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Thromboembolism and thrombophilia
ARTICLE IN PRESS Current Obstetrics & Gynaecology (2004) 14, 11–22
www.elsevier.com/cuog
Thromboembolism and thrombophilia Joanna Girling* Department of Obstetrics and Gynaecology, West Middlesex University Hospital, Twickenham Road, Isleworth, TW7 6AF, UK
KEYWORDS Pulmonary embolus; Deep vein thrombosis; Inherited thrombophilia
Summary Thromboembolism remains the major cause of maternal mortality in the United Kingdom. There are important differences in the diagnosis and treatment of thrombosis in pregnant patients compared with the non-pregnant patient. Thromboprophylaxis should be considered for high-risk women (for example those who had previously experienced thrombosis). For women in high-risk obstetric situations (for example those who had experienced Caesarean section). Inherited and acquired thrombophilias increase the risk of thrombotic episodes during pregnancy, and may play a role in adverse obstetric events. & 2003 Published by Elsevier Ltd.
Introduction Thrombosis may be fatal. Survivors of thrombotic events have an increased risk of recurrence, and many suffer the painful consequences of venous insufficiency. This article will discuss the aetiology, diagnosis and treatment of thrombosis in pregnancy, the prevention of thrombosis and the roles that thrombophilias may play in obstetric practice.
Thromboembolism Incidence Thromboembolism remains the leading cause of maternal mortality in the United Kingdom. In the triennium 1997–1999, thromboembolism caused 1.4 deaths per 100 000 maternities and accounted for one third of direct deaths. The Report on Confidential Enquiries into Maternal Mortality (CEMD) emphasises the importance of vigilance for thromboembolic events throughout the whole of pregnancy and the puerperium, and the need for *Tel.: þ 44-(0)-208-565-5114; fax: þ 44-(0)-208-565-5428. E-mail address: [email protected] (J. Girling). 0268-0890/$ - see front matter & 2003 Published by Elsevier Ltd. doi:10.1016/j.curobgyn.2003.10.001
thromboprophylaxis in high-risk situations. Thirty one women died from thromboembolic disease (TED) during 1997–1999, 14 (45%) antenatally: 9 of these occurred in the first trimester, of which only 1 patient died following surgery (termination of pregnancy or ectopic pregnancy). Only in 1 of the antenatal cases was the diagnosis reached before post-mortem. In the remaining cases women were given other diagnoses including muscle strain, anxiety, chest infection and sore throat. It is imperative that healthcare professionals working with pregnant women are aware that TED may strike at any gestation, and they should have a low threshold for investigating relevant leg or chest symptoms. During the same period (1997–1999), 14 women died postnatally. Only 4 (29%) of these deaths followed Caesarean section and all were in the first week. All of these women had additional risk factors other than surgery but none had received adequate thromboprophylaxis. Ten deaths occurred after vaginal delivery, all but 1 more than a week later, and all but 1 showed risk factors for thrombosis. The deaths following Caesarean section have fallen from 15 during 1994–1996, presumably as a reflection of improved surgical thromboprophylaxis. More action is now required to reduce the number of events after vaginal deliveries (see later).
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Although there are accurate data on fatal TED, there are less robust data relating to non-fatal events. Overall, a reasonable estimate is that a thromboembolic event occurs in 1 in 1000–1 in 1500 pregnancies. A number of studies have suggested that antenatal deep vein thrombosis (DVT) occurs in 0.06–0.09% of pregnancies, being twice as common in women over 35 years of age as those under 35 years of age. Similarly, in the puerperium DVT is related to maternal age and mode of delivery (see Table 1). Although the data are conflicting, it is likely that more DVTs occur throughout the antenatal period (and not at any particular gestation) rather than during the postnatal period, although the risk per week of an event is greater in the latter than the former (since pregnancy lasts 9 months and the puerperium 6 weeks). Pulmonary emboli are more common in the puerperium, especially following Caesarean section.
Aetiology The risk of TED is increased six fold in pregnancy, due to prothrombotic physiological changes in all three arms of Virchow’s triad. There is an increase in: coagulation factors I (fibrinogen), V, VII, VIII, IX, X, XII; von Willebrand factor antigen and ristocetin cofactor activity and a decrease in some endogenous anticoagulants (antithrombin, protein S and activated protein C resistance) which are most marked near term and following delivery. There is also impaired fibrinolysis during pregnancy, due to placentally-derived plasminogen activator II, and raised endothelial and hepatic plasminogen activator I, which revert to normal at delivery. Peripheral vasodilatation occurs in normal pregnancy, resulting in a marked fall in velocity of blood flow. This is evident from early in the second
Table 1 Risk of TED (expressed per 1000 maternities) in relation to maternal age, pregnancy and mode of delivery Thromboembolic event
under 35 years
over 35 years
Antenatal DVT Postnatal DVT Postnatal pulmonary embolus DVT after emergency LSCS DVT after elective LSCS
0.615 0.304 0.108
1.216 0.72 0.405
0.431
1.248
0.238
0.68
trimester, and reaches a nadir from 34 weeks to term; it does not return to normal until 6 weeks postnatally. This fall in blood flow velocity is most marked in women delivering their babies by Caesarean section. It also occurs to a greater extent in the left femoral vein compared with the right. This is secondary 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. This explains the predominance of left sided DVTs in pregnancy (85% left vs. 15% right sided). Finally, trauma to the pelvic veins may occur as the baby’s head passes through the pelvis, and this may be worsened by operative or abdominal delivery. The immobility and dehydration of labour may also contribute to the risk of postnatal DVT. The risk of TED is further increased in obese women; those subjected to bed-rest or undergoing Caesarean section; older women and those with intercurrent medical conditions such as preeclampsia, diabetes or dehydration from any cause (for example hyperemesis gravidarum or ovarian hyperstimulation syndrome). Women who have a personal history of TED are at increased risk, especially if they have an inherited or acquired thrombophilia, or a family history (itself suggestive of an inherited thrombophilia).
Diagnosis In pregnancy it is essential that chest and/or leg symptoms which may be attributable to TED are investigated, and a diagnosis of thrombosis definitely confirmed or excluded. Data from nonpregnant individuals suggests that 16% of patients with untreated DVT develop pulmonary embolus, and 13% of these patients die, although anticoagulation substantially reduces these risks. Thus a positive diagnosis of TED has important implications for immediate management. But as this treatment it is not without risk, it is vital that the diagnosis is secure. The diagnosis of TED also has important implications for future pregnancy and in later life. Clinical awareness of TED in pregnant women makes it much easier to reach the correct diagnosis. Although chest X-ray is rarely diagnostic, it should not be withheld solely because of the pregnancy. If the clinical impression is that it will facilitate management, it should be performed with confidence in that the amount of radiation is negligible (o10 mGyFequivalent to a one-way flight to New York from London, when compared with a recommended upper limit of exposure in pregnancy to 50 000 mGy). If the clinical impression is that it will facilitate management. Arterial blood
ARTICLE IN PRESS Thromboembolism and thrombophilia
gas analysis should be performed in the sitting or left lateral position: when supine, inferior vena caval compression by the gravid uterus and functional reduction in pulmonary residual capacity and closing volume may give a false impression of hypoxia. In uncomplicated pregnancy, the pO2 is unchanged compared with the non-pregnant situation, but falls by around 2 kPa (17 mmHg) when lying supine (pO2 13 kPa [100 mmHg] standing, 11 kPa [83 mmHg] supine); pCO2 in normal pregnancy falls from 5 kPa (35–40 mmHg) to 4 kPa (30 mmHg). Electrocardiography usually lacks sufficient specificity to be helpful, particularly as normal pregnancy may result in right axis deviation, and both T-wave inversion and Q-wave in lead 111, findings that outside pregnancy would be suggestive of pulmonary embolus. Outside pregnancy, a low D dimer concentration is a valuable negative discriminator for thrombosis; in pregnancy, D dimers may be elevated as a result of the prothrombotic changes which occur, and therefore are not helpful. There should be a low threshold for performing either Doppler ultrasound of the femoral veins or lung ventilation/perfusion scanning. It is unusual for a clot to be isolated in the iliac vessels, and so the inability to visualise these with ultrasound is not usually problematic. Treatment should be initiated during the investigations if the clinical suspicion is high, and then revised accordingly once all the results are available.
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heparin (LMWH) for 6–12 weeks. Currently the Royal College of Obstetricians and Gynaecologists recommends that a treatment dose of LMWH be used from the outset. In the treatment of DVT outside of pregnancy, this has been shown to reduce mortality and haemorrhagic complications compared with unfractionated heparin. When used for treatment of pulmonary emboli the two options are equally effective (see later). Higher doses of heparin are required in pregnancy than outside of pregnancy, largely because of increased renal clearance, haemodilution and the action of placental heparinase. For example, outside pregnancy, dalteparin is used at 10000–18000 units once daily, depending on weight. In pregnancy 100 units/ kg twice daily to a maximum of 18000 units is advised; enoxaparin is used outside pregnancy at 1.5 mg/kg/day, but in pregnancy 1.0 mg/kg/twice daily is advised: see Table 2 for suggested regimen. The target therapeutic range for LMWH is a peak anti Xa level of 0.4–1.0 u/ml 3 to 4 h post-injection. It is relatively uncommon to need to adjust the dose of LMWH, and frequent monitoring does not seem to be helpful. Therefore, the first measurement can be made on the first normal working day after treatment is commenced, and then approximately every 4 weeks. The affected leg should initially be elevated to minimise oedema, but mobilisation must be encouraged. A full leg graduated compression stocking should be worn.
