Pruritus in Third Trimester of Pregnancy with Normal LFTs

Diagnostic Algorithm

Overview

• No primary lesions (only excoriations from scratching) → Think Intrahepatic Cholestasis of Pregnancy (ICP), but...
• With primary skin lesions in the third trimester → Consider PEP/PUPPP, Gestational Pemphigoid, or AEP

The Critical Point: Normal LFTs Does NOT Rule Out ICP

"Pruritus can precede abnormal findings of liver function tests or total serum bile acids, and follow-up testing for obstetric cholestasis may be needed for itchy pregnant patients with initially normal findings."

• Creasy & Resnik's Maternal-Fetal Medicine, p. 1716

"Cholestatic itching correlates better with elevated serum bile acid levels than with the results of other biochemical liver function tests such as alkaline phosphatase, AST, ALT, and bilirubin."

• Creasy & Resnik's Maternal-Fetal Medicine, p. 1716

Differential Diagnosis: Pruritic Conditions in Third Trimester

1. Intrahepatic Cholestasis of Pregnancy (ICP)

• Occurs in 1.5-2% of pregnant women
• Presents with generalized pruritus without rash, worse on palms and soles, worse at night
• Jaundice in only 0.02% of pregnancies
• Key diagnostic test: fasting serum bile acids (>10 µmol/L = ICP; >40 µmol/L = severe ICP with higher fetal risk)
• LFTs lag behind bile acid elevation - always order bile acids even with normal LFTs
• Resolves within 2 weeks of delivery; recurs in ~50% of subsequent pregnancies
• Treatment: Ursodeoxycholic acid (UDCA) - reduces pruritus and improves fetal outcomes
• Creasy & Resnik's Maternal-Fetal Medicine, p. 1716

2. Polymorphic Eruption of Pregnancy (PEP / PUPPP)

• Most common pregnancy rash
• Onset in 3rd trimester, begins in abdominal striae
• Erythematous urticarial papules and plaques; umbilicus typically spared
• Spreads to thighs, buttocks, proximal arms; face spared
• Associated with: primigravida, multiple gestation, increased weight gain
• All labs normal (DIF, H&E, LFTs all nonspecific)
• No fetal risk
• Does NOT recur in subsequent pregnancies (unlike ICP)
• Treatment: Topical corticosteroids + antihistamines; oral steroids for severe cases
• Creasy & Resnik's Maternal-Fetal Medicine, p. 1717

3. Gestational Pemphigoid (Pemphigoid Gestationis)

• Rare autoimmune blistering disorder
• Periumbilical involvement - vesiculobullous + urticarial eruption
• DIF: linear C3 deposition along the dermal-epidermal junction (diagnostic)
• Associated with small-for-dates babies and prematurity
• Treatment: Corticosteroids + antihistamines

4. Atopic Eruption of Pregnancy (AEP)

• Typically presents before the third trimester (75% < 3rd trimester)
• 80% are first occurrence of atopic disease; 20% are flares of pre-existing atopic dermatitis
• Trunk and extremities involved
• ± elevated IgE; no fetal risk
• Treatment: Corticosteroids + antihistamines + UVB

5. Benign Pruritus Gravidarum

• Generalized itching without cholestasis, without rash
• Associated with: twin pregnancy, fertility treatments, diabetes, nulliparity
• Up to 14% of pregnant women experience itching; most is benign
• No adverse perinatal outcomes when there is no cholestasis
• Treatment: emollients, topical antipruritics, oral antihistamines, UV light

Clinical Approach with Normal LFTs

Normal LFTs + Pruritus in 3rd trimester
          ↓
Check SERUM BILE ACIDS (fasting)
          ↓
├── Bile acids >10 µmol/L → ICP → UDCA + fetal monitoring
│   (LFTs may normalize or lag - bile acids are the gold standard)
│
└── Bile acids normal → Does patient have primary skin lesions?
         ├── Urticarial papules in striae, umbilicus spared → PEP/PUPPP
         ├── Vesiculobullous, periumbilical → Gestational Pemphigoid (DIF)
         ├── Eczematous, trunk+limbs, early onset → AEP
         └── No lesions, no bile acid elevation → Benign Pruritus Gravidarum

Key Takeaways

1. Normal LFTs do not exclude ICP - serum bile acids must always be checked separately
2. ICP = pruritus without primary skin lesions - excoriations are secondary
3. PEP/PUPPP is the most common rash in 3rd trimester and is benign
4. ICP carries real fetal risk (prematurity, fetal distress, stillbirth) - must not be missed
5. If initial bile acids are normal but suspicion remains high, repeat testing as levels can fluctuate
6. Serum glutathione S-transferase-α is a specific marker distinguishing ICP from benign pruritus gravidarum

Hypertensive Emergency vs. Hypertensive Urgency

Diagnostic Algorithm

Core Definition - The Fundamental Distinction

"A hypertensive emergency is defined by the presence of target-organ damage (TOD), NOT by the degree of BP elevation."

