MORTALITY FROM BLOOD CLOT EMBOLISM-A WORRYING TREND!

A case

An obese primigravida had a breech presentation diagnosed at 34 weeks. At just under 34 weeks she was admitted with ruptured membranes and underwent caesarean section. She went home on day 4 with a haemoglobin level of 8.4g%. The next day, the midwife noted that she was breathless and had pain in her upper back. The GP visited her at home. On day 6 she collapsed at home and despite intensive care treatment she died 2 weeks later.

Mortality rates /100000 live births

YEAR NO. RATE

1997 3 0.56

1998 4 0.75

1999 11 2.14

2000 13 2.51

Introduction

Venous thromboembolism (VTE) covers a spectrum of disorders characterized by thrombosis in the venous circulation with its often fatal sequelae.

Pathogenesis

Virchow’s Triad (1860):

Increase in venous stasis

Hypercoagulability

Vascular injury

There is an increasing incidence of VTE among the Asian population partly because of greater awareness among doctors & patients themselves. The worldwide incidence exceeds 1 per 1000. Nordstrom M, et al 1992

Warning!!!

All health care providers looking after or involved in the care of the pregnant or recently pregnant mother should consider pain in the leg, chest pain and dyspnoea in an otherwise healthy woman to be due to thrombosis or pulmonary embolism until proven otherwise and ensure appropriate treatment is instituted.

VTE remains the leading cause of maternal mortality in the UK, accounting for 36% of direct deaths. Report on CEMD UK, 1998

In Malaysia, pulmonary embolism is the third cause of maternal deaths. Report on CEMD Malaysia, 1991 – 1996

There are less robust data relating to non-fatal events. Overall, a reasonable estimate is that a thromboembolic event occurs in 1 in 1500 pregnancies. Girling J, 2001

Antenatal DVT occurs in 0.06 to 0.09% of pregnancies, being twice as common in women over 35 years as those under 35 years. Girling J, 2001

In the puerperium, DVT is related to maternal age and mode of delivery.

It is likely that more DVT occur throughout the antenatal period than the postnatal period, although the risk of an event per week is greater in the latter than the former.

Pulmonary emboli are more common in the puerperium, especially following LSCS.

Risk of VTE (expressed per 1000 maternities) in relation to maternal age, pregnancy and mode of delivery

Thromboembolic event

Under 35 years Over 35 years

Antenatal DVT 0.615 1.216

Postnatal DVT 0.304 0.72

Postnatal pulmonary embolus

0.108 0.405

DVT after emergency LSCS

0.431 1.248

DVT after elective LSCS

0.238 0.68

Aetiology

Risk of VTE is increased ten-fold, due to prothrombotic physiological changes:

1. Increase in coagulation factors

2. Decrease in anticoagulants

3. Impaired fibrinolysis

Peripheral vasodilatation occurs in normal pregnancy, resulting in fall in velocity of blood flow. This reaches a nadir at 34 weeks gestation.

This fall in flow velocity is most marked in women delivering by LSCS and to a greater extent in the left femoral vein compared to the right, due to compression of the left iliac vein by the right iliac artery and the ovarian artery which only crosses over the vein on the left side.

Hence, there is a predominance of left sided DVTs in pregnancy (85% vs 15% right sided). Green IA et al, 1997

The risk of VTE is further increased in obese women, after LSCS, older women and those with intercurrent conditions such as pre-eclampsia, diabetes or dehydration from any cause.

Those with inherited or acquired thrombophilias are at particular risk.

Prevalence rates for thrombophilia in an European population

Thrombophilic defect Prevalence (per 1000 population)

MTHFR C-677 T homozygosity 100

Factor V Leiden 20-70

Lupus inhibitors 30 Anticardiolipin antibodies 30

Prothrombin 20210A 20

Antithrombin deficiency 2.5-5.5

Protein C deficiency 2.0-3.3

Pathopysiology of PE

Physical occlusion of the vascular system

Platelet activation within the thrombus release of 5hydroxytryptamine and thromboxane A2 pulmonary vasoconstriction increased pulmonary vascular resistance

Increased right ventricular afterload right heart failure left ventricular filling reduction low cardiac output

Diagnosis

Chest and leg symptoms in pregnancy which may be attributed to VTE must be investigated.

Data from non-pregnant individuals suggest that 16% of patients with untreated DVT develop pulmonary embolus, and 13% of these die, although anticoagulation substantially reduces these risks.

The diagnosis also has important implications for future pregnancy and later life.

Diagnosis

The clinical diagnosis of DVT in pregnancy is not reliable. The diagnosis was confirmed in less than 10% of pregnancies with clinical suspicion of DVT compared with 25% in non-pregnant patients.