Treatment If a DVT or pulmonary embolus (PE) is diagnosed (or strongly suspected) in pregnancy, anticoagulation with heparin should be commenced. Warfarin should not be used in first-line management of TED in pregnant women, as not only is it teratogenic in the first trimester, but also as it crosses the placenta, which in effect anticoagulates the fetus, increasing the risk of spontaneous haemorrhage in utero especially within the brain. However, heparins and warfarin are safe to take during lactation. Blood should be taken to check for the presence of inherited or acquired thrombophilia, when possible before heparin is commenced; results of some nongenetic tests must be treated with caution as pregnancy can cause false positive results (see later). Initial treatment Recently treatment of TED in pregnancy has changed. Previously, intravenous unfractionated heparin (UH) was advised for 5–7 days, followed by a treatment dose of low molecular weight
Maintenance treatment Therapeutic doses of LMWH should be continued for 3–6 months, determined on an individual basis according to gestation at diagnosis and presence of on-going risk factors. If this takes the patient to less than 6 weeks post-delivery (the time thought to be required for the risk factors of pregnancy to resolve), she should change onto a thromboprophylactic dose of LMWH (see later) until then 6 weeks is thought to be the time required for the risk factors of pregnancy to resolve.
Table 2 Starting dose of enoxaparin in treatment of TED in pregnancy Early pregnancy weight (kg)
Initial dose of enoxaparin
o50 50–69 70–89 490 kg
40 mg twice daily 60 mg twice daily 80 mg twice daily 100 mg twice daily
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After delivery, the patient can switch to warfarin from day 2 if she prefers, continuing heparin until her INR is in the target range of 2.0–3.0. She will need to attend a clinic regularly for measurement of her prothrombin time. She should not take warfarin during pregnancy (see above). Recent evidence outside pregnancy suggests that long-term use of low intensity warfarin, aiming for a target INR of 1.5–2.0, reduces the risk of recurrent TED by at least 64% over a 4 year period, without increasing the risk of haemorrhage in those with and without inherited thrombophilia. It remains to be seen how much this will influence clinical practice in women of childbearing age. Treatment during labour and delivery The main issue in this period relates to the use of regional analgesia. Women should have this option available to them whenever possible, and however unlikely their requirement for this may seem, to minimise the need for general anaesthetic and its attendant complications (which include thrombosis). This should be discussed with the patient before the onset of labour, and appropriate alterations to their therapy instituted. There should be a locally agreed policy involving obstetricians and anaesthetists. Women should be advised not to inject if they believe that they are in early labour, instead they should contact the delivery suite for assessment. Regional analgesia should not be sited for 12–24 h following an injection of LMWH (for prophylactic and treatment doses respectively), and then only if the platelets and clotting are normal, in order to minimise the risk of spinal haematoma and its potentially disastrous complications. Although this is a rare event, both the Royal College of Obstetricians and Gynaecologists and the Report on Confidential Enquiries into Maternal Morbidity recommend this policy. There are 3 options for the heparin regimen in labour, one of which is usually appropriate: *
*
if the thromboembolic event was early in pregnancy, the patient can be switched from her prophylactic dose of LMWH to a prophylactic dose of unfractionated heparin, 10000 units twice daily at 36–37 weeks gestation. In this case, only a 4 h window is required from last injection to regional technique; the second option is to plan delivery, preferably vaginally if other obstetric risk factors make this appropriate. A cervical sweep followed by induction of labour can be planned to coincide with a change to the thromboprophylactic regime as outlined above. The timing of this
*
needs to be balanced to minimise the risks of both ‘prematurity’, onset of labour before the agreed gestation period and recurrent TED. This has the potential advantage for women at high-risk of recurrence, of minimising the number of days they are off their treatment regimen. Unfortunately it has the disadvantage of risking immobilisation and dehydration on an antenatal ward. This option may be most appropriate for those women thought to have a substantial chance of a further clot, including those in the first few months of a treatment dose of LMWH; the third option, especially for women who are confident they will not require epidural for analgesia and in whom the chance of a emergency Caesarean in labour seems low, is to stay on the LMWH without instituting any changes: this is only potentially applicable to women on thromboprophylactic doses.
If Caesarean section is indicated on obstetric grounds, the woman should have a thromboprophylactic dose of LMWH on the day prior to surgery. Her operation should be performed as soon as possible in the morning, and she should have another thromboprophylactic dose as soon as possible after removal of the epidural catheter, usually 3–6 h depending on local policy. That evening she should return to her treatment dose (as appropriate: see above). Emergency or ‘rescue’ treatment A temporary caval filter can be positioned when recurrent pulmonary emboli occur despite treatment, or when anticoagulation therapy is contraindicated. Thrombolysis, percutaneous catheter thrombus fragmentation or surgical embolectomy can be considered if life-threatening massive pulmonary embolus occurs outside pregnancy, although there is no clear evidence that these improve the clinical outcome of TED. Experience of thrombolytic treatment in pregnancy is even more limited, and it can therefore only be recommended for use in life-threatening circumstances.
Follow-up Women who have experienced a thrombosis during pregnancy should be followed-up, preferably by a doctor with an interest in the management of thrombosis in pregnancy. Once they have discontinued anticoagulant therapy and are at least 6 weeks postnatal, a thrombophilia screen must be performed in order to assess the risk of recurrence
ARTICLE IN PRESS Thromboembolism and thrombophilia
and to plan management during future pregnancies (see below). Contraception should also be discussed, since the oestrogen-containing combined oral contraceptive pill is contraindicated in women who have had a thrombosis. Other forms of contraception both hormonal and nonhormonal are permissible. Patients should be advised to wear a graduated compression stocking on the affected leg for 2 years, as this reduces the risk of post-thrombotic syndrome from 23% to 11% in this time frame.
Thromboprophylaxis Prevention of TED is important, and should be offered to women considered to be at high-risk. An assessment of every pregnant woman’s inherent risk of thromboembolic disease should be made at booking, by establishing whether she has a personal or family history of TED. In addition, every pregnant woman who enters a high-risk situation should have her risk of TED re-evaluated. Ideally each maternity unit should have an obstetrician or a physician (or both), who have an active interest in this field and can give up to date advice on management of these sometimes complex cases.
Table 3
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Previous thromboembolic event Women who have experienced a single previous thromboembolic event, but have no family history and a negative thrombophilia screen, should take aspirin 75 mg daily throughout pregnancy, and LMWH at a thromboprophylactic dose from the onset of labour until 6 weeks postnatally. Women who have had more than one thromboembolic event or who have had a single event but have a family history or positive thrombophilia screen should take LMWH from early pregnancy until 6 weeks postnatally. Usually therapy is started at around 5–6 weeks into gestation once an ultrasound scan has demonstrated a beating fetal heart. If patients have antithrombin deficiency (see below), depending on the titre in the weeks leading up to delivery, an antithrombin infusion may be required before and/or during labour.
High-risk obstetric situation In 1995, the Royal College of Obstetricians and Gynaecologists issued guidelines relating to thromboprophylaxis in pregnancy, which included guidelines following Caesarean section (LSCS) (see Table 3).
Thromboprophylaxis at Caesarean section
Risk category
Definition
Management Early mobilisation Good hydration
Low * * *
Elective LSCS Uncomplicated pregnancy No other risk factors TED stockings or subcutaneous heparin
Moderate * * * * * * * *
Emergency LSCS in labour Age 435 years Obese 480 kg Gross varicose veins Current infection Pre-eclampsia Immobilisation prior to LSCS 44 days Major current illness e.g. heart or lung disease, inflammatory bowel disease, nephrotic syndrome, diabetes
High * *
* * *
3 or more moderate risk factors Extended abdominal or pelvic surgery e.g. Caesarean hysterectomy Personal or family history of TED Antiphospholipid syndrome Paralysis of lower limbs
TED stockings plus subcutaneous heparin (commencing during LSCS and continuing until day 5)
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Each unit should have a locally agreed policy, based upon these guidelines, which is strictly adhered to. Many hospitals have chosen to give heparin to the majority of, if not all, women undergoing LSCS. Anticoagulation therapy is usually commenced intra-operatively, and continued until the woman is freely mobile or 5 days postnatally. In addition, women with multiple risk factors should also be considered for antenatal and/or postnatal thromboprophylaxis regardless of the mode of delivery: for example an obese, pregnant woman who smokes, has pre-eclampsia and is admitted to hospital may benefit from LMWH. Immobility, dehydration, maternal age and intercurrent infections or medical conditions may also substantially increase the risk of thrombosis. The most recent CEMD contains a guideline for thrombosis prophylaxis after vaginal delivery (see Table 4).
Positive thrombophilia screen Increasingly, women discover they have a thrombophilia when a family member is screened following a thromboembolic event. The implications of these results are not entirely clear. It may be appropriate to give low-dose aspirin antenatally and/or LMWH during the puerperium, though this should be determined on an individual basis.
Table 4
Air travel In 2001, the Royal College of Obstetricians and Gynaecologists published an opinion paper giving advice for pregnant women planning to travel by air. The advice was extrapolated from non-pregnant patients, and is summarised in Table 5. In essence, pregnant women who choose to fly should minimise their risk factors by keeping active and well hydrated on-board, and in certain cases by wearing compression stockings and taking low molecular weight heparin or aspirin. Similar advice should be considered if prolonged and continuous travel by any means is being considered.
