Differential Diagnosis of Vaginal Bleeding: A Comprehensive Guide for Clinicians

Introduction

Vaginal bleeding, defined as any bleeding from the vagina that is not related to normal menstruation, is a prevalent gynecological concern across all age groups. It presents a diagnostic challenge due to its wide array of potential etiologies, ranging from benign conditions to serious underlying pathologies, including malignancies and obstetric complications. Understanding the differential diagnosis of vaginal bleeding is crucial for healthcare professionals to effectively evaluate, manage, and provide optimal care for affected individuals. This article offers a detailed review of the evaluation and management of vaginal bleeding, emphasizing a systematic approach to differential diagnosis and the vital role of interprofessional collaboration in achieving positive patient outcomes. Accurate diagnosis and timely intervention are paramount to addressing the underlying cause, alleviating patient anxiety, and preventing potential complications associated with vaginal bleeding.

Etiology of Vaginal Bleeding

Vaginal bleeding originates from any part of the female genital tract, encompassing the vulva, vagina, cervix, uterine body, and adnexa. The causes are broadly categorized into gynecologic, obstetric, and systemic etiologies. It is essential to consider malignancy of any genital organ as a potential cause in the differential diagnosis of vaginal bleeding.

Gynecologic Etiologies

Gynecologic causes are further divided into uterine and non-uterine origins.

Uterine Causes

Abnormal Uterine Bleeding (AUB) is a frequent cause of vaginal bleeding, particularly in adolescents and adults. The International Federation of Gynecology and Obstetrics (FIGO) classification system, PALM-COEIN, provides a structured framework for categorizing AUB etiologies and is widely adopted by organizations like the American College of Obstetricians and Gynecologists (ACOG). This system is applicable to both reproductive-aged and postmenopausal women in considering the differential diagnosis of vaginal bleeding.

PALM (Structural Causes):

Polyps: Endometrial polyps are common benign growths in the uterine lining that can cause intermenstrual or postmenopausal bleeding.
Adenomyosis: This condition involves the invasion of endometrial tissue into the uterine myometrium, leading to heavy and painful periods.
Leiomyomas (Fibroids): Uterine fibroids are benign tumors of the uterine muscle, often causing heavy or prolonged bleeding, depending on their location and size.
Malignancy and Hyperplasia: Endometrial hyperplasia and cancer are significant considerations, especially in postmenopausal bleeding, and require thorough evaluation in the differential diagnosis of vaginal bleeding.

COEIN (Non-Structural Causes):

Coagulopathy: Bleeding disorders can manifest as heavy menstrual bleeding or intermenstrual bleeding.
Ovulatory Dysfunction: Hormonal imbalances, such as in Polycystic Ovary Syndrome (PCOS), thyroid dysfunction, hyperprolactinemia, and extremes of reproductive age (menarche and menopausal transition), can lead to irregular or unpredictable bleeding.
Endometrial Abnormalities: Endometritis (inflammation of the endometrium) and endometrial atrophy (thinning of the endometrium, especially in postmenopausal women) can cause bleeding.
Iatrogenic Causes: Hormonal contraceptives, hormone therapy, and medications like anticoagulants are common iatrogenic causes of vaginal bleeding.
Not Otherwise Classified: Rare causes such as arteriovenous malformations and uterine sarcoidosis fall into this category.

Neonatal withdrawal bleeding, occurring in the first week of life due to the decrease in maternal hormones, is a benign and self-limiting cause of vaginal bleeding in newborns, distinct from other considerations in the differential diagnosis of vaginal bleeding across the lifespan.

Non-uterine Causes

Vulvar and vaginal causes of bleeding include:

Trauma: Injury to the vulva or vagina can result in bleeding.
Ulcers: Conditions like herpes or Behçet’s disease can cause vaginal ulcers and bleeding.
Neoplasia: Vulvar or vaginal cancers can present with bleeding.
Atrophy: Vaginal atrophy, particularly in postmenopausal women due to estrogen deficiency, can lead to fragile tissues and bleeding.
Erosion: Prolapse of pelvic organs, foreign bodies (retained tampons, surgical mesh), or radiation therapy can cause erosions and bleeding.

Cervical causes include:

Infection: Cervicitis due to Chlamydia trachomatis, candidiasis, or bacterial vaginosis can cause cervical friability and bleeding, especially post-coital bleeding.
Neoplasia: Cervical cancer and precancerous lesions can cause abnormal vaginal bleeding.
Polyps and Fibroids: Cervical polyps and fibroids, though less common, can bleed.
Cervical Ectropion: The eversion of the endocervical canal onto the vaginal portion of the cervix can be a source of contact bleeding.

