Prof Beverley Hunt, Guy’s & St Thomas’ NHS Foundation Trust

Kings College, LondonMedical Director of Thrombosis UK

Twitter @bhwords

Venous thromboembolism in pregnancy

VTE in pregnancy

VTE in 1/1000 pregnancies

>70% of DVT in left side

>70% ileofemoral

>70% post-phlebitic syndrome

How to diagnose?

How to treat?

How to prevent?

Pregnancy is a prothrombotic state

Increased venous stasis

Endothelial changes

Hypercoagulable changes

• Increased levels of fibrinogen, Factor Vc, Factor VIIIc and vWF*

• Reduced levels of total and free Protein S• Activated Protein C sensitivity ratio falls• Increased levels of PAI-1 and PAI-2 from placenta†

• Gradual increase in Prothrombin Factor 1 +2, TAT‡ and D-dimers

• Persist for up to 6 weeks post-partum

*vWF = von Willebrand Factor; †PAI = plasminogen activator inhibitor; ‡TAT = thrombin antithrombin

Distribution of VTE in pregnancy & puerperium

Jacobsen et al. Am J Obstet Gynecol 2008;198(2):233.e1–7

49.3% of VTE occurred during the first 6 weeks

postpartum

VTE incidence:1st trimester: 10.1%2nd trimester: 10.4%3rd trimester: 28.4%

12 24 36 1 6 12

VTE

(n)

0102030405060708090

Antepartum PostpartumWeeks Delivery

Rate of venous thromboembolism per 100 000 person years by weeks after discharge during antepartum period: 12 events in weeks 1-2 after discharge, 7 events in weeks 3-4

after discharge, and 12 events in weeks 5-10 after discharge.

Sultan A et al. BMJ 2013;347:bmj.f6099©2013 by British Medical Journal Publishing Group

HOSPITAL ACQUIRED VTE & PREGNANCY

Weeks Postpartum

VTEOR

95% CI

0-6 12.1 7.9 to 18.6

7-12 2.2 1.4 to 3.3

13-18 1.6 1.0 to 2.5

18-24 0.9 0.5 to 1.4

Kamel et al New Engl J Med Feb 2014

Treatment

Prevention

The RCOG guidelines

Sharp and statistically significant fall in mortality rate: 1.94 (95% CI 1.43-2.63) per 100,000 maternities 2003-5

0.79 (95% CI 0.49-1.25 ) per 100,000 maternities 2006-8.

Thrombosis & thromboembolismMortality rates 1985-87 to 2006-08

RCOG Thromboprophylaxis Guideline 2004 (an + post vd)

RCOG Working Party thromboprophylaxis gynaecology and obstetrics. 1995 (post CS)

Risk factor for VTE aOR 95% CIPrevious VTE 1 24.8 17.1-36

Age > 35 4 1.3 1.0-1.7

BMI > 30 21

5.34.4

2.1-13.53.4-5.7

Smoking 3 2.7 1.5-4.9Parity >3 4 2.4 1.8-3.1

Medical Conditions1

Sickle cell disease, SLE, Heart disease, anaemia, infection, Hyperemesis

2.0 – 8.7

2.51 2.0-3.2Immobility 3 7.7 (an)

10.8 (pn)3.2-194-28.8

Pre-eclampsia3

+Fetal Growth Restricition3.15.8

1.8-5.32.1-16

ART 3 4.3 2.0-9.4

Twins3 2.6 1.1-6.2

APH 1 2.3 1.8-2.8

PPH 3 4.1 2.3-7.3

Caesarean section 4 3.6 3.0-4.3

Varicose veins 2.4 1.04-5.4

Transfusion1 7.6 6.2-9.4

1.James et al 2006; 2.Larsen et al 2007; 3.Jacobsen et al 2008; 4.Lindqvist et al 1999

Any woman with THREE or more (TWO or more if admitted) current or persisting risk factors should receive prophylactic LMWH antenatally.

Any woman with TWO or more current or persisting risk factors should receive prophylactic LMWH postpartum.

Graduated compression stockings

Only 1,000 patients in clinical trials

Never shown to reduce the risk of death due to PE

The CLOT study Dennis M et al, Lancet 2009; 373: 19582,500 stroke ptsThigh length anti-embolic stockings v nothing10% v 9.5% VTE rate on USS BUT5% with stockings had skin problems

Do not offer stockings to patients who have:Suspected peripheral arterial diseasePeripheral arterial bypass graftingPeripheral neuropathy or other causes of sensory impairmentAny local condition in which stockings may cause damageKnown allergy to material of manufactureCardiac failure/severe leg oedemaUnusual leg size or shapeIf arterial disease suspected seek expert opinionEncourage them to wear them day and night until they no longer have reduced mobilityRemove daily for hygiene purposes and to inspect skin 2-3 times a day for integrity or sensory impairment and discontinue if problems develop.