Side effects of unfractionated and low molecular weight heparin Heparin, whether unfractionated or low molecular weight does not cross the placenta or into breast milk, and is therefore safe from a fetal point of view. There are 3 potential maternal side effects to be considered, which should be discussed with every patient for whom heparin is prescribed. The pregnant woman is at risk of heparin-induced thrombocytopenia (HIT), osteopenia, and haemorrhage. These complications are less likely with LMWH than unfractionated heparin (UH) in trials on
Thromboprophylaxis after vaginal delivery for women who have never had a thrombosis
Risk category
Definition
Management
Low
Uncomplicated pregnancy
Early mobilisation Good hydration
Moderate
Any 2 of the following: * Age 435 years * Weight 4 80 kg at booking * Para 4 or more * Labour 412 h * Gross varicose veins * Current infection * Pre-eclampsia * Immobility prior to labour 44 days * Midcavity or rotational forceps delivery
LMWH once daily as soon as possible after delivery, until discharge
High * * * * *
4 or more moderate risk factors Extended surgery Family history of TED Lower limb paralysis Lupus anticoagulant or anticardiolipin antibodiesn
LMWH plus graduated stockings form as soon as possible after delivery until either discharge or if n6 weeks
ARTICLE IN PRESS Thromboembolism and thrombophilia
Table 5
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Prevention of TED in pregnant women travelling by air
Any gestation and until 6 weeks postnatal
Short haul (o 3 h)
Long haul (43 h)
No additional risk factors * * * *
Additional risk factors
Calf exercises Mobilise during flight Avoid dehydration Minimise alcohol and caffeine intake
As low-risk short haul plus * Wear well-fitting elastic below knee compression stockings
non-pregnant individuals and it seems likely that this holds true in pregnant women: *
*
*
bleeding complications are less likely since the shorter polysaccharide chain of LMWH (average molecular weight 4000 to 5000 Da) is only able to bind to antithrombin (AT) which results in the inhibition of factor Xa, but not to thrombin (factor IIa) (which requires a longer chain) (Fig. 1). Thus LMWH has very little anticoagulant activity (anti IIa) but good antithrombotic activity (anti Xa); UH (molecular weight 12000 to 14000 Da) has approximately equal amounts of each; HIT may occur acutely within the first week of treatment or chronically with prolonged use, but is rare in either form. Thrombocytopenia is less likely with LMWH than UH, since chains with a molecular weight of less than 8000 Daltons are unable to interact with platelets, although this has only been proven in non-pregnant patients; there are a few studies concerning bone loss with LMWH use in pregnancy and it is seems likely that it causes less osteopenia than UH. Indeed, bone loss with LMWH is probably comparable to that occurring in normal pregnancy, that is 5% in the lumbar spine L2–4. Vertebral fractures have been reported after as little as 7 weeks of low dose UH treatment. It is possible that these fractures reflect in part an unmasking of a pre-existing low bone mass (rather than being caused purely by the effects of pregnancy and heparin), which when combined with the additional bone stresses of pregnancy (due for example to increased weight,
As short haul plus Wear well-fitting elastic below knee compression stockings
*
As low risk long haul plus LMWH on day of flight and day after Or * Aspirin 75 mg daily for 3 days before travel and on day of flight *
1. Factor Xa inhibited by both UH and LMWH. A pentasaccharide sequence, which is preserved in LMWH, is required for the binding of heparin to AT. Once heparin has bound to AT, a conformational change occurs, allowing the heparin-AT complex to bind to and inhibit Xa. Thus antithrombotic activity is preserved in LMWH.
AT
fXa
AT
UH
fXa
LM W H
2. Thrombin only inhibited by UH, and not by LMWH. Binding of the AT-heparin complex to thrombin requires an additional 18 _ 20 unit monosaccharide sequence, which is absent in LMWH. Hence the latter has much reduced antithrombin (anticoagulant) activity. AT
thrombin
UH
AT
thrombin
LMWH
18 _ 20 unit monosaccharide chain
pentasaccharide sequence Heparin
Figure 1 Mechanisms of action of standard unfractionated heparin (UH) and low molecular weight heparin (LMWH) (fXa: activated factor X; AT: antithrombin).
change in lordosis etc) renders some women unduly susceptible to heparin. Women taking heparin for more than 6 weeks should be warned that there is a 2% risk of symptomatic vertebral collapse with UH and a maximum risk of 0.2% with LMWH. They should be encouraged to report severe back or hip pain. This bone loss is usually reversible. Women who have taken
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heparin for more than 8 weeks should be offered a bone densitometry scan when the baby is 1 year old (to allow time for reversal of any bone loss), if there is any possibility of future pregnancies (and therefore subsequent exposure to heparin).
gestation and has 2 positive antiphospholipid antibody measurements at least 6 weeks apart (see above). The patient’s lifetime risk of a further thrombosis is high, and may approach 70%.
There are several LMWHs available, each have slightly different levels of anti-Xa activity in the recommended doses (prefilled syringes) and each produce different amounts of actual anti-Xa activity for a uniform dose. As the clinical significance of these differences is uncertain, the individual LMWHs should be considered as separate medications and should not be interchanged without due consideration. Doctors prescribing them should gain experience with one particular preparation. The dose required in pregnancy is higher than that required outside pregnancy (see above). For thromboprophylaxis, enoxaparin is required at the higher dose of 40 mg (4000 iu anti-Xa activity) (rather than the nonpregnant dose of 20 mg) to ensure that anti-Xa activity is demonstrated.
Antithrombin (previously called antithrombin 111) is a naturally occurring anticoagulant with intrinsic importance for slowing down the coagulation cascade. When it is deficient, lack of anticoagulant capacity results in procoagulant tendencies. Antithrombin inactivates thrombin, Xa, IXa, XIa, and XIIa, and this inactivation is enhanced 40 103 fold by the presence of endogenous heparins. Antithrombin deficiency, which has a number of subtypes, is the most thrombogenic of the thrombophilic states, but is also one of the least common, affecting only 1 in 5000 individuals.
Thrombophilias, inherited and acquired The thrombophilias comprise a rapidly expanding, heterogeneous group of inherited deficiencies of naturally occurring anticoagulants including: AT; protein C and protein S deficiency; activated protein C resistance (APCR); the G20210A mutation of the prothrombin gene; hyperhomocysteinaemia secondary to homozygosity for the thermolabile variant (C677 T) of methylenetetrahydrofolate reductase (MTHFR). The antiphospholipid syndrome is an acquired thrombophilia characterised by either positive anticardiolipin antibodies or the lupus anticoagulant, in association with a relevant clinical event. Other acquired thrombophilias such as nephrotic syndrome, malignancy and polycythaemia are rare in pregnancy and not discussed further. The thrombophilias are important because they increase the chance of further thrombosis.
Antiphospholipid syndrome The antiphospholipid syndrome is present if a woman presents with one of the following: a thrombotic event (arterial or venous); recurrent pregnancy loss before 10 weeks of gestation; a single unexplained fetal loss beyond 10 weeks of gestation; pre-eclampsia; intrauterine growth restriction requiring delivery before 34 weeks of
Antithrombin
Proteins C and S Both protein C and protein S are naturally occurring anticoagulants. Protein C inactivates factors Va and VIIa, and this is enhanced by protein S which acts as a co-factor. Antigenic and functional protein C levels are unaffected by pregnancy. Free protein S concentrations fall with advancing pregnancy and should accordingly be interpreted with caution, and tests should be repeated outside pregnancy when the patient is not taking anticoagulation. Protein C deficiency occurs in 1 in 500 individuals. The partner of a heterozygote adult should be screened for the condition: if both are positive, their offspring have a 25% of being homozygous for protein C deficiency and developing the potentially fatal purpura fulminans.
Factor V Leiden mutation (FV L) APCR is due to FV L in at least 90% of cases. The factor V Leiden mutation is a mutation in factor V that prevents activated protein C from inactivating it (Fig. 2). It is said to be present if the ratio of the APTT of the test plasma with added activated protein C is less than double that of the APTT of the test plasma to which activated protein C has not been added. FV L occurs in 5% of most western populations, but is less common in people of African or Asian origin. In normal pregnancy, acquired resistance to activated protein C occurs, so if the diagnosis is required before the end of the puerperium, it must be confirmed with DNA analysis for the factor V Leiden mutation.
ARTICLE IN PRESS Thromboembolism and thrombophilia
Figure 2 Mechanism of action of activated protein c resistance. (A) Usually, activated protein C inactivates factor Va, resulting in the slowing of the coagulation cascade, as part of nature’s system for controlling clot formation. (B) Factor V Leiden is resistant to inactivation by activated protein C, resulting in continuation of the clotting cascade.
