SUMMARY:  

Pregnancy is a well-known hypercoagulable state and inherited thrombophilias can further increase the risk for maternal venous thromboembolism (VTE).  The ACOG recommendations (July 2018) address the different thrombophilias as well as associations with possible adverse pregnancy outcomes.

• Who to Screen
• What to Include in the Screening Panel
• What is High or Low Risk Thrombophilia?
• Anticoagulation for VTE Prophylaxis
• VTE in Pregnancy – The Basics
• Clinically Relevant Thrombophilias
• Adverse Pregnancy Outcomes
• Anticoagulation Medications in Pregnancy
• Definitions – Anticoagulation Regimens (ACOG)

Who to Screen  

Consider screening for inherited thrombophilias in the following scenarios 

• A personal history of VTE 
  • With or without a recurrent risk factor 
    • Recurrent risk factor examples: Pregnancy or OCP use 
    • Non-recurrent risk factor examples: Surgery or immobilization  
• Family history 
  • First-degree relative with a history of high-risk inherited thrombophilia 

Screening is not recommended for the following 

• Personal history of  
  • Fetal loss  
  • Abruption 
  • Preeclampsia 
  • Fetal growth restriction

Note: Consider testing for acquired antiphospholipid syndrome antibodies in women with recurrent pregnancy loss or stillbirth

What to Include in the Screening Panel

• Factor V Leiden pathogenic variant  
• Prothrombin G20210A pathogenic variant  
• Antithrombin deficiency (activity <60%) 
• Protein S deficiency (functional assay <55%)  
• Protein C deficiency (activity <65%)  
• Antiphospholipid antibodies (acquired thrombophilia)

Note: If possible, screen 

• >6 weeks from VTE  
• Nonpregnant  
• Not on anticoagulation or hormonal therapy

What is High or Low Risk Thrombophilia?

High Risk Thrombophilia

• Antithrombin deficiency
• Antiphospholipid syndrome (APS)
• Factor V Leiden or Prothrombin pathogenic variants
  • Homozygosity or compound heterozygosity

Low Risk Thrombophilia

• Factor V Leiden or Prothrombin pathogenic variant
  • Heterozygote state
  • Protein C or S deficiency

Anticoagulation for VTE Prophylaxis

Low-risk thrombophilia without personal VTE history 

• Antepartum
  • Surveillance without anticoagulation therapy 
• Postpartum
  • Surveillance without anticoagulation therapy or 
  • Postpartum prophylactic anticoagulation therapy if additional risk factors (e.g., obesity, immobilization, cesarean section)  

Low-risk thrombophilia plus first-degree relative VTE history 

• Antepartum
  • Surveillance without anticoagulation therapy or 
  • Prophylactic LMWH/UFH  
• Postpartum
  • Postpartum prophylactic anticoagulation therapy or 
  • Intermediate-dose LMWH/UFH  

Low-risk thrombophilia with single episode of VTE (not receiving long-term anticoagulation therapy)  

• Antepartum
  • Prophylactic or intermediate-dose LMWH/UFH 
• Postpartum
  • Postpartum prophylactic anticoagulation therapy or
  • Intermediate-dose LMWH/UFH 

High-risk thrombophilia without previous VTE

• Antepartum:
  • Prophylactic or intermediate-dose LMWH/UFH 
• Postpartum
  • Postpartum prophylactic anticoagulation therapy or
  • Intermediate-dose LMWH/UFH 

High-risk thrombophilia with one previous episode of VTE or affected first-degree relative (not receiving long-term anticoagulation therapy) 

• Antepartum
  • Prophylactic or
  • Intermediate-dose LMWH/UFH or
  • Adjusted-dose LMWH/UFH  
• Postpartum
  • Postpartum prophylactic anticoagulation therapy or
  • Intermediate-dose LMWH/UFH or
  • Adjusted-dose LMWH/UFH for 6 weeks (therapy level should equal selected antepartum treatment)  

Thrombophilia with ≥2 VTE episodes (not receiving long-term anticoagulation therapy) 

• Antepartum
  • Intermediate-dose LMWH/UFH or
  • Adjusted-dose LMWH/UFH 
• Postpartum
  • Intermediate-dose LMWH/UFH or
  • Adjusted-dose LMWH/UFH for 6 weeks (therapy level should equal selected antepartum treatment) 