• Symptom to Diagnosis: An Evidence-Based Guide, 4e

Side-by-Side Comparison

Organs at Risk in Hypertensive Emergency

Hypertensive Encephalopathy - A Key Emergency to Know

• Severe BP elevation + obtundation, visual disturbances, altered sensorium, seizures
• Marked hypertensive retinopathy ± papilledema
• Absence of focal neurologic findings (if focal findings present, think stroke)
• A subset have posterior reversible leukoencephalopathy syndrome (PRES) - symmetrical vasogenic edema in occipital regions on MRI
• Goldman-Cecil Medicine, p. 759

Important Clinical Pearl: BP Level ≠ Emergency

Common Causes of Both

• Medication nonadherence (most common)
• Abrupt cessation of clonidine or beta-blockers (rebound hypertension)
• CKD / renovascular disease
• Sympathomimetic drugs (cocaine, PCP, methamphetamine)
• Eclampsia
• Postoperative state
• Pheochromocytoma, Cushing syndrome (less common)

Treatment

Hypertensive Urgency

• Restart stopped medications or switch to longer-acting agents
• Start oral antihypertensives in treatment-naive patients
• Schedule prompt follow-up within 3-10 days
• Avoid rapid BP reduction - risk of precipitating ischemia
• Do NOT routinely transfer to ED or hospitalize

Hypertensive Emergency

• For most emergencies (not requiring rapid correction): reduce MAP by ≤20-25% in the first 1-2 hours, then gradually normalize over 24-48 hours
• For select emergencies requiring immediate reduction (ACS, aortic dissection, cardiogenic pulmonary edema): faster, more aggressive targets

IV Drug Class Summary (Lippincott Pharmacology)

• Calcium channel blockers: Nicardipine, Clevidipine (titratable, predictable)
• Nitric oxide vasodilators: Nitroprusside (rapid, short-acting; cyanide toxicity risk), Nitroglycerin (preferred in ACS/pulmonary edema)
• Adrenergic antagonists: Labetalol (α+β blocker, workhorse agent), Esmolol (β1-selective, very short-acting - ideal for aortic dissection), Phentolamine (for pheochromocytoma)
• Vasodilator: Hydralazine (arteriolar; used in pregnancy)
• Dopamine agonist: Fenoldopam (renal-protective, useful in AKI)

Key Exam Points

1. Emergency = TOD present → IV drug, ICU admission
2. Urgency = no TOD → oral drug, outpatient follow-up
3. Aortic dissection: needs both HR and BP control simultaneously - beta-blocker first, then vasodilator; target HR <60 and sBP <120
4. Acute ischemic stroke: avoid over-lowering BP (disrupts autoregulation in ischemic penumbra); only treat if >220/120 or if giving thrombolytics (>185/110)
5. Eclampsia: MgSO4 is for seizure prophylaxis/treatment - NOT an antihypertensive; add labetalol or nicardipine for BP control
6. DO NOT use nitroprusside in pregnancy (fetal cyanide toxicity)
7. The term "malignant hypertension" (older term) = accelerated hypertension with papilledema + retinopathy - now classified under hypertensive emergency

BRCA1/2 Negative with Family History of Breast Cancer - What Does It Mean?

The Most Important Message First

A negative BRCA1/2 test in an unaffected person with family history does NOT mean she is at average population risk.

Understanding the Test Result

Three Possible Outcomes of BRCA Testing

Why Negative ≠ "Normal" in Her Case

Scenario A: No Affected Family Member Was Tested First (Her Case - Most Likely)

"In a family with a history suggestive of hereditary breast cancer and no previously tested member, the most informative strategy is first to test an affected family member."

• Schwartz's Principles of Surgery 11e

• We don't know what mutation the family carries
• Her negative test cannot be compared to a known family mutation
• She may still carry a mutation not yet identified, or the family cancer may be due to a different gene entirely
• Her risk reduction CANNOT be confirmed

Scenario B: If an Affected Relative Was Tested and Found Positive, THEN She Was Tested

• A negative result = "true negative" - she has NOT inherited that specific mutation
• Her risk reverts toward population risk for that specific gene
• BUT she still has elevated risk from other genes and shared environmental/lifestyle factors

Why BRCA Negative Doesn't Equal No Risk

BRCA1/2 explain only a fraction of hereditary breast cancer

"Hereditary breast cancer (HBC) accounts for only 5-10% of all breast cancers. Familial breast cancer (FBC) - affecting several members of a family but NOT attributable to any known mutation - accounts for 20-30%."