Hyperhomocysteinaemia Homocysteine is produced solely from the metabolism of the essential amino acid methionine. In normal circumstances it is rapidly catabolised to either methionine or cysteine via one of several pathways. Inherited hyperhomocysteinaemia results from genetic defects affecting the methionine homocysteine metabolism, and may be adversely influenced by environmental factors including folate, vitamin B6 or vitamin B12 deficiencies and antifolate medication such as methotrexate. Mild (16–24 mmol/l) and moderate (25–100 mmol/l) fasting hyperhomocysteinaemia may be due to either heterozygous cystathionine synthase defi-
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ciency or homozygosity for the thermolabile mutant of methylene tetrahydrofolate reductase. The latter occurs in about 11% of white Europeans. It is now apparent that although such individuals do not have the general phenotypic features of homocystinuria (severe hyperhomocysteinaemia), they are at increased risk of atherosclerosis and venous thrombosis. Homozygosity for the common 667C-T mutation of methylene-tetrahydrofolate reductase, which results in a less active and thermolabile enzyme, doubles the risk of a pregnancy being complicated by neural tube defect. As this mutation increases the dependence on folic acid for adequate remethylation of homocysteine to methionine, and results in lower red cell folate levels in homozygotes in pregnancy, it neatly explains the mechanism by which folate supplementation may be effective in reducing neural tube defects in some women. It also illustrates the interaction between genetic and environmental factors. Although a range of adverse events are associated with hyperhomocysteinaemia, there is as yet little evidence that treatment aimed at lowering the concentration of homocysteine is beneficial to the patient or her baby (although there is some evidence that vitamin supplementation can reduce circulating levels of homocysteine). It is therefore unclear whether screening for this condition should be added to the list of inherited thrombophilias likely to be associated with thrombosis or adverse pregnancy outcome. It would seem appropriate at this time to test only those women in whom there is high clinical suspicion e.g. a family history of symptomatic hyperhomocysteinaemia or a particularly poor obstetric or thromboembolic history, for which other causes have not been elucidated. As normal levels of homocysteine (either fasting or after a methionine challenge) in pregnancy are debated, in circumstances when screening is felt to be appropriate, PCR should be used to detect the 667C-T thermolabile mutation directly. Hopefully clinical trials will show whether folate supplementation can improve outcome, although the widespread introduction of such supplementation for other reasons, such as prevention of neural tube defect may make this logistically difficult.
Prothrombin gene mutation Prothrombin is a precursor of thrombin, and is encoded by a gene on the long arm of chromosome 11. A mutation in the prothrombin gene has been detected which is associated with an increased risk
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of thrombosis. In the 30 -untranslated region at nucleotide 20210, transition from guanine to adenosine (G20210A) is found in 18% of selected patients (those with a personal and family history of thromboembolic disease but other known causes of thrombophilia are excluded), 6% of unselected patients (those with a personal history of thromboembolism) and 2% of healthy controls. Carriers of the G20210A allele also have higher plasma concentrations of prothrombin and a 2.8 fold increased risk of thrombosis.
Thrombophilia and thrombosis Each of these thrombophilias increase the risk of thromboembolism, although the degree of risk is different for each. They occur with greater frequency in people who have thromboembolic events than in those that do not. However, although 50% of thromboembolic events in pregnancy and the puerperium occur in women with an identifiable thrombophilia, these thrombophilias also occur in at least 15% of an asymptomatic Western population. Positive predictive values for a thromboembolic event in pregnancy for carriers of some inherited thrombophilias have been calculated (see Table 6), these figures are helpful in advising women who are planning pregnancy. It is becoming increasingly apparent that the variable phenotypic expression of these conditions is due to a range of genotypic abnormalities. It is likely that the known inherited thrombophilias are just ‘the tip of the iceberg’ and that many others exist, making it a multiple gene disease. This ‘multi-hit’ phenomenon explains why some individuals with an inherited thrombophilia never develop a thrombosis. Thrombophilic families who develop clots are presumed to have
Table 6 Positive predictive value of inherited thrombophilias for TED event in pregnancy Thrombophilia
Positive predictive value for TED in pregnancy
None Factor V Leiden G20210A prothrombin gene mutation Protein C deficiency Antithrombin deficiency, type I Antithrombin deficiency, type II
1 in 3000 1 in 400 1 in 200 1 in 113 1 in 2.8 1 in 42
other (as yet undetected) genetic defects resulting in a sufficient procoagulant tendency to cause a thrombosis.
Thrombophilia and adverse obstetric events There has been much interest regarding, possible association between inherited thrombophilias and adverse obstetric events such as abruption, intrauterine growth restriction, pre-eclampsia, first and second trimester miscarriage and stillbirth. The proposed pathophysiology of this association is logical, namely that the thrombophilia enhances placental thromboses, which impair function and result in an untoward outcome. However, there is poor correlation between thrombophilic status and pathological changes to the placenta in women with severe complications in pregnancy. This proposal is an extension of the postulated mechanism by which the antiphospholipid syndrome accounts for first and second trimester pregnancy losses, and possibly other adverse outcomes. Recent work suggests that anticardiolipin may have a directly damaging effect on placental tissue, and not a thrombotic effect. If this is proven, the value of heparin in prevention of adverse obstetric outcome should be even more carefully questioned. Finally, it is also possible that fetal or paternal carriage of thrombophilia may increase the risk of pregnancy loss. A number of studies since the mid 1990s have suggested that there is an increased risk of adverse obstetric outcome with each of the known thrombophilias and that these risks are greatly enhanced in the presence of more than one detectable thrombophilia. These studies were mostly retrospective case series or case control studies of varying quality, and are additionally bedevilled by a lack of genetic confirmation of the thrombophilic status in most of the series. The largest prospective case control study, reported in 1996, of 1524 pregnancies in 571 women with thrombophilia and 1019 pregnancies in 395 women without thrombophilia showed an increase in the rate of stillbirth in women with antithrombin, protein C and protein S deficiencies, and the highest still birth rates in women with combinations of these (odds ratio 14, confidence limits 2–86). A case control study of 110 women with only genetically determined thrombophilias showed that hyperhomocysteinaemia and factor V Leiden were more common in women with adverse outcome but that the prothrombin gene mutation was not.
ARTICLE IN PRESS Thromboembolism and thrombophilia
Antiphospholipid syndrome In patients with antiphospholipid syndrome, it is agreed that there is an increased risk of recurrent pregnancy loss, but there is uncertainty about the best treatment. Two randomised control studies in the mid 1990s showed that unfractionated heparin and aspirin were superior to aspirin alone in improving the outcome in women with recurrent first trimester miscarriage. In the aspirin groups, 42–44% had a live birth, compared with 71–80% in the aspirin and heparin groups. In this century, 2 further randomised studies, one of LMWH plus aspirin against aspirin alone and the other of aspirin against placebo have questioned this: the ‘control’ arms had a live birth-rate of 72–80%, and the treatment arms 78–85%. These 4 studies used a total of less than 300 patients. It is unclear whether the differences between these studies relate to subject selection or whether heparin is of variable benefit, depending on the pathogenic nature of the anticardiolipin antibodies (see above). Regardless of the underlying mechanisms, careful consideration should be given to the regimen recommended to women with recurrent miscarriage and antiphospholipid antibodies. Even more careful thought must be applied before these results are extrapolated to other high-risk thrombophilic situations.
21
mended in the investigation or treatment of adverse pregnancy outcome.
Practice points *
*
*
*
*
*
Always consider thromboembolic disease if a pregnant woman has chest or leg symptoms that do not have a clear cause Lung ventilation/perfusion scanning can be used in pregnancy for the diagnosis of pulmonary embolus LMWH is used for acute treatment and maintenance treatment of TED and for thromboprophylaxis After the puerperium, women who suffer a thrombosis in pregnancy should be screened for thrombophilia, as should those who present antenatally with a history of TED who have not already been investigated Antiphospholipid syndrome should be tested for in women who have an adverse obstetric outcome There is insufficient evidence to routinely screen women with adverse outcome such as recurrent miscarriage, severe preeclampsia, IUGR or abruption for inherited thrombophilia
Inherited thrombophilias Research directions It has been suggested that in women with inherited thrombophilia aspirin or aspirin plus heparin may enhance pregnancy outcome. Although this is logical, it is not clear whether it is correct. As heparin is not without side effects (see above), if it is not indicated because of a thromboembolic event, there should be careful consideration of individual cases before this treatment is prescribed, particularly in the light of recent studies relating to antiphospholipid syndrome (see above). Indeed, further studies have recently suggested that in some populations at least, the association between inherited thrombophilia and adverse outcome may be weak or non-existent. Two randomised controlled trials are currently ongoing. These are looking at the effect of aspirin plus or minus LMWH on the outcome of pregnancy in women with inherited thrombophilia who have or have not had an adverse outcome previously. Until the situation becomes clearer, neither the wholesale use of inherited thrombophilia screens nor widespread use of heparin can be recom-
*
*
*
Effect of inherited thrombophilias on pregnancy outcome and optimal treatment if an association is confirmed Relevance of inherited thrombophilia for asymptomatic women embarking on a pregnancy, and determination of need for thromboprophylaxis Role of fetal and or paternal thrombophilia on pregnancy outcome
Further reading RCOG Scientific Advisory Committee. Advice on preventing deep vein thrombosis for pregnant women travelling by air. Opinion Paper 1, October 2001. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol. 2002;100:408–13. Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, Sandmann W, Zotz RB. Prothrombin and factor V
ARTICLE IN PRESS 22
mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–80. Kupferminc MJ, Eldor A, Steinman VN, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9–13. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Br Med J 1997;314: 253–7. Royal College of Obstetricians and Gynaecologists. Report of the RCOG Working Party on prophylaxis against thromboembolism in gynaecology and obstetrics. London: Chameleon Press Ltd, 1995.
