Under what circumstances do we start Hydroxychloroquine (HCQ) tablets for a patient with a history of Recurrent Pregnancy Loss (RPL)?

Hydroxychloroquine for Recurrent Pregnancy Loss

Hydroxychloroquine should be started in patients with RPL only when they have confirmed obstetric antiphospholipid syndrome (OB APS) that has failed standard therapy with low-dose aspirin and prophylactic heparin/LMWH, or when they have primary APS meeting diagnostic criteria. 1

Clear Indications for HCQ in RPL Context

1. Refractory Obstetric APS (Conditional Recommendation)

• Add HCQ to standard therapy (aspirin + prophylactic heparin/LMWH) when pregnancy loss occurs despite standard treatment 1
• This applies to patients who meet formal criteria for OB APS (≥3 consecutive early miscarriages <10 weeks, or ≥1 unexplained fetal death ≥10 weeks, or ≥1 premature birth <34 weeks due to preeclampsia/placental insufficiency) 1
• Standard therapy alone fails in approximately 25% of OB APS pregnancies 1

2. Primary APS with Pregnancy (Conditional Recommendation)

• Add HCQ to prophylactic-dose heparin/LMWH and low-dose aspirin for patients with primary APS 1
• Recent small studies suggest HCQ may decrease pregnancy complications in APS 1

3. Systemic Lupus Erythematosus with RPL (Strong Recommendation)

• If the patient has SLE (with or without RPL history), strongly recommend continuing HCQ during pregnancy if already taking it 1
• If not taking HCQ, conditionally recommend starting it if no contraindications exist 1
• HCQ provides maternal and pregnancy benefits with low risk for mother and fetus 1

When NOT to Start HCQ

Situations Where HCQ is NOT Recommended

Do NOT start HCQ in the following circumstances:

• Positive antiphospholipid antibodies WITHOUT meeting criteria for APS and WITHOUT another indication (such as SLE) - conditionally recommend AGAINST 1
• Unexplained RPL without confirmed APS or autoimmune disease - no established benefit 2
• Simple autoantibody positivity without clinical APS criteria - empirical use is common but not evidence-based 3

The ACR guidelines explicitly state a conditional recommendation AGAINST treating with prophylactic HCQ in pregnant women with positive aPL who do not meet APS criteria and lack another indication 1

Clinical Algorithm for Decision-Making

Step 1: Establish Diagnosis

• Test for antiphospholipid antibodies (LAC, aCL, anti-β2GPI) once before or early in pregnancy 1
• Determine if patient meets formal criteria for OB APS or thrombotic APS 1
• Screen for underlying SLE or other autoimmune diseases 1

Step 2: Initiate Standard Therapy First

• For confirmed OB APS: Start low-dose aspirin (81-100 mg daily) + prophylactic-dose heparin/LMWH 1
• For thrombotic APS: Start low-dose aspirin + therapeutic-dose heparin/LMWH 1
• Begin aspirin before 16 weeks gestation 1

Step 3: Consider HCQ Addition

Add HCQ only if:

• Standard therapy has failed (pregnancy loss despite aspirin + heparin) 1
• OR patient has primary APS (consider adding from the start) 1
• OR patient has SLE (strong indication regardless of APS status) 1

Step 4: High-Risk Scenarios Requiring Discussion

In specific high-risk circumstances, HCQ may be considered after physician-patient discussion weighing risks and benefits 1:

• Triple-positive antiphospholipid antibodies
• Strongly positive lupus anticoagulant
• Advanced maternal age
• IVF pregnancy
• Previous thrombosis (arterial and/or venous) 4
• Previous ischemic placenta-mediated complications 4

Important Caveats and Pitfalls

Common Pitfalls to Avoid

• Overdiagnosis and empirical HCQ use is common but not evidence-based - avoid starting HCQ without clear diagnostic criteria 3
• Do NOT use HCQ as monotherapy - it should always be added to standard anticoagulation therapy in APS, never used alone 1
• Do NOT add prednisone to standard therapy for refractory OB APS - strongly recommended against due to lack of benefit and potential risks 1
• Do NOT increase LMWH dose or add IVIG for refractory cases - conditionally recommended against as not demonstrably helpful 1

Evidence Limitations

• Recent prospective data from the FALCO registry showed that the number of previous miscarriages was the only factor predicting pregnancy success beyond 12 weeks, not HCQ exposure 2
• HCQ exposure in early pregnancy for women with RPL history does not appear to prevent further miscarriages, suggesting limited impact on maternal immune mechanisms 2
• Clinical data on HCQ improving pregnancy outcome in women with aPL are very limited, with only small cohort studies available 4

Safety Profile

• HCQ readily crosses the placenta but no retinal toxicity, ototoxicity, cardiotoxicity, or growth/developmental abnormalities have been observed in children exposed in utero 5
• Published data have not established an association between HCQ use during pregnancy and major birth defects, miscarriage, or adverse maternal/fetal outcomes 5
• HCQ is present in breast milk at low levels with no adverse reactions reported in breastfed infants 5

Contraindications to HCQ

• Allergy to hydroxychloroquine 1
• Adverse side effects or intolerance to the medication 1
• Severe hepatic or renal impairment (dose reduction may be necessary) 5