False-Negative Pregnancy Test (Negative IPT) in a Pregnant Woman

1. Hook Effect (Most Clinically Important)

• When hCG levels are extremely high (typically >1,000,000 mIU/mL), the assay is overwhelmed
• Excess hCG saturates both the fixed solid-phase antibody and the labeled soluble antibody simultaneously, preventing sandwich complex formation - so no colored line appears
• Classically seen in:
  • Gestational trophoblastic disease (hydatidiform mole, choriocarcinoma) - this is the high-yield scenario
  • Multiple gestation pregnancy (twins/triplets can raise hCG enough to trigger hook effect)
• Fix: Dilute the urine sample 1:10 or 1:50 and repeat the test - a positive result will appear

• Tintinalli's Emergency Medicine, p. 736-739
• Tietz Textbook of Laboratory Medicine 7th Ed, p. 445-446

2. hCG Beta Core Fragment Interference

• After the 5th week of pregnancy, the predominant hCG variant in urine is the beta core fragment (hCGβcf), not intact hCG
• hCGβcf can bind one of the two anti-hCG antibodies in the sandwich assay, but because it lacks the other epitope, it blocks the intact hCG from forming a complete sandwich
• This leads to a false-negative result even at moderate-to-high concentrations
• This is more device-specific - affects some POC devices more than others

• Tietz Textbook of Laboratory Medicine 7th Ed, p. 445-446

3. Too Early in Pregnancy (Timing Error)

• Most IPT devices have a detection threshold of ~20-25 mIU/mL
• In the first days after implantation, hCG may be <20 mIU/mL
• At 1 week post-conception: only 5-50 mIU/mL
• Home tests are only 50-97% sensitive on the first day of missed period, rising to ~100% at 11 days after missed period
• Fix: Repeat the test in 48-72 hours

• Tintinalli's Emergency Medicine, p. 737
• Textbook of Family Medicine 9e, p. 814

4. Dilute Urine

• Particularly problematic when hCG is <50 mIU/mL (very early pregnancy)
• Low urine specific gravity (e.g., after high fluid intake) can bring hCG below the detection threshold
• Fix: Use first-morning urine (most concentrated), or send serum quantitative hCG

• Tintinalli's Emergency Medicine, p. 739

5. Drug Interference

• Phenothiazines (chlorpromazine, perphenazine, promethazine) can cause both false-positive and false-negative pregnancy test results
• Mechanism involves interference with the immunologic reagents

• Kaplan & Sadock's Comprehensive Textbook of Psychiatry

Summary Table

Key Management Point

1. Send quantitative serum beta-hCG - nearly 100% sensitive when threshold is ≥5 mIU/mL
2. Dilute the urine sample and repeat if hook effect is suspected (e.g., very high clinical suspicion + gestational trophoblastic disease signs)
3. Do a pelvic ultrasound - particularly important to rule out ectopic pregnancy even when the test is negative but clinical suspicion persists

False-Negative UPT in a Pregnant Woman

Causes

1. Hook Effect (High-Dose Hook Effect)

• hCG extremely elevated (>1,000,000 mIU/mL) saturates both antibodies in the lateral flow assay - no sandwich complex forms, no line appears
• Classic settings: hydatidiform mole, choriocarcinoma, multiple gestation
• Fix: Dilute urine 1:10 to 1:50 and repeat

2. Too Early in Pregnancy

• hCG <20-25 mIU/mL (below detection threshold of most UPT strips)
• At <1 week post-conception, hCG is only 5-50 mIU/mL
• Home UPTs are only 50-97% sensitive on day 1 of missed period
• Fix: Repeat in 48-72 hours using first-morning urine

3. Dilute Urine

• High fluid intake lowers urine hCG concentration below the detection threshold
• More significant when hCG is already low (very early pregnancy)
• Fix: Use first-morning urine (most concentrated)

4. hCG Beta Core Fragment Interference

• After 5th week, beta core fragment dominates urine hCG - it blocks one antibody arm of the assay, preventing intact hCG from forming a positive signal
• Device-specific; affects some POC/strip UPTs more than others
• Fix: Serum quantitative beta-hCG

5. Drug Interference

• Phenothiazines (promethazine, chlorpromazine, perphenazine) can cause false-negative results
• Fix: Serum quantitative beta-hCG

What To Do When UPT is Negative But Pregnancy Suspected

Prozone Phenomenon

Definition

Immunological Basis - The Precipitin Curve

• Tietz Textbook of Laboratory Medicine 7th Ed, p. 3513-3520

Classical Clinical Example: Syphilis Serology

• In secondary syphilis, antibody titers can become so high that the test is paradoxically negative
• This is why secondary syphilis is sometimes called "the great imitator" - the rash appears, but the VDRL/RPR is negative
• The prozone phenomenon occurs more frequently in HIV co-infected patients (immune dysregulation causes massively elevated antibody levels)

Many laboratories do NOT routinely check for the prozone phenomenon, so clinicians must specifically request it in the appropriate setting (e.g., a patient with a suspicious rash and a negative nontreponemal test).