GAPS: Graduated compression as an Adjunct to Pharmacoprophylaxis

in Surgery

3,250 moderate risk surgical patients receive LMWH +/-stockings

Primary outcome: symptomatic & asymptomatic vTE

Page 15

National register-based cohort study, 1995 to 2005.All Danish pregnancies conceived by IVF (n = 18 787)48 cases VTE

VTE incidence- 3 fold increase in pregnancies after IVF; especially in the first trimester and in the first 6 weeks post-partum.

Cumulative incidence of VTE in the puerperal period in IVF pregnancies, and reference pregnancies.

Hansen A et al. Hum. Reprod. 2014;29:611-617

© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Difficulties in diagnosing VTE in pregnancy:

Wells score and D-dimer not validated in pregnancy

Non-thrombotic causes of symptoms such as leg swelling and shortness of breath are common in pregnancy

“Maintain a low threshold for performing objective testing”

Systemic review & meta-analysis of pregnant patients referred for suspected PE to Emergency

Kline et al, Academic Emergency Medicine 2014;21:949-59

Identified 17 studies with 25,339 patients

506 were pregnant 4.1% positive imaging

Non-pregnant – 12.4% positive

Conclusion: In the ED setting physicians test for PE in pregnant pts at a low threshold, resulting in a low rate of VTE diagnosis.

11 studies of poor quality looking at 1300+ pregnant women

Scanning with either CTPA or V/Q appeared to be appropriate for excluding PE in pregnancy, but comparative studies necessary

But they noted:

Only 3% of all women scanned had a PE

Cochrane review: scanning imaging techniques for the exclusion of PE in pregnancy

van Mens et al Jan 2017

Radiation doses for diagnosing PE in pregnancy

CTPA V only V/QEffe

Effective dose 21 mSiv 1.04 1.29

Breast absorbed 44 mGy 0.28 0.37

Uterus absorbed 0.48 mGy 0.25 0.40

Some authorities say risk of breast cancer increases by 10% if CTPA used in fertile women

From Detection of pulmonary embolism during pregnancy:comparing radiation doses of CTPA and pulmonary

scintigraphy.Astani et al. Nucl Med comm 2014;35: 704

V/Q SPECT – how it works

Camera head rotates around patient

CT VQSPECT

Roach et al Seminars Nuclear Medicine 2010:40:455-466

Co-registered CTPA/perfusion SPECT showing perfusion defects corresponding with bilateral PE

14

Head to Head: VQ SPECT & CTPA in suspected PE

Reinharz: JNM 2004: 45: 1501-8

n Sensitivity Specificity

VQ SPECT 81 97% 91%CTPA 4-slice 81 86% 98%

Gutte JNM 2009:50: 1987-92

n Sensitivity Specificity

VQ SPECT 81 97% 88%CTPA 16-slice 81 68% 100%

V/Q SPECT plus low dose CT raised specificity to 100% (Gutte et al, 2009)

5

Difficulties in diagnosing PE in pregnancyDiPEP: Diagnosis of Pulmonary Embolism (PE) in

Pregnancy

ISRCTN: 21245595

REC ref: 14/LO/1695

HTA ref: 13/21/01

This project is funded by the National Institute for Health Research Health Technology Assessment Programme (13/21/01)

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Health Technology Assessment Programme, NIHR, NHS or the Department of Health.

Aims

Develop new rule to select pregnant or postpartum women with suspected PE for imaging

Estimate the diagnostic accuracy of expert-derived clinical decision rules

Test existing Clinical Decision Rules (Wells, Geneva, PERC) in a pregnant population used for a non-pregnant population

Explore the diagnostic value of biomarkers

DiPEP study

Design: Multicentre, case-control design in the UK

Suspected PE- Prospective data collection (n=250), across from 11 NHS Trusts

Diagnosed PE- UK-wide Obstetric Surveillance System (UKOSS), retrospective data collection (n=150)

Inclusion criteria: Pregnant and Postpartum women (42 days) requiring diagnostic imaging for PE.