Adnexal bleeding, though less frequent, can originate from:

Salpingitis: Inflammation of the fallopian tubes.
Malignancy: Ovarian or fallopian tube cancers.
Ruptured Hemorrhagic Cysts: Rupture of ovarian cysts can sometimes present as vaginal bleeding.

Obstetric Etiologies

Obstetric causes are critical in the differential diagnosis of vaginal bleeding for pregnant individuals.

First Half of Pregnancy:

Subchorionic Hematoma: Bleeding between the chorion and the uterine wall.
Pregnancy Loss (Miscarriage): Bleeding is a common symptom of miscarriage.
Ectopic Pregnancy: Implantation of the pregnancy outside the uterus, a life-threatening condition.
Gestational Trophoblastic Disease (GTD): Abnormal proliferation of trophoblastic tissue.

Second Half of Pregnancy:

Placental Abruption: Premature separation of the placenta from the uterine wall.
Abnormal Placentation: Placenta previa (placenta covering the cervix), vasa previa (fetal vessels crossing the cervix), placenta accreta spectrum (abnormal placental attachment).
Uterine Rupture: Tearing of the uterine wall, especially in women with prior Cesarean sections.
Cervical Dilation: Bleeding associated with the onset of labor.

Postpartum Period:

Postpartum Hemorrhage: Excessive bleeding after delivery, most commonly due to uterine atony (failure of the uterus to contract).
Retained Placental Fragments: Incomplete expulsion of the placenta.
Trauma: Cervical or perineal lacerations during delivery.
Uterine Inversion: Turning inside out of the uterus.
Disseminated Intravascular Coagulopathy (DIC): A rare but serious bleeding disorder.

Caption: Common causes of vaginal bleeding, categorized by gynecologic, obstetric, and systemic factors, crucial for differential diagnosis.

Epidemiology of Vaginal Bleeding

Vaginal bleeding can affect any individual with female anatomy at any point in life. Due to the broad definition of “vaginal bleeding,” specific epidemiologic patterns are better understood when considering etiologies or age groups.

First Trimester Pregnancy: Vaginal bleeding occurs in approximately 25% of first-trimester pregnancies.
Postmenopausal Bleeding: Incidence ranges from 5% to 10%, highest in the first year post-menopause.

Age-Based Etiologies in Differential Diagnosis of Vaginal Bleeding

Age is a critical factor in narrowing down the differential diagnosis of vaginal bleeding.

Prepubertal Children: Vulvovaginitis (often due to foreign bodies), trauma (accidental or abuse), urethral prolapse, follicular cysts, estrogen-secreting tumors (ovarian granulosa cell tumors), McCune-Albright syndrome, and exogenous estrogen exposure.
Reproductive-Aged Individuals: AUB due to ovulatory dysfunction and leiomyomas are most common. Malignancy is less frequent but increases with age within this group.
Postmenopausal Individuals: Malignancy risk is significantly higher; therefore, endometrial cancer and other cancers must be prioritized in the differential diagnosis of vaginal bleeding in this age group.

History and Physical Examination

A thorough history and physical exam are paramount in guiding the differential diagnosis of vaginal bleeding.

History Taking

The history should assess patient stability, bleeding acuity (acute vs. chronic), and relevant patient characteristics (age, menstrual status, anatomy).

Patient Demographics: Determine if the patient is premenarchal, adolescent, reproductive-aged, peri- or postmenopausal, pregnant, postpartum, or gender diverse. Note any prior hysterectomy.
Menstrual History: For menstruating individuals, record the last menstrual period (LMP) date.
Contraceptive History: Review contraceptive methods used.
Pregnancy Status: In reproductive-aged individuals, confirm pregnancy status with a test, regardless of patient perception.

Characterize the bleeding:

Onset: Sudden or gradual.
Frequency: Intermittent, continuous, cyclical.
Duration: How long has the bleeding lasted?
Severity: Assess blood volume by asking about pad/tampon saturation and frequency of changes.

Identify precipitating factors:

Trauma: Recent injuries.
Hormone Changes: New contraceptives or hormone therapy changes.
Contact Bleeding: Bleeding after intercourse or pelvic exam, suggesting cervical friability or endometrial issues (polyps).

Associated symptoms:

Pelvic Pressure/Pain: Dyspareunia, constipation, urinary frequency (mass effect).
Dysmenorrhea: Leiomyomas or adenomyosis.
Unintentional Weight Loss: Malignancy or hyperthyroidism.
Galactorrhea/Hirsutism: Hyperprolactinemia or hyperandrogenism (PCOS, congenital adrenal hyperplasia).
Bleeding History: Personal or family history of bleeding disorders (coagulopathy).
Pelvic Pain/Discharge/Pruritus: Infection.

