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Current obstetric guidelines on thromboprophylaxis in the United Kingdom: evidence based medicine?
European Journal of Obstetrics & Gynecology and Reproductive Biology, 1, 168, pages 7 - 11
In the United Kingdom, the national guidance from Royal College of Obstetricians and Gynaecologists (RCOG) and National Institute for Health and Clinical Excellence (NICE) encourages the use of low molecular weight heparin thromboprophylaxis in high risk pregnancies. The recommendation, however, is based largely on expert opinion with almost no evidence from randomised controlled trials or meta-analyses. Here we examine the evidence for and against use of thromboprophylaxis and suggest that careful consideration is needed in implementing change in practice with follow-up of complications due to a real risk of unintended consequences. Therefore, large-scale and well-designed studies are urgently needed. We find that health economic assessments, which should be central to any major health policy change, appear entirely absent in this context.
Keywords: Obstetrics, Thromboprophylaxis, National policy.
Venous thromboembolism (VTE) is the third commonest cause of direct maternal death in the United Kingdom (UK) and Europe  and . Recent guidance from Royal College of Obstetricians and Gynaecologists (RCOG) and National Institute for Health and Clinical Excellence (NICE) encourages the use of low molecular weight heparin (LMWH) thromboprophylaxis in high risk pregnancies  and . The recommendation, however, is largely based on expert opinion and pays insufficient attention to the potential haematological, neurological and medical side effects, nor has a formal health economic assessment been carried out. Here we examine the evidence for and against thromboprophylaxis guidelines that are now applied to approximately 700,000 women per year in the UK  .
Incidence of VTE in pregnancy and puerperium
The Eighth Report on Confidential Enquiries into Maternal Deaths in the UK (2006–2008) estimated 0.79 VTE deaths/100,000 maternities; 16 from pulmonary embolism (PE) and 2 from cerebral vein thrombosis  . The UK's Obstetric Surveillance System (UKOSS) estimates an incidence of 1.3 PE/10,000 maternities, with 143 cases reported from February 2005 to August 2006  .
During pregnancy, the risk of VTE is 5–10 fold higher than that outside pregnancy  ; its incidence in pregnancy and the puerperium is 1–2/1000  and . There is no consensus as to whether VTE is more likely antenatally or postpartum  and .
An RCOG ‘green-top’ guideline estimated 700–1400 pregnancy-related VTE episodes/year nationally, in addition to those related to miscarriage and termination of pregnancy. This translates into an overall case fatality for VTE in pregnancy of approximately 1%  .
Evidence for thromboprophylaxis
The evidence underlying the importance of risk factors of VTE in pregnancy is drawn mainly from case control or population studies and derived risk assessments and decision models  .
Thromboprophylaxis was deemed to be safe in a prospective cohort study with risk stratification which recruited 810 pregnant women  . The medium and high risk groups received both antenatal and postnatal dalteparin at routine and higher doses respectively, whilst the low risk group received postnatal dalteparin only. A clinically relevant bleed was found in 4.6% with 1.1% thought to be dalteparin-related: 0.1% developed osteoporosis and 2.2% had thrombocytopenia but without features of heparin-induced thrombocytopenia (HIT). In another prospective study of 286 high risk patients with a history of VTE and/or thrombophilia, serious bleeding occurred in 0.35% of cases but no instances of HIT or osteoporosis were seen  . All patients received postnatal LMWH prophylaxis for at least 6 weeks while 61.8% were given antenatal prophylaxis: 0.35% suffered a DVT antepartum and 0.7% postpartum.
A decision model was constructed to evaluate the risks and benefits associated with a seven-day regimen of prophylactic LMWH following caesarean section (CS), compared with no treatment  . LMWH prophylaxis led to the highest quality-adjusted life expectancy, with a net gain of 1.5–2.8 days. The model showed the incidence of VTE after CS to be 0.15–0.22% with the haemorrhagic risk due to LMWH 0.23–0.35%. This compares favorably with 0.5% incidence of VTE following caesarean delivery without LMWH prophylaxis.
Evidence against routine thromboprophylaxis
The 2010 Cochrane review on prophylaxis for VTE in pregnancy and puerperium examined 13 randomised trials involving 1774 women  . There was insufficient evidence on which to base recommendations for thromboprophylaxis during pregnancy and the early postnatal period. For antenatal prophylaxis, LMWH was associated with fewer bleeding episodes compared with unfractionated heparin (UFH). New to the 2010 version, there was some evidence of side effects associated with heparin (UFH or LMWH) thromboprophylaxis in women undergoing CS (n = 796): with more bleeding or bruising episodes (risk ratio 5.15)  . Current RCOG and NICE guidelines reference the 2002 version of the Cochrane review which included only 8 trials involving 649 women  .