• Fitzpatrick's Dermatology, p. 1979; Red Book 2021, p. 131

Other Clinical Settings Where Prozone Occurs

Prozone vs. Hook Effect

Key Points for Exams

1. Prozone = antibody excess = false negative in precipitation assays
2. Classic setting: secondary syphilis with high VDRL/RPR titers - especially with HIV co-infection
3. Fix = dilute the serum and repeat
4. Equivalent in sandwich immunoassays = hook effect (antigen excess)
5. Clinicians must specifically request dilution studies - labs do not routinely perform them

Mirena (Levonorgestrel Intrauterine System / LNG-IUS)

Basic Profile

• Berek & Novak's Gynecology, p. 203; Textbook of Family Medicine 9e, p. 691

Mechanism of Action (Triple Action)

1. Thickened, scant cervical mucus - impedes sperm penetration
2. Endometrial atrophy - profound progestogenic effect makes endometrium hostile to implantation
3. Local intrauterine inflammatory response - impairs sperm motility and function

• Berek & Novak's Gynecology, p. 202-203

Contraceptive Efficacy

• Failure rate: <0.2 per 100 woman-years (among the most effective methods available)
• Total pregnancies over 7 years: only 1.1 per 100 women
• Comparable to tubal sterilization but fully reversible

Non-Contraceptive / Therapeutic Uses

• Berek & Novak's Gynecology, p. 222-226

Contraindications

• Current or suspected pregnancy
• Abnormal uterine cavity (distorting fibroids, congenital anomaly)
• Active or recurrent PID / endometritis
• Known or suspected endometrial/cervical malignancy
• Unexplained genital bleeding
• Allergy to IUD components

• Breastfeeding/lactation
• History of VTE
• Smokers
• Women at increased cardiovascular risk

Risks and Complications

1. Infection (PID)

• Risk is elevated only in the first 20 days after insertion (insertion-related)
• After that, rate returns to baseline (~1.6 per 1,000 women/year) - the same as the general population
• The major risk factor is STI exposure, not the IUD itself
• Actinomycosis is the one pelvic infection unequivocally linked to IUD use
• If PID develops: treat with antibiotics; remove only if no improvement after 72 hours

2. Ectopic Pregnancy

• IUD prevents most pregnancies, so overall ectopic rate is very low (0.02 per 100 woman-years)
• BUT: if pregnancy occurs despite an IUD, the proportion that are ectopic is higher
• Always rule out ectopic if a Mirena user presents with pelvic pain + positive beta-hCG

3. Expulsion

• Occurs in ~2-10% of users, more common in the first year
• Higher risk in women with heavy periods or younger age

4. Perforation

• Rate: 0.6-1.6 per 1,000 insertions
• Higher risk in the 6-8 weeks postpartum (so postpartum placement is delayed)

5. Menstrual Changes

• Irregular spotting common in the first 3-6 months
• Amenorrhea or oligomenorrhea develops in 20-50% by 1 year (from endometrial atrophy) - this is expected and benign, not a sign of pregnancy

Fertility After Removal

• Contraceptive effects reverse promptly after removal
• 1-year pregnancy rate after removal: 89 per 100 women under age 30 - equivalent to women who used no contraception
• No evidence of tubal factor infertility from LNG-IUD itself (only from STI exposure)

• Berek & Novak's Gynecology, p. 252

Key Summary Points

• Mirena is one of the most effective reversible contraceptives available (failure rate <0.2%)
• Works mainly via local cervical/endometrial effects - not primarily by blocking ovulation
• Major therapeutic value for heavy menstrual bleeding, endometriosis, adenomyosis, and endometrial protection
• PID risk is insertion-related only (first 20 days); thereafter no increased risk
• Amenorrhea with Mirena = expected effect, not a pathological finding
• If pregnancy occurs while on Mirena - always exclude ectopic

Medical Management of Uterine Fibroids (Leiomyomas)

When to Treat (Indications)

