Thrombosis

Thrombosis in pregnancy: maternal and fetal issues

Ian A Greer Pulmonary thromboembolism is the main cause of maternal death in the UK and current trends show an increase. Deep-vein thrombosis underlies this disorder. Important issues include pathophysiology, diagnosis, and management of thrombosis in pregnancy, especially the use of anticoagulants. Congenital and acquired thrombophilias contribute to the pathophysiological processes that underlie miscarriage, intrauterine growth restriction, and pre-eclampsia, and raises new possibilities for intervention. The high prevalence of thrombophilic defects in the population, the association of defects with maternal and fetal disorders, and special considerations for management make it essential for obstetricians to understand this area. In the UK, pulmonary thromboembolism is the leading cause of maternal death.1 Deep-vein thrombosis (DVT) underlies this disorder and is frequently unrecognised.2 DVT in pregnancy is associated with an increased risk of further thrombosis and deep-vein insufficiency. Risk factors for DVT include congenital and acquired thrombophilias, which probably play a part in the pathogenesis of miscarriage, intrauterine growth restriction, and pre-eclampsia. Perhaps the most compelling evidence is the association between thrombophilia due to antiphospholipid antibodies and the activation of the coagulation-system3 and placental infarction. A randomised controlled trial4 has shown that aspirin and heparin given to reduce coagulation activity improved the outcome of pregnancy. The role of anticardiolipin antibody syndrome in such complications is explored later in this series by Michael Greaves.5 This paper focuses on maternal and fetal issues associated with venous thrombosis and congenital thrombophilias. Other factors that underlie venous thromboembolism in pregnancy include weight over 80 kg, family or personal history of thrombosis, and thrombophilia.8 Venous thromboembolism during pregnancy is associated with an increased risk of future venous thromboembolism. Almost two-thirds of women with venous thromboembolism during pregnancy develop deep-vein insufficiency in the affected leg,9 a rate substantially higher than would be expected after DVT outside of pregnancy. This increase may reflect the higher incidence of iliofemoral vein thrombosis during pregnancy.

Pathogenesis of venous thromboembolism

Virchows triad of underlying factors in venous thrombosishypercoagulability, venous stasis, and vascular damageall occur in pregnancy. During pregnancy there are increases in procoagulant factors, such as von Willebrand factor, factor VIII, factor V, and fibrinogen, that occur together with an acquired resistance to the endogenous anticogulant, activated protein C, and a reduction in protein S, the co-factor for protein C. 10 These changes are accompanied by impaired fibrinolysis through increases in plasminogen activator inhibitors 1 and 2, the latter being produced by the placenta.11 These changes represent the physiological preparation for the haemostatic challenge of delivery. Venous stasis occurs in pregnancy by the end of the first trimester and reaches a nadir at 36 weeks.12 Endothelial damage to pelvic vessels can occur during vaginal or abdominal delivery. Thus, the scene is set for the development of thrombosis in pregnancy. Almost 90% of DVT affect the left side among pregnant women compared with 55% among women who are not pregnant.8,9 This difference may reflect compression of the left iliac vein by the right iliac and the ovarian arteries which cross the vein on the left side only. Furthermore, in pregnancy most cases of DVT are ileofemoral rather than calf vein thrombosis (72% vs 9%), and iliofemoral DVT is more likely than calf-vein thrombosis to lead to pulmonary thromboembolism. DVT in pregnancy can present, or be associated with, lower abdominal pain due to periovarian collateral circulation or thrombosis. When coupled with the mild pyrexia and leucocytosis of venous thromboembolism, this pain can be mistaken for other intra-abdominal disorders, such as urinary tract infection or appendicitis.

Epidemiology of maternal venous thromboembolism

The overall incidence of fatal pulmonary thromboembolism associated with pregnancy has fallen since the early 1950s, especially among women after vaginal delivery (figure 1). However, since the 1980s, this downward trend has been reversed,1 which highlights the need for thromboprophylaxis after vaginal delivery in all women at risk of thromboembolism. The rate of non-fatal events is more difficult to establish than that for fatal ones. The incidence of antenatal DVT is about 0615 per 1000 pregnancies in women aged younger than 35 years and 1216 per 1000 in women older than 35 years.6 The rate of postpartum DVT is about 0304 per 1000 pregnancies in women younger than 35 years and 072 per 1000 in women older than 35 years. Antenatal DVT is more common than postpartum DVT,6,7 for which data may not be accurate and complete because women may present to internal medicine rather than to obstetric services. Almost 40% of postpartum DVT manifests after discharge from hospital. Age and operative delivery are major risk factors for venous thromboembolism (figure 2).
Lancet 1999; 353: 125865
Department of Obstetrics and Gynaecology, University of Glasgow, Glasgow Royal Infirmary, Glasgow G31 2ER, UK (Prof I A Greer MD)