Chest X -ray

Although CXR is rarely diagnostic, it should not be withheld solely because of pregnancy, and should be performed with confidence that the amount of radiation is negligible (equivalent to a trans-Atlantic flight) if it will facilitate management.

Arterial blood gases

Arterial blood gas analysis should be performed in sitting or left lateral position.

When supine, caval compression by the gravid uterus and functional reduction in pulmonary residual capacity and closing volume may easily give a false impression of hypoxia.

ECG

ECG usually lacks specificity, and normal pregnancy may result in right axis deviation, and both T wave inversion and Q wave in lead III, findings which outside pregnancy would suggest pulmonary embolus.

When signs and symptoms suggest PE, the absence of ECG abnormalities has a poor negative predictive value.

D-dimers

High negative predictive value in the non-pregnant state.

In pregnancy, D-dimers may be elevated as a result of the prothrombotic changes which occur, and therefore are not helpful.

Also elevated in preterm labour, placental abruption & pre-eclampsia

Simply RED D-dimer (SRDD) assay

There should be a low threshold for performing either Doppler ultrasound of the femoral veins or a V/Q scan.

A spiral/ helical CT scan can be useful in detection of pulmonary embolus.

Suspected deep vein thrombosis

CUS

Normal Abnormal

Clinical suspicion of iliac vein thrombosis

DVT diagnosed

Yes No

Consider duplex doppler Serial CUS

Flow present No duplex available

Absent flow Abnormal Normal

Consider venography or MRI

DVT diagnosed DVT absent

Suspected pulmonary embolism

Algorithm a, b or c

Algorithm a Helical CT

Algorithm b V/Q scan

Algorithm c Bilateral CUS

PE Normal Inconclusive Normal HP ND Normal Abnormal

Treat PE ruled out

CUS or PA

PE ruled out

PE treat

? PE

CUS, CT or PA

Algorithm a or b

PE diagnosed

Treatment

If a DVT or pulmonary embolus is diagnosed (or strongly suspected) in pregnancy, anticoagulation with heparin should be commenced.

Warfarin should not be used first line; not only is it teratogenic in first trimester, but also as it crosses the placenta and increases the risk of haemorrhage in utero.

Treatment of VTE is divided into acute and chronic phases.

In pregnancy, all women experiencing an acute VTE event who completed their chronic phase treatment before 6 weeks postnatal should take thromboprophylaxis until 6 weeks after delivery. This time is chosen as it is thought to represent the end of the period of increased risk due to elevated clotting factors.

Acute phase treatment

Traditionally, immediate treatment is with intravenous infusion of unfractionated heparin (UH).

However, outpatient treatment with low molecular weight heparin (LMWH) is now commonly used and is as effective as UH in preventing further VTE events.

(LEVEL B EVIDENCE) Thompson AJ et al,2000

Chronic phase treatment

When intravenous infusion of UH is used for acute phase, chronic phase treatment is commenced after 5 to 7 days. It is given as 10,000u twice daily subcutaneously.

However, LMWH is now often used in these circumstances. It is continued in treatment dose to complete 6 to 12 weeks of therapy, it is then replaced by a thromboprophylactic dose which is continued until 6 weeks postnatally.

As warfarin does not cross the breast, few women who do not get used to injecting heparin during pregnancy may wish to change to warfarin after delivery, once the risk of postpartum haemorrhage has passed.

They will however need regular measurement of prothrombin time.

Antenatal prophylactic and therapeutic doses of LMWH

Prophylaxis Enoxaparin Dalteparin Tinzaparin

50-90kg 40mg daily 5000u daily 4500u daily

<50kg 20mg daily 2500u daily 3500u daily

>90kg 40mg

12-hourly

5000u

12-hourly

4500u

12-hourly

Therapeutic dose

1mg/ kg

12-hourly

90u/ kg

12-hourly

90u/ kg

12-hourly

Thrombolysis

In non-pregnant situation, there is no clear evidence that thrombolysis improves clinical outcomes. Experience of thrombolytic therapy in pregnancy is even more limited, and can therefore only be recommended for use in life-threatening circumstances.

Follow up

Once anticoagulation is discontinued after 6 weeks postnatal, a thrombophilia screen must be performed, in order to assess their risk of recurrence and to plan their future pregnancies.

Contraception should be discussed, since oestrogen containing combined oral contraceptive pill is contraindicated in women who have had a thrombosis.