• Heavy menstrual bleeding (HMB) / menorrhagia
• Pelvic pressure/bulk symptoms
• Pre-operative downsizing before myomectomy or hysterectomy
• Treating anaemia before surgery
• Women approaching menopause (bridging therapy - fibroids regress after menopause)

• Berek & Novak's Gynecology, p. 4695-4697

Medical Therapy Options

1. GnRH Agonists (e.g. Leuprolide, Goserelin, Nafarelin)

2. GnRH Antagonists (e.g. Elagolix, Relugolix, Linzagolix)

• Faster onset of action than agonists (no initial stimulatory "flare" phase)
• Elagolix (Oriahnn) - FDA approved specifically for heavy menstrual bleeding due to fibroids
• Relugolix combination tablet - approved for fibroids with add-back oestrogen/progestin
• Dose-dependent amenorrhoea and fibroid volume reduction
• Used with add-back therapy for longer-term use

3. Progestin-Releasing IUD (LNG-IUS / Mirena)

• Reduces HMB by up to 90%
• Does not shrink fibroids or reduce bulk
• Most effective for controlling bleeding when cavity is not significantly distorted
• May be less effective with submucosal or distorting fibroids
• Also treats dysmenorrhoea and offers contraception

4. Selective Progesterone Receptor Modulators (SPRMs)

• UPA (Esmya) was approved in Europe for intermittent long-term use but faced regulatory restrictions due to rare hepatotoxicity cases (European Medicines Agency review 2020)
• Unlike GnRH agonists, SPRMs cause PAEC (progesterone receptor modulator-associated endometrial changes) - a benign, reversible histological change that must not be confused with endometrial hyperplasia

5. Combined Oral Contraceptives (COCPs)

• Control HMB and dysmenorrhoea effectively
• Do not shrink fibroids and do not consistently reduce fibroid growth
• No definitive relationship between OCP use and fibroid development or growth
• Useful for symptom control in women who also need contraception
• Avoid if large fibroids with pressure symptoms

6. Progestin-Only Pills / Depot Medroxyprogesterone Acetate (DMPA)

• Reduce HMB by inducing endometrial atrophy
• Do not reliably shrink fibroids
• DMPA (Depo-Provera) causes amenorrhoea in many users

7. Tranexamic Acid

• Antifibrinolytic - inhibits plasminogen activation in the endometrium
• Reduces HMB by ~40-50% per cycle
• Taken only during menstruation (not continuous)
• No effect on fibroid size
• Non-hormonal option - suitable for women wanting to conceive

8. NSAIDs (e.g. Mefenamic Acid, Ibuprofen)

• Reduce HMB by ~20-35% via prostaglandin inhibition
• Good for dysmenorrhoea associated with fibroids
• Weakest effect on bleeding among the medical options
• Non-hormonal; safe and well tolerated

9. Iron Supplementation

• Not directly treating the fibroid but essential for managing iron-deficiency anaemia from chronic HMB
• Often used in combination with any of the above before surgery

Summary Comparison Table

Key Points

1. GnRH agonists are the most potent pre-operative medical therapy - used to shrink fibroids, correct anaemia, and reduce surgical complexity; not a long-term solution
2. GnRH antagonists (elagolix, relugolix) are the newer oral agents approved specifically for fibroid-related HMB with add-back therapy
3. LNG-IUS is best for controlling HMB without shrinking fibroids - highly effective when cavity is not distorted
4. SPRMs offer fibroid volume reduction with amenorrhoea but are limited by hepatotoxicity concerns
5. None of the medical treatments permanently cure fibroids - all are either temporizing or symptom-controlling measures
6. Watchful waiting is appropriate for mildly symptomatic women, especially those approaching menopause

• Berek & Novak's Gynecology, pp. 4632-4634, 4695-4715

Adenomyosis

Definition

• Can be diffuse (throughout the myometrium) or focal (adenomyoma - a discrete mass)
• Often coexists with endometriosis and uterine fibroids

• Robbins & Kumar Basic Pathology, p. 548; Sabiston Textbook of Surgery, p. 2982

Epidemiology

• Prevalence: Extremely variable (1-70% depending on diagnostic criteria used) - historically underdiagnosed because it required histology at hysterectomy
• Found in ~30% of women of reproductive age; increases with age toward menopause
• More common in multiparous women than nulliparous
• Predominantly affects women in their 4th and 5th decades

Pathogenesis

• Invagination/downward invasion - endometrial epithelium invades the endomyometrial junction and penetrates into myometrium
• Molecular interaction between displaced endometrial cells and adjacent myometrial cells causes hypertrophy and inflammation
• Shares pathophysiology with endometriosis
• The junctional zone (JZ) is the target tissue - disruption of the JZ by uterine instrumentation, surgery, or repeated trauma may facilitate invasion