In pregnant patients beyond the first trimester:

Pain/Contractions: Painful bleeding suggests abruption, rupture, or labor; painless bleeding suggests previa.
Fluid Loss: Rupture of membranes.
Fetal Movement: Decreased fetal movement.

Postpartum/post-miscarriage patients:

Delivery/Loss Details: Manual placental extraction (retained fragments), prolonged bleeding (retained products of conception, GTD).

General inquiries:

Anemia Symptoms: Pallor, dizziness, fatigue.
Malignancy Risk Factors: Unopposed estrogen, family history, cervical cancer screening history.
Medication Review: Identify medications affecting bleeding.
Comprehensive History: Obstetric, gynecologic, medical, surgical, and family history.

Physical Examination

The physical exam aims to:

Assess patient stability.
Identify the bleeding source.
Detect trauma or foreign bodies.
Look for infection signs (discharge, ulcers, tenderness).
Detect neoplasms (lesions, masses).
Identify endocrinopathy signs (thyroid enlargement, hirsutism).

In pregnant patients:

Assess cervical dilation, membrane status, fetal heart rate. Caution: Avoid cervical exam before ruling out placenta previa via ultrasound.

Postpartum patients:

Manual uterine cavity exploration for retained placental fragments.

Premenarchal Children:

Maternal age of menarche, trauma history (abuse), endocrine symptoms, puberty signs.
External introitus exam for trauma, masses, foreign bodies (knee-chest position preferred). Speculum exam usually avoided, anesthesia if needed.

Postmenopausal Adults:

Focus on malignancy signs (weight loss, bruising, masses, lesions).
Speculum exam with care due to atrophy and potential discomfort.

Transgender and Gender Diverse Individuals:

Preferred name, pronouns, body part terminology.
Clarify organs present and hormone medications.
Speculum exam with sensitivity and clinical judgment, considering potential anxiety and pain due to testosterone-induced atrophy.

Evaluation and Diagnostic Tests

The evaluation is tailored to the patient’s age and reproductive status, crucial for an effective differential diagnosis of vaginal bleeding.

Initial Evaluation Steps

Estimate Blood Loss: History (pad counts).
CBC, Coagulation Panel, Type and Crossmatch: Indicated for heavy bleeding.

Reproductive-Aged Patients

Pregnancy Test: First step, unless pregnancy is confirmed.

Positive Pregnancy Test

First Half of Pregnancy: Rule out ectopic pregnancy, pregnancy loss, subchorionic hematoma, GTD, and non-obstetric causes.

Pregnancy Location: Pelvic ultrasound is primary. If intrauterine pregnancy unclear, quantitative serum beta-hCG levels. Serial hCG levels and ultrasounds may be needed. Rule out ectopic pregnancy.
Pregnancy Viability: Fetal cardiac activity (FCA) on ultrasound confirms viability. If no FCA, serum hCG. Serial ultrasounds for follow-up. Criteria for early pregnancy failure if no FCA.
Gestational Age: EDD from LMP and ultrasound biometry. ACOG guidelines for EDD determination.

GTD: Suspect molar pregnancies (ultrasound: vesicular mass, theca lutein cysts, high hCG) and gestational trophoblastic neoplasia (GTN) (persistent elevated hCG post-pregnancy).

Second Half of Pregnancy

Evaluate for placental abruption, placenta/vasa previa, uterine rupture, labor, non-obstetric causes. Fetal well-being assessment (non-stress test (NST), obstetric ultrasound). Ultrasound assesses placenta, uterine scars. Cervical exam (after previa exclusion) for dilation, membranes, bleeding volume. Kleihauer-Betke test (feto-maternal hemorrhage), Rh D immune globulin if Rh-negative.

Placental Abruption: Clinical diagnosis: painful bleeding, contractions, fetal distress. Ultrasound may show retroplacental hematoma.
Placenta Previa: Painless bleeding, ultrasound diagnosis of placenta location.
Uterine Rupture: Painful bleeding (prior uterine incision), fetal distress (bradycardia), tetanic contractions, loss of fetal station.

Puerperium

Postpartum hemorrhage: clinical diagnosis (blood loss estimate, uterine atony, lacerations). CBC, coagulation panel, type and cross-match if bleeding persists. Ultrasound for retained products of conception (if lochia heavy/prolonged). Persistent elevated hCG suggests GTD.

Nonpregnant Patients

Reproductive-Aged Group: History, exam, PALM-COEIN framework. Pelvic ultrasound, bloodwork, endometrial tissue sampling (rule out hyperplasia).