1258

THE LANCET Vol 353 April 10, 1999

during pregnancy among women with thrombophilia in the absence of anticoagulant therapy was initially judged to be about 60% among pregnant women with antithrombin deficiency.14,20 However, retrospective studies20,23 of symptomatic kindred showed the incidence of venous thromboembolism among these women to be 32% to 44%. For pregnant women with abnormalities of the protein C and protein S system the risk is substantially lower than for antithrombin-deficient women, and postpartum thromboses are more common than antepartum thrombosis. The risk of thrombosis in pregnancy is 310% for protein C deficiency and 06% for protein S deficiency. In postpartum women the risk is 719% for protein C deficiency and 722% for protein S deficiency.2023 Activated protein C resistance, this defect was found in up to 78% of women investigated for venous thrombosis in pregnancy,24 whereas the factor V Leiden genotype was found in up to 46%.25 These studies, however, investigated women with Figure 1: Number of cases of fatal pulmonary thromboembolism in pregnancy venous thromboembolism and provide and the puerperium in England 195584, UK 198596 limited information about the risk of Data from Confidential Enquiries into Maternal Deaths. thrombosis in previously symptom-free women with the mutation. In a study of 43 women with Congenital thrombophilia and maternal venous the factor V Leiden mutation from symptomatic families, thromboembolism the overall incidence of pregnancy-associated thrombosis The thrombophilias, which were discussed by Fritz was 14%.22 This risk may be higher postpartum.26 Rosendaal13 earlier in this series, underlie many Thus, pregnancy seems to be a significant factor that can 14 thrombotic disorders in pregnancy. The main congenital precipitate venous thromboembolic complications in thrombophilias are deficiencies of antithrombin, protein women with this mutation. However, these studies C, and protein S, and the presence of factor V Leiden, assess symptomatic kindred and so may overestimate the the prothrombin gene variant, and homozygosity for risk. the thermolabile variant of methylenetetrahydrofolate In McColl and colleagues 1997 retrospective study8 of reductase (MTHFR). Factor V Leiden manifests as about 72 000 pregnancies, pregnant women with venous resistance to activated protein C and is the most common thromboembolism were screened for thrombophilia. The 16 defect underlying venous thrombembolism, but such underlying prevalence of congenital thrombophilia in resistance can be caused by disorders other than factor V this population had already been established and the Leiden, including antiphospholipid antibody syndrome investigators estimated the risk of venous thromboand other genetic defects in the factor V molecule. The embolism in pregnancy to be 1 in 437 for factor V resistance can also be acquired in pregnancy as a result of Leiden, 1 in 113 for protein C deficiency, 1 in 28 for increases in factor V and factor VIII.10,16 type I (quantitative) antithrombin deficiency, and 1 in 42 17 The genetic variation in the prothrombin gene has been linked to venous thromboembolism in pregnancy.18 However, more information is needed about this defect in pregnancy, particularly because it may be found with other inherited thrombophilias such as factor V Leiden. Hyperhomocysteinaemia is an established risk factor for venous and arterial thrombosis, and is most commonly caused by homozygosity for the thermolabile variant of MTHFR.19 Pregnancy is associated with decreased concentrations of homocysteine and folic acid supplements will also lower homocysteine concentrations. However, the contribution of homocysteine to venous thromboembolism in pregnancy is unclear. The risk of maternal venous thromboembolism with underlying thrombophilia will depend on the underlying thrombophilic defect(s), history of thrombotic events, and additional risk factors. As Rosendaal13 has pointed out, clinical thrombosis is now considered a multicausal Figure 2: Incidence of postpartum deep-vein thrombosis disease, resulting from interaction between congenital and pulmonary thromboembolism by maternal age and and acquired risk factors. The risk of thromboembolism method of delivery 1259

THE LANCET Vol 353 April 10, 1999

Study and study design

Study population protein C resistance, or both Cases: women with >3 miscarriages (a) confined to first trimester (b) including at least one second trimester miscarriage Controls: parous women with no history of miscarriage Cases: women with >2 miscarriages Controls: parous women with no history of miscarriage Cases: women with spontaneous miscarriage Controls: unselected pregnancies Cases: women with >3 miscarriages Controls: parous women Cases: women with >2 consecutive first-trimester miscarriages Controls: parous women with no history of miscarriage Cases: women with >3 consecutive first or second-trimester miscarriages

Prevalence of factor V Leiden, activated protein C resistance, or both Cases (a) 4/70 (57%) (b) 10/50 (20%)* Controls 3/70 (43%)

Rai et al 276 Case-control to assess prevalence of activated protein C resistance

Grandone et al28 Case-control to assess prevalence of factor V Leiden Dizon-Townson et al30 Case-control to assess prevalence of factor V Leiden Dizon-Townson et al32 Case-control to assess prevalence of factor V Leiden Belasch et al31 Case-control to assess prevalence of factor V Leiden Brenner et al29 Cohort to assess activated protein C resistance and factor V Leiden

7/42 (163%)

5/118 (42%)

12/176 (68%)

17/403 (42%)

0/40

0/25

1/50 (2%)

1/50 (2%)

19/39 (48%)

Not available

*p<002 versus controls and first-trimester miscarriage group. p<002 versus controls; cases were also more likely to have second-trimester loss (p<005). An additional 5/39 had activated protein C resistance without factor V Leiden.

Table 1: Miscarriage, activated protein C resistance, and factor V Leiden

for type II (qualitative) antithrombin deficiency. There is a pressing need for more information on the natural history of these disorders in pregnancy so that obstetricians can assess risk and provide appropriate thromboprophylaxis. Because the risk in symptom-free women with a familial thrombophilic trait, excluding antithrombin deficiency, is uncertain in pregnancy, a randomised placebo-controlled trial of thromboprophylaxis is justified to guide practice.