Exclusion Criteria: women with PE diagnosed as an incidental finding, requiring life support at presentation, diagnosed with PE earlier in the current pregnancy, aged <16 years, unable to give informed consent, previously recruited to the study

Data Collection: Standard clinical assessment, potential predictor variables, diagnostic test results and management

Suspected PE: Blood sample, 30 day follow up (medical records and patient questionnaire

Methods

No blood sample for UKOSS (cases) as consent cannot be obtained retrospectively.

We anticipated that only a small number (~5) of those with suspected PE would actually have PE.

To increase statistical power to estimate sensitivity of biomarkers, data collection and blood sample collected on pregnant and postpartum women diagnosed with DVT (~20)

Reference standard classification

All Suspected PE and Diagnosed PE classified as PE present or PE absent based on the results of diagnostic imaging, thromboembolic events, evidence of treatment for PE, and adverse events

Two independent assessors (and 3rd adjudicator), blind to clinical predictors and blood results

Methods cont.

Planned analyses

D-Dimers (ELISA)D-dimers (Innovance)Plasmin-antiplasmin assay (PAP)

Prothrombin fragment 1+2 (PF 1 +2)

Thrombin GenerationProthrombin time (PT)Activated partial thromboplastin time (APTT)Clauss FibrinogenSoluble Tissue Factor (sTF)Troponin IB-type natriuretic peptideC- Reactive Protein (CRP)MRproAMP

Biomarkers; Existing CDR’s;

Simplified Geneva ScoreWellsPERC

The accuracy of each index test was assessed by reporting and comparing the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). The combined sensitivity and specificity was assessed plotting Receiver Operating Characteristic (ROC) curves

(LASSO) regression modelling, recursive partitioning to create data derived rulePerformance of consensus derived CDR

Recruitment period: February 2015- September 2016

Recruitment totals

Suspected PE n= 324

Diagnosed PE n= 198

Diagnosed DVT n=18

Primary analysis classifications

PE- 181

No PE- 259

Exclude- 82

Biomarkers data;

Women who received anticoagulation prior to blood sampling (n=240) have APTT and ETP results removed

Results

Figure 1: Suspected PE recruitment

Heart rate

Respiratory rate

Oxygen saturation

Performance of existing rules

Score AUCPERC 0.586Simplified Revised Geneva 0.514

Wells 0.525

Biomarkers

Marker False -ve

False +ve

True -ve

True +ve Sensitivity Specificity PPV NPV FPR FNR FDR Accuracy

Clauss Fibrinogen 18 0 241 0 0 1 0 0.931 0 1 0 0.931D-Dimer (ELISA) 16 8 237 2 0.111 0.967 0.2 0.937 0.033 0.889 0.8 0.909D-Dimer (Innovan) 16 6 239 2 0.111 0.976 0.25 0.937 0.024 0.889 0.75 0.916Plasmin (Antiplasmin) 16 5 240 2 0.111 0.98 0.286 0.938 0.02 0.889 0.714 0.92

Soluble Tissue Factor 18 0 245 0 0 1 0 0.932 0 1 0 0.932

Troponin 18 0 247 0 0 1 0 0.932 0 1 0 0.932Aprothombin 3 0 60 0 0 1 0 0.952 0 1 0 0.952Prothombin (Time) 18 1 236 0 0 0.996 0 0.929 0.004 1 1 0.925Prothombin Fragments 18 0 245 0 0 1 0 0.932 0 1 0 0.932

Thrombin Generation (Endogenous Potential)

3 0 60 0 0 1 0 0.952 0 1 0 0.952

Thrombin Generation (Lag Time)

3 0 60 0 0 1 0 0.952 0 1 0 0.952

Thrombin Generation (Peak) 3 0 60 0 0 1 0 0.952 0 1 0 0.952

Thrombin Generation (Time to Peak)

3 0 60 0 0 1 0 0.952 0 1 0 0.952

D-dimer (ELISA) and (Innovance)

D-dimer ELISA values according to gestation

:

Clinical prediction scores used outside of pregnancy are NOT suitable in pregnancy

Single biomarkers are not helpful in diagnosing or excluding PE in pregnancy

Conclusion

DiPEP Thank you!

