The CMQCC Toolkit: Pregnancy Related Risk Factors & Thrombophilia Defined
SUMMARY:
The CMQCC Task Force has released guidance on the prevention of PE and DVT in pregnancy. The document also helps clarify terminology to provide clarity when performing risk assessment at various time points in pregnancy (see ‘Related ObG Topics’ below). In addition, the CMQCC Task Force provides the anti-coagulation regimens recommended by ACOG.
Risk Factors
FAMILY HISTORY of VTE
VTE occurring in a first-degree relative prior to age 50
HIGH RISK THROMBOPHILIA
Antithrombin III deficiency
Antiphospholipid syndrome (APS)
Requires at least one clinical and one laboratory criteria be met
Factor V Leiden or Prothrombin pathogenic variant
Homozygosity or compound heterozygosity
LOW RISK THROMBOPHILIA
Factor V Leiden or Prothrombin pathogenic variant
Heterozygote state
Protein C or S deficiency
Anticoagulation Regimens (ACOG)
LMWH – PROPHYLACTIC DOSE
Enoxaparin, 40 mg SC once daily
Dalteparin, 5,000 units SC once daily
Tinzaparin, 4,5000 units SC once daily
Nadroparin, 2,850 units SC once daily
LMWH – INTERMEDIATE DOSE
Enoxaparin, 40 mg SC every 12 hours
Dateparin, 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
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 (1.5-2.5) 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
VTE risk assessment should be performed prepregnancy or early in pregnancy and repeated if complications develop, particularly those necessitating hospitalization or prolonged immobility
Notes:
Anti-Xa level testing is available to monitor activity of LMWH agents
CMQCC defines ‘LMWH therapeutic dose’ as enoxaparin, 1mg/kg SC every 12 hours, adjusted to target Xa 0.6-1.0 units/mL 4-6 hours after injection with acute VTE
aPTT testing is used to determine UFH dosing, not LMWH activity
Anti-Xa level testing is not currently mandated due to cost, inconvenience and lack of high quality data
Dose adjustment may be considered with extremes of body weight (< 50 kg or > 90 kg)
Consultation and ongoing collaboration with Anesthesia is strongly recommended
The CMQCC Toolkit: Venous Thromboembolism Prevention and Management at Delivery
SUMMARY:
The CMQCC Maternal VTE Task Force protocols are modeled on risk stratification. VTE risk is separated in to three levels (Low, Medium, High), with thromboprophylaxis targeted to each level. The Task Force also identified key moments in pregnancy that require specific risk assessment, including delivery.
For women undergoing cesarean birth, CMQCC recommends
Pharmacologic prophylaxis for women undergoing cesarean section with BMI ≥ 35 kg/m2
Other women with a single major or two or more minor risk factors should also receive in-house post cesarean pharmacologic prophylaxis
VTE and Cesarean Section
Major VTE Risk Factors for Use With Algorithm Below
BMI >35 kg/m2 @ delivery
Low-risk thrombophilia
Postpartum hemorrhage requiring
Transfusion
Further operation (e.g., hysterectomy, D&C)
Interventional Radiology procedure
Infection requiring antibiotics
Antepartum hospitalization ≥ 72 hours, current or within the last month
Chronic medical conditions
Sickle Cell disease
Systemic Lupus Erythematosus
Significant Cardiac disease
Active Inflammatory Bowel Disease
Active cancer
Nephrotic syndrome
Minor VTE Risk Factors
Multiple gestation
Age >40 years
Postpartum hemorrhage ≥1000 ml but not requiring
Transfusion
Further operation (e.g., hysterectomy, D&C)
Interventional Radiology procedure
Family history of VTE
VTE occurring in a first-degree relative prior to age 50
Smoker
Preeclampsia
Cesarean Section Risk Assessment
LOW RISK
Not meeting medium or high risk criteria
MECHANICAL PROPHYLAXIS
MEDIUM RISK
Cesarean Delivery with 1 Major or >2 Minor Risk Factors (see above)
MECHANICAL PROPHYLAXIS and PROPHYLACTIC DOSE LMWH/UFH (postpartum, until discharge)
HIGH RISK
High-risk thrombophilia (including acquired such as APS) with no prior history of VTE and regardless of family history
Prior provoked, idiopathic, or estrogen related VTE
