Introduction
Abnormal uterine bleeding (AUB) and its subgroup heavy menstrual bleeding (HMB) affect 12 percent to 25 percent of reproductive-age women [1,2]. Additionally, HMB affects about 30 percent of adolescent females presenting to the gynecologist [3] and between 10 percent and 100 percent of those with bleeding disorders, depending on the type and severity of the underlying condition [4].
HMB is defined as excessive menstrual blood loss that interferes with the individual’s physical, emotional, social, and material quality of life and can occur alone or in combination with other symptoms [5]. A 2006 study showed that HMB affected adolescents’ ability to participate in physical education or sports, resulted in at least one day of missed school during each menses, disrupted their hobbies and leisure activities, and increased their level of fatigue [6]. Management of HMB in adolescents must take into consideration the desire to maintain future fertility, contraceptive needs, and improved quality of life.
Definitions
In 2011, the International Federation of Gynecology and Obstetrics published a classification system to describe the causes of AUB in reproductive-age women. This system, which was later adopted by different national societies of obstetricians and gynecologists [7,8], includes the following: acute AUB describes “an episode of heavy bleeding that, in the opinion of the clinician, is of sufficient quantity to require immediate intervention to prevent further blood loss” [9]. Chronic AUB is uterine bleeding that has been present for the majority of the past 6 months. A patient’s perception of increased menstrual bleeding may be considered sufficient to make the diagnosis of HMB [9]. In fact, both the Royal College of Obstetricians and Gynaecologists and the American College of Obstetricians and Gynecologists prefer the patient-centered definition of HMB as an indication for investigation and treatment options. Hence, surrogate objective measurements of volume such as pictorial blood-loss assessment chart scores are not recommended in routine clinical practice [10].
Bleeding is then further categorized according to etiology by using the acronym PALM-COEIN: Polyp (AUB-P), Adenomyosis (AUB-A), Leiomyoma (AUB-L), Malignancy and hyperplasia (AUB-M) and Coagulopathy (AUB-C), Ovulatory dysfunction (AUB-O), Endometrial (AUB-E), Iatrogenic (AUB-I), and Not yet classified (AUB-N) [9]. The differential diagnosis of AUB etiology in adolescents is similar to that in adult women; however, proportions of causes differ between the two groups.
Pathophysiology and Differential Diagnosis
The most common cause of AUB in adolescents is ovulatory dysfunction. For the first several years after menarche, some adolescents experience irregular menses due to an immature hypothalamic-pituitary-ovarian axis and subsequent anovulatory cycles [11]. In such cases, the ovaries produce estrogen continuously, hindering ovulation. Without ovulation, no corpus luteum secretes progesterone to stabilize the endometrium. Instead, the endometrium is maintained in the proliferative phase, resulting in thickening and incomplete shedding, which causes irregular, often heavy, menses.
The age at presentation is important when considering etiologies other than an immature hypothalamic-pituitary-ovarian axis. Oligomenorrhea more than 2 years post-menarche is often predictive of persistent cycle irregularity and warrants further assessment to exclude endocrinopathies such as hyperandrogenism, hyperprolactinemia, or thyroid dysfunction. Anovulation may also be induced by obesity.
Severe acute bleeding and heavy menstrual bleeding at menarche with chronic heavy bleeding during the entire reproductive life are common manifestations of inherited or acquired hemorrhagic disorders. In up to 48 percent of cases, adolescents presenting with HMB at or close to menarche (particularly those who require frequent visits to the emergency department, hospital admission, or blood transfusion) have a bleeding disorder, most commonly Von Willebrand disease (vWD) [12,13] (Figure 7A.1). Other medical conditions that can disrupt normal blood clotting and result in HMB include idiopathic thrombocytopenic purpura, hepatitis, chronic renal disease, diabetes mellitus, hypothyroidism, and systemic lupus erythematosus [14].