Congenital thrombophilia and fetal loss

The association between acquired resistance to activated protein C and disorders such as anticardiolipin antibody syndrome (an underlying cause of recurrent miscarriage), prompted investigation of the effect of congenital activated protein C resistance on miscarriage Rai and colleagues27 found a significantly higher prevalence of such resistance in women with recurrent miscarriages (including at least one second-trimester loss) than in women with recurrent fetal loss in the first trimester or in a parous control group (table 1). This link to fetal loss during the second trimester was supported by Grandone and colleagues case-control study28 which showed a significantly higher prevalence of factor V Leiden in recurrent miscarriage, particularly in the second trimester. Brenner and colleagues cohort study29 of women with recurrent fetal loss showed a 48% prevalence of the factor V Leiden mutation; in women with factor V Leiden, only 19% of 128 pregnancies ended in livebirths. Other studies3032 have shown no relation between recurrent miscarriage and factor V Leiden (table 2). These data from case-control and cohort studies suggest that recurrent first-trimester miscarriage is not associated with factor V Leiden, although second-trimester miscarriage may be. A possible explanation for this discrepancy is that first-trimester miscarriages reflect a failure in implantation and second-trimester miscarriages reflect thrombotic event in the placenta. The cohort study by Dizon-Townson and colleagues30 showed a link with fetal genotype: 86% of 1260

aborted fetuses carried the genotype for factor V. This finding accords with the higher frequency of placental infarction in pregnancies associated with maternal and fetal carriage of factor V Leiden.30,33 These case-control and cohort studies focused on women with a history of miscarriage. Taking another approach, Preston and colleagues34 investigated pregnancy outcome in a cohort of women with thrombophilia. Compared with data from a healthy control population, there was an increased risk of fetal loss (odds ratio 135 [95% CI 101182]) and stillbirth (36 [1494]), however, the risk of miscarriage was not significantly increased (127 [094171]) (table 2). The investigators also found no difference in the number of pregnancies or fetal losses between women with and those without thrombophilic partners.34 Sanson and colleagues,35 found an increased incidence of pregnancy loss in women with a deficiency of antithrombin, protein C, and protein S, with an odds ratio of 20 (1233) for all deficiencies combined. 35 Other thrombophilic defects such as dysfibrinogenaemia have also been linked to fetal loss.36 These data come from case-control or retrospective cohort studies. Prospective longitudinal studies are needed to define the risk of pregnancy-related complications in women with thrombophilic abnormalities. Nonetheless, available data are consistent with the concept that maternal thrombophilia carries an increased risk of fetal loss due to placental vascular disorders.

Thrombophilia, intrauterine growth restriction, and pre-eclampsia

Since pre-eclampsia is associated with vascular injury, which in turn is associated with a disturbance in coagulation, the congenital thrombophilias could have a role in this disorder. Dekker and colleagues cohort study37 of 101 patients with a history of pre-eclampsia found that 15% of the women had underlying activated protein C resistance, although genotyping for factor V Leiden was not done. These investigators also found that

THE LANCET Vol 353 April 10, 1999

Type of thrombophilia

Number of cases (pregnancies) 108 (250) 162 (430) 145 (378) 141 (410) 15 (46)

Odds ratio (95% CI)* All spontaneous fetal losses 21 (1236) 14 (0922) 13 (0821) 10 (0617) 20 (0581) Miscarriages 17 (1028) 14 (0922) 12 (0719) 09 (0515) 08 (0236) Stillbirths 52 (15181) 23 (0683) 33 (10113) 20 (0577) 143 (24860)

Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden Combined defects

Data are from refs 3034. Control group n=395 with 1019 pregnancies. *Adjusted for number of pregnancies and centre (data from Preston and colleagues34).

Table 2: Odds ratios for fetal loss in women with thrombophilia compared with a control group by type of thrombophilia

25% of the women had a prevalence of protein S deficiency, and that 18% of patients had a positive result to a methionine load test, which assesses the possibility of hyperhomocysteinaemia, Furthermore, 30% of patients had anticardiolipin antibodies.37 Several patients had combined disorders, but the only combination that recurred was protein S deficiency and a moderate increase of anticardiolipin antibodies. De Vries and colleagues38 assessed 62 women who had had placental abruption, intrauterine death, or a small-for-gestational age infant in the absence of antihypertensive disorders, and found that 65%, 56%, and 85%, respectively, had underlying thrombophilic disorders. Overall, 26% had protein S deficiency, 24% of women had hyperhomocysteinaemia, and 6% had protein C deficiency; no women had a deficiency of antithrombin.38 Several case reports have also described activated protein C resistance in pregnancies complicated by HELLP syndrome (haemolysis elevated liver enzymes and low platelets), a variant of pre-eclampsia, severe pre-eclampsia, intrauterine growth restriction, and fetal loss.29,39 Although these studies point to a possible link between thrombophilia, pre-eclampsia, abruption, and intrauterine growth restriction, interpretation is limited by the observational design. However, some case-control studies have examined activated protein C resistance and factor V Leiden. Dizon-Townson and colleagues40 case-control study showed that 89% of women with severe pre-eclampsia were heterozygous for the factor V Leiden mutation, compared with 42% of controls. In another case-control study, Grandone and colleagues41 reported a prevalence of 105% for factor V Leiden in women with preeclampsia versus 23% in controls, which gave an odds ratio of 49 (13183). These researchers also assessed underlying homozygosity for the thermolabile variant of MTHFR: 298% of the pre-eclamptic patients had this variant, compared with 186% of controls, with an odds ratio of 18 (1035). This finding suggests that hyperhomocysteinaemia may be a risk factor for preeclampsia, presumably because of the toxic effects that homocysteine has on the endothelium. If so, it may be useful to measure folic acid, and vitamin B6 and B12 in women with adverse pregnancy outcome, since a deficiency of these vitamins can lead to acquired hyperhomocysteinaemia, which is treatable with folic acid and vitamin B6 supplements.42 In a case-control study by Lindoff and colleagues43 22% of the 50 women with previous pre-eclampsia had activated protein C resistance, compared with 10% of the 50 controls. There was no difference in concentrations of protein C or antithrombin concentrations between the groups and no association between intrauterine growth restriction and activated protein C resistance. However, Lindqvist and colleagues 44 found that 18% of 122 women

