1. Venous Thromboembolism in Pregnancy
Professor Catherine Nelson-Piercy
Guy’s & St Thomas’ Foundation Trust and
Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare Trust

2. Causes of maternal death
74% of women who died had a pre-existing medical disorder
Solid bars show indirect causes, hatched bars show direct causes

3. Maternal deaths from VTE

4. The new RCOG guidelines
Treatment Prevention

5. Diagnosis of DVT in Pregnancy
88% on left (vs. 55% in non pregnant)
71% proximal (vs. 9% in non pregnant)
64% were restricted to the iliac and/or femoral vein.
Chan WS et al. CMAJ 2010; 182:657-60

6. Unless pregnancy specific ranges are used
Diagnosis
DVT
Doppler US PE
CXR
V/Q Lung scan
CTPA
D dimers are useless!!
Unless pregnancy specific ranges are used

7. Diagnosis - problems
US may miss below knee / above inguinal ligament. Solution:
If US negative and high level of clinical suspicion of DVT……
continue anticoagulation and repeat US day 3 and 7
Do MR venogram
Prevalence of ultimately diagnosed PE in pregnant women with suspected PE is 2–6%. Solution:
Stop irradiating women without good history!
Half dose perfusion only

8. 2014;21:949–959
frequency of VTE 506 preg 4.1% (95% CI = 2.6% to 6.0%)
frequency of VTE non-preg 12.4% (95% CI = 9.0% to 16.3%)

9. Radiation exposure
Rads mGy CXR <0.001 <0.01 Perfusion scan <0.08 <0.8 Ventilation scan <0.01 <0.1 CTPA / Helical CT <0.013 <0.13 Max recommended <0.5 5

10. V/Q versus CTPA
Increased risk of fatal childhood cancer to the age of 15 following in utero radiation exposure = 0.006% per mGy, (1 in per mGy).
The fetal radiation exposure associated with CTPA = 0.1 mGy
V/Q = 0.5 mGy
10 mGy radiation (CTPA) to a woman’s breast increases lifetime risk of developing breast cancer by 13.6% above her background risk
V/Q investigation of first choice for young women especially if FH of breast CA or patient has had previous chest CT scan
Higher rate of nondiagnostic scans in pregnancy with CTPA (37.5%)
V/Q (4%)
(may be related to the imaging protocol employed).
Ridge CA, et al. Am J Roentgenol 2009;193:1223–7.

11. CTPA vs V/Q
304 women with a clinical suspicion of PE Primary outcome = nondiagnostic study for PE (CTPA) "low or intermediate probability" in the V/Q group. initial diagnostic test = CTPA in 108 (35.1%) V/Q in 196 (64.9%) Higher rate of nondiagnostic study CTPA (17.0% compared with 13.2%, P=.38) subgroup of women with a normal chest X-ray, CTPA more likely to yield a nondiagnostic result than V/Q even after adjusting 30.0% compared with 5.6%, adjusted odds ratio 5.4, 95% CI , P<.01). Cahill AG et al. Obstet Gynecol Jul;114(1):124-9

12. Diagnostic algorithm for PE in pregnancy
Suspected PE
ABG, ECG, CXR
Start anticoagulation LMWH treatment dose
UNSTABLE
STABLE
Clinically urgent
(out of hours)
DOPPLER USS LEGS
+ve
-ve
Portable echo
CXR normal
CXR abnormal
V/Q scan
-ve
CTPA
Still suspicious of PE
-ve
+ve
Suggestive of
massive PE
+ve
Ventilation/perfusion (V/Q) scanning is a useful first imaging test for suspected PE in pregnancy; however, in one study, 21% of scans were non-diagnostic, which meant that further imaging was required (Bourjeily et al. 2010).
Advantages of CT pulmonary angiography over V/Q scanning are that CT offers an alternative diagnosis in patients with respiratory symptoms, and may help exclude other diagnoses.
Some centres use V/Q scanning before CT if the chest X-ray is normal and no other pathology is suspected.
Reference:
Bourjeily G et al. Pulmonary embolism in pregnancy. Lancet 2010;375:500–12.
Scarsbrook AF et al. Diagnosis of suspected venous thromboembolic disease in pregnancy Clin Radiol 2006;61:1-12
Stop anticoagulation
Thrombolysis/i.v. heparin/ thrombectomy
Anticoagulate with LMWH
ABG, arterial blood gas;
ECG, electrocardiogram;
CXR, Chest X-ray;
USS, ultrasound sonography;
CTPA, computerised tomography pulmonary angiography
Modified from: Scarsbrook et al. Clin Radiol 2006;61:1–12
Pregnancy slide kit D321 Feb to LEO