Low risk thrombophilia AND family history of VTE OR single prior VTE
Patients already receiving LMWH/UFH as outpatient
Multiple prior VTE
Prior VTE with High Risk thrombophilia (including APS)
(1) MECHANICAL PROPHYLAXIS and PROPHYLATIC DOSE LMWH/UFH (postpartum, until 6 weeks from date of delivery or
(2) MECHANICAL PROPHYLAXIS and THERAPEUTIC DOSE LMWH/UFH (postpartum dose ≥ antepartum dose) in hospital and continued until 6 weeks from delivery date after discharge
Vaginal Birth Risk Assessment
LOW RISK
Delivery BMI >40 kg/m2
MECHANICAL PROPHYLAXIS
MEDIUM RISK
Delivery BMI > 40 kg/m2 and Antepartum hospitalization ≥ 72 hours is anticipated currently or within past month
Delivery BMI > 40 kg/m2 and Low Risk Thrombophilia
MECHANICAL PROPHYLAXIS and PROPHYLACTIC DOSE LMWH / UFH (postpartum hospitalization)
Note: Consider LMWH/UFH continuation for 6 weeks postpartum if BMI≥40 kg/m2 and thrombophilia
HIGH RISK
High-risk thrombophilia with no prior history of VTE regardless of family history
Prior provoked, idiopathic, or estrogen related VTE
Low risk thrombophilia AND family history of VTE
ANY single prior VTE
Patients already receiving LMWH/UFH as outpatient
Multiple prior VTE
Prior VTE with high risk thrombophilia or APS
(1) MECHANICAL PROPHYLAXIS and PROPHYLACTIC DOSE LMWH/UFH (postpartum in hospital until 6 weeks from date of delivery after discharge) or
(2) MECHANICAL PROPHYLAXIS and THERAPEUTIC DOSE LMWH / UFH (Postpartum in hospital and continued until 6 weeks from date of delivery after discharge, with postpartum dose ≥antepartum dose)
Notes:
Mechanical prophylaxis should be placed prior to cesarean and continued until ambulatory
The CMQCC Maternal VTE Task Force supports the ACOG recommendations that women with prior VTE events, high-risk thrombophilia, or low risk thrombophilia with family history of VTE receive postpartum pharmacologic prophylaxis
Internal California data corroborate the finding of increased risk for maternal VTE mortality with increasing BMI and immobility >72 hours during hospitalization
Therefore, CMQCC has included BMI ≥40 kg/m2 in combination with current, anticipated or recent (within the past month) hospitalization for ≥72 hours for intrapartum mechanical prophylaxis and/or postpartum pharmacologic prophylaxis
KEY POINTS:
At all risk levels, all women undergoing cesarean section should
Be encouraged to ambulate
Avoid dehydration
Receive mechanical prophylaxis
Definitions – Risk Factors
FAMILY HISTORY of VTE
VTE occurring in a first-degree relative prior to age 50
HIGH RISK THROMBOPHILIA
Antithrombin III deficiency
Antiphospholipid syndrome (APS)
Requires at least one clinical and one laboratory criteria be met
Factor V Leiden or Prothrombin pathogenic variant
Homozygosity or compound heterozygosity
LOW RISK THROMBOPHILIA
Factor V Leiden or Prothrombin pathogenic variant
Heterozygote state
Protein C or S deficiency
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 SC every 12 hours
UFH – PROPHYLACTIC
UFH, 5,000 to 7,500 units SC every 12 hours in first trimester
UFH, 7,500 to 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 to 2.5 X control) 6 hours after the injection
POSTPARTUM ANTICOAGULATION
Prophylactic, intermediate or adjusted dose LMWH for 6 to 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
VTE risk assessment should be performed prepregnancy or early in pregnancy and repeated if complications develop, particularly those necessitating hospitalization or prolonged immobility
Notes:
Anti-Xa level testing is available to monitor activity of LMWH agents
CMQCC defines ‘LMWH therapeutic dose’ as enoxaparin, 1mg/kg SC every 12 hours, adjusted to target Xa 0.6-1.0 units/mL 4-6 hours after injection with acute VTE
aPTT testing is used to determine UFH dosing, not LMWH activity
Anti-Xa level testing is not currently mandated due to cost, inconvenience and lack of high quality data
Dose adjustment may be considered with extremes of body weight (<50 kg or >90 kg)
Consultation and ongoing collaboration with Anesthesia is strongly recommended