Pelvic Ultrasound: First-line for structural uterine anomalies (leiomyomas, adenomyosis).
Hysteroscopy/Saline-Infusion Sonogram: Better for polyps, intracavitary pathology. Operative hysteroscopy for biopsy and treatment.
Pelvic MRI: Further characterizes pelvic organs (fibroids, complex masses).
Endometrial Evaluation: Required for malignancy risk factors (>45 years, obesity, unopposed estrogen). Endometrial biopsy or dilation and curettage (D&C).
Coagulopathy Testing: Consider in acute AUB or HMB since menarche, especially in adolescents. CBC, coagulation panel initially. Further testing for specific coagulopathies, iron panel, liver function tests.
Thyroid Evaluation: TSH level for thyroid disorders causing irregular bleeding. Prolactin, HbA1c as indicated.
Non-Uterine Causes: Pelvic exam, cervical cancer screening (if needed), STI testing (cervicitis), colposcopy/biopsy for suspicious lesions.

Caption: Pelvic ultrasound imaging, a crucial tool in evaluating the causes of vaginal bleeding, particularly structural uterine abnormalities.

Premenarchal Children

Testing based on history/exam: STI testing (abuse suspicion), endocrinopathies, coagulopathies, exam under anesthesia.

Postmenopausal Patients

Rule out malignancy. Endometrial cancer risk up to 14%.

Transvaginal Ultrasound (TVUS): First-line. Endometrial stripe ≤4 mm: low cancer risk. Endometrial stripe ≥5 mm: endometrial tissue sampling.
Endometrial Sampling: Alternative first-line test.
Cervical Cancer Testing: Cytology, biopsy of abnormal lesions.
Infection Testing: Consider STIs.

Treatment and Management

Management depends on the underlying etiology identified through the differential diagnosis of vaginal bleeding.

Initial Management of Acute Bleeding

Patient Stabilization (ABCs): Airway, Breathing, Circulation.
Vaginal Packing: To slow blood loss in severe bleeding.
Blood Transfusions: May be necessary.
Iron Supplementation: For iron deficiency anemia.

Acute, Heavy AUB in Nonpregnant Adolescents and Adults

Medical management is first-line: hormone therapy. Surgical management for specific indications.

Medical Options:

IV conjugated equine estrogen
Oral progestins
Combination oral contraceptive pills (OCPs)
Tranexamic acid

Coagulopathy Considerations: Hematology consultation. Desmopressin, recombinant factor VIII, von Willebrand factor, or factor-specific replacement if bleeding disorder-related. Avoid NSAIDs.

Surgical Options: For hemodynamic instability, uncontrolled bleeding, medical contraindications, or medical management failure.

Dilation and curettage (D&C) ± hysteroscopy
Endometrial ablation (completed childbearing)
Uterine artery embolization (UAE) (completed childbearing)
Hysterectomy (completed childbearing)
Uterine tamponade (balloon catheter/gauze) – temporary measure.

Long-term Management: Address underlying etiology to prevent recurrence. Medical/surgical treatments for chronic AUB. OCPs, LNG-IUD, elective surgery for fibroids/polyps. Malignancy treatment (surgery, chemo-, radiation therapies).

Mild Acute or Chronic AUB in Nonpregnant Adolescents and Adults

Management tailored to etiology.

Adenomyosis/COEIN Etiologies: Hormone therapy (OCPs, patch, ring), TXA during menses, LNG-IUD. Endometrial ablation, UAE, hysterectomy for definitive management (completed childbearing).
Chronic Endometritis: Doxycycline.
Polyps: Hysteroscopic removal.
Leiomyomas: Small fibroids: hormone therapy, TXA, LNG-IUD. Larger fibroids: UAE, myomectomy, hysterectomy. GnRH antagonists/agonists to shrink fibroids.
Malignancies: Management based on histology, stage, grade (surgery, chemotherapy, radiation, hormonal therapy).

Acute Non-Uterine Vaginal Bleeding

Treat underlying cause. Trauma: suturing. Infectious cervicitis: antimicrobials. Cervical dysplasia/malignancy: excision/radiation. Mesh erosion: topical vaginal estrogen.