Thrombophilia with ≥2 VTE episodes (receiving long-term anticoagulation therapy) 

• Antepartum
  • Adjusted-dose LMWH/UFH 
• Postpartum
  • Resumption of long-term anticoagulation therapy  
    • Oral route may be considered, depending on therapy duration, breastfeeding and patient preference

KEY POINTS:  

VTE in Pregnancy – The Basics 

• Maternal VTE covers two potentially life-threatening events during the antepartum and postpartum periods   
  • 80% – Deep vein thrombosis (DVT)   
  • 20% – Pulmonary embolism (PE)   
• VTE affects approximately 1 to 4 /1000 pregnancies   
• There is a greater than 5-fold risk of VTE during pregnancy   
• Antepartum: Highest risk in 1st and 3rd trimesters  
• Postpartum: Highest risk in first 6 weeks   
• Virchow’s triad is exacerbated by pregnancy    
  • Hypercoagulability  
  • Stasis  
  • Endothelial vascular damage  
• Leading cause of maternal morbidity and mortality    
  • 15% of maternal deaths in the developed world are related to PE (WHO data)  
  • Data indicates high percentage of deaths may have been preventable

Clinically Relevant Thrombophilias 

Factor V Leiden  

• Prevalence dependent on ethnicity/race  
  • Caucasians: 5.27% 
  • Hispanic Americans: 2.21% 
  • African Americans: 1.23% 
  • Asian Americans: 0.45% 
  • Native Americans: 1.25% 
• Heterozygote state: VTE risk in pregnancy  
  • Without a personal history of VTE or an affected first-degree relative <age 50: Slight increased risk (5-12/1,000 deliveries)  
  • Affected first-degree relative but no personal history of VTE: Slight increased risk (15/1,000 deliveries)  
  • Personal history of VTE: 10% risk 
• Homozygosity: VTE risk in pregnancy  
  • Without a personal history of VTE or an affected first-degree relative <age 50: 1–2% risk 
  • Personal history of VTE or an affected first-degree relative <age 50: 17% risk

Prothrombin G20210A 

• Prevalence dependent on race/ethnicity  
  • Caucasians: 3.6% 
  • Hispanic Americans: 3.5% 
  • African Americans: 0-1.7% 
  • Asian Americans: 0.0% 
  • Native Americans: 0-0.6% 
• Heterozygote state: VTE risk in pregnancy 
  • Without personal history of VTE: <1% risk 
  • Affected first-degree relative but no personal history of VTE: Slight increased risk 
  • Personal history of VTE: 10% risk  
• Homozygosity: VTE risk in pregnancy  
  • Without personal or family history: 2–3% risk of VTE 

Note: Compound heterozygosity: Factor V Leiden and Prothrombin pathogenic variant: 4-5% risk (even without family or personal history)

Protein C Deficiency 

• Multiple variants and clinical presentations  
  • Hematology consult may be helpful if patient has an abnormal protein C result 
• VTE risk in pregnancy with protein C deficiency 
  • Personal or family history: 2-8% risk  
  • No family history: 0.7 %  
  • Family history of VTE: 1.7%  
• Neonatal purpura fulminans (rare) 
  • Newborns who are homozygous for protein C deficiency  
  • DIC and hemorrhagic skin necrosis  
  • May also occur with Protein S deficiency

Protein S Deficiency 

• Caused by either 
  • Silenced gene or  
  • Pathogenic variant, reducing protein S antigen levels  
• Prevalence unknown 
• Testing in pregnancy may be unreliable  
  • If necessary, screening in nonpregnancy advised if possible  
• Family or personal history: 5–7% risk

Antithrombin Deficiency 

• Rare (1/2500 heterozygote state), but confers high risk for VTE  
• Multiple pathogenic variants are known to reduce antigen level and/or activity  
• Antithrombin deficiency is considered a high-risk thrombophilia

Methylenetetrahydrofolate Reductase Variants 

• ACOG states “There is insufficient evidence to support assessment of methylenetetrahydrofolate reductase (MTHFR) polymorphisms or measurement of fasting homocysteine levels in the evaluation of a thrombophilic etiology for VTE.” (see ‘Related ObG Topic’, below)

