Protein S Deficiency Testing in Pregnancy is Unreliable
Protein S deficiency cannot be reliably diagnosed during pregnancy and testing should be deferred until at least 6 weeks postpartum. Pregnancy causes a physiological decrease in protein S levels that makes interpretation of results impossible and leads to false-positive diagnoses 1, 2, 3.
Why Testing During Pregnancy Fails
Physiological Changes That Confound Results
- Protein S functional levels drop dramatically during normal pregnancy, with all third-trimester patients in one study showing levels well below the reference range despite being healthy 1
- Mean functional protein S activity decreases to approximately 46% of normal levels by mid-pregnancy 4
- This decline begins in the first trimester and continues throughout pregnancy 3
- Free protein S antigen levels also decrease, though less dramatically than functional assays 1
The Clinical Problem
The functional assay (clot-based) is the standard screening test for protein S deficiency subtypes, but it should not be used during pregnancy as it will misdiagnose normal pregnant women as deficient 1. This leads to:
- Inappropriate anticoagulation therapy
- Unnecessary anxiety and interventions
- Inability to distinguish true hereditary deficiency from pregnancy-related physiological changes 2
When to Test
Wait at least 6 weeks postpartum before testing for protein S deficiency 3. Some experts recommend waiting even longer (40 days minimum) 2. This allows:
- Protein S levels to return to baseline
- Accurate distinction between hereditary deficiency and acquired pregnancy-related changes
- Meaningful interpretation of both functional and antigenic assays
Management Without Definitive Testing
The ASH 2018 guidelines address this diagnostic limitation by providing risk-stratified recommendations for women with suspected protein S deficiency 5:
Antepartum Management
- Clinical surveillance only (regardless of family history of VTE)
- No routine antithrombotic prophylaxis recommended
- Grade 2C recommendation (conditional, very low certainty evidence)
Postpartum Management
- Without family history of VTE: Clinical surveillance only
- With family history of VTE: Prophylactic- or intermediate-dose LMWH for 6 weeks
- Grade 2C recommendation 5
Critical Pitfalls to Avoid
- Do not diagnose protein S deficiency based on testing during pregnancy - you will create false positives
- Do not test during the immediate postpartum period - wait at least 6 weeks for levels to normalize
- Do not use oral contraceptives or hormone therapy when testing postpartum, as these also lower protein S levels
- Be aware that Factor V Leiden can falsely reduce protein S activity by up to 15% 6
Additional Confounding Factors
Recent evidence shows that drugs acting on the central nervous system (opioids, antidepressants, antiepileptics) may be more common in patients with protein S abnormalities (33% prevalence) 7, though causality is unclear. Consider medication effects when interpreting borderline results postpartum.
The bottom line: defer all protein S testing until well after pregnancy to avoid misdiagnosis. Manage based on clinical risk factors and family history during pregnancy rather than attempting laboratory confirmation.