Risk Factors

• Bailey & Love's Short Practice of Surgery 28th Ed, p. 2624-2635

Clinical Features

Symptoms (the classic triad)

1. Menorrhagia / heavy menstrual bleeding (AUB) - most common
2. Dysmenorrhoea - secondary, colicky, worsening premenstrually
3. Chronic pelvic pain / dyspareunia

Signs

• Enlarged, globular, tender uterus - symmetrically enlarged (unlike fibroids which cause irregular enlargement)
• Uterine tenderness on bimanual examination, especially premenstrually
• Abnormalities at hysteroscopy: irregular endometrium, cystic haemorrhagic lesions, altered vascularisation

Diagnosis

1. Transvaginal Ultrasound (TVUS)

• Accuracy: 68-86% for diffuse adenomyosis
• Typical features (MUSA criteria - ≥3 features usually required):
  • Enlarged globular uterus with asymmetric wall thickening
  • Myometrial cysts (2-6 mm subendometrial cysts) - present in 50%
  • Echogenic subendometrial linear striations
  • Hyperechogenic islands within myometrium
  • Fan-shaped shadowing
  • Poor definition of the endomyometrial interface
  • "Rain shower" appearance - multiple fine areas of attenuation
  • Speckled pattern on colour Doppler

2. MRI (Most Accurate Non-Invasive Tool)

• Junctional zone (JZ) thickening - the key diagnostic criterion:
  • JZ ≥12 mm → high accuracy for adenomyosis
  • JZ ≤8 mm → excludes adenomyosis
  • JZ 8-12 mm → indeterminate (need ancillary criteria)
• Ill-defined low-signal intensity areas within myometrium (smooth muscle hyperplasia)
• High T2 signal foci within low-signal myometrium = ectopic endometrial islands
• High T1 signal foci (punctate haemorrhage within ectopic tissue) - 95% PPV for adenomyosis
• High T2 linear striations (finger-like projections from endometrium into myometrium)
• Rare: cystic adenomyosis (extensive haemorrhage)

3. Histology (Gold Standard)

• Nests of endometrial glands and stroma deep in the myometrium, interposed between muscle bundles
• Traditionally required hysterectomy specimen - limits pre-operative diagnosis
• Not feasible in women wishing to preserve fertility

Adenomyosis vs. Fibroids - Key Differences

Management

Medical (First-Line for Symptom Control)

Radiological / Minimally Invasive

• Uterine Artery Embolisation (UAE) - reduces blood supply to adenomyotic tissue; symptoms recur in some; post-embolisation syndrome (fever, pain, nausea) is common SE; concerns about ovarian reserve
• High-Intensity Focused Ultrasound (HIFU) / MR-guided Focused Ultrasound (MRgFUS) - non-invasive thermal ablation of adenomyotic tissue; SE include abdominal pain, skin burns, rare sciatic nerve injury

Surgical (Uterus-Preserving)

• Non-excisional: thermal coagulation of diseased myometrium
• Partial reductive surgery: wedge resections, H-incisions (for diffuse disease)
• Complete adenomyotic excision: double/triple-flap method, asymmetric dissection (for focal adenomyoma)
• Endometrial ablation/resection - for HMB without fertility wish; works best for superficial disease
• Risk: uterine rupture ~6% after adenomyomectomy (cf. 0.26% after myomectomy)

Surgical (Definitive)

• Total hysterectomy - only definitive cure
• Preferred over subtotal as adenomyosis can recur in the cervical stump and rectovaginal septum
• Reserved for women who have failed medical management and do not desire future fertility

Key Points

1. Adenomyosis = endometrial tissue within the myometrium (vs. endometriosis = outside the uterus)
2. Classic presentation: globular tender uterus + menorrhagia + secondary dysmenorrhoea in a multiparous woman in her 40s
3. MRI is the best imaging - JZ ≥12 mm is diagnostic; T1 bright foci (haemorrhage) have 95% PPV
4. LNG-IUS (Mirena) is the first-choice medical treatment - up to 90% reduction in HMB
5. Hysterectomy is the only definitive cure
6. Commonly coexists with endometriosis and fibroids - always look for both
7. Regresses after menopause (oestrogen-dependent)

• Bailey & Love's 28th Ed, pp. 2587-2706; Robbins Basic Pathology p. 548-550; Grainger & Allison's Radiology pp. 987-1013; Sabiston Surgery p. 2982-2984