Figure 7A.1 Flow diagram for acute management of HMB in adolescents
The presence of regular cycles with moliminal symptoms, such as breast discomfort, cramps, and bloating prior to each menses, are suggestive of ovulatory cycles. Intermenstrual bleeding may suggest an anatomic problem (a partially obstructed outflow tract, for example).
In sexually active adolescents, two common causes of AUB that are not included in the PALM-COIEN classification system are pregnancy-related bleeding (miscarriage, extra-uterine pregnancy) and sexually transmitted infection (STI). STI may lead to cervicitis, endometritis, and pelvic inflammatory disease, resulting in intermenstrual bleeding. Unscheduled endometrial bleeding that occurs during the use of gonadal steroid therapy, “break-through bleeding,” is the major component of the AUB-I classification. Iatrogenic causes in adolescents are often related to contraceptive use, especially long-acting progestin-only methods, or suboptimal compliance with combined oestro-progestatives. Compliance issues include forgetfulness, irregular intake, or concomitant use of medication that reduces contraceptive efficiency [9].
Other mechanisms may cause HMB by disrupting vasculogenesis within the endometrium. These include increased endometrial endothelial cell proliferation, reduced proliferation and differentiation of vascular smooth muscle cells around spiral arterioles, altered synthesis of uterine vasodilatory prostanoids, reduced endothelin expression, and increased expression of endometrial-bleeding-associated factor [1]. An increase in total prostaglandin release and disproportional rise in prostaglandin E2 have also been demonstrated in ovulatory HMB [15,16].
Evaluation
Medical and Menstrual History
Differential diagnosis is aided by the patient’s medical history, which should cover the nature of the bleeding, related symptoms that might suggest structural or histological abnormality, impact on quality of life, and full personal medical history. The wide range and natural variability of blood loss in menstrual cycles should be discussed and explained to the adolescent. If uncertain, use of a menstrual calendar or smartphone application may be helpful in objectifying the bleeding pattern. Inquiry should be made about the number of pads or tampons, including their absorbency, used over both a 24-hour period and the whole duration of the menses. Inquiries should be made about heavy bleeding from the onset of menarche, presence of clots (size and frequency), and soaking through clothes or leaking, especially overnight; such symptoms may be associated with a bleeding disorder.
After confirming confidentiality, all adolescents should be privately asked about history of sexual activity, including both consensual and coerced sex.
Further evaluation for blood coagulopathy should be considered if there is family history of an underlying bleeding disorder such as postpartum hemorrhage, surgery-related bleeding, bleeding associated with dental work, and any two of the following symptoms: bruising (1–2/month), epistaxis (1–2/month), frequent gum bleeding, or other bleeding symptoms [14].
Physical Examination
Clinical examination in patients with prolonged or heavy bleeding should always begin with vital signs because tachycardia, hypotension, or orthostatic changes may be the only signs of severe anemia in young patients. A cardiac examination may reveal a flow murmur in anemic patients. Weight and body mass index should be noted. The abdomen should be palpated per usual for masses or hepatosplenomegaly, with special attention on assessing the uterine fundus, which can suggest a pregnancy.
The skin should be examined for bruising and petechia, which would suggest an underlying bleeding disorder; signs of androgen excess (acne, hirsutism, or acanthosis nigricans); and conjunctival or nail bed pallor suggestive of anemia. The patient’s thyroid gland should be palpated to detect enlargement or nodules.
In a sexually active adolescent, the physical examination should not differ from that applied to an adult woman. Examination per speculum and bimanual examination can confirm whether bleeding is from the vagina or cervix and is related to trauma, inflammation, or infection (such as cervicitis or pelvic inflammatory disease). However, in the nonsexually active adolescent, assessment would generally not include a speculum or bimanual examination but should rely on external assessment of the genitalia, including the clitoris to assess for signs of virilization, urethral prolapse, active bleeding, or trauma, in accordance with the patient’s history [2,7,11,14,17].