with pre-eclampsia, intrauterine growth restriction, or both had factor V Leiden, compared with 10% of 465 healthy pregnant controls. In their case-control study of women with pregnancy complications (pre-eclampsia, abruption, growth restriction, and stillbirth), Kupferminc and colleagues45 reported odds ratios of 37 (1590), 31 (1471), and 39 (11146) in women with factor V Leiden, homozygosity for the thermolabile variant of MTHFR, and the prothrombin gene variant, respectively. These data suggest that factor V Leiden and homozygosity for the thermolabile variant of MTHFR predispose women to pre-eclampsia. Of interest is the fairly high rate (210%) of the factor V Leiden gene in the populations studied. Why such a genotype persists in the population warrants further investigation. Analogies have been made with sickle-cell disease, in which the presence of sickle-cell trait affords protection against malaria. Lindqvist and colleagues44 reported a fall in the number of women with a blood loss at vaginal delivery of greater than 600 mL and the development of postpartum anaemia in the women with factor V Leiden. Activated protein C resistance can be acquired during pregnancy, probably because of high concentrations of factor VIII and factor V.10 However, acquired resistance does not account for all of the association of activated protein C resistance with pre-eclampsia. The disturbance of the coagulation system in pre-eclampsia means that vascular damage may result from the combination of an underlying thrombophilic disorder, the physiological changes in activated protein C resistance in pregnancy, and the pathological changes of pre-eclampsia.

Screening for congenital thrombophilia

There is no evidence to support routine screening of all pregnant women for congenital thrombophilia. The natural history of many of the congenital thrombophilias in individuals is not known, nor is therapy for them. Moreover, the cost of screening is likely to be high. There is no doubt that screening is indicated for women with venous thromboembolism in pregnancy or who have a personal or family history of this disorder. About 50% of such women will be found to have a thrombophilic defect. Although the need for antenatal thromboprophylaxis may be uncertain for some disorders for example, symptomless factor V Leiden, the consensus is that women with a personal history of venous thromboembolism and an underlying thrombophilic trait should receive thromboprophylaxis during pregnancy (see below). There are no data to suggest that screening for congenital thrombophilia in women with recurrent firsttrimester fetal loss is justified, but patients with recurrent pregnancy loss, including a second-trimester miscarriage or a history of an intrauterine death, should be screened. Screening is also justified for women with severe or 1261

THE LANCET Vol 353 April 10, 1999

recurrent intrauterine growth restriction or pre-eclampsia. However, in a patient with recurrent pregnancy loss and an underlying thrombophilic trait management is uncertain. Some extrapolation can be made from the benefits of aspirin plus heparin in women with antiphospholipid antibody syndrome, but controlled trials are needed to assess the effectiveness of such intervention for women who screen positive.

Management of venous thromboembolism

The objective diagnosis of venous thromboembolism during pregnancy is crucial. The diagnosis has serious implications not only for management of the pregnancy, but also for other features of the womans life, such as contraception and management of future pregnancies. All women with symptoms or signs compatible with venous thromboembolism must have appropriate investigation. Most events occur outside of hospital and carers of pregnant women in the community must be aware of this possibility and the underlying risk factors for venous thromboembolism. Real time or duplex ultrasonography is the first-line diagnostic tool,54 particularly because most cases of DVT are iliofemoral. If the initial investigation is negative and there is continuing concern about possible DVT, then the women should undergo repeat ultrasonography. If pulmonary thromboembolism is suspected then ventilation-perfusion lung scan should be done; in the first instance, perfusion scanning can be used alone. Lung scans should be combined with ultrasound venography. The radiation dose to the fetus from limited venography with abdominal shielding, ventilation-perfusion lung scan, and chest radiography, even taken together, is small and deemed to pose a negligible risk. If the diagnosis of pulmonary thromboembolism remains uncertain after lung scan, the results of ultrasonography are useful. If positive, anticoagulant therapy should be started. Pulmonary angiography is the gold standard for diagnosis of pulmonary thromboembolism but is rarely necessary, although it should be considered in cases with a high clinical probability of the disorder and inconclusive test reports. If there is a persistent clinical suspicion of venous thromboembolism in the face of a negative or lowprobability test result, treatment should be started and tests repeated within 7 days and therapy discontinued if tests remain negative. Therapeutic doses of unfractionated or low-molecularweight heparin are used, 55 with thromboembolic deterrent stockings, and continued throughout the pregnancy. Twice daily subcutaneous administration is appropriate and the patient should be taught how to self-inject. The activated partial thromboplastin time is unreliable for monitoring doses of unfractionated heparin in pregnancy because of the pregnancy-associated increase in factor VIII,51,55 so antifactor Xa concentrations may offer a better alternative way to measure heparin concentrations in pregnancy. The dose of low-molecular-weight heparin depends on maternal weight, and although monitoring is not required in the women who are not pregnant, measurement of peak antifactor Xa concentrations (target range 0410 /mL) may be of value until more experience is gained of low-molecular-weight heparin in pregnancy.56 The dose of unfractionated and lowmolecular-weight heparin is reduced during delivery to prophylactic concentrations and the timing of administration is adjusted to allow epidural or spinal anaesthesia. Warfarin can be used postpartum, particularly to avoid the risk of osteoporosis associated with heparin, although many women prefer to stay on low-molecular-weight heparin. Treatment should continue for at least 6 weeks and 3 months is often more appropriate.