J. Girling
Royal College of Obstetricians and Gynaecologists. Report on Confidential Enquiry into Maternal Deaths in the United Kingdom 1997–1999. London: RCOG, 2001. Ridker PM, Goldhaber SZ, Danielson E et al. Long-term lowintensity warfarin therapy for the prevention of recurrent idiopathic venous thromboembolism. N Engl J Med 2003;348: 1425–34. Rodie VA, Thomson AJ, Stewart FM, Quinn AJ, Walker ID, Greer IA. Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series. Br J Obstet Gynaecol 2002;109:1020–4. Royal College of Obstetricians and Gynaecologists. Thromboembolic disease in pregnancy and the puerperium: acute management. RCOG Guideline no. 28. London: RCOG, April 2001.
www.elsevier.com/cuog
Thromboembolism and thrombophilia Joanna Girling* Department of Obstetrics and Gynaecology, West Middlesex University Hospital, Twickenham Road, Isleworth, TW7 6AF, UK
KEYWORDS Pulmonary embolus; Deep vein thrombosis; Inherited thrombophilia
Summary Thromboembolism remains the major cause of maternal mortality in the United Kingdom. There are important differences in the diagnosis and treatment of thrombosis in pregnant patients compared with the non-pregnant patient. Thromboprophylaxis should be considered for high-risk women (for example those who had previously experienced thrombosis). For women in high-risk obstetric situations (for example those who had experienced Caesarean section). Inherited and acquired thrombophilias increase the risk of thrombotic episodes during pregnancy, and may play a role in adverse obstetric events. & 2003 Published by Elsevier Ltd.
Introduction Thrombosis may be fatal. Survivors of thrombotic events have an increased risk of recurrence, and many suffer the painful consequences of venous insufficiency. This article will discuss the aetiology, diagnosis and treatment of thrombosis in pregnancy, the prevention of thrombosis and the roles that thrombophilias may play in obstetric practice.
Thromboembolism Incidence Thromboembolism remains the leading cause of maternal mortality in the United Kingdom. In the triennium 1997–1999, thromboembolism caused 1.4 deaths per 100 000 maternities and accounted for one third of direct deaths. The Report on Confidential Enquiries into Maternal Mortality (CEMD) emphasises the importance of vigilance for thromboembolic events throughout the whole of pregnancy and the puerperium, and the need for *Tel.: þ 44-(0)-208-565-5114; fax: þ 44-(0)-208-565-5428. E-mail address: [email protected] (J. Girling). 0268-0890/$ - see front matter & 2003 Published by Elsevier Ltd. doi:10.1016/j.curobgyn.2003.10.001
thromboprophylaxis in high-risk situations. Thirty one women died from thromboembolic disease (TED) during 1997–1999, 14 (45%) antenatally: 9 of these occurred in the first trimester, of which only 1 patient died following surgery (termination of pregnancy or ectopic pregnancy). Only in 1 of the antenatal cases was the diagnosis reached before post-mortem. In the remaining cases women were given other diagnoses including muscle strain, anxiety, chest infection and sore throat. It is imperative that healthcare professionals working with pregnant women are aware that TED may strike at any gestation, and they should have a low threshold for investigating relevant leg or chest symptoms. During the same period (1997–1999), 14 women died postnatally. Only 4 (29%) of these deaths followed Caesarean section and all were in the first week. All of these women had additional risk factors other than surgery but none had received adequate thromboprophylaxis. Ten deaths occurred after vaginal delivery, all but 1 more than a week later, and all but 1 showed risk factors for thrombosis. The deaths following Caesarean section have fallen from 15 during 1994–1996, presumably as a reflection of improved surgical thromboprophylaxis. More action is now required to reduce the number of events after vaginal deliveries (see later).
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Although there are accurate data on fatal TED, there are less robust data relating to non-fatal events. Overall, a reasonable estimate is that a thromboembolic event occurs in 1 in 1000–1 in 1500 pregnancies. A number of studies have suggested that antenatal deep vein thrombosis (DVT) occurs in 0.06–0.09% of pregnancies, being twice as common in women over 35 years of age as those under 35 years of age. Similarly, in the puerperium DVT is related to maternal age and mode of delivery (see Table 1). Although the data are conflicting, it is likely that more DVTs occur throughout the antenatal period (and not at any particular gestation) rather than during the postnatal period, although the risk per week of an event is greater in the latter than the former (since pregnancy lasts 9 months and the puerperium 6 weeks). Pulmonary emboli are more common in the puerperium, especially following Caesarean section.
Aetiology The risk of TED is increased six fold in pregnancy, due to prothrombotic physiological changes in all three arms of Virchow’s triad. There is an increase in: coagulation factors I (fibrinogen), V, VII, VIII, IX, X, XII; von Willebrand factor antigen and ristocetin cofactor activity and a decrease in some endogenous anticoagulants (antithrombin, protein S and activated protein C resistance) which are most marked near term and following delivery. There is also impaired fibrinolysis during pregnancy, due to placentally-derived plasminogen activator II, and raised endothelial and hepatic plasminogen activator I, which revert to normal at delivery. Peripheral vasodilatation occurs in normal pregnancy, resulting in a marked fall in velocity of blood flow. This is evident from early in the second
Table 1 Risk of TED (expressed per 1000 maternities) in relation to maternal age, pregnancy and mode of delivery Thromboembolic event
under 35 years
over 35 years
Antenatal DVT Postnatal DVT Postnatal pulmonary embolus DVT after emergency LSCS DVT after elective LSCS
0.615 0.304 0.108
1.216 0.72 0.405
0.431
1.248
0.238
0.68
trimester, and reaches a nadir from 34 weeks to term; it does not return to normal until 6 weeks postnatally. This fall in blood flow velocity is most marked in women delivering their babies by Caesarean section. It also occurs to a greater extent in the left femoral vein compared with the right. This is secondary 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. This explains the predominance of left sided DVTs in pregnancy (85% left vs. 15% right sided). Finally, trauma to the pelvic veins may occur as the baby’s head passes through the pelvis, and this may be worsened by operative or abdominal delivery. The immobility and dehydration of labour may also contribute to the risk of postnatal DVT. The risk of TED is further increased in obese women; those subjected to bed-rest or undergoing Caesarean section; older women and those with intercurrent medical conditions such as preeclampsia, diabetes or dehydration from any cause (for example hyperemesis gravidarum or ovarian hyperstimulation syndrome). Women who have a personal history of TED are at increased risk, especially if they have an inherited or acquired thrombophilia, or a family history (itself suggestive of an inherited thrombophilia).
Diagnosis In pregnancy it is essential that chest and/or leg symptoms which may be attributable to TED are investigated, and a diagnosis of thrombosis definitely confirmed or excluded. Data from nonpregnant individuals suggests that 16% of patients with untreated DVT develop pulmonary embolus, and 13% of these patients die, although anticoagulation substantially reduces these risks. Thus a positive diagnosis of TED has important implications for immediate management. But as this treatment it is not without risk, it is vital that the diagnosis is secure. The diagnosis of TED also has important implications for future pregnancy and in later life. Clinical awareness of TED in pregnant women makes it much easier to reach the correct diagnosis. Although chest X-ray is rarely diagnostic, it should not be withheld solely because of the pregnancy. If the clinical impression is that it will facilitate management, it should be performed with confidence in that the amount of radiation is negligible (o10 mGyFequivalent to a one-way flight to New York from London, when compared with a recommended upper limit of exposure in pregnancy to 50 000 mGy). If the clinical impression is that it will facilitate management. Arterial blood
ARTICLE IN PRESS Thromboembolism and thrombophilia
gas analysis should be performed in the sitting or left lateral position: when supine, inferior vena caval compression by the gravid uterus and functional reduction in pulmonary residual capacity and closing volume may give a false impression of hypoxia. In uncomplicated pregnancy, the pO2 is unchanged compared with the non-pregnant situation, but falls by around 2 kPa (17 mmHg) when lying supine (pO2 13 kPa [100 mmHg] standing, 11 kPa [83 mmHg] supine); pCO2 in normal pregnancy falls from 5 kPa (35–40 mmHg) to 4 kPa (30 mmHg). Electrocardiography usually lacks sufficient specificity to be helpful, particularly as normal pregnancy may result in right axis deviation, and both T-wave inversion and Q-wave in lead 111, findings that outside pregnancy would be suggestive of pulmonary embolus. Outside pregnancy, a low D dimer concentration is a valuable negative discriminator for thrombosis; in pregnancy, D dimers may be elevated as a result of the prothrombotic changes which occur, and therefore are not helpful. There should be a low threshold for performing either Doppler ultrasound of the femoral veins or lung ventilation/perfusion scanning. It is unusual for a clot to be isolated in the iliac vessels, and so the inability to visualise these with ultrasound is not usually problematic. Treatment should be initiated during the investigations if the clinical suspicion is high, and then revised accordingly once all the results are available.
13
heparin (LMWH) for 6–12 weeks. Currently the Royal College of Obstetricians and Gynaecologists recommends that a treatment dose of LMWH be used from the outset. In the treatment of DVT outside of pregnancy, this has been shown to reduce mortality and haemorrhagic complications compared with unfractionated heparin. When used for treatment of pulmonary emboli the two options are equally effective (see later). Higher doses of heparin are required in pregnancy than outside of pregnancy, largely because of increased renal clearance, haemodilution and the action of placental heparinase. For example, outside pregnancy, dalteparin is used at 10000–18000 units once daily, depending on weight. In pregnancy 100 units/ kg twice daily to a maximum of 18000 units is advised; enoxaparin is used outside pregnancy at 1.5 mg/kg/day, but in pregnancy 1.0 mg/kg/twice daily is advised: see Table 2 for suggested regimen. The target therapeutic range for LMWH is a peak anti Xa level of 0.4–1.0 u/ml 3 to 4 h post-injection. It is relatively uncommon to need to adjust the dose of LMWH, and frequent monitoring does not seem to be helpful. Therefore, the first measurement can be made on the first normal working day after treatment is commenced, and then approximately every 4 weeks. The affected leg should initially be elevated to minimise oedema, but mobilisation must be encouraged. A full leg graduated compression stocking should be worn.
