Intermenstrual bleeding

Intermenstrual bleeding is vaginal bleeding between regular menstrual periods. It is usually caused by hormonal contraception, cervical ectropion, polyps or ovulation, but it can signal pregnancy complications, infection, endometrial hyperplasia or cancer, and cervical cancer.

Physiology. A mid cycle fall in oestradiol around ovulation can cause light spotting for 1 to 2 days in some women. Hormonal contraception and an intrauterine device cause breakthrough bleeding through endometrial fragility and local changes.

Classification. By cause: structural (polyp, adenomyosis, leiomyoma, malignancy and hyperplasia) or non structural (coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic causes, and others). By pattern: ovulatory spotting, premenstrual or postmenstrual spotting, and random bleeding. By age: adolescent, reproductive, perimenopausal.

Key distinctions. Spotting at the same point each cycle suggests ovulation. Bleeding that begins after changing or starting contraception suggests breakthrough bleeding. Bleeding with postcoital bleeding suggests a cervical cause. Persistent bleeding in a woman over 45, or with risk factors, needs endometrial assessment.

History

• Pattern: day of cycle, duration, volume, relation to intercourse, pain, discharge, regularity of main periods.
• Contraception: type, missed pills, vomiting or diarrhoea, new interacting drugs, recent change, intrauterine device insertion date.
• Pregnancy: last menstrual period, possible conception, early pregnancy symptoms, recent miscarriage or termination.
• Drug interactions: enzyme inducers that lower oestrogen and progestogen levels (rifampicin, carbamazepine, phenytoin, phenobarbital, topiramate, efavirenz, St John's wort).
• Other drugs: tamoxifen, anticoagulants, antiplatelet drugs, antipsychotics, SSRIs, herbal products.
• Risk factors for endometrial neoplasia: obesity, polycystic ovary syndrome, diabetes, nulliparity, tamoxifen, Lynch syndrome, family history.
• Infection risk and cervical screening history.
• Symptoms of thyroid disease, hyperprolactinaemia, bleeding disorders (heavy bleeding since menarche, easy bruising, bleeding after dental work), and hirsutism.
• Weight, exercise, stress, and eating disorder.

Examination

• Vital signs, BMI, pallor, thyroid, hirsutism, galactorrhoea, bruising.
• Abdomen for masses or tenderness.
• Speculum: cervix (ectropion, polyp, lesion, friability), vagina, intrauterine device threads, blood source.
• Bimanual: uterine size, tenderness, mobility, adnexal mass.

Red flags

• Positive pregnancy test with pain or shock (ectopic pregnancy).
• New persistent bleeding in a woman over 45, or over 3 months in a woman with risk factors.
• Visible cervical lesion or postcoital bleeding.
• Pelvic mass or ascites.
• Heavy bleeding with haemodynamic change.
• Unexplained iron deficiency anaemia.
• Tamoxifen use with abnormal bleeding.

Special groups. Adolescents: anovulation is common in the first years after menarche, but a bleeding disorder and pregnancy must be considered. Perimenopause: cycle variability is common, but persistent bleeding needs endometrial assessment. Pregnancy: bleeding is never normal until proven otherwise.

Organised by structural and functional mechanisms.

Physiological and hormonal

• Ovulation bleeding.
• Hormonal contraception breakthrough bleeding (combined, progestogen only, implant, depot medroxyprogesterone acetate).
• Intrauterine device or levonorgestrel system bleeding.
• Drug interactions reducing contraceptive efficacy.
• Perimenopausal anovulation.
• Thyroid disease and hyperprolactinaemia.
• Polycystic ovary syndrome.

Pregnancy related. Implantation bleeding, miscarriage, ectopic pregnancy, gestational trophoblastic disease, retained products of conception.

Cervical and vaginal

• Cervical ectropion, cervical polyp, cervicitis (chlamydia, gonorrhoea, Mycoplasma genitalium, trichomoniasis, herpes simplex virus).
• Serious: cervical cancer, vaginal cancer.
• Atrophic vaginitis, vaginal trauma, foreign body.

Uterine

• Endometrial polyp, submucous fibroid, adenomyosis.
• Chronic endometritis and pelvic inflammatory disease.
• Caesarean scar defect (isthmocele) with postmenstrual spotting.
• Arteriovenous malformation.
• Serious: endometrial hyperplasia, endometrial cancer, uterine sarcoma.

Ovarian. Oestrogen secreting ovarian tumours (granulosa cell tumour), functional cysts.

Systemic. Coagulopathy (von Willebrand disease, platelet disorders), liver disease, anticoagulant use.

Non genital sources. Urethral caruncle, bladder lesions, rectal and anal bleeding.