Anticoagulants and antithrombotic techniques

Unfractionated and low-molecular-weight heparins do not cross the placenta and, so, there is no risk of teratogenesis or fetal haemorrhage. These drugs are not secreted in breastmilk and can be used during lactation. The disadvantages are osteoporosis, heparin-induced thrombocytopenia, and allergy.46,47 Warfarin is not secreted in breastmilk in clinically significant amounts and is safe to use during lactation. However, this drug crosses the placenta, and warfarin embryopathy may occur in 45% of fetuses exposed to the drug between 6 and 9 weeks of gestation.48 Warfarin embryopathy can be prevented by substitution of heparin for warfarin during the first trimester. Central-nervoussystem abnormalities reported with warfarin exposure in the fetus may be due to spontaneous intracerebral bleeding. Since the liver is immature and concentrations of vitamin-K-dependent coagulation factors are low in the fetus, maternal warfarin therapy maintained in the therapeutic range is associated with excessive anticoagulation and potential bleeding in the fetus. Warfarin should, particularly, be avoided beyond 36 weeks of gestation,48,50 because of the excessive risk of haemorrhage to both mother and fetus in the peripartum period. Dextran has been used for peripartum thromboprophylaxis, particularly during caesarean section, and carries a substantial risk of anaphylactic and anaphylactoid reactions. Of greater concern in pregnancy is the risk of maternal anaphylactoid reactions associated with uterine hypertonus, profound fetal distress, and a high incidence of fetal death or profound neurological damage.51 Thus, dextran should be avoided in pregnancy. Since thromboembolic-deterrent stockings are effective in women who are not pregnant, they might be useful in pregnancy. These stockings stop overdistenstion of veins and so prevent endothelial damage and exposure of subendothelial collagen.52 Other mechanical techniques such as intermittent pneumatic compression are of value during caesarean section and immediately postpartum. Aspirin can prevent DVT,53 and its effectiveness in pregnancy, compared with heparin, remains to be established. The effectiveness of aspirin is likely to be less than that of heparin and low-molecular-weight heparin. In women who are unable to take heparin or in whom the balance of risk is not deemed sufficient to merit heparin, aspirin may be useful. Low doses (6075 mg daily) of aspirin are not associated with adverse pregnancy outcome. Hirudin is used in women who are not pregnant for treatment of thrombocytopenia induced by heparin, but is also used for postoperative prophylaxis. Since hirudin crosses the placenta it should not be used in pregnancy; its use after delivery has not been assessed. The best option seems to be the established thromboprophylactic agents. 1262

THE LANCET Vol 353 April 10, 1999

Thromboprophylaxis in pregnancy and the puerperium

All patients with a personal or family history of venous thromboembolism should be considered for antenatal prophylaxis and be screened for a thrombophilia. Thromboprophylaxis is also indicated when there are additional risk factors, such as hyperemesis or surgery or when patients are obese or immobile, particularly if they also have pre-eclampsia or concurrent medical conditions associated with thrombosis, such as nephrotic syndrome, inflammatory bowel disease, or infection. If previous DVT is the only risk factor, antenatal anticoagulation is controversial, because of the potential hazards of heparin, although use of low-molecular-weight heparin reduces the hazards. However, controlled trials are needed to guide management. Anticoagulant therapy for thromboprophylaxis in pregnancy usually consists of unfractionated heparin in a dose of 10 000 IU twice daily during the latter half of pregnancy, or for low-molecular-weight heparin, 40 mg enoxaparin daily or 5000 IU dalteparin daily. There is no need to adjust the dose of low-molecular-weight heparin during pregnancy.45,57 Women with a bodyweight of less than 50 kg are likely to have satisfactory heparin concentrations on low doses (20 mg enoxaparin, 2500 IU dalteparin),58 whereas obese women (>80 kg) may require higher doses. In women with multiple thrombotic events during previous pregnancies, antenatal prophylaxis should start at least 46 weeks in advance of the gestation at which the previous events occurred. If previous thrombosis was not associated with pregnancy, then prophylaxis should start by about the mid point (20 weeks) of pregnancy or sooner, particularly if additional risk factors are present. Indeed, with the low incidence of side-effects with low-molecular-weight heparin there is a case to start prophylaxis from much earlier in pregnancy. Since the risk of venous thromboembolism is likely to be high in patients with past thromboses, low-molecular-weight or unfractionated heparin should be combined with graduated elastic compression stockings. If heparin is contraindicated, graduated elastic compression stockings and low-dose aspirin may be used. After delivery, thromboprophylaxis should be continued for a minimum of 6 weeks, but in patients with severe thrombocytic problems, for 3 months. Patients on heparin must be told of the risk of osteoporosis with heparin. If the patient wants to change to warfarin it can be started 48 h after delivery with the heparin continued until the international normalised ratio is between 2 and 25. Unfractionated heparin is prescribed in a dose of 750010 000 IU twice daily, and low-molecular-weightheparin such as enoxaparin or dalteparin in doses of 40 mg or 5000 IU daily, respectively. Gibson and colleagues59 reported that low-molecular-weight heparin provided better antifactor Xa concentrations than did unfractionated heparin in conventional doses after caesarean section.59 Many patients with underlying congenital or acquired thrombophilia will require antenatal prophylaxis, the timing of which will depend on the patients history and thrombophilic disorder.14 In patients with symptomatic protein C deficiency, protein S deficiency, and factor V Leiden, standard treatment is unfractionated or lowmolecular-weight heparin antenatally in the doses