Laboratory Investigations
The initial laboratory assessment in adolescents does not differ from that recommended for adult women: screening for pregnancy (urine pregnancy test and/or quantitative serum ß-HCG) is paramount, as not all patients disclose their sexual history despite reassurance about confidentiality. A complete blood cell count (CBC) including differential, platelet count, and a reticulocyte count are essential [11,14]. A serum ferritin test may reflect chronic blood loss and direct replacement therapy but does not provide any more information than a CBC in relation to management of HMB [2,5]. Further testing is directed by history, symptoms, and physical examination.
If a bleeding disorder is suspected, the following tests should be conducted: prothrombin time; activated partial thromboplastin time; fibrinogen; platelet aggregation; and a Von Willebrand panel, which includes Von Willebrand factor (vWF) antigen, ristocetin cofactor assay, and factor VIII [2,5,7,8,17]. Note that vWF is lower in patients with blood type O and during the first three days of menses and higher during pregnancy or when using contraceptives with estrogens.
Thyroid testing should only be performed if signs and symptoms of thyroid disease are present. Female hormone testing should not be carried out on women with HMB, except in patients with irregular cycles or amenorrhea before the onset of the heavy bleeding. In these situations, testing should include follicle stimulating hormone; luteinizing hormone; serum estradiol; total and free testosterone; dehydroepiandrosterone; and, possibly, prolactin to screen for polycystic ovarian syndrome, primary ovarian insufficiency, and hyperprolactinemia [11,14].
Given the high prevalence of STIs in sexually active adolescents, nucleic acid amplification tests for Chlamydia trachomatis and Neisseria gonorrhoeae, either in urine or cervical swabs, are highly recommended [7,18].
Investigation for Structural and Histological Abnormalities
Pelvic sonography, both abdominal (suprapubic) and transvaginal (in sexually active adolescents), is recommended as a first-line procedure to rule out the rare structural cause of AUB in adolescents [2,17], especially when HMB is accompanied by pelvic pain or pressure. Sonography may also delineate endometrial thickness, which is useful in selection of the proper hormonal treatment. Imaging should be undertaken if the uterus is palpable abdominally, vaginal examination reveals a pelvic mass of uncertain origin, or when pharmaceutical treatment fails [2]. Doppler ultrasonography provides additional information useful for characterizing endometrial and myometrial abnormalities [17]. Endometrial biopsy, hysteroscopy, saline infusion sonography, or magnetic resonance imaging are rarely used in adolescents in the context of HMB [7].
Treatment
Principles
The management objectives of AUB are to stop bleeding, restore a stable hemodynamic state, and treat and prevent anemia. Identification of the underlying cause can guide both acute treatment and maintenance therapy to establish regular menses and improve the adolescent’s quality of life [2,3,6,7,14,]. (See Table 7A.1.)