• Bailey & Love's Surgery 28e

Women who tested negative for BRCA before 2014 are being offered repeat testing with contemporary panels because many additional genes have since been identified.

• Current Surgical Therapy 14e

What Should Be Done Now

Step 1: Clarify Who Was Tested in the Family

• Was the mother or grandmother (affected members) tested for BRCA?
• If not, the most informative next step is to test the affected family member first
• If the mother's mutation is identified and your colleague tests negative for that specific mutation = true reassurance
• If no affected member is available to test, your colleague's negative test is uninformative

Step 2: Expand the Genetic Panel

• BRCA1, BRCA2, CHEK2, PALB2, ATM, CDH1, PTEN, TP53
• Some centers test 77+ genes
• Current Surgical Therapy 14e

Step 3: Risk Assessment with a Validated Model

• BOADICEA (most accurate for family history)
• IBIS (Tyrer-Cuzick) model
• Gail model (less accurate for strong family history)

Step 4: Refer to Genetic Counselor

"Genetic testing should not be offered in isolation, but only in conjunction with patient education and counseling, including referral to a genetic counselor."

• Schwartz's Principles of Surgery 11e

Indications for Genetic Risk Evaluation in Her Family Situation

• Breast cancer at any age with two or more affected relatives - her mother AND grandmother qualify

Surveillance Recommendations for Her (Regardless of BRCA Result)

"Annual MRI screening as an adjunct to annual screening mammography is recommended beginning at age 30 for females at high lifetime risk."

• Sabiston Textbook of Surgery

Risk-Reduction Options if She Is High-Risk

Summary: What to Tell Your Colleague

1. Her BRCA1/2 negative result is NOT reassuring by itself - it is likely uninformative because no affected family member was tested first
2. She needs:
   • Expanded multi-gene panel testing (not just BRCA1/2)
   • Ideally, testing of her mother (affected) first, then comparison
   • Formal genetic counseling with 3-generation pedigree
   • Risk model calculation (BOADICEA/IBIS)
3. If lifetime risk ≥20-25%: annual mammogram + annual MRI starting from age 30 (or earlier based on youngest age of cancer in family)
4. Familial breast cancer (without identifiable mutation) still carries elevated risk and needs surveillance
5. She does NOT need prophylactic mastectomy unless a confirmed pathogenic mutation is found

Labetalol - Complete Dosage Reference

Mechanism

• Oral: α₁:β blocking ratio = 1:3
• IV: β-blocking potency is more prominent
• Net effect: reduces heart rate, cardiac output, and peripheral vascular resistance

I. INTRAVENOUS DOSAGE - Hypertensive Emergency

A. Intermittent IV Bolus Method

"20 mg IV, followed by doubled doses up to 80 mg (20→40→80) every 10 min; maximum total dose 220 mg"

• Tintinalli's Emergency Medicine

B. Continuous IV Infusion Method

"Labetalol 20-80 mg bolus every 10 minutes up to maximum dose of 300 mg, or 0.5-2 mg/min infusion"

• Plum & Posner's Diagnosis and Treatment of Stupor and Coma

"10 mg IV over 1-2 min, may repeat once; IV infusion 2-8 mg/min"

• Comprehensive Clinical Nephrology 7e (for stroke-associated hypertension)

C. Onset and Duration (IV)

• Onset: 2-5 minutes
• Peak: 5-15 minutes
• Duration: 3-6 hours

II. ORAL DOSAGE - Chronic Hypertension

"The usual initial dosages for treatment of hypertension are 100 mg orally twice daily, increasing gradually to a maintenance dosage of 200-400 mg twice or thrice daily."

• Brenner and Rector's The Kidney 2-Volume Set

III. Special Clinical Situations

IV. Pharmacokinetics

V. Contraindications

• Sinus bradycardia / heart block (>1st degree)
• Decompensated heart failure
• Severe bronchospasm / reactive airway disease (blocks β₂)
• Cardiogenic shock
• Note: In stroke with raised ICP, labetalol is preferred over nitroprusside because it does not increase ICP and does not lower cerebral blood flow - Comprehensive Clinical Nephrology 7e

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