorrectly or not recorded at all, this may have misidentified or omitted some patients. Strengths of our database include a large and diverse population representative of the U.S. population. To minimize concerns about selection bias and external validity, we oversampled commercially insured patients to have the largest possible sample. Although we do not know the states that were represented by the Medicaid patients, we do know that the 14 states are representative of each region in the United States. Although we did not have geographic data for publicly insured patients, we hypothesize that distance barriers are as important (if not more) for publicly insured patients. In our prior work with Ohio Medicaid data, distance was a factor that affected screening frequency.12
Because bleeding disorders in women tend to be less severe than hemophilia, it can be more difficult for physicians and patients to recognize symptoms, and the average time to diagnosis can be as long as 4–16 years.15–17 Although patients in our study who met criteria for severe heavy menstrual bleeding were more likely to be screened than nonsevere patients, the screening rate remained less than one in five and was lower than our prior report of Ohio Medicaid patients.12 Females with bleeding disorders are more likely to undergo hysterectomy and also undergo hysterectomy at an earlier age than women without bleeding disorders.18 Early recognition of von Willebrand disease can help prevent subsequent bleeding episodes during pregnancy, postpartum hemorrhage, bleeding during surgical procedures, and potentially unnecessary hysterectomies.
The multiple other causes of heavy menstrual bleeding can be a barrier to diagnosing von Willebrand disease. Anovulatory and dysfunctional uterine bleeding is commonly seen in adolescents, and these diagnoses may discourage the health care provider from testing for a bleeding disorder if he or she makes the assumption that these diagnoses are the cause of heavy menstrual bleeding. A personal or family history of heavy menstrual bleeding; postpartum hemorrhage; iron deficiency requiring therapy or transfusion; unusual, unexpected, or excessive surgical bleeding; unexplained or frequent epistaxis; oral bleeding; or easy bruising should further prompt health care providers to screen for von Willebrand disease.5,19 Additionally, validated bleeding scores have been published and can be used in clinical practice but are not without limitations, especially if used in adolescents.5 In a recent North American Society of Pediatric and Adolescent Gynecology committee opinion, recommendations for acute treatment of heavy menstrual bleeding in adolescents were to first address symptomatic anemia or severe bleeding with blood products if needed. Then high-dose estrogen-only, progesterone-only (if estrogen is contraindicated), or combined contraceptive pills can be used to stabilize the endometrium, resulting in bleeding cessation. Iron deficiency should be corrected with supplementation, either oral or intravenous.5
It is essential to understand how to interpret von Willebrand disease results that warrant hematology referral and also recognize testing limitations and factors that may affect testing accuracy. A concern for possible von Willebrand disease arises when there is low von Willebrand factor antigen, activity (ristocetin cofactor), or both or when the platelet function analysis (closure time) is prolonged, because this test was developed as a screening test for von Willebrand disease. Von Willebrand disease screening is highly specific (greater than 98%) for von Willebrand disease, but sensitivity is much lower as a result of various conditions that may affect testing. Many centers send out these tests to commercial laboratories, which can cause falsely low levels as a result of delays in processing and elevated sample temperature. Anemia and high-dose estrogen therapy, which is commonly used to treat severe heavy menstrual bleeding, can increase von Willebrand factor antigen and activity.20 Von Willebrand disease testing should be postponed until a patient is off high-dose estrogen therapy. Standard or low-dose estrogen treatment would be much less likely to interfere with von Willebrand disease testing, and we routinely screen for von Willebrand disease in patients on standard-dose combined contraceptives in clinical practice. Von Willebrand factor is an acute-phase reactant and may also be elevated in the setting of illness or stress. Thus, a hematology referral may be warranted should a clinical history of bleeding be present, even if test results are negative. Von Willebrand factor antigen, activity levels above the upper limit of normal, or both are rarely clinically significant and do not warrant hematology referral unless there are persistent and otherwise unexplainable bleeding concerns.
In conclusion, our study demonstrates that despite more than 15 years of ACOG recommendations, approximately 90% of postpubertal girls and adolescents with heavy menstrual bleeding are not being screened for von Willebrand disease. We showed that a variety of health care providers are the “first responders” for girls and adolescents with heavy menstrual bleeding, which emphasizes the need for increased awareness of von Willebrand disease among all health care providers taking care of adolescent females and recognition that heavy menstrual bleeding is the most common and often the first bleeding symptom in young women with von Willebrand disease.
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