A systematic review including 2777 pregnancies showed that despite LMWH use, VTE still occurred in 0.86% of pregnancies. Bleeding, generally associated with primary obstetric causes, occurred in 1.98%, allergic skin reactions in 1.80%, HIT in 0%, thrombocytopenia in 0.11%, and osteoporotic fractures in 0.04% of pregnancies  .
Anaesthetic implications of anticoagulation in pregnancy
The current RCOG and NICE guidelines for prevention of VTE in pregnancy and the puerperium have the potential to impact on the use of regional analgesia and anaesthesia in pregnant patients  and . Concurrent use of anticoagulation with central neuraxial blocks (CNB) increases the risk of vertebral canal haematoma (both spinal and epidural haematoma)  . Vertebral canal haematoma, defined as symptomatic bleeding within the spinal neuraxis, is a rare and potentially catastrophic complication of spinal or epidural anaesthesia. It requires neurosurgical intervention (ideally within 8 h) to achieve the best chance of complete neurological recovery.
In the UK, it is recommended that 10–12 h elapse between administering LMWH and performing CNB  . This equates to twice the elimination half-life of LMWH and it is therefore considered safe to perform CNB after this time  . For this reason it is usual to prescribe pre-operative LMWH for the evening before surgery so that CNB may occur safely on the day of elective surgery. The nature of obstetric interventions, however, means that they are unpredictable and the recommended 10–12 h may not have elapsed before CNB is required for labour analgesia or CS  . Women with a raised body mass index (>30 kg/m2), in association with two other risk factors, should be anticoagulated antenatally  . This means that the very parturients in whom an anaesthetist is likely to recommend early regional analgesia for labour or regional anaesthesia for CS may be prevented from this and require general anaesthesia for urgent CS, with the associated risks of failed intubation and/or pulmonary aspiration. Additionally, there is the risk of an increased incidence of spinal/epidural haematoma if CNB is inadvertently performed less than 10–12 h since the administration of LMWH  .
The incidence of neurologic dysfunction resulting from haemorrhagic complications associated with CNB is unknown. As 13 cases of spinal haematoma were identified after 850,000 epidural anaesthetics and 7 cases among 650,000 spinal techniques, the calculated incidence is less than 1 in 150,000 epidural and less than 1 in 220,000 spinal anesthetics  . Recent case series and epidemiologic surveys suggest the risk of vertebral canal haematoma is 1 in 168,000 to 1 in 200,000 for CNB due to obstetric indications  . The risk is substantially higher with epidural than spinal anaesthesia. Bleeding complications occur more rarely after epidural anaesthesia in obstetrics than in female orthopaedic patients (1 in 3600)  , so major complications of CNB are probably less frequent in the obstetric population than the general population. These risks, however, were calculated before the new guidelines for prophylaxis had been introduced.
Additional caution is required in groups at high risk of bleeding with LMWH. Renal impairment, concomitant administration of an antiplatelet agent or other anticoagulant may also increase the risk of haematoma  and . This may occur during pregnancy since the NICE guidelines for the treatment of hypertension in pregnancy encourage the use of aspirin daily from 12 weeks until delivery in women at high risk of pre-eclampsia  .
Other side effects of LMWH
The reported rate of allergic skin reactions to LMWH varies between 0.6% and 2%  . Enoxaparin has been associated with local reactions, such as erythema and ecchymosis  . Up to 6% of patients in trials receiving enoxaparin for other indications had reversible elevations in ALT or AST levels to over three times the normal level. This has also been reported with UFH and other LMWH  .
A 1.3–1.98% risk of bleeding due to LMWH use, such as antenatal bleeding, postpartum haemorrhage >500 mL and wound haematoma, has been reported in meta-analysis, prospective and retrospective studies  and . Maternal thrombocytopenia arising from enoxaparin use in pregnancy has been shown to occur in 1.6% out of 624 pregnancies in a retrospective case-note review  . The low rate of HIT (0.08%)  support the United States (US) recommendation that monitoring of platelet counts is unnecessary in pregnant women treated exclusively with LMWH as HIT is often induced by previous exposure to UFH.
Although osteoporosis is associated with long-term heparin use, the incidence of osteoporosis is thought to be lower with LMWH than UFH. One case of osteoporosis occurred out of 486 pregnancies treated with LMWH  . In a prospective observational study of 123 pregnant women with antiphospholipid syndrome, there was no difference in bone mineral density between UFH and enoxaparin treatment  .
Other points to consider are that LMWHs are costly and the subcutaneous route of administration makes long-term treatment painful and inconvenient for the patient. According to pricing in the British National Formulary, the cost of a 1-week course of enoxaparin, tinzaparin or dalteparin prophylaxis is £28.28, £24.92 or £19.71 (35.51, 31.29 or 24.75 Euros), respectively for a woman weighing between 50 and 90 kg.