13. Diagnosis of PE in pregnancy
Women with suspected PE should be advised that, compared with CTPA, V/Q scanning may carry a slightly increased risk of childhood cancer but is associated with a lower risk of maternal breast cancer; in both situations, the absolute risk is very small. Recent studies have shown a superior sensitivity and specificity when using V/Q single photon emission computed tomography (SPECT) in diagnosing PE than conventional planar V/Q scintigraphy and this may safely be performed in pregnancy.

14. Dose and pregnancy Worst case scenario:- Dose to fetus:-
Perfusion (technetium): 2.2mSv Ventilation (krypton): 0.29mSv Ventilation (technetium): 1mSv 1mSv: 1 in 20,000 chance of fatal cancer 1 year in London: 2 mSv 1 year in Cornwall: 8 mSv
Perfusion: 0.44 mSv Ventilation: 1.5 micro Sv Risk of fatal malignancy in child: 1 in 40,000 due to V/Q dose Natural risk of 1 in 500

15. V/Q single photon emission computed tomography (SPECT)
V/Q planar
V/Q SPECT
Injected dose for perfusion = double planar Pregnancy use half ie. Same as planar

16. Abnormal VQ SPECT
PERF
VENT
PERF
VENT
PERF
VENT

17. Treatment: Dose of LMWH
Give while waiting for confirmation Enoxaparin 1mg/kg/bd NOT 1.5 mg/kg od (= non-pregnant dose) Higher doses of dalteparin also recommended

18. 123 women requiring antenatal LMWH
795 anti-Xa activities for pharmacokinetic modeling purposes
3 anti-Xa activities (trough and 1 and 3 hours after dose).
Compartmental pharmacokinetic modeling was conducted using nonlinear mixed-effects modeling.

19. A and B, Simulated 3-hour (red) and trough (blue) anti-Xa activity, once-daily (A) and twice-daily (B) enoxaparin.
A and B, Simulated 3-hour (red) and trough (blue) anti-Xa activity, once-daily (A) and twice-daily (B) enoxaparin. Lines represent the 5th, median (solid), and 95th percentile anti-Xa activity.
Patel J P et al. Circulation. 2013;128:
Copyright © American Heart Association, Inc. All rights reserved.

20. As pregnancy progresses:
Population Pharmacokinetics of Enoxaparin During the Antenatal Period Jignesh P. Patel, PhD; Bruce Green, DClinPharm; Raj K. Patel, MD; Michael S. Marsh, MD; J. Graham Davies, PhD; Roopen Arya, PhD
As pregnancy progresses:
3-hour anti-Xa activity decreases (increased clearance)
trough anti-Xa activity increases (increased volume of distribution, prolonging t1/2 of enoxaparin)
3-hour target of 0.5 to 1.2 achieved without a need for a change in dose for the duration of pregnancy with once and twice daily regimes.
Elimination half-life is a function of both clearance and volume of distribution.
Increase in volume of distribution during pregnancy leads to a prolongation of enoxaparin half-life, so once-daily dosing is adequate.

22. RCOG - VTE Risk Assessment

23. Thrombosis and thromboembolism
Mortality rates to
RCOG Working Party thromboprophylaxis gynaecology and obstetrics. 1995
(post CS)
RCOG Thromboprophylaxis Guideline 2004 (an + post vd)
Sharp and statistically significant fall in mortality rate:
1.94 (95% CI ) per 100,000 maternities
0.79 (95% CI ) per 100,000 maternities

25. Key Recommendations
C All women should undergo an assessment of risk factors for VTE in early pregnancy or before pregnancy. This assessment should be repeated if the woman is admitted to hospital or develops other intercurrent problems and after delivery.