Stepwise reasoning

1. Exclude pregnancy first.
2. Assess adherence, interacting drugs and contraceptive type.
3. Examine the cervix and test for infection.
4. Image the uterus and decide on endometrial sampling.
5. Investigate persistent bleeding despite treatment with hysteroscopy.

Tests

• Urine pregnancy test; serum beta hCG if ectopic pregnancy or trophoblastic disease is possible.
• Nucleic acid amplification tests for chlamydia, gonorrhoea, Trichomonas vaginalis and Mycoplasma genitalium. Vaginal swab for pH and microscopy.
• Full blood count and ferritin.
• Thyroid stimulating hormone; prolactin if oligomenorrhoea, galactorrhoea or headache.
• Coagulation screen, von Willebrand factor antigen and activity, and factor VIII when history suggests a bleeding disorder.
• Cervical screening if due; colposcopy for a suspicious cervix.
• Transvaginal ultrasound: endometrial thickness, polyps, fibroids, adenomyosis, scar defect, ovarian masses.
• Endometrial biopsy for age 45 or over with persistent bleeding, and for younger women with risk factors, failed treatment or thickened endometrium. A pipelle sample is highly sensitive for endometrial cancer when the whole cavity is abnormal, and misses focal lesions such as polyps.
• Saline infusion sonography or hysteroscopy with directed biopsy for persistent bleeding with normal first line tests.
• MRI pelvis for suspected adenomyosis, fibroids or tumour staging.

Limitations. Ultrasound endometrial thickness thresholds apply mainly to postmenopausal women. Endometrial biopsy can be non diagnostic. Normal investigations are frequent in women with contraceptive related bleeding.

Immediate steps. Refer suspected ectopic pregnancy the same day. Resuscitate heavy bleeding. Treat infection found.

Hormonal contraception breakthrough bleeding

• Check adherence, missed pills, vomiting, and interacting drugs; use a longer or alternative method when an enzyme inducer cannot be stopped (copper intrauterine device, depot medroxyprogesterone acetate, levonorgestrel intrauterine system).
• Combined pill: continue taking it for 3 months because bleeding often settles. If bleeding persists, change to a pill with higher ethinylestradiol (30 to 35 microgram) or a different progestogen. Smoking increases bleeding.
• Depot medroxyprogesterone acetate or progestogen implant: tranexamic acid 1 g orally three times daily for up to 4 days from onset (maximum 4 g daily; reduce for renal impairment: serum creatinine 120 to 249 micromol/L, 1 g twice daily; 250 to 500 micromol/L, 1 g once daily), or mefenamic acid 500 mg orally three times daily with food for up to 5 days (maximum 1.5 g daily; avoid in peptic ulcer, renal impairment and NSAID sensitive asthma). A combined pill taken for 3 months is an option when oestrogen is not contraindicated; evidence is limited.
• Levonorgestrel intrauterine system or copper device: reassure that spotting is common in the first 3 to 6 months; check threads and position; exclude infection.

Cause specific treatment

• Chlamydia: doxycycline 100 mg orally twice daily for 7 days (azithromycin 1 g orally once in pregnancy). Gonorrhoea: ceftriaxone 1 g intramuscularly once.
• Cervical ectropion or polyp: review contraception; polyp removal with histology; cautery for persistent troublesome bleeding.
• Endometrial polyp or submucous fibroid: hysteroscopic removal.
• Hyperplasia without atypia: levonorgestrel 52 mg intrauterine system, with biopsy at 6 months; hyperplasia with atypia or cancer: hysterectomy under specialist care.
• Hypothyroidism: levothyroxine 1.6 microgram/kg daily to start (25 to 50 microgram daily in older adults or heart disease), with TSH at 6 to 8 weeks. Hyperprolactinaemia: cabergoline 0.25 mg orally twice weekly, titrated under specialist care.
• Ovulation bleeding: reassure; a combined pill suppresses ovulation if bothersome.
• Bleeding disorder: tranexamic acid and haematology review.
• Endometritis: ceftriaxone 1 g intramuscularly once, doxycycline 100 mg orally twice daily for 14 days and metronidazole 400 mg orally twice daily for 14 days.

Monitoring. Review at 3 months. Repeat the pregnancy test when bleeding changes. Check haemoglobin if bleeding is heavy or prolonged. Follow tamoxifen users yearly.

Referral and escalation. Refer urgently within 2 weeks for suspected cancer. Refer to gynaecology for persistent bleeding over 3 months, abnormal ultrasound, failed treatment, or a woman over 45 with new bleeding. Refer to haematology for suspected bleeding disorder. Refer to endocrinology for hyperprolactinaemia or thyroid disease.

Admission criteria. Ectopic pregnancy, heavy bleeding with instability, and sepsis.

Discharge and follow up. Most women are outpatients. Provide a bleeding diary and review.

Safety netting. Return for heavy bleeding, pain, fever, a positive pregnancy test, or no improvement within 3 months.