The CMQCC Toolkit: Venous Thromboembolism and Antepartum Admission (Non-Delivery)
SUMMARY:
The Joint Commission has recommended guidance for non-pregnant patients who are admitted to hospital. However, due to lack of data, despite known increased risk, pregnant women were not included in this directive. The CMQCC Maternal VTE task force provides recommendations to address this gap. Pregnant women who are admitted to hospital should be encouraged to
Maintain full ambulation
Risks of activity restriction and bedrest are proven and include VTE, bone loss, poor maternal weight gain and rapid deconditioning
There is also evidence that there may be risk of anxiety, and peri and postpartum depression
There is no evidence that bedrest improves outcomes for multiple gestations, preterm labor, hypertensive disease of pregnancy or IUGR
Ensure hydration
Prophylaxis
Mechanical: Utilize mechanical prophylaxis (knee length sequential compression devices) while in bed
Pharmacologic: Based on data that length of stay ≥3 days is associated with high risk for VTE, the toolkit document states
The CMQCC Maternal VTE Task Force supports NPMS and RCOG recommendations for pharmacological thromboprophylaxis for all antepartum patients hospitalized for ≥ 72 hours who are not at high risk for bleeding or imminent delivery.
Antepartum Hospital Admission VTE Risk Assessment
LOW RISK
All patients not in high risk category with anticipated admission <72 hours
Treatment
MECHANICAL PROPHYLAXIS (reassess at 72 hours)
MEDIUM RISK
All patients admitted not in high risk category with anticipated or actual length of stay >72 hours
Treatment
MECHANICAL PROPHYLAXIS and PROPHYLACTIC DOSE LMWH OR UFH
HIGH RISK
High risk thrombophilia
Low risk thrombophilia and family history of VTE
Antiphospholipid Syndrome (APS), even without prior VTE regardless of family history
Prior provoked, idiopathic, or estrogen related VTE (i.e., personal history of any VTE)
Patients already receiving LMWH or UFH as outpatient for multiple prior VTE episodes or for prior VTE with high risk thrombophilia or APS
Treatment
(1) MECHANICAL PROPHYLAXIS + PROPHYLACTIC DOSE LMWH/UFH or
(2) MECHANICAL PROPHYLAXIS + PROPHYLACTIC or THERAPEUTIC DOSE LMWH/UFH (consistent with antepartum dosing)
Notes:
Mechanical prophylaxis should be placed on admission and continued through discharge
Prophylactic-dose LMWH or UFH should be determined in collaboration with anesthesia
Obtain anesthesia consultation at the time of antepartum admission for all patients who are potential candidates for pharmacologic prophylaxis
Obstetricians and anesthesiologists should maintain ongoing and close communication, ensuring that all providers are involved in the anticoagulation plan
Multidisciplinary approach will address
Neuraxial anesthesia
Dose adjustments of pharmacologic prophylaxis
Coagulation testing when indicated
KEY POINTS:
Patient at high risk VTE but also at risk for delivery or bleeding
Mechanical prophylaxis or low dose UFH 5000 units subcutaneous every 12 hours may be utilized
If pharmacologic prophylaxis deemed appropriate by multidisciplinary team, low dose UFH 5000 units subcutaneous every 12 hours is preferred due to
Rapid reversal, shorter half-life, and facilitation of regional anesthesia
Patient at high risk for imminent delivery and/or requiring neuraxial anesthesia
Hold pharmacological prophylaxis and utilize mechanical prophylaxis due to risk benefit analysis
Competing risks (DVT vs bleeding) underlie the CMQCC Task Force’s strong recommendation to obtain anesthesia input prior to a decision to initiate pharmacologic prophylaxis
Definitions – Risk Factors
FAMILY HISTORY of VTE
VTE occurring in a first-degree relative prior to age 50
HIGH RISK THROMBOPHILIA
Antithrombin III deficiency
Antiphospholipid syndrome (APS)
Requires at least one clinical and one laboratory criteria be met
Factor V Leiden or Prothrombin pathogenic variant
Homozygosity or compound heterozygosity
LOW RISK THROMBOPHILIA
Factor V Leiden or Prothrombin pathogenic variant
Heterozygote state
Protein C or S deficiency