discussed above. In women with antithrombin deficiency, the risk may be substantially greater and the dose of heparin needs to be adjusted throughout the pregnancy. Antithrombin preparations can be added at times of particularly high risk, such as delivery. Symptom-free carriers of thrombophilia require special consideration. Since the risk varies with the type of thrombophilia, all patients with thrombophilia should be referred to a unit that specialises in the management of thromophilia in pregnancy. During labour thromboprophylaxis should be continued, but because of the risk of epidural haematoma associated with heparin, the timing of the insertion (and removal) of the epidural catheter, caesarean section, or heparin dose may need to be adjusted to avoid peak heparin concentration at the time of placement of the catheter.50 There have been postmarketing reports in the US Food and Drug Administration of low-molecularweight heparin and epidural haematoma. Most of these events have occurred in elderly women (median age 75 years) undergoing orthopaedic surgery. Additional risk factors have included concomitant use of non-steroidal anti-inflammatory agents or multiple puncture attempts at spinal or epidural. The true incidence of epidural haematoma is impossible to determine because of lack of denominator data. In addition, the dose of enoxaparin given in Europe is 40 mg daily, compared with 30 mg twice daily in North America. However, caution is needed in giving epidural anaesthesia in patients on lowmolecular-weight heparin. There must be vigilence for signs of cord compression. Epidural anaesthesia must be avoided in patients on therapeutic anticoagulation. In women on prophylactic doses of unfractionated and lowmolecular-weight heparin, epidural anaesthesia should be avoided around the time of peak-heparin concentrations. Thus placement of the epidural catheter must be delayed for 4 h with unfractionated heparin and longer with lowmolecular-weight heparin the delay is arbitrary, since it is broadly extrapolated from the time of peak concentrations and pharmacokinetics of the drugs. In my unit the delay is at least 6 h, but others suggest a delay of 12 h. 60 Unfractionated and low-molecular-weight heparin can be restarted 2 h after catheter removal. Knowledge of thromboprophylaxis for women with no personal or family history of venous thromboembolism, but with congenital thrombophilia and a history of fetal loss or pre-eclampsia is limited. Aspirin is not beneficial in the prevention of pre-eclampsia. The combination of low-dose aspirin and heparin is effective in preventing recurrent fetal loss in women with anticardiolipin antibodies,4 and could be considered for women with congenital thrombophilia and fetal loss, pre-eclampsia, or both. Caesarean section, particularly emergency caesarean section, carries substantial increased risk of thromboembolic disease and guidelines have been drawn up for management according to risk.61 Patients at low risk are those who undergo elective caesarean section with an uncomplicated pregnancy and no additional risk factors. Women at moderate risk are those who undergo caesarean section and have another risk factor such as age older than 35 years or obesity, or if the caesarean section is an emergency procedure. Women at high risk are those with multiple risk factors or severe disorders such as thrombophilia or paralysis of the lower limbs. These women should receive unfractionated or low-molecularweight heparin thromboprophylactically; duration of 1263

THE LANCET Vol 353 April 10, 1999

therapy depends on the magnitude of the risk. In view of the increase in death after vaginal delivery, guidelines should also be developed for the management of women with risk factors after vaginal delivery.

19 20

Conclusion
Thrombosis in pregnancy and underlying thrombophilia have serious implications for mother and fetus. Evidence is accumulating to link congenital thrombophilia to fetal loss, intrauterine growth restriction, pre-eclampsia and maternal venous thromboembolism. However, the knowledge is based mostly on case-control and cohort studies, so the natural history of these conditions in symptom-free individuals is uncertain and large-scale, prospective, longitudinal studies are needed. Only when the implications of thrombophilic defects are known, can appropriate intervention be assessed, ideally in large randomised trials. In the meantime, women with a personal or family history of venous thromboembolism, second-trimester fetal loss, intrauterine death, and severe or recurrent intrauterine growth restriction and preeclampsia, should be screened for thrombophilia and consideration given to thromboprophylaxis.
References
1 Department of Health, Welsh Office, Scottish Home and Health Department and Department of Health and Social Services Northern Ireland. Confidential Enquiries into Maternal Deaths in the United Kingdom 199497. London: TSO, 1998. Greer IA, de Swiet M. Thrombosis prophylaxis in obstetrics and gynaecology. Br J Ostet Gynaecol 1993; 100: 3740. Vincent T, Rai R, Regan L, Cohen H. Increased thrombin generation in women with recurrent miscarriage. Lancet 1998; 353: 116. 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). BMJ 1997; 314: 25357. Greaves M. Antiphospholipid antibodies and thrombosis. Lancet (in press). Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience. Scot Med J 1996; 41: 8386. Rutherford S, Montoro M, McGhee W, Strong T. Thromboembolic disease associated with pregnancy: an 11 year review. Am Obstet Gynecol 1991; 164 (suppl): 286. McColl M, Ramsay JE, Tait RC, et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78: 118388. Lindhagen A, Bergqvist A, Bergqvist D, Hallbook T. Late venous function in the leg after deep venous thrombosis occurring in relation to pregnancy. Br J Obstet Gynaecol 1986; 93: 34852. Clark P, Brennand J, Conkie JA, McCall F, Greer IA, Walker ID. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79: 116670. Greer IA. Haemostasis and thrombosis in pregnancy. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD, eds. Haemostasis and thrombosis. Edinburgh: Churchill Livingstone, 1994: 9871015. Macklon NS, Greer IA, Bowman AW. An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Br J Obstet Gynaecol 1997; 104: 19197. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 116773. Walker ID. Congenital thrombophilia. In: Greer IA, ed. Baillieres clinical obstetrics and gynaecologythromboembolic disease in obstetrics and gynaecology. London: Bailliere Tindall, 1997: 43145. Zoller B, Holm J, Dahlback B. Resistance to activated protein C due to factor V gene mutation: the most common inherited risk factor of thrombosis. Trends Cardiovasc Med 1996; 6: 45. Bokarewa MI, Wramsby N, Bremme K, Blomback M. Variability of the response to activated protein C during normal pregnancy. Blood Coag Fibrinol 1997; 8: 239. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the three untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3638. McColl MD, Walker ID, Greer IA. A mutation in the prothrombin 21

