The differential diagnosis of abnormal vaginal bleeding includes pregnancy complications, benign or malignant reproductive tract lesions, and systemic pathologies. Further, urinary and gastrointestinal tract abnormalities can present similarly to reproductive tract pathology. For this reason, urinalysis or stool guiac tests are often a critical step in the work-up of abnormal vaginal bleeding.

Pregnancy complications

Complications of early pregnancy associated with bleeding include threatened, incomplete or missed abortions, trophoblastic diseases, placental abnormalities and ectopic gestation. Ectopic pregnancy is the leading cause of death in the first trimester and often presents in patients who are unaware they are pregnant. For this reason, abnormal vaginal bleeding in women of child-bearing age should be considered an ectopic pregnancy until proven otherwise and should prompt a urine pregnancy test. If positive, transvaginal ultrasound and, possibly, serial quantitative assays for human chorionic gonadotropin (hCG) should follow.

The combination of ultrasound and hCG is a powerful tool to evaluate for extrauterine pregnancy. A hCG level of 1500 mIU/mL is usually associated with visualization of a gestational sac on ultrasound with a probe of 5.0–7.0 MHz or higher. If the hCG is > 1500 mIU/mL and no sac is seen, suspicion for ectopic gestation must be high. Very rarely (1 in 3000–10,000 pregnancies) combined intrauterine and extrauterine (heterotopic) pregnancy does exist. This risk increases after fertility treatment.

Trophoblastic disease must also be considered in reproductive-age women with abnormal bleeding, especially in those with a recent pregnancy. A sensitive β-hCG assay and sonogram will aid this diagnosis.

Lastly, if intrauterine pregnancy is confirmed, the diagnosis is threatened, inevitable, incomplete or missed abortion. The distinction between these entities depends on history, physical exam and ultrasound findings.

Malignancy

Endometrial cancer, cancer of the cervix, vaginal, vulvar and fallopian tube cancers and estrogen-secreting ovarian tumors may all cause abnormal vaginal bleeding.

The incidence of endometrial cancer increases with age. Approximately 10% of all abnormal uterine bleeding in perimenopausal women and 25% of bleeding in postmenopausal women is due to cancer. Further, women of any age with a long history of oligomenorrhea or anovulatory menstrual cycles are at risk for endometrial carcinoma. Eighty percent of women who develop endometrial carcinoma before age 40 have polycystic ovarian disease (PCOS), an estrogen-dominated syndrome. If abnormal uterine bleeding occurs in the setting of long-standing unopposed estrogen at any age or in the peri/postmenopausal period, the endometrium should be sampled.

Human papilloma virus (HPV) vaccines may decrease the incidence of cervical cancer by up to 70% over the coming decades. Currently, a quadrivalent vaccine against HPV types 6, 11, 16 and 18 is available in the United States. A bivalent vaccine against HPV types 16 and 18 is pending FDA approval. Presently, however, cervical cancer is still a significant cause of abnormal vaginal bleeding and must be considered in the differential diagnosis. This is especially true in women who have never had a Pap smear, as this group makes up more than 50% of cervical cancer cases in the United States.

Benign lesions

Benign lesions such as submucosal myomas or endometrial and cervical polyps may also lead to abnormal bleeding. The mechanisms behind such bleeding are likely related to distorted vascularity and chronic inflammatory processes which accompany these lesions.

Occasionally, a submucosal myoma may protrude completely into the uterine cavity and then dilate the cervix. This is referred to as an aborting myoma and can be associated with copious bleeding. An aborting myoma identified on speculum exam may be twisted off at its base, followed by a sharp curettage. Rarely, carcinoma may present in this fashion. Thus, if suspicion is high, a biopsy and rapid frozen section should be obtained prior to removal.

Smaller endometrial cavity abnormalities, such as polyps, can be more difficult to diagnose. Once bleeding has stopped, hydrosonography or hysterosalpingography are both adequately sensitive to detect the vast majority of lesions.

Infection/vaginitis

Inflammation of the vaginal mucosa can result from a host of causes ranging from bacterial colonization to atrophy. In each of these settings, the inflammatory cascade leads to erythema, vascular fragility and potential bleeding. Consideration of the clinical scenario, a detailed history as well as focused physical exam with wet mount and vaginal pH determination will allow appropriate diagnosis and treatment.

Anovulation

Anovulation occurs when the hormonal interaction between pituitary, hypothalamus and ovary fails to recruit, stimulate and release an oocyte. In response, the endometrial lining becomes disorganized and sheds in an irregular and unpredictable manner. A host of conditions can lead to anovulatory bleeding, but PCOS is the most common cause.

According to the National Institutes of Health, PCOS is defined by evidence of clinical or biochemical hyperandrogenism, irregular menses and exclusion of other causes of irregular menses (hyperprolactinemia, congenital adrenal hyperplasia, etc.). Treatment for this condition will depend on the patient’s wishes and ranges from hormonal contraception to ovulation induction.

Coagulation disorders

Platelet deficiency due to leukemia, severe sepsis, idiopathic thrombocytopenic purpura or hypersplenism as well as platelet dysfunction and conditions like von Willebrand’s disease or prothrombin deficiency may all present as abnormal uterine bleeding. Blood dyscrasias usually can be identified by a history of easy bleeding or bruising, a family history of a bleeding disorder, bleeding from other orifices and excessive bleeding associated with minor trauma.

Approximately 20% of adolescent females hospitalized for excessive uterine bleeding are found to have a blood dyscrasia. Therefore, teenage patients with abnormal uterine bleeding, especially that which started with menarche, should be evaluated for a blood dyscrasia.

Liver disease

The liver is central in production of coagulation factors and is also important in estrogen metabolism. Therefore, liver disease could contribute to abnormal bleeding due to impaired coagulation as well as abnormal endometrial proliferation. A history of hepatitis, heavy alcohol ingestion and associated physical findings such as jaundice or hepatomegaly indicate the need to evaluate liver function.

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