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 SC every 12 hours
UFH – PROPHYLACTIC
UFH, 5,000 to 7,500 units SC every 12 hours in first trimester
UFH, 7,500 to 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 to 2.5 x control) 6 hours after the injection
POSTPARTUM ANTICOAGULATION
Prophylactic, intermediate or adjusted dose LMWH for 6 to 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
VTE risk assessment should be performed prepregnancy or early in pregnancy and repeated if complications develop, particularly those necessitating hospitalization or prolonged immobility
Notes:
Anti-Xa level testing is available to monitor activity of LMWH agents
CMQCC defines ‘LMWH therapeutic dose’ as enoxaparin, 1mg/kg SC every 12 hours, adjusted to target Xa 0.6-1.0 units/mL 4-6 hours after injection with acute VTE
aPTT testing is used to determine UFH dosing, not LMWH activity
Anti-Xa level testing is not currently mandated due to cost, inconvenience and lack of high quality data
Dose adjustment may be considered with extremes of body weight (<50 kg or >90 kg)
Consultation and ongoing collaboration with Anesthesia is strongly recommended
Results from the SPREE Trial: How Does First Trimester Preeclampsia Screening Compare to Current Guidelines?
BACKGROUND AND PURPOSE:
Current NICE guidelines use maternal characteristics and medical history to identify women at high risk for preeclampsia (PE) who could benefit from aspirin
NICE guideline considers a pregnant woman at high risk if
Any one major factor
History of hypertensive disease in previous pregnancy
Chronic kidney disease
Autoimmune disease
Diabetes mellitus
Chronic hypertension
OR any two moderate factors
First pregnancy at age ≥ 40 years
Interpregnancy interval > 10 years
BMI at first visit ≥ 35 kg/m2
Family history of PE
Using more traditional approach of professional committees, each factor is considered separately
Tan et al. (Ultrasound in Obstetrics & Gynecology, 2018) compared the above NICE approach to screening PE to a method that uses Bayes’ theorem that combines maternal factors with biomarkers
METHODS:
Prospective multicenter cohort study
Screening program for pre-eclampsia (SPREE) study
Participants: Singleton pregnancies at 11–13 weeks’ gestation had recording of maternal characteristics and medical history and measurements of
The performance of screening for PE by the Bayes’ theorem‐based method was compared with that of the NICE method
Primary outcome
Detection rate (DR) using NICE method vs mini‐combined test (maternal factors, MAP and PAPP‐A) in the prediction of PE at any gestational age (all‐PE) for the same screen‐positive rate determined by the NICE method
Secondary comparisons
DR of screening recommended by the NICE guidelines vs 3 Bayes’ theorem‐based methods for prediction of preterm PE (requiring delivery <37weeks)
Maternal factors, MAP and PAPP‐A
Maternal factors, MAP and PlGF
Maternal factors, MAP, UtA‐PI and PlGF
RESULTS:
17,051 women were eligible and outcome data were obtained from 16,747
All-PE developed in 2.8% of the 16,747 pregnancies and preterm PE developed in 0.8%
NICE method for PE
Screen positive rate: 10.3%
DR for all‐PE: 30.4%
DR for preterm PE: 40.8%
There was only 23% compliance with aspirin recommendation
Mini-combined method for PE
DR of the mini‐combined test for all‐PE was 42.5%
Superior to that of the NICE method by 12.1% (95% CI, 7.9–16.2%)
Screening for preterm PE compared to NICE
Maternal factors, MAP and PlGF: DR was 69.0%, which was superior to NICE method by 28.2% (95% CI, 19.4–37.0%)
Maternal factors, MAP, UtA‐PI and PlGF: DR was 82.4%, which was to NICE method by 41.6% (95% CI, 33.2–49.9%)
CONCLUSION:
NICE detection rates and compliance were lower than using a Bayesian approach that incorporates serum markers
The authors state that a PE methodology that combines biomarkers with maternal factors is a substantial improvement over current recommendations
Results from the PROPER Trial: What are the Pulmonary Embolism Rule-Out Criteria (PERC) and Do They Really Work?