Adverse Pregnancy Outcomes 

• Larger prospective studies (NICHD / MFMU network) do not support the association between inherited thrombophilias and adverse pregnancy outcomes including  
  • Preeclampsia 
  • Fetal loss 
  • Fetal Growth Restriction 
  • Placental Abruption 
• ACOG states “There is insufficient evidence to recommend anticoagulation as an intervention to prevent adverse pregnancy outcomes among women with inherited thrombophilias” 

Anticoagulation Medications in Pregnancy  

• LMWH (preferred therapy) and unfractionated heparin do not cross the placenta  
• Avoid oral direct thrombin inhibitors (dabigatran) and anti-Xa inhibitors (rivaroxaban, apixaban)
  • Insufficient safety data during pregnancy and lactation
• To provide neuraxial anesthesia (e.g., epidural) option prior to induction of labor 
  • Adjusted-dose low-molecular-weight heparin: Hold for 24 hours prior to induction 
  • Prophylactic LMWH: Hold for 12 hours prior to induction  
  • Alternative option: Substitute unfractionated heparin close to delivery  
    • SOAP recommends holding unfractionated heparin for 12 hours if dose >7,500 units and normal aPTT result  
• Patients receiving anticoagulation 
  • Hold injections with onset of labor 
  • Rapid reversal: Protamine sulfate, with dosing dependent on medication and route

Note: Consider sequential compression devices (SCDs)  

• Intrapartum
  • Indicated in patients with known thrombophilia until fully ambulatory postpartum  
• Cesarean section
  • All women undergoing cesarean delivery
  • Add pharmacologic prophylaxis depending on clinical scenario (see guidelines, above)

Definitions – Anticoagulation Regimens (ACOG)  

LMWH – Prophylactic

• Enoxaparin, 40 mg SC once daily  
• Dalteparin, 5,000 units SC once daily  
• Tinzaparin, 4,500 units SC once daily  
• Nadroparin, 2,850 units SC once daily

LMWH-Intermediate Dose

• Enoxaparin, 40 mg SC every 12 hours 
• Dalteparin, 5,000 units SC every 12 hours

LMWH – Adjusted Dose (Therapeutic)    

• Enoxaparin, 1mg/kg SC every 12 hours
• Dalteparin, 200 units/kg SC once daily
• Tinzaparin, 175 units/kg SC once daily
• Dalteparin, 100 units/kg every 12 hours 

Note: anti-Xa level 

• 0.6-1.0 units/mL 4 hr after last injection for q12 hr regimen 
• Slightly higher doses for daily regimen

UFH – Prophylactic 

• UFH, 5,000-7,500 units SC every 12 hours in first trimester  
• UFH, 7,500-10,000 units SC every 12 hours in the second trimester  
• UFH, 10,000 units SC every 12 hours in the third trimester, unless the aPTT is elevated   

UFH – Adjusted Dose (Therapeutic)

• UFH, 10,000 units or more SC every 12 hours in doses adjusted to target aPTT in the therapeutic range (1.5-2.5x) 6 hours after the injection     

Postpartum Anticoagulation 

• Prophylactic, intermediate or adjusted dose LMWH for 6-8 weeks as indicated 
• Oral anticoagulants may be considered postpartum based upon planned duration of therapy, lactation and patient preference 

Surveillance    

• Clinical vigilance and appropriate objective investigation of women with symptoms suspicious of deep vein thrombosis or pulmonary embolism 
• Perform VTE risk assessment prepregnancy or early in pregnancy and repeat if complications develop 

Learn More – Primary Sources:

ACOG Practice Bulletin 197: Inherited Thrombophilias in Pregnancy

Related ObG Topics:

The CMQCC Toolkit: Pregnancy Related Risk Factors & Thrombophilia Defined

The CMQCC Toolkit: Venous Thromboembolism in Early Pregnancy

The CMQCC Toolkit: Venous Thromboembolism Prevention and Management at Delivery

The CMQCC Toolkit: Venous Thromboembolism and Antepartum Admission (Non-Delivery)

MTHFR Polymorphism Testing – The Evidence Isn’t There

Which Thrombophilias in Pregnancy Warrant Thromboprophylaxis?