Treatment If a DVT or pulmonary embolus (PE) is diagnosed (or strongly suspected) in pregnancy, anticoagulation with heparin should be commenced. Warfarin should not be used in first-line management of TED in pregnant women, as not only is it teratogenic in the first trimester, but also as it crosses the placenta, which in effect anticoagulates the fetus, increasing the risk of spontaneous haemorrhage in utero especially within the brain. However, heparins and warfarin are safe to take during lactation. Blood should be taken to check for the presence of inherited or acquired thrombophilia, when possible before heparin is commenced; results of some nongenetic tests must be treated with caution as pregnancy can cause false positive results (see later). Initial treatment Recently treatment of TED in pregnancy has changed. Previously, intravenous unfractionated heparin (UH) was advised for 5–7 days, followed by a treatment dose of low molecular weight
Maintenance treatment Therapeutic doses of LMWH should be continued for 3–6 months, determined on an individual basis according to gestation at diagnosis and presence of on-going risk factors. If this takes the patient to less than 6 weeks post-delivery (the time thought to be required for the risk factors of pregnancy to resolve), she should change onto a thromboprophylactic dose of LMWH (see later) until then 6 weeks is thought to be the time required for the risk factors of pregnancy to resolve.
Table 2 Starting dose of enoxaparin in treatment of TED in pregnancy Early pregnancy weight (kg)
Initial dose of enoxaparin
o50 50–69 70–89 490 kg
40 mg twice daily 60 mg twice daily 80 mg twice daily 100 mg twice daily
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J. Girling
After delivery, the patient can switch to warfarin from day 2 if she prefers, continuing heparin until her INR is in the target range of 2.0–3.0. She will need to attend a clinic regularly for measurement of her prothrombin time. She should not take warfarin during pregnancy (see above). Recent evidence outside pregnancy suggests that long-term use of low intensity warfarin, aiming for a target INR of 1.5–2.0, reduces the risk of recurrent TED by at least 64% over a 4 year period, without increasing the risk of haemorrhage in those with and without inherited thrombophilia. It remains to be seen how much this will influence clinical practice in women of childbearing age. Treatment during labour and delivery The main issue in this period relates to the use of regional analgesia. Women should have this option available to them whenever possible, and however unlikely their requirement for this may seem, to minimise the need for general anaesthetic and its attendant complications (which include thrombosis). This should be discussed with the patient before the onset of labour, and appropriate alterations to their therapy instituted. There should be a locally agreed policy involving obstetricians and anaesthetists. Women should be advised not to inject if they believe that they are in early labour, instead they should contact the delivery suite for assessment. Regional analgesia should not be sited for 12–24 h following an injection of LMWH (for prophylactic and treatment doses respectively), and then only if the platelets and clotting are normal, in order to minimise the risk of spinal haematoma and its potentially disastrous complications. Although this is a rare event, both the Royal College of Obstetricians and Gynaecologists and the Report on Confidential Enquiries into Maternal Morbidity recommend this policy. There are 3 options for the heparin regimen in labour, one of which is usually appropriate: *
*
if the thromboembolic event was early in pregnancy, the patient can be switched from her prophylactic dose of LMWH to a prophylactic dose of unfractionated heparin, 10000 units twice daily at 36–37 weeks gestation. In this case, only a 4 h window is required from last injection to regional technique; the second option is to plan delivery, preferably vaginally if other obstetric risk factors make this appropriate. A cervical sweep followed by induction of labour can be planned to coincide with a change to the thromboprophylactic regime as outlined above. The timing of this
*
needs to be balanced to minimise the risks of both ‘prematurity’, onset of labour before the agreed gestation period and recurrent TED. This has the potential advantage for women at high-risk of recurrence, of minimising the number of days they are off their treatment regimen. Unfortunately it has the disadvantage of risking immobilisation and dehydration on an antenatal ward. This option may be most appropriate for those women thought to have a substantial chance of a further clot, including those in the first few months of a treatment dose of LMWH; the third option, especially for women who are confident they will not require epidural for analgesia and in whom the chance of a emergency Caesarean in labour seems low, is to stay on the LMWH without instituting any changes: this is only potentially applicable to women on thromboprophylactic doses.
If Caesarean section is indicated on obstetric grounds, the woman should have a thromboprophylactic dose of LMWH on the day prior to surgery. Her operation should be performed as soon as possible in the morning, and she should have another thromboprophylactic dose as soon as possible after removal of the epidural catheter, usually 3–6 h depending on local policy. That evening she should return to her treatment dose (as appropriate: see above). Emergency or ‘rescue’ treatment A temporary caval filter can be positioned when recurrent pulmonary emboli occur despite treatment, or when anticoagulation therapy is contraindicated. Thrombolysis, percutaneous catheter thrombus fragmentation or surgical embolectomy can be considered if life-threatening massive pulmonary embolus occurs outside pregnancy, although there is no clear evidence that these improve the clinical outcome of TED. Experience of thrombolytic treatment in pregnancy is even more limited, and it can therefore only be recommended for use in life-threatening circumstances.
Follow-up Women who have experienced a thrombosis during pregnancy should be followed-up, preferably by a doctor with an interest in the management of thrombosis in pregnancy. Once they have discontinued anticoagulant therapy and are at least 6 weeks postnatal, a thrombophilia screen must be performed in order to assess the risk of recurrence
ARTICLE IN PRESS Thromboembolism and thrombophilia
and to plan management during future pregnancies (see below). Contraception should also be discussed, since the oestrogen-containing combined oral contraceptive pill is contraindicated in women who have had a thrombosis. Other forms of contraception both hormonal and nonhormonal are permissible. Patients should be advised to wear a graduated compression stocking on the affected leg for 2 years, as this reduces the risk of post-thrombotic syndrome from 23% to 11% in this time frame.
Thromboprophylaxis Prevention of TED is important, and should be offered to women considered to be at high-risk. An assessment of every pregnant woman’s inherent risk of thromboembolic disease should be made at booking, by establishing whether she has a personal or family history of TED. In addition, every pregnant woman who enters a high-risk situation should have her risk of TED re-evaluated. Ideally each maternity unit should have an obstetrician or a physician (or both), who have an active interest in this field and can give up to date advice on management of these sometimes complex cases.
Table 3
15
Previous thromboembolic event Women who have experienced a single previous thromboembolic event, but have no family history and a negative thrombophilia screen, should take aspirin 75 mg daily throughout pregnancy, and LMWH at a thromboprophylactic dose from the onset of labour until 6 weeks postnatally. Women who have had more than one thromboembolic event or who have had a single event but have a family history or positive thrombophilia screen should take LMWH from early pregnancy until 6 weeks postnatally. Usually therapy is started at around 5–6 weeks into gestation once an ultrasound scan has demonstrated a beating fetal heart. If patients have antithrombin deficiency (see below), depending on the titre in the weeks leading up to delivery, an antithrombin infusion may be required before and/or during labour.
High-risk obstetric situation In 1995, the Royal College of Obstetricians and Gynaecologists issued guidelines relating to thromboprophylaxis in pregnancy, which included guidelines following Caesarean section (LSCS) (see Table 3).
Thromboprophylaxis at Caesarean section
Risk category
Definition
Management Early mobilisation Good hydration
Low * * *
Elective LSCS Uncomplicated pregnancy No other risk factors TED stockings or subcutaneous heparin
Moderate * * * * * * * *
Emergency LSCS in labour Age 435 years Obese 480 kg Gross varicose veins Current infection Pre-eclampsia Immobilisation prior to LSCS 44 days Major current illness e.g. heart or lung disease, inflammatory bowel disease, nephrotic syndrome, diabetes
High * *
* * *
3 or more moderate risk factors Extended abdominal or pelvic surgery e.g. Caesarean hysterectomy Personal or family history of TED Antiphospholipid syndrome Paralysis of lower limbs
TED stockings plus subcutaneous heparin (commencing during LSCS and continuing until day 5)
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J. Girling
Each unit should have a locally agreed policy, based upon these guidelines, which is strictly adhered to. Many hospitals have chosen to give heparin to the majority of, if not all, women undergoing LSCS. Anticoagulation therapy is usually commenced intra-operatively, and continued until the woman is freely mobile or 5 days postnatally. In addition, women with multiple risk factors should also be considered for antenatal and/or postnatal thromboprophylaxis regardless of the mode of delivery: for example an obese, pregnant woman who smokes, has pre-eclampsia and is admitted to hospital may benefit from LMWH. Immobility, dehydration, maternal age and intercurrent infections or medical conditions may also substantially increase the risk of thrombosis. The most recent CEMD contains a guideline for thrombosis prophylaxis after vaginal delivery (see Table 4).
Positive thrombophilia screen Increasingly, women discover they have a thrombophilia when a family member is screened following a thromboembolic event. The implications of these results are not entirely clear. It may be appropriate to give low-dose aspirin antenatally and/or LMWH during the puerperium, though this should be determined on an individual basis.
Table 4
Air travel In 2001, the Royal College of Obstetricians and Gynaecologists published an opinion paper giving advice for pregnant women planning to travel by air. The advice was extrapolated from non-pregnant patients, and is summarised in Table 5. In essence, pregnant women who choose to fly should minimise their risk factors by keeping active and well hydrated on-board, and in certain cases by wearing compression stockings and taking low molecular weight heparin or aspirin. Similar advice should be considered if prolonged and continuous travel by any means is being considered.
