13.3 Thyroid Disease & Venous Thromboembolism in Pregnancy

1. Thyroid Disease in Pregnancy

Gestational Thyroid Physiology

Pregnancy profoundly alters maternal thyroid physiology through two primary mechanisms:

1. Estrogen Stimulation: High circulating estrogen induces hepatic synthesis and glycosylation of Thyroid-Binding Globulin (TBG) while decreasing TBG clearance, resulting in a doubling of serum TBG levels. Consequently, Total T4 and Total T3 levels increase by ~50% (1.5x non-pregnant baseline), while free T4 and free T3 remain in the normal range.
2. hCG Cross-Reactivity: Human chorionic gonadotropin (hCG) shares an identical alpha subunit with TSH and exerts weak agonist activity on the thyroid follicular TSH receptor. Peak hCG levels at 10 to 12 weeks gestation stimulate thyroid hormone production, producing a transient physiologic suppression of serum TSH during the first trimester.

• Trimester-Specific TSH Reference Ranges: First trimester TSH lower limit is ~0.1 mIU/L (upper limit ~2.5-3.0 mIU/L); second trimester 0.2-3.0 mIU/L; third trimester 0.3-3.0 mIU/L.

Hypothyroidism in Pregnancy

• Clinical Significance: Maternal thyroxine is critical for fetal neurocognitive development, as the fetal thyroid gland does not produce endogenous thyroid hormone until 10 to 12 weeks of gestation. Untreated maternal hypothyroidism increases risks of miscarriage, preeclampsia, placental abruption, low birth weight, and impaired child neurodevelopment.
• Management:
  • In patients with pre-existing overt hypothyroidism on Levothyroxine, the Levothyroxine dose must be increased by 25% to 30% immediately upon confirmation of pregnancy (e.g., instructing the patient to take two extra daily doses per week, or increasing the daily dose by 25-50 mcg).
  • Check serum TSH every 4 weeks through the first half of pregnancy (until 20 weeks) and at least once around 30 weeks gestation, titrating Levothyroxine to maintain TSH within trimester-specific reference ranges (<2.5 mIU/L).

Hyperthyroidism in Pregnancy

• Etiology: Graves' disease accounts for >85% of cases. Must be distinguished from Gestational Transient Thyrotoxicosis (hCG-mediated hyperthyroidism associated with hyperemesis gravidarum, which is self-limiting and does not require antithyroid medications).
• Pharmacotherapy Selection:
  • First Trimester: Propylthiouracil (PTU) is the drug of choice during the first trimester (weeks 1-12) because Methimazole is teratogenic during organogenesis, causing methimazole embryopathy (aplasia cutis congenita, choanal atresia, and tracheoesophageal fistula).
  • Second & Third Trimesters: Switch from PTU to Methimazole at the beginning of the second trimester (week 13-14) because PTU carries a significant risk of severe, fulminant drug-induced hepatotoxicity and acute liver failure.
  • Target: Maintain maternal Free T4 in the high-normal range using the lowest effective antithyroid dose to prevent iatrogenic fetal hypothyroidism and fetal goiter (since both PTU and Methimazole cross the placenta).

2. Venous Thromboembolism (VTE) in Pregnancy

Hypercoagulability & Risk Profile

• Pregnancy confers a 4- to 5-fold increased risk of VTE, which rises to a 20-fold increased risk in the first 6 weeks postpartum.
• Pathophysiology represents all three elements of Virchow's triad: hypercoagulability (increased factors I, VII, VIII, IX, X, von Willebrand factor, and PAI-1; decreased protein S), venous stasis (gravid uterus compresses the inferior vena cava and left common iliac vein), and vascular endothelial injury during delivery.

• 80% of deep vein thromboses in pregnancy occur in the left lower extremity due to anatomic compression of the left common iliac vein by the crossing right common iliac artery and gravid uterus (May-Thurner anatomy).

Diagnostic Pathway

1. Suspected DVT:
   • Compression Duplex Ultrasonography of the proximal and distal lower extremity veins is first-line.
   • If initial ultrasound is negative but clinical suspicion is high (e.g., severe left leg/groin swelling suggesting iliac vein thrombosis), perform repeat compression ultrasound in 3 to 7 days or Magnetic Resonance Venography (MRV) of the pelvic/iliac veins.
   • Critical Pearl: Serum D-dimer is physiologically elevated in normal pregnancy and has a very high false-positive rate; a positive D-dimer cannot confirm VTE, and a negative D-dimer should not be relied upon to rule out VTE in pregnancy.
2. Suspected Pulmonary Embolism (PE):
   • First step: Obtain a Chest X-ray (CXR).
   • If CXR is normal: Perform a Ventilation-Perfusion (V/Q) Scan. V/Q scan delivers lower radiation to maternal breast tissue than CTPA and negligible fetal radiation exposure.
   • If CXR is abnormal (infiltrate, atelectasis, effusion) or V/Q scan is unavailable/indeterminate: Perform Computed Tomography Pulmonary Angiography (CTPA) (with abdominal lead shielding; fetal radiation is minimal at <0.1 mGy, well below the 50 mGy teratogenic threshold).

Anticoagulation Management & Peripartum Timing

• Anticoagulant of Choice: Low-Molecular-Weight Heparin (LMWH) (e.g., Enoxaparin 1 mg/kg SC every 12 hours for therapeutic anticoagulation; or 40 mg SC daily for thromboprophylaxis).
  • LMWH does not cross the placenta and does not cause fetal bleeding or teratogenicity.
  • Anti-Xa level monitoring is not routinely required for all patients, but is recommended in patients with renal impairment (eGFR <30 mL/min), extremes of body weight (<50 kg or >100 kg), or recurrent thrombosis. Peak anti-Xa target is 0.6 to 1.0 IU/mL (drawn 4 hours post-dose for twice-daily dosing).
• Neuraxial Anesthesia (Spinal/Epidural) Timing Rules:
  • Therapeutic LMWH: Must be held for at least 24 hours prior to placement of neuraxial anesthesia or scheduled induction/cesarean delivery to prevent catastrophic spinal/epidural hematoma.
  • Prophylactic LMWH: Must be held for at least 12 hours prior to neuraxial blockade.
  • Transitioning near term: Many centers switch patients on therapeutic LMWH to intravenous Unfractionated Heparin (UFH) at 36 weeks gestation; UFH can be stopped 4 to 6 hours prior to delivery and is rapidly reversible with IV Protamine Sulfate.
• Postpartum Anticoagulation: Resume anticoagulation 6 to 12 hours after uncomplicated vaginal delivery (12 to 24 hours after cesarean delivery) and continue for a minimum of 6 weeks postpartum and at least 3 months total therapy.
• Contraindicated Anticoagulants in Pregnancy:
  • Warfarin: Teratogenic (Warfarin embryopathy: nasal hypoplasia, chondrodysplasia punctata, microcephaly, optic atrophy, fetal hemorrhage). Strictly contraindicated except in high-risk mechanical heart valves where low-dose warfarin (<5 mg/day) may be continued after specialist counseling.
  • Direct Oral Anticoagulants (DOACs: Apixaban, Rivaroxaban, Dabigatran): Cross the placenta with unknown fetal toxicity; contraindicated in pregnancy and during breastfeeding.