26. Distribution of VTE in pregnancy and puerperium90
VTE incidence:
1st trimester: 10.1%
2nd trimester: 10.4%
3rd trimester: 28.4%
49.3% of VTE occurred during the first 6 weeks postpartum 80 70 60
VTE (n) 50 40 30 20 10
A register-based, case-control study with 613,232 pregnancies from 1990–2003 in 11 Norwegian counties identified 615 cases of VTE (Jacobsen et al. 2008). Analysis of the medical data from these patients revealed that DVT was more common antenatally than postnatally (0.43 vs per 1,000 deliveries, respectively). Conversely, PE incidence was higher postnatally (0.22 vs per 1,000 deliveries).
Similar results were seen in a retrospective analysis of 33,311 deliveries between June 2003 and June 2008 in the USA which revealed 51.6% of VTEs occurred in the postnatal period; the majority of which (68%) were seen in patients who had delivered by caesarean section (O’Connor et al. 2010). Of those that had a VTE during pregnancy, 28% were in their first trimester, 25% in the second and 47% in the third.
References:
Jacobsen AF et al. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium – a register-based case-control study. Am J Obstet Gynecol 2008;198(2):233.e1–7.
O’Connor DJ et al. Incidence and characteristics of venous thromboembolic disease during pregnancy and the postnatal period: a contemporary series. Ann Vasc Surg 2011;25(1):9–14. 12 24 36 1 6 12
Antepartum
Postpartum
Weeks
Delivery
Jacobsen et al. Am J Obstet Gynecol 2008;198(2):233.e1–7
Pregnancy slide kit D321 Feb to LEO

27. First trimester risk factors – ART / IVF
Norway, adjusted OR for VTE 4.3 (95% CI, (Jacobsen J Thromb Haemost 2008;6:905-12) Korea, adjusted OR for VTE 4.2 (Korean Circ J 2011;41:23-27) Swedish study ( ) Henricksson et al, BMJ 2013; 346
IVF
Natural
Hazard ratio n
23,498
116,960
VTE (n) 99
291
VTE/1000
4.2
2.5
1.8 ( )
T1 VTE/1000
1.5
0.3
4.2 ( )
T1 PE/10,000
3.0
0.4
7.0 (2.2-22)

28. National register-based cohort study, 1995 to 2005.
All Danish pregnancies conceived by IVF (n = )
48 cases VTE
VTE incidence was significantly increased in pregnancies after IVF; especially in the first trimester and in the first 6 weeks post-partum.

29. Hansen et al. Human Reproduction 2014
VTE incidence rate (per woman-years) IVF: 28.6 (95% CI 20.6–39.6) reference: 10.7 Post-partum VTE IR (per woman-years) IVF: 27.9 (95% CI 15.8–49.1) reference: 17.5 Overall VTE IRR IVF compared with reference pregnancies = 3.0 (95% CI 2.1–4.3). 2.8 (95% CI 1.9–4.1) in singleton 4.4 (95% CI 2.4–8.3) in multiple Postpartum VTE IRR 1.2 (95% CI 0.6–2.8) for singleton 3.9 (95% CI 1.7–8.8) for multiple The post-partum VTE risk was higher in multiple IVF pregnancies compared with singleton IVF pregnancies

30. Cumulative incidence of VTE during pregnancy.
Cumulative incidence of VTE during pregnancy. Singleton and multiple pregnancies, and reference pregnancies.
Hansen A et al. Hum. Reprod. 2014;29:
© The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please

31. Cumulative incidence of VTE in the puerperal period in IVF pregnancies, and reference pregnancies.
Hansen A et al. Hum. Reprod. 2014;29:
© The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please

33. Rate of VTE per 100,000 person years by antenatal admission to hospital and after hospital stay
Variable
No of VTE
Rate* (95% CI)
Adjusted IRR (95% CI)†
Time outside hospital
150
97 (83 to 114)
1.00
Hospital admission 6
1752 (787 to 3900)
17.5 (7.69 to 40.0)
After discharge 20
676 (436 to 1048)
6.27 (3.74 to 10.5)
Variation by duration of hospital stay (combining admission/after discharge)
<3 days 13
558 (331 to 943)
4.05 (2.23 to 7.38)
³3 days
1511 (858 to 2661)
12.2 (6.65 to 22.7)
IRR=incidence rate ratio.
*Rate calculated per person years.
†Adjusted for maternal age, calendar year, BMI, gestational infection, cardiac disease, varicose vein, gestational diabetes, and hyperemesis.
Sultan A et al. BMJ 2013;347:bmj.f6099