Side effects of unfractionated and low molecular weight heparin Heparin, whether unfractionated or low molecular weight does not cross the placenta or into breast milk, and is therefore safe from a fetal point of view. There are 3 potential maternal side effects to be considered, which should be discussed with every patient for whom heparin is prescribed. The pregnant woman is at risk of heparin-induced thrombocytopenia (HIT), osteopenia, and haemorrhage. These complications are less likely with LMWH than unfractionated heparin (UH) in trials on
Thromboprophylaxis after vaginal delivery for women who have never had a thrombosis
Risk category
Definition
Management
Low
Uncomplicated pregnancy
Early mobilisation Good hydration
Moderate
Any 2 of the following: * Age 435 years * Weight 4 80 kg at booking * Para 4 or more * Labour 412 h * Gross varicose veins * Current infection * Pre-eclampsia * Immobility prior to labour 44 days * Midcavity or rotational forceps delivery
LMWH once daily as soon as possible after delivery, until discharge
High * * * * *
4 or more moderate risk factors Extended surgery Family history of TED Lower limb paralysis Lupus anticoagulant or anticardiolipin antibodiesn
LMWH plus graduated stockings form as soon as possible after delivery until either discharge or if n6 weeks
ARTICLE IN PRESS Thromboembolism and thrombophilia
Table 5
17
Prevention of TED in pregnant women travelling by air
Any gestation and until 6 weeks postnatal
Short haul (o 3 h)
Long haul (43 h)
No additional risk factors * * * *
Additional risk factors
Calf exercises Mobilise during flight Avoid dehydration Minimise alcohol and caffeine intake
As low-risk short haul plus * Wear well-fitting elastic below knee compression stockings
non-pregnant individuals and it seems likely that this holds true in pregnant women: *
*
*
bleeding complications are less likely since the shorter polysaccharide chain of LMWH (average molecular weight 4000 to 5000 Da) is only able to bind to antithrombin (AT) which results in the inhibition of factor Xa, but not to thrombin (factor IIa) (which requires a longer chain) (Fig. 1). Thus LMWH has very little anticoagulant activity (anti IIa) but good antithrombotic activity (anti Xa); UH (molecular weight 12000 to 14000 Da) has approximately equal amounts of each; HIT may occur acutely within the first week of treatment or chronically with prolonged use, but is rare in either form. Thrombocytopenia is less likely with LMWH than UH, since chains with a molecular weight of less than 8000 Daltons are unable to interact with platelets, although this has only been proven in non-pregnant patients; there are a few studies concerning bone loss with LMWH use in pregnancy and it is seems likely that it causes less osteopenia than UH. Indeed, bone loss with LMWH is probably comparable to that occurring in normal pregnancy, that is 5% in the lumbar spine L2–4. Vertebral fractures have been reported after as little as 7 weeks of low dose UH treatment. It is possible that these fractures reflect in part an unmasking of a pre-existing low bone mass (rather than being caused purely by the effects of pregnancy and heparin), which when combined with the additional bone stresses of pregnancy (due for example to increased weight,
As short haul plus Wear well-fitting elastic below knee compression stockings
*
As low risk long haul plus LMWH on day of flight and day after Or * Aspirin 75 mg daily for 3 days before travel and on day of flight *
1. Factor Xa inhibited by both UH and LMWH. A pentasaccharide sequence, which is preserved in LMWH, is required for the binding of heparin to AT. Once heparin has bound to AT, a conformational change occurs, allowing the heparin-AT complex to bind to and inhibit Xa. Thus antithrombotic activity is preserved in LMWH.
AT
fXa
AT
UH
fXa
LM W H
2. Thrombin only inhibited by UH, and not by LMWH. Binding of the AT-heparin complex to thrombin requires an additional 18 _ 20 unit monosaccharide sequence, which is absent in LMWH. Hence the latter has much reduced antithrombin (anticoagulant) activity. AT
thrombin
UH
AT
thrombin
LMWH
18 _ 20 unit monosaccharide chain
pentasaccharide sequence Heparin
Figure 1 Mechanisms of action of standard unfractionated heparin (UH) and low molecular weight heparin (LMWH) (fXa: activated factor X; AT: antithrombin).
change in lordosis etc) renders some women unduly susceptible to heparin. Women taking heparin for more than 6 weeks should be warned that there is a 2% risk of symptomatic vertebral collapse with UH and a maximum risk of 0.2% with LMWH. They should be encouraged to report severe back or hip pain. This bone loss is usually reversible. Women who have taken
ARTICLE IN PRESS 18
J. Girling
heparin for more than 8 weeks should be offered a bone densitometry scan when the baby is 1 year old (to allow time for reversal of any bone loss), if there is any possibility of future pregnancies (and therefore subsequent exposure to heparin).
gestation and has 2 positive antiphospholipid antibody measurements at least 6 weeks apart (see above). The patient’s lifetime risk of a further thrombosis is high, and may approach 70%.
There are several LMWHs available, each have slightly different levels of anti-Xa activity in the recommended doses (prefilled syringes) and each produce different amounts of actual anti-Xa activity for a uniform dose. As the clinical significance of these differences is uncertain, the individual LMWHs should be considered as separate medications and should not be interchanged without due consideration. Doctors prescribing them should gain experience with one particular preparation. The dose required in pregnancy is higher than that required outside pregnancy (see above). For thromboprophylaxis, enoxaparin is required at the higher dose of 40 mg (4000 iu anti-Xa activity) (rather than the nonpregnant dose of 20 mg) to ensure that anti-Xa activity is demonstrated.
Antithrombin (previously called antithrombin 111) is a naturally occurring anticoagulant with intrinsic importance for slowing down the coagulation cascade. When it is deficient, lack of anticoagulant capacity results in procoagulant tendencies. Antithrombin inactivates thrombin, Xa, IXa, XIa, and XIIa, and this inactivation is enhanced 40 103 fold by the presence of endogenous heparins. Antithrombin deficiency, which has a number of subtypes, is the most thrombogenic of the thrombophilic states, but is also one of the least common, affecting only 1 in 5000 individuals.
Thrombophilias, inherited and acquired The thrombophilias comprise a rapidly expanding, heterogeneous group of inherited deficiencies of naturally occurring anticoagulants including: AT; protein C and protein S deficiency; activated protein C resistance (APCR); the G20210A mutation of the prothrombin gene; hyperhomocysteinaemia secondary to homozygosity for the thermolabile variant (C677 T) of methylenetetrahydrofolate reductase (MTHFR). The antiphospholipid syndrome is an acquired thrombophilia characterised by either positive anticardiolipin antibodies or the lupus anticoagulant, in association with a relevant clinical event. Other acquired thrombophilias such as nephrotic syndrome, malignancy and polycythaemia are rare in pregnancy and not discussed further. The thrombophilias are important because they increase the chance of further thrombosis.
Antiphospholipid syndrome The antiphospholipid syndrome is present if a woman presents with one of the following: a thrombotic event (arterial or venous); recurrent pregnancy loss before 10 weeks of gestation; a single unexplained fetal loss beyond 10 weeks of gestation; pre-eclampsia; intrauterine growth restriction requiring delivery before 34 weeks of
Antithrombin
Proteins C and S Both protein C and protein S are naturally occurring anticoagulants. Protein C inactivates factors Va and VIIa, and this is enhanced by protein S which acts as a co-factor. Antigenic and functional protein C levels are unaffected by pregnancy. Free protein S concentrations fall with advancing pregnancy and should accordingly be interpreted with caution, and tests should be repeated outside pregnancy when the patient is not taking anticoagulation. Protein C deficiency occurs in 1 in 500 individuals. The partner of a heterozygote adult should be screened for the condition: if both are positive, their offspring have a 25% of being homozygous for protein C deficiency and developing the potentially fatal purpura fulminans.
Factor V Leiden mutation (FV L) APCR is due to FV L in at least 90% of cases. The factor V Leiden mutation is a mutation in factor V that prevents activated protein C from inactivating it (Fig. 2). It is said to be present if the ratio of the APTT of the test plasma with added activated protein C is less than double that of the APTT of the test plasma to which activated protein C has not been added. FV L occurs in 5% of most western populations, but is less common in people of African or Asian origin. In normal pregnancy, acquired resistance to activated protein C occurs, so if the diagnosis is required before the end of the puerperium, it must be confirmed with DNA analysis for the factor V Leiden mutation.
ARTICLE IN PRESS Thromboembolism and thrombophilia
Figure 2 Mechanism of action of activated protein c resistance. (A) Usually, activated protein C inactivates factor Va, resulting in the slowing of the coagulation cascade, as part of nature’s system for controlling clot formation. (B) Factor V Leiden is resistant to inactivation by activated protein C, resulting in continuation of the clotting cascade.