Table 7A.1 Treatment options for Heavy Menstrual Bleeding in Adolescents
| Treatment | Product | Advantages | Disadvantages |
|---|---|---|---|
| NSAID | Naproxen | Self-administered | GI upset (take with food or milk) |
| 275–500 mg PO q 6-8 h (US) | Also treats primary dysmenorrhea | Monitor renal and hepatic function | |
| 250–500 mg PO × 2–4/day | May reduce bleeding | ||
| Ibuprofen | |||
| Up to 1200/day | |||
| Mefenamic acid | |||
| Initial dose 500 mg the 250 mg q 6 hr | |||
| Iron | Oral ferrous sulfate 325 mg (65 mg elemental iron) multiple preparations are available | Correction of iron deficiency anemia and low iron stores Low cost | GI upset and constipation Poorly tolerated with inflammatory bowel disease |
| Intravenous multiple preparations are available | For those who do not tolerate side effects of oral therapy | Transient fever, arthralgias, myalgias, flushing, (rare) anaphylactic reactions | |
| Combined hormone contraception (CHC) | Combined oral contraceptive pill | Self-administered | In higher doses (3 or 4 times a day) for acute HMB can cause nausea |
| 30–35 mcg EE + Progestin 3 or 4 times a day until bleeding stops then taper dose as bleeding improves to once daily for maintenance | Provides contraception | ||
| Transdermal patch weekly for maintenance | May use in extended cycles | ||
| Vaginal ring every 3 or 4 weeks for maintenance | Retain fertility when stopped | ||
| Estrogen only | Conjugated equine estrogen | Rapid action | Nausea |
| 25 mg Intravenous every 6 hours* until bleeding stops then transition to oral CHC | |||
| Progestin only | Medroxyprogesterone acetate | Self-administered | Does not provide contraception |
| 10 mg/day for maintenance | |||
| 20–40 mg TID* acute HMB | |||
| Norethindrone acetate | Fertility preserving | ||
| 5 mg /day (US) for maintenance | |||
| 10–40 mg/day * acute HMB | |||
| Depo Medroxyprogesterone acetate | Provides contraception | Intramuscular dosing may result in hematoma in at risk patients | |
| Intramuscular 150–300 mg q 12 weeks | |||
| Progestin-only pill | Self-administered | Breakthrough bleeding | |
| Fertility preserving when stopped | |||
| Progestin releasing vaginal ring | Self-administered | Break through bleeding | |
| Not available in US | |||
| Etonogestrel subdermal implant | Not recommended | Inability to predict bleeding patterns | |
| LNG IUS for maintenance | Provides contraception | Replace every 5 years | |
| Remains 5 year | May take 6 cycles to relieve HMB | ||
| Retain fertility when IUS removed | |||
| Requires skilled placement | |||
| Antifibrinolytics | Tranexamic acid | Non-invasive | May increase chance of clot or stroke if combined with CHC |
| Oral 1 gram X 3–4/day | |||
| Oral 650 mg two tablets TID (US) | Self-administered | Will not induce amenorrhea | |
| Intravenous 10 mg/kg every hours | Retain fertility throughout | ||
| Anti-diuretic hormone | Desmopressin acetate | Use in mild to moderate von Willibrand disease (type I) and Hemophilia A with factor VIII levels >5% | Contraindicated with history |
| 0.3 mcg/kg IV over 15–30 minutes | hyponatremia | ||
| 150–300 mcg intranasal | Monitor renal function | ||
| GnRH agonists | Leuprolide acetate (for cancer patients) Ideally start before induction of myelosuppressive therapy and 4 weeks before the onset of thrombocytopenia Intramuscular 3.75–7.5 mg/month 11.25–22.5 mg IM every 3 months Subcutaneously 3.75 mg | Initial rise in circulating GN and sex steroids (flare) Long term use increases osteoporosis risk Consider add-back with estrogens or calcium and Vitamin D |
Satisfaction and continuation of any given treatment will be influenced not only by efficacy but also by the adolescent’s goals and tolerance of side effects. The decision to proceed with any medical treatment should be based on a discussion of patient preference, need for contraception, underlying medical conditions or contraindications, presence of dysmenorrhea, and severity of the bleeding [19].
Medical therapy is the preferred first-line treatment for AUB in adolescents. Irregular or prolonged bleeding is most effectively treated with hormonal options that regulate cycles, thus decreasing the likelihood of unscheduled and potentially heavy bleeding episodes, preserving fertility, and often providing contraceptive benefits.
The criteria for hospitalization are hemodynamic instability, HMB in an already anemic patient, or acute active HMB and a hemoglobin of less than 8 mg/dl in a chronically anemic patient [20,21]. Intravenous crystalloids for blood volume are given initially, but other blood products (clotting factor replacements, platelet transfusions, plasma-derived vWF concentrate, or Factor VII concentrate) and anti-fibrinolytics should be used in specific deficiencies and given judiciously after discussion with the pediatric hematologist.
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