34. Fig 2 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.
Fig 2 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

35. Risk factor for VTE aOR 95% CI
Previous VTE 1
24.8
Age > 35 4
1.3
BMI > 30 2 1
5.3
4.4
Smoking 3
2.7
Parity >3 4
2.4
Medical Conditions1
Sickle cell disease, SLE, Heart disease, anaemia, infection,
Hyperemesis
2.0 – 8.7
2.51
Immobility 3
7.7 (an)
10.8 (pn)
3.2-19
4-28.8
Pre-eclampsia3
+Fetal Growth Restricition
3.1
5.8
2.1-16
ART 3
4.3
Twins3
2.6
APH 1
2.3
PPH 3
4.1
Caesarean section 4
3.6
Varicose veins
Transfusion1
7.6
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.
1.James et al 2006; 2.Larsen et al 2007; 3.Jacobsen et al 2008; 4.Lindqvist et al 1999

36. Sultan AA, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ
Sultan AA, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ. Risk of first venous thromboembolism in and around pregnancy: A population-based cohort study.
Br J Haematol Feb;156(3):

37. So …….antenatally
Previous VTE - LMWH from early Four risk factors - LMWH throughout Three risk factors - LMWH from 28 weeks Admission – LMWH unless contraindications / bleeding First trimester -OHSS – LMWH for T1 -IVF – LMWH if 3 other risk factors -HG – LMWH for admission

38. Absolute and relative rates of VTE by risk factors Postpartum
Variable
VTE
Rate1
95 %CI
IRR2
95%CI
Age=35 – 44 years 81
497
399 – 618
1.51
1.15 – 1.98
Obese (≥30) 79
926
742 – 1554
3.75
2.76 – 5.07
Current smokers 80
403
324 – 502
1.31
1.01 – 1.71
Caesarean delivery 83
637
1.99
1.52 – 2.58
3 or more previous births 25
904
611 – 1338
2.07
1.34 – 3.20
Stillbirth 6
2444
1098 – 5440
6.24
2.77 – 14.1
Pre-term birth 51
854
649 – 1124
2.69
1.99 – 3.65
Obstetric haemorrhage 10
963
518 – 1791
2.89
1.53 – 5.43
Acute systemic infection 43
455
1.33
0.96 – 1.85
Varicose veins
1330
899 – 1969
3.83
2.51 – 5.82
Cancer 5
446
185 – 1073
1.21
0.49 – 2.96
Inflammatory bowel disease
1514
630 – 3638
4.56
1.88 – 11.0
Cardiac disease 2
2258
6.58
1.63 – 26.5
Sultan AA et al. Blood May 9;121(19):

39. 1.7 million women, first delivery
California,
1.7 million women, first delivery
1015 thrombotic events in 1 year and 24 weeks post delivery
47 MI; 248 CVA; 720 VTE

40. Weeks
Post
partum
VTE OR
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

41. So………Postnatal
All previous VTE – 6 weeks All em CS- 10 days Any woman with 2 risk factors including: CS PPH / transfusion Infection Stillbirth Preterm labour

44. Thrombophilia
Women with a family history of VTE and either antithrombin deficiency or where the specific thrombophilia has not been detected should be tested for antithrombin deficiency. Women with an unprovoked VTE should be tested for the presence of antiphospholipid antibodies. Heterozygosity for factor V Leiden or prothrombin gene mutation or antiphospholipid antibodies are considered as risk factors for thrombosis in asymptomatic women. In the presence of three other risk factors such women may be considered for antenatal thromboprophylaxis, if there are two other risk factors thromboprophylaxis should be considered from 28 weeks and if there is one other risk factor postnatal thromboprophylaxis for 10 days should be considered. Women with no personal history or risk factors for VTE but who have a family history of an unprovoked or estrogen-provoked VTE in a first-degree relative when aged under 50 years should be considered for thrombophilia testing. This will be more informative if the relative has a known thrombophilia.