Barts Health NHS Trust

Bolton NHS Foundation Trust

Bradford Teaching Hospitals NHS Foundation Trust

Hull and East Yorkshire Hospitals NHS Trust

The Leeds Teaching Hospitals NHS Trust

Central Manchester University Hospitals NHS Foundation Trust

We would like to extend our thanks to the following sites:

Nottingham University Hospitals NHS Trust

Portsmouth Hospitals NHS Trust

Royal Berkshire NHS Foundation Trust

Sheffield Teaching Hospitals NHS Foundation Trust

Guy’s and St Thomas’ NHS Foundation Trust

Why are we not using MR direct thrombus imaging to diagnose DVT in pregnancy? Moody A et al

MR direct thrombus imaging in comparison to venography in imaging DVT

N. BDoppler ultrasound:Operator dependentPoor in calf & pelvis

Fetal risks of coumarins in pregnancy

Teratogenic 1–2% risk of: Hare lip and cleft palateBone abnormalities

Between 6-14 weeks

Risk of fetal haemorrhagein 2nd and 3rd trimesters due to hepatic immaturity

Risk greatest if maternal dose > 5mgs

BUT coumarins remain the preferred option in women with mechanical valves and previous catastrophic or cerebral antiphospholipid syndrome

Fetal risks of DOACs in pregnancy

Unknown effects in humans

What to do if require long term anticoagulation & want to get pregnant?

ISTH recommendation-switch to warfarin preconceptually

BUT

Switching from unknown fetal risk to known fetal risk!

Switch to LMWH?

Stay on DOAC & switch as soonas pregnant

In pregnancy: use LMWH in preference to UFH

At least equivalent efficacyMore practical

Longer half-life than UFHReliable pharmacokinentics compared with UFH

Better safety……

Safety and efficacy of LMW heparins in pregnancyC Nelson Piercy, I Greer, Blood 2005; 106: 401

• 2,777 pregnancies included in a systematic review.174 patients for VTE, 2603 for thromboprophylaxis or adverse

pregnancy outcome• No maternal deaths

• Recurrent VTE and arterial thrombosis in 0.86% and 0.5%• Bleeding in 1.98%, allergic skin reaction in 1.8%• No cases of HITT

• Osteoporotic fracture in 0.04%• Live births in 94%

Current problems with LMWHs during pregnancy

LMWHs are still unlicensed for use in pregnancy

Dosing

Monitoring

Regional anaesthesia

Formulation

LMW heparin dosing in pregnancy

In treatment of VTE practice has been dictated by experience outside of pregnancy but pharmacokinetics are different due to improved renal function

e.g. enoxaparin 1 mg/kg b.i.d. vs 1.5 mg/kg in non-parous women

Lessons from surveys: Voke et al Brit J Haem 2007; 139: 545-58

126 antenatal VTE events

Once daily LMWH in 66%, twice daily in 31%

Outcomes- no recurrences, no deaths

? Can one reduce the dose to an intermediate dose after 6-8 weeks?

Continue for 6 weeks post-partum/switch to a vitamin K antagonist

Should LMW heparin be monitored in pregnancy?

LMWH has reliable pharmacokinetics unlike UF heparin and warfarin.

Studies would suggest this is true in pregnancy.

What is the target value?

Ultimately efficacy should be judged by clinical outcome studies NOT anti-Xa levels attained

…and does monitoring anti-Xa levels produce a reliable results?

LMWH (S01/10) u/ml

Regional anaesthesia, anticoagulants and pregnancy

Risk of spinal or epidural haematomas described in elderly with intermediate dose LMWH

Full anticoagulation is an absolute contraindication

Proceed if:

• Last dose of LMWH 24 hours prior to procedure and

• Normal clotting screen and platelet count >75x109/L

LMWH: Preservatives & supply

Tinzaparin (syringes): none

(multi-dose vial): benzyl alcohol

(20,000iu/ml) : Na metabisulphite [stabiliser]

Dalteparin (syringes): none

(multi-dose vial): benzyl alcohol

Other problems: previous USA alert on degree of sulphation

intermittent supply

Other agents for treatment of VTE in pregnancy

UFH (need larger doses than non-parous)Danaparoid — monitor with anti-Xa levels, safe to breastfeed

(few reports)Recombinant hirudin- case report in pregnancy, no adverse

outcomeFondaparinux — minor transplancental passageDOACs –direct oral anticoagulants — little human dataIVC filters — temporary or permanent – only necessary if

recent DVTEmergency thromboembolectomy

Post thrombotic syndrome70% have post thrombotic syndrome after iliofemoral

DVT- We are entering a new age of endovascular

management of post- thrombotic syndrome- watch this space!!

Management in future pregnancies?

The aftermath Page 52

Still a major modern problem in pregnancy

Can we find better diagnostic tools to reduce the exposure to radiation?

LMWH is here to stay – can there be more trials?

Ultimately prevention is better than treatment…..

VTE in pregnancy Page 53