Obstetric Bleeding

Ectopic Pregnancy: Methotrexate or surgical excision. Expectant management in select cases (low, declining hCG, close follow-up). hCG monitoring post-treatment.
Miscarriage: Expectant, medical (misoprostol), or surgical (uterine aspiration/D&C) management.
Late Pregnancy Bleeding: Emergent Cesarean delivery for severe placental abruption, uterine rupture. Management of smaller abruptions, previa, dilation based on gestational age, bleeding amount, membranes, contractions, fetal well-being. Corticosteroids for fetal lung maturity (<37 weeks). GBS prophylaxis.
Postpartum Hemorrhage: Uterotonics (oxytocin, methylergonovine, prostaglandin, misoprostol). Laceration repair. Bimanual uterine massage. Uterine tamponade (balloon/gauze). Surgical management (vascular ligation, uterine compression sutures, hysterectomy).
Rh D Immune Globulin: For Rh-negative patients after sensitizing events.
GTD: Uterine evacuation, chemotherapy for GTN. hCG monitoring. Hysterectomy consideration (completed childbearing).

Differential Diagnosis

A comprehensive differential diagnosis of vaginal bleeding is essential for accurate management.

Causes in Adolescents and Adults

Structural Uterine (“PALM”):

Polyps
Adenomyosis
Leiomyomas
Malignancy/Hyperplasia

Non-Structural Uterine (“COEIN”):

Coagulopathy
Ovulatory Dysfunction
Endometrial Dysfunction
Iatrogenic
Not Otherwise Classified

Vulvovaginal (Nonpregnant):

Trauma
Infection (condyloma acuminata)
Ulcers (herpes, Behçet’s)
Neoplasia
Atrophy
Erosion (foreign body, prolapse)
Vaginal Endometriosis

Cervical (Nonpregnant):

Infectious Cervicitis
Neoplasia
Polyps
Fibroids
Ectropion

Adnexal (Nonpregnant):

Neoplasia
Ruptured Hemorrhagic Cysts
Salpingitis

Obstetric:

Ectopic Pregnancy
Early Pregnancy Loss
Subchorionic Hematoma
GTD/GTN
Placental Abruption
Placenta Previa
Uterine Rupture
Cervical Dilation/Labor
Postpartum Atony
Retained Placenta
Obstetric Lacerations

Causes in Children

Vulvovaginitis (foreign bodies)
Trauma (accidental, abuse)
Urethral Prolapse
Estrogen-Secreting Tumors
Exogenous Estrogen Exposure
Neonatal Withdrawal Bleeding (first week of life)

Prognosis

Prognosis varies widely depending on the etiology. Benign causes have excellent prognoses. Severe bleeding, malignancy, and obstetric complications carry less favorable prognoses. Gestational age and bleeding severity impact neonatal prognosis in pregnancy.

Complications

Nonpregnant Patients:

Anemia
Acute Kidney Injury
Hemodynamic Instability
Transfusion Reactions
Surgical Complications (organ injury, infection, infertility)
Thromboembolic Events (high-dose hormone therapy)

Obstetric Complications:

Preterm Delivery
Cesarean Delivery
Postpartum Hemorrhage
Adverse Fetal/Neonatal Outcomes (prematurity, hypoxia)
Ruptured Ectopic Pregnancy: Hemorrhage, maternal death.

Consultations

Gynecologic Specialist: Heavy acute vaginal bleeding.
Hematologist: Coagulopathy.
Gynecologic Oncologist: Malignancy.
Obstetric Professional: Pregnant patients.
Pediatrician/Pediatric Gynecologist: Children.
Abuse Specialist: Suspected abuse in children.

Deterrence and Patient Education

Evaluate vaginal bleeding in childhood, pregnancy, postmenopause.
Condoms for STI prevention (cervicitis).
Regular cervical cancer screening.

Pearls and Other Issues

Acute uterine bleeding often medically managed (hormone therapy), surgery for severe cases.
Pregnancy test for all reproductive-age patients with acute vaginal bleeding.
Obstetric/trauma-related bleeding can be severe, leading to hemorrhagic shock.
Prioritize patient stabilization (ABCs) in severe bleeding.
Diagnoses not to miss: malignancy, ectopic pregnancy, uterine rupture, abruption, postpartum hemorrhage.
Postmenopausal bleeding: rule out malignancy.
Pregnancy bleeding: rule out ectopic pregnancy.
Postpartum hemorrhage “4 Ts”: Tone, Tissue, Trauma, Thrombin.
Current cervical cancer screening.

Enhancing Healthcare Team Outcomes

Interprofessional team (physicians, advanced practitioners, nurses, pharmacists) essential for patient-centered care. Collaboration for diagnosis, risk assessment, personalized treatment plans. Effective communication, shared information, coordinated care. Nursing critical in stabilization, triage, monitoring, outpatient coordination. Continuous training, interdisciplinary meetings improve team dynamics.

Health care professionals working as an interprofessional team enhance patient care, improve outcomes, prioritize safety, and optimize team performance in managing abnormal vaginal bleeding.

Review Questions

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References

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