THROMBOPROPHYLAXIS Women with previous VTE should be

offered postpartum prophylaxis with LMWH. It may be reasonable not to use antenatal prophylaxis with a single previous VTE associated with a temporary risk factor that has resolved. LEVEL C

Women with previous recurrent VTE and a family history of VTE in a first-degree relative should be offered thromboprophylaxis with LMWH and for at least 6 weeks postpartum. LEVEL C

Women with previous VTE and thrombophilia should be offered thromboprophylaxis with LMWH antenatally and for at least 6 weeks postpartum

Women with asymptomatic inherited or acquired thrombophilia may qualify for antenatal or postnatal thromboprophylaxis, depending on the specific thrombophilia and the presence of other risk factors.

Low dose aspirin (75mg) is safe in pregnancy, although its use for thromboprophylaxis in this setting has never been assessed by a controlled trial. Therefore, the use of 75mg aspirin daily may be appropriate in situations where the risk of VTE is increasedRCOG, 2004 but is not deemed high enough to warrant the use of antenatal LMWH; e.g. women with previous provoked VTE without thrombophilia. Women should be advised of the lack of evidence for benefit of aspirin use for thromboprophylaxis in pregnancy.

In such women, LMWH at a thromboprophylactic dose can also be given from the onset of labour until 6 weeks postnatal.

Risk assessment – Low risk

Elective caesarean section – uncomplicated and no other risk factors

Risk assessment – moderate risk

Age > 35 years

Obesity > 80kg

Para 4 or more

Gross varicose veins

Current infection

Pre-eclampsia

Immobility prior to surgery (> 4 days)

Major current illness

Emergency caesarean section in labour

Risk assessment – high risk

Patient with 3 or more risk factors

Extended major pelvic surgery – caesarean hysterectomy

Patients with personal or family history of DVT or PE

Patients with antiphospholipid antibody

Summary of protocol for thromboprophylaxis in women with previous VTE and/ or thrombophilia

Risk Previous VTE and/ or thrombophilia status

Prophylaxis

Very high

Previous VTE (± thrombophilia) on long-term warfarin

Antenatal high prophylactic or therapeutic dose LMWH and at least six weeks of postnatal warfarin

Summary of protocol for thromboprophylaxis in women with previous VTE and/ or thrombophilia

Risk

Previous VTE and/ or thrombophilia status

Prophylaxis

High Previous recurrent VTE not on long-term warfarin

Antenatal and 6 weeks postnatal prophylactic LMWH

Previous VTE + thrombophilia

Previous VTE + family history of VTE

Asymptomatic thrombophilia (antithrombin deficiency, combined defects, homozygous FVL or prothrombin gene defect)

Summary of protocol for thromboprophylaxis in women with previous VTE and/ or thrombophilia

Risk Previous VTE and /or thrombophilia status

Prophylaxis

Moderate Single previous provoked VTE without thrombophilia, family history or other risk factors

6 weeks of postnatal prophylactic LMWH ± antenatal low-dose aspirin

Asymptomatic thrombophilia (except antithrombin deficiency, combined defects, homozygous FVL or prothrombin gene defect)

Madam SR

37 year old, Para 7.

Successful induction of labour for gestational hypertension on 06/10/07.

Was on Tab. Labetolol 100mg tds.

Delivered 3.5kg boy, without any complications.

Discharged with anti-HPT on D1.

Readmitted on 19/10/07 at D13 postnatal.

Acute onset of dyspnoea and right sided chest pain.

Clinically no pallor, but tachypnoeic (RR 28/ min).

BP: 128/ 80mmHg.

PR: 120bpm (tachycardic).

Obese (BMI 37).

SpO2: 90%

Generalised rhonchi in both lung fields, re-examination later showed no breath sounds at right lower lobe and stony dullness to percussion.

No cardiac arrythmias or murmurs.

ECG: sinus tachycardia.

ABG: respiratory alkalosis.

Hb: 12.6g/ dl

TWC: 25,000

Renal profile: acute renal failure, but resolved by D4.

Diagnosis: pulmonary embolism

Treated with nebuliser and given s/c enoxaprine 80mg bd for presumptive diagnosis of pulmonary embolism.

Spiral CT: “There is no filling defect detected in the main pulmonary trunk, right & left main pulmonary artery down to 2nd degree bronchus. Extensive right sided pleural effusion with collapse consolidation of the posterobasal segment of right lung”.

Impression: cannot rule out pulmonary embolism still.

Right pleural tapping done: 600cc straw coloured fluid.

Pleural tap FEME: predominant polymorphs.

Pleural tap biochemistry: exudative.

Impression: Collapse consolidation right lower lobe lung, cannot rule out pulmonary embolism

Treated with oxygen support, s/c enoxaprine decreased to 40mg od (prophylactic dose).

Lessons from the CEMD:

- Deaths due to suboptimal care:

Failure to appreciate the significant risk factors

Failure to deliver adequate prophylaxis

Failure to diagnose and deliver appropriate treatment

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