22

23

24

25

26

27

28

29

2 3 4

30

31

32

5 6 7

33

34 35

36

10

37

38

11

39

12

40

13 14

41

15

42

16

43

17

44

18

gene contributing to venous thrombosis in pregnancy. Br J Obstet Gynaecol 1998; 105: 92325. Den Heijer M, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep vein thrombosis. N Engl J Med 1998; 334: 75962. Conard J, Horellou MH, van Dreden P, Le Compte T, Samama M. Thrombosis in pregnancy and congenital deficiencies in AT III, protein C or protein S: study of 78 women. Thromb Haemost 1990; 63: 31920. de Stefano V, Leone G, Masterangela S, et al. Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein Cprotein S. Thromb Haemost 1994; 71: 799800. Hough RE, Makris N, Preston FR. Pregnancy in women with thrombophilia: incidence of thrombosis and pregnancy outcome. Br J Haematol 1996; 93 (suppl 2): 136 (abstr). Pabinger I and the Study Group on Natural Inhibitors. Thrombotic risk in hereditary anti-thrombin III, protein C or protein S deficiency. Arter Thromb Vasc Biol 1996; 16: 74248. Hallak M, Senderowica J, Cassel A, et al. Activated protein C resistance (factor V Leiden) associated ith thrombosis in pregnancy. Am J Obstet Gynecol 1997; 176: 88993. Bokarewa MI, Bremme K, Blomback M. Arg 506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 1996; 92: 47378. de Stefano V, Leone G, Masterangelo S, et al. Thrombotic risk during pregnancy and puerperium in women with APC resistance: effective subcutaneous heparin prophylaxis in a pregnant patient. Thromb Haemost 1995; 74: 79394. Rai RS, Regan L, Hadley E, Dave M, Cohen H. Second trimester pregnancy loss is associated with activated Protein C resistance. Br J Haematol 1996; 92: 48990. Grandone E, Margaglione M, Colaizzo D, et al. Factor V Leiden is associated with repeated and recurrent explained fetal losses. Thromb Haemostas 1997; 77: 82224. Brenner B, Mandel H, Lanir N, Younis J, Rothbart H. Activated protein C resistance can be associated with recurrent fetal loss. Br J Haematol 1997; 97: 55154. Dizon-Townson DS, Meline L, Nelson LM, Barner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 1997; 177: 40205. Dizon-Townson DS, Kinney S, Branch DW, Ward K. The factor V Leiden mutation is not a common cause of recurrent miscarriage. J Reprod Immunol 1997; 34: 21723. Belasch J, Riverter JC, Fabregues F, et al. First trimester repeated abortion is not associated wtih activated protein C resistance. Hum Reprod 1997; 12: 109497. Rai RS, Regan L, Chitolie A, Donald JG, Cohen H. Placental thrombosis in second trimester miscarriage in association with activated Protein C resistance. Br J Obstet Gynaecol 1996; 103: 84244. Preston FE, Rosendaal FR, Walker ID, et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 91316. Sanson BJ, Friederich PW, Simioni P, et al. The risk of abortion and stillbirth in antithrombin, Protein S and Protein S deficient women. Thromb Haemost 1996; 75: 38788. Havercate F, Samama M. Familial dysfibrinogenaemia and thrombophiliareport on a study of the SSC sub-committee on fibrinogen. Thromb Haemostas 1995; 73: 15161. Dekker GA, de Vries JIP, Doelitzsch PM, et al. Underlying disorders associated with severe early onset of pre-eclampsia. Am J Obstet Gynecol 1996; 173: 10445. De Vries JIP, Dekker J, Huijgens PC, Jakobs C, Blomberg BME, van Geijn HP. Hyperhomocysteinaemia and Protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol 1997; 104: 124854. Rotmensch S, Liberati M, Mittlemann M, Ben-Rafael Z. Activated protein C resistance and adverse pregnancy outcome. Am J Obstet Gynecol 1997; 177: 17073. Dizon-Townson DS, Nelson LM, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe pre-eclampsia. Am J Obstet Gynaecol 1996; 175: 90205. Grandone E, Margagilione M, Colazzo D, et al. Factor V Leiden. C>TMTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemostas 1997; 77: 105254. Leeda M, Riyazi N, de Vries JIP, Jakobs C, van Geijn HP, Dekker GA. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of pre-eclampsia or fetal growth restriction. Am J Obstet Gynecol 1998; 179: 13639. Lindoff C, Ingemarsson I, Martinsson G, Segelmark M, Thysell H, Astedt B. Pre-eclampsia is associated with a reduced response to activated protein C. Am J Obstet Gynecol 1997; 176: 45760. Lindqvist PG, Svensson PJ, Dahlback B, Masal K. Factor V Q506 mutation (activated protein C resistance) associated with reduced intrapartum blood lossa possible evolutionary selection mechanism. Thromb Haemost 1998; 79: 6973.