BACKGROUND AND PURPOSE:
The Pulmonary Embolism Rule-Out Criteria (PERC), an 8-item set of clinical criteria that serves as a predictive tool, has not been evaluated using a randomized trial (RCT)
Each PERC criteria is scores as ‘0’ (no) or ‘+1’ (yes) and a 0 score indicates no further work-up is needed, with a <2% chance of PE
Arterial oxygen saturation (Sp02) of ≤94%
Pulse rate of at least 100/min
Patient age of 50 years or older
Unilateral leg swelling
Hemoptysis
Recent trauma or surgery
Prior PE or deep venous thrombosis (DVT)
Exogenous estrogen use
Freund et al. (JAMA, 2018) aimed to validate the safety of the PERC-based strategy to exclude PE
METHODS:
A noninferiority, crossover cluster randomized controlled trial
14 EDs in France were involved for two 6-month periods separated by a 2-month washout period
Patients who came to the ED with a suspicion of PE were eligible
Inclusion criteria included
new-onset presence or worsening of shortness of breath or chest pain
Low probability of PE (clinician’s pre-test probability is <15%), based on physicians unstructured impression of risk (low, moderate, or high)
Evidence that unstructured ‘gestalt’ performs as well as structured assessment
Each center was randomized to determine sequence of intervention periods
During the PERC period, the diagnosis of PE was excluded with a PERC score of 0, with no further follow up
During the non-PERC period, usual diagnostic strategy was followed for low level of suspicion for PE
D-dimer testing
If D-dimer testing is positive, computed tomographic pulmonary angiography (CTPA) was performed
If both negative, PE was ruled out and no further follow-up
Primary outcome
Percentage of failure of the diagnostic strategy
Secondary outcomes
Rate of CTPA use
Median length of stay in the emergency department
Rate of hospital admission
RESULTS:
1916 patients were cluster-randomized (mean age 44 years, 980 [51%] women)
962 were assigned to the PERC group
954 were assigned to the control group
A total of 1,749 patients completed the trial
A PE was diagnosed at initial presentation in
26 (2.7%) of patients in the control group vs 14 (1.5%) in the PERC group
Mean difference, 1.3% (95% CI, −0.1% to 2.7%; P = .052)
Primary outcome: One symptomatic PE (0.1%) at 3 months was diagnosed during follow-up in the PERC group vs none in the control group
The proportion of patients undergoing CTPA in the PERC group vs control group was 13% vs 23%
Mean difference, 9.7% (95% CI, 6.1% to 13.2% P < .001)
In the PERC group
Median length of emergency department stay rates were significantly reduced
Mean reduction, 36 minutes (95% CI, 4 – 68)
Hospital admission rates were significantly reduced (13% vs 16%)
Mean difference, 3.3% (95% CI, 0.1% to 6.6%)
CONCLUSION:
Among low-risk patients for PE, using the PERC strategy did not result in an inferior rate of thromboembolic events over 3 months
Authors point out limitations of this study, including low initial prevalence of PE at 2.7% and may be explained by low average age
This study supports the use of PERC for very low-risk patients presenting at the emergency department
NOTE: PERC HAS NOT BEEN VALIDATED IN PREGNANCY OR POSTPARTUM
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This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.
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presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
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