Hyperhomocysteinaemia Homocysteine is produced solely from the metabolism of the essential amino acid methionine. In normal circumstances it is rapidly catabolised to either methionine or cysteine via one of several pathways. Inherited hyperhomocysteinaemia results from genetic defects affecting the methionine homocysteine metabolism, and may be adversely influenced by environmental factors including folate, vitamin B6 or vitamin B12 deficiencies and antifolate medication such as methotrexate. Mild (16–24 mmol/l) and moderate (25–100 mmol/l) fasting hyperhomocysteinaemia may be due to either heterozygous cystathionine synthase defi-
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ciency or homozygosity for the thermolabile mutant of methylene tetrahydrofolate reductase. The latter occurs in about 11% of white Europeans. It is now apparent that although such individuals do not have the general phenotypic features of homocystinuria (severe hyperhomocysteinaemia), they are at increased risk of atherosclerosis and venous thrombosis. Homozygosity for the common 667C-T mutation of methylene-tetrahydrofolate reductase, which results in a less active and thermolabile enzyme, doubles the risk of a pregnancy being complicated by neural tube defect. As this mutation increases the dependence on folic acid for adequate remethylation of homocysteine to methionine, and results in lower red cell folate levels in homozygotes in pregnancy, it neatly explains the mechanism by which folate supplementation may be effective in reducing neural tube defects in some women. It also illustrates the interaction between genetic and environmental factors. Although a range of adverse events are associated with hyperhomocysteinaemia, there is as yet little evidence that treatment aimed at lowering the concentration of homocysteine is beneficial to the patient or her baby (although there is some evidence that vitamin supplementation can reduce circulating levels of homocysteine). It is therefore unclear whether screening for this condition should be added to the list of inherited thrombophilias likely to be associated with thrombosis or adverse pregnancy outcome. It would seem appropriate at this time to test only those women in whom there is high clinical suspicion e.g. a family history of symptomatic hyperhomocysteinaemia or a particularly poor obstetric or thromboembolic history, for which other causes have not been elucidated. As normal levels of homocysteine (either fasting or after a methionine challenge) in pregnancy are debated, in circumstances when screening is felt to be appropriate, PCR should be used to detect the 667C-T thermolabile mutation directly. Hopefully clinical trials will show whether folate supplementation can improve outcome, although the widespread introduction of such supplementation for other reasons, such as prevention of neural tube defect may make this logistically difficult.
Prothrombin gene mutation Prothrombin is a precursor of thrombin, and is encoded by a gene on the long arm of chromosome 11. A mutation in the prothrombin gene has been detected which is associated with an increased risk
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J. Girling
of thrombosis. In the 30 -untranslated region at nucleotide 20210, transition from guanine to adenosine (G20210A) is found in 18% of selected patients (those with a personal and family history of thromboembolic disease but other known causes of thrombophilia are excluded), 6% of unselected patients (those with a personal history of thromboembolism) and 2% of healthy controls. Carriers of the G20210A allele also have higher plasma concentrations of prothrombin and a 2.8 fold increased risk of thrombosis.
Thrombophilia and thrombosis Each of these thrombophilias increase the risk of thromboembolism, although the degree of risk is different for each. They occur with greater frequency in people who have thromboembolic events than in those that do not. However, although 50% of thromboembolic events in pregnancy and the puerperium occur in women with an identifiable thrombophilia, these thrombophilias also occur in at least 15% of an asymptomatic Western population. Positive predictive values for a thromboembolic event in pregnancy for carriers of some inherited thrombophilias have been calculated (see Table 6), these figures are helpful in advising women who are planning pregnancy. It is becoming increasingly apparent that the variable phenotypic expression of these conditions is due to a range of genotypic abnormalities. It is likely that the known inherited thrombophilias are just ‘the tip of the iceberg’ and that many others exist, making it a multiple gene disease. This ‘multi-hit’ phenomenon explains why some individuals with an inherited thrombophilia never develop a thrombosis. Thrombophilic families who develop clots are presumed to have
Table 6 Positive predictive value of inherited thrombophilias for TED event in pregnancy Thrombophilia
Positive predictive value for TED in pregnancy
None Factor V Leiden G20210A prothrombin gene mutation Protein C deficiency Antithrombin deficiency, type I Antithrombin deficiency, type II
1 in 3000 1 in 400 1 in 200 1 in 113 1 in 2.8 1 in 42
other (as yet undetected) genetic defects resulting in a sufficient procoagulant tendency to cause a thrombosis.
Thrombophilia and adverse obstetric events There has been much interest regarding, possible association between inherited thrombophilias and adverse obstetric events such as abruption, intrauterine growth restriction, pre-eclampsia, first and second trimester miscarriage and stillbirth. The proposed pathophysiology of this association is logical, namely that the thrombophilia enhances placental thromboses, which impair function and result in an untoward outcome. However, there is poor correlation between thrombophilic status and pathological changes to the placenta in women with severe complications in pregnancy. This proposal is an extension of the postulated mechanism by which the antiphospholipid syndrome accounts for first and second trimester pregnancy losses, and possibly other adverse outcomes. Recent work suggests that anticardiolipin may have a directly damaging effect on placental tissue, and not a thrombotic effect. If this is proven, the value of heparin in prevention of adverse obstetric outcome should be even more carefully questioned. Finally, it is also possible that fetal or paternal carriage of thrombophilia may increase the risk of pregnancy loss. A number of studies since the mid 1990s have suggested that there is an increased risk of adverse obstetric outcome with each of the known thrombophilias and that these risks are greatly enhanced in the presence of more than one detectable thrombophilia. These studies were mostly retrospective case series or case control studies of varying quality, and are additionally bedevilled by a lack of genetic confirmation of the thrombophilic status in most of the series. The largest prospective case control study, reported in 1996, of 1524 pregnancies in 571 women with thrombophilia and 1019 pregnancies in 395 women without thrombophilia showed an increase in the rate of stillbirth in women with antithrombin, protein C and protein S deficiencies, and the highest still birth rates in women with combinations of these (odds ratio 14, confidence limits 2–86). A case control study of 110 women with only genetically determined thrombophilias showed that hyperhomocysteinaemia and factor V Leiden were more common in women with adverse outcome but that the prothrombin gene mutation was not.
ARTICLE IN PRESS Thromboembolism and thrombophilia
Antiphospholipid syndrome In patients with antiphospholipid syndrome, it is agreed that there is an increased risk of recurrent pregnancy loss, but there is uncertainty about the best treatment. Two randomised control studies in the mid 1990s showed that unfractionated heparin and aspirin were superior to aspirin alone in improving the outcome in women with recurrent first trimester miscarriage. In the aspirin groups, 42–44% had a live birth, compared with 71–80% in the aspirin and heparin groups. In this century, 2 further randomised studies, one of LMWH plus aspirin against aspirin alone and the other of aspirin against placebo have questioned this: the ‘control’ arms had a live birth-rate of 72–80%, and the treatment arms 78–85%. These 4 studies used a total of less than 300 patients. It is unclear whether the differences between these studies relate to subject selection or whether heparin is of variable benefit, depending on the pathogenic nature of the anticardiolipin antibodies (see above). Regardless of the underlying mechanisms, careful consideration should be given to the regimen recommended to women with recurrent miscarriage and antiphospholipid antibodies. Even more careful thought must be applied before these results are extrapolated to other high-risk thrombophilic situations.
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mended in the investigation or treatment of adverse pregnancy outcome.
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Always consider thromboembolic disease if a pregnant woman has chest or leg symptoms that do not have a clear cause Lung ventilation/perfusion scanning can be used in pregnancy for the diagnosis of pulmonary embolus LMWH is used for acute treatment and maintenance treatment of TED and for thromboprophylaxis After the puerperium, women who suffer a thrombosis in pregnancy should be screened for thrombophilia, as should those who present antenatally with a history of TED who have not already been investigated Antiphospholipid syndrome should be tested for in women who have an adverse obstetric outcome There is insufficient evidence to routinely screen women with adverse outcome such as recurrent miscarriage, severe preeclampsia, IUGR or abruption for inherited thrombophilia
Inherited thrombophilias Research directions It has been suggested that in women with inherited thrombophilia aspirin or aspirin plus heparin may enhance pregnancy outcome. Although this is logical, it is not clear whether it is correct. As heparin is not without side effects (see above), if it is not indicated because of a thromboembolic event, there should be careful consideration of individual cases before this treatment is prescribed, particularly in the light of recent studies relating to antiphospholipid syndrome (see above). Indeed, further studies have recently suggested that in some populations at least, the association between inherited thrombophilia and adverse outcome may be weak or non-existent. Two randomised controlled trials are currently ongoing. These are looking at the effect of aspirin plus or minus LMWH on the outcome of pregnancy in women with inherited thrombophilia who have or have not had an adverse outcome previously. Until the situation becomes clearer, neither the wholesale use of inherited thrombophilia screens nor widespread use of heparin can be recom-
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Effect of inherited thrombophilias on pregnancy outcome and optimal treatment if an association is confirmed Relevance of inherited thrombophilia for asymptomatic women embarking on a pregnancy, and determination of need for thromboprophylaxis Role of fetal and or paternal thrombophilia on pregnancy outcome
Further reading RCOG Scientific Advisory Committee. Advice on preventing deep vein thrombosis for pregnant women travelling by air. Opinion Paper 1, October 2001. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol. 2002;100:408–13. Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, Sandmann W, Zotz RB. Prothrombin and factor V
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mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000;342:374–80. Kupferminc MJ, Eldor A, Steinman VN, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999;340:9–13. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Br Med J 1997;314: 253–7. Royal College of Obstetricians and Gynaecologists. Report of the RCOG Working Party on prophylaxis against thromboembolism in gynaecology and obstetrics. London: Chameleon Press Ltd, 1995.
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Royal College of Obstetricians and Gynaecologists. Report on Confidential Enquiry into Maternal Deaths in the United Kingdom 1997–1999. London: RCOG, 2001. Ridker PM, Goldhaber SZ, Danielson E et al. Long-term lowintensity warfarin therapy for the prevention of recurrent idiopathic venous thromboembolism. N Engl J Med 2003;348: 1425–34. Rodie VA, Thomson AJ, Stewart FM, Quinn AJ, Walker ID, Greer IA. Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series. Br J Obstet Gynaecol 2002;109:1020–4. Royal College of Obstetricians and Gynaecologists. Thromboembolic disease in pregnancy and the puerperium: acute management. RCOG Guideline no. 28. London: RCOG, April 2001.