1264

THE LANCET Vol 353 April 10, 1999

45 Kupferminc MJ, Amiram E, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 1: 913. 46 Macklon NS, Greer IA, Reid AW, Walker ID. Thrombocytopenia antithrombin deficiency and extensive thromboembolism in pregnancytreatment with low molecular weight heparin. Blood Coag Fibrinol 1995; 6: 67275. 47 Nelson-Piercy C. Hazards of heparin: allergy, heparin-induced thrombocytopenia and osteoporosis. In: Greer IA, ed. Baillieres clinical obstetrics and gynaecologythromboembolic disease in obstetrics and gynaecology. London: Bailliere Tindall, 1997: 489509. 48 Bates SM, Ginsberg JS. Anticoagulants in pregnancy: fetal defects. In: Greer IA, ed. Baillieres clinical obstetrics and gynaecology thromboembolic disease in obstetrics and gynaecology. London: Bailliere Tindall, 1997: 47988. 49 Warkentin TE, Levine MN, Hisch J, et al. Heparin induced thrombocytopenia in patients treated wtih low molecular weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 133035. 50 Letsky E. Peripartum prophylaxis of thromboembolism. In: Greer IA, ed. Baillieres clinical obstetrics and gynaecologythromboembolic disease in obstetrics and gynaecology. London: Bailliere Tindall, 1997: 2343. 51 Greer IA. Epidemiology, risk factors, and prophylaxis of venous thromboembolism in obstetrics and gynaecology. In: Greer IA, ed. Baillieres clinical obstetrics and gynaecologythromboembolic disease in obstetrics and gynaecology. London: Bailliere Tindall, 1997: 40330. 52 Macklon NS, Greer IA. Technical note: compression stockings and posturea comparative study of their effects on the proximal deep veins in the leg at rest. Br J Radiol 1995; 68: 51518.

53 Thrombombolic risk factors (THRIFT) Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients. BMJ 1992; 305: 56774. 54 Macklon NS. Diagnosis of deep venous thrombosis and pulmonary embolism. In: Greer IA, eds. Baillieres clinical obstetrics and gynaecologythromboembolic disease in obstetrics and gynaecology. London: Bailliere Tindall, 1997: 46377. 55 Lowe GDO. Treatment of venous thromboembolism. In: Greer IA, ed. Baillieres clinical obstetrics and gynaecologythromboembolic disease in obstetrics and gynaecology. London: Bailliere Tindall, 1997: 51121. 56 Thomson AJ, Walker ID, Greer IA. Low molecular weight heparin for immediate management of thromboembolic disease in pregnancy. Lancet 1998; 352: 1904. 57 Brennand JE, Walker ID, Greer IA. Anti-activated factor X profiles in pregnant women receiving antenatal thromboprophylaxis with Enoxaparin. Acta Haematol 1999; 101: 5355. 58 Blomback M, Bremme K, Hellgren M, Lindberg H. A pharmacokinetic study of dalteparin (Fragmin) during late pregnancy. Blood Coag Fibrinol 1998; 9: 34350. 59 Gibson JL, Ekevall K, Walker ID, Greer IA. Puerperal thromboprophylaxis: comparison of the anti-Xa activity of enoxaparin and unfractionated heparin. Br J Obstet Gynaecol 1998; 105: 79597. 60 Horlocker TT, Heit JA. Low molecular weight heparin: biochemistry, pharmacology, perioperative prophylaxis regimens and guidelines for regional anesthetic management. Anesth Analg 1997; 85: 87485. 61 Report of the RCOG Working Party on Prophylaxis Against Thromboemolism in Gynaecology and Obstetrics. London: Royal College of Obstetricians and Gynaecologists, 1995.

Essay

Helen
Peter Reagan She pointed to her left cheek and said, You can kiss me now. Right here. Taken by surprise, and extremely moved, I kissed her lightly and sat back. She smiled and looked up brightly. Afterwards she asked me for some brandy. Beth had diluted it fifty-fifty with a soft drink. She wasnt used to drinking much alcohol, and she choked on it just a little as it went down. Beth offered her a mint, but she waved it away and said she was sleepy. Douglas held her right hand and arm, as I held her left. Beth massaged her feet. Her breathing was slow, even, and relaxed. About a minute later I asked her how she was doing and she mumbled, Tired. We took two of the pillows from behind her head so she could sit back more easily, and Helen fell into a deep sleep. The three of us sat around her bed talking quietly about the emotional struggle wed each been through. 3 weeks earlier, I had received a phone call from a retired colleague about a patient who wanted help ending her life under the new Oregon Death With Dignity Law (see Lancet 1994; 344: 149394). Her previous physicians had not been prepared to offer a life-ending prescription. Could I see her soon? 5 days later she was sitting in a wheelchair in an examination room with her son Douglas and her daughter Beth. She was elderly, frail, and hooked to
Lancet 1999; 353: 126567
2406 NE 19th Avenue, Portland, OR 97212, USA (P Reagan MD)

oxygen, but completely astute, with a delightful twinkle; I liked her immediately. She and her family carefully detailed her history of breast cancer, her years since her first mastectomy, the recurrence on the other side, the metastases, and the downhill course. The second tumour had developed when she was 82; she had refused all treatment for it after the lumpectomy. Her husband had suffered a lingering death a decade earlier; she was opting for life while it was good and then a clean exit. I discussed the requirements of the law with her. When I got to the part about a written request, she handed me a notarised statement signed by Douglas and a neighbour. I looked into her eyes and shivered as I contemplated the enormity of what I was facing. I took a deep breath and we started discussing her attempts to get help with dying. She had asked her original physician, but he was about to relocate his practice and didnt want to be involved. He had recommended hospice care and had referred her to a second primary physician who, he thought, might have been open to aid in dying. The second physician had seen her twice, ordered a chest radiograph, and also encouraged hospice care. He agreed that she had a short life-expectancy but recorded in her notes that she was probably depressed. Helen and her family felt he was not ready to provide assistance and was buying time. She said, He made me wait 24 days, and he never intended to help me. I think he still expected me to come back to him. He should have told me at the beginning. 1265

THE LANCET Vol 353 April 10, 1999