An Irish study reviewed 100 consecutive deliveries in 2010 and found that 51% would have been deemed intermediate or high VTE risk at some point in pregnancy and required LMWH treatment if the RCOG guideline were adopted. They calculated the cost would have risen by 17-fold to €2973.60 compared with the actual expenditure of €173.46  . This cost estimation does not include that of staff education, time taken for risk stratification and patient teaching of self-administration, needle care and disposal. A separate English series of 97 deliveries suggested risk scores necessitating antenatal or postnatal LMWH treatment were present in 2.1% or 40% of the cohort  . They also calculated the annual cost of TEDS, medication and equipment to be £44,847 per 1000 deliveries, and £2.6 million for each life saved. In this study, 10% of normal-weight postnatal women who achieved a vaginal birth had a risk score requiring thromboprophylaxis of at least 1 week.
In terms of compliance to local thromboprophylaxis guidelines, a Scottish audit showed that 31% (4 out of 13) spontaneous vaginal births and 22% (4 out of 18) of assisted instrumental deliveries in which thromboprophylaxis was indicated actually received the required treatment  . In a prospective study from Ireland, there was 100% adherence to the recommendation of thromboprophylaxis following a caesarean section (n = 60)  , but only 6% of these women received the optimum dose of LMWH. A more recent study indicated compliance with the hospital guidelines in 60% (3 out of 5) antenatal versus 68% (166 out of 244) postnatal patients  .
Thromboprophylaxis recommendations in other countries have incorporated most or parts of the RCOG guideline (Table 1 and Table 2). Within the UK, NICE and RCOG guidelines differ. For obstetric inpatients, only one additional risk factor is required before considering anticoagulation according to NICE  , whereas the RCOG suggests two or more risk factors  . The main differences between international and the RCOG guidelines are outlined below.
|All women should undergo a documented assessment of risk factors for VTE in early pregnancy or before pregnancy. This assessment should be repeated if the woman is admitted to hospital for any reason or develops other intercurrent problems||Australia and New Zealand [McLintock C, Brighton T, Chunilal S, Dekker G, McDonnell N, McRae S, et al. Recommendations for the prevention of pregnancy-associated venous thromboembolism. The Australian & New Zealand Journal of Obstetrics & Gynaecology 2012; 52(1):3–13.]|
|Europe [Nicolaides AN, Fareed J, Kakkar AK, Breddin HK, Goldhaber SZ, Hull R, et al. Prevention and treatment of venous thromboembolism. International Consensus Statement (Guidelines according to scientific evidence). International Angiology: A Journal of the International Union of Angiology 2006; 25:101–61.]|
|Germany [Beckmann MW, Boosz AS. Prophylaxe der venösen Thrombembolie (S3). Kurzfassung der Leitlinie “Prophylaxe der venösen Thrombembolie” für die Deutsche Gesellschaft für Gynäkologie und Geburtshilfe. 2009.]|
|Antenatal thromboprophylaxis should begin as early in pregnancy as practical||Australia and New Zealand|
|Spain [Protocolos SEGO: Complicaciones thrombolicas de la gestation. Prog Obstet Ginecol. 2007;51(3):181–93.]|
|Any woman with 3 or more current or persisting risk factors listed in Table 2 should be considered for prophylactic LMWH antenatally||Australia and New Zealand|
|Women with a previous single provoked (excluding estrogen-related) VTE and no other risk factors require close surveillance; antenatal LMWH is not routinely recommended||Australia and New Zealand|
|United States [Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e691S–736S.]|
|Women with previous recurrent VTE or a previous unprovoked or estrogen or pregnancy-related VTE or a previous VTE and a history of VTE in a first-degree relative (or a documented thrombophilia) or other risk factors should be offered antenatal thromboprophylaxis with LMWH||Australia and New Zealand|
|France [Samama CM, Albaladejo P, Benhamou D, Bertin-Maghit M, Bruder N, Doublet JD, et al. Venous thromboembolism prevention in surgery and obstetrics: clinical practice guidelines. European Journal of Anaesthesiology 2006; 23(2):95–116.]|
|Women with asymptomatic inherited or acquired throbmbophilia may be managed with close surveillance antenatally. Exceptions are women with antithrombin deficiency, those with more than one thrombophilic defect (including homozygosity for factor V Leiden) or those with additional risk factors, where advice of a local expert should besought and antenatal prophylaxis considered|
|All women should be encouraged to mobilise both during labour and postpartum. Dehydration should be avoided||Germany|
|Women with 2 or more persisting risk factors listed in Table 2 should be considered or LMWH for 7 days after delivery||Spain|
|Women with 3 or more persisting risk factors listed in Table 2 should be given graduated compression stockings in addition to LMWH||Europe|
|All women with class-three obesity: body mass index (BMI) > 40 kg/m2, should be considered for thromboprophylaxis with LMWH for 7 days after delivery|
|All women who have had an emergency caesarean section should be considered for thromboprophylaxis with LMWH for 7 days after delivery.||Spain|
|All women who have had an elective caesarean section who have one or more additional risk factors (such as age over 35 years, BMