What are the next steps for a patient with a history of positive Antiphospholipid (APL) antibodies who is now testing negative and is considering In Vitro Fertilization (IVF)?

Management of APL-Positive Patient Now Testing Negative Proceeding to IVF

For a patient with a history of positive antiphospholipid antibodies who is now testing negative and planning IVF, you should confirm persistent negativity with repeat testing at least 12 weeks apart, then consider prophylactic low-dose aspirin (81-100 mg daily) starting with ovarian stimulation, with the option to add prophylactic LMWH given the high-risk context of IVF, after shared decision-making about risks and benefits. 1, 2

Confirm True APL Negativity

• Repeat APL testing at least 12 weeks after the initial negative result to confirm persistent negativity, as transient fluctuations can occur and persistent negativity (at least two consecutive negative tests ≥12 weeks apart) is required to establish true seroreversion 3
• Test the complete APL panel including lupus anticoagulant (LAC), anticardiolipin antibodies (aCL) IgG/IgM, and anti-β2-glycoprotein I (anti-β2GPI) IgG/IgM to ensure comprehensive assessment 2
• Approximately 9% of APS patients experience APL negativization over time, most commonly in those who were previously single-positive rather than double or triple-positive 3

Risk Stratification Based on History

• Determine whether the patient had asymptomatic APL positivity alone, obstetric APS (prior pregnancy losses meeting APS criteria), or thrombotic APS (prior thrombotic events) 1
• The American College of Rheumatology notes that IVF pregnancy is specifically identified as a high-risk circumstance where treatment benefits may outweigh risks even in patients who don't meet full APS criteria 1
• IVF creates additional thrombotic risk through supraphysiologic estrogen levels, ovarian hyperstimulation, and the hypercoagulable state induced by controlled ovarian stimulation 2, 4

Treatment Recommendations for IVF Cycle

For Patients with History of Positive APL Now Testing Negative:

• Start low-dose aspirin (81-100 mg daily) beginning on day 1 of controlled ovarian stimulation and continue through the IVF cycle 1, 5
• The American College of Rheumatology conditionally recommends consideration of treatment in women with a history of positive APL who are currently testing negative and have no history of clinical APS, particularly in high-risk contexts like IVF 1

Consider Adding Prophylactic LMWH:

• Prophylactic-dose LMWH (enoxaparin 40 mg subcutaneously daily or equivalent) should be strongly considered given that IVF is explicitly mentioned as a high-risk circumstance where combination therapy benefits may outweigh risks 1, 2
• The combination of heparin and aspirin has demonstrated significantly improved viable pregnancy rates (49% vs 16%) in APL-positive women undergoing IVF compared to no treatment 5
• LMWH provides both anticoagulant effects and anti-inflammatory properties that may prevent complement-mediated pregnancy loss associated with APL 6

If Pregnancy is Achieved

For Patients with Prior Asymptomatic APL Only (No Prior Pregnancy Loss or Thrombosis):

• Continue low-dose aspirin (81-100 mg daily) throughout pregnancy as preeclampsia prophylaxis, starting before 16 weeks and continuing through delivery 1
• The American College of Rheumatology conditionally recommends against routine heparin/LMWH in asymptomatic APL-positive patients who don't meet APS criteria, though individual circumstances may warrant treatment 1

For Patients with Prior Obstetric APS:

• Immediately initiate combined low-dose aspirin and prophylactic-dose LMWH if not already started, as this is strongly recommended for all patients meeting obstetric APS criteria 1, 2
• Continue this combination throughout pregnancy and postpartum period 1

For Patients with Prior Thrombotic APS:

• Escalate to therapeutic-dose LMWH plus low-dose aspirin throughout pregnancy and postpartum, as these patients require full anticoagulation 1

Critical Monitoring During IVF

• Assess for ovarian hyperstimulation syndrome (OHSS) severity by monitoring abdominal girth, respiratory status, and signs of hemoconcentration, as OHSS creates a hypercoagulable state that compounds APL-related thrombotic risk 4
• Check coagulation studies and renal function if severe OHSS develops, as this significantly increases thrombotic risk 4
• Consider freezing all embryos rather than fresh transfer if severe OHSS develops, as pregnancy will worsen the hypercoagulable state 4

Important Caveats

• Avoid estrogen-containing contraceptives both before and after the IVF cycle, as estrogen increases thrombosis risk in APL-positive patients even when currently testing negative 1
• The fact that APL has turned negative is reassuring and suggests lower risk than persistent positivity, but the history of positivity combined with IVF-related risks justifies prophylactic treatment 3
• Patients who were previously single-positive (rather than double or triple-positive) have the highest rates of seroreversion and likely represent lower baseline risk 3
• Document the shared decision-making discussion about adding LMWH, weighing the increased bleeding risk against potential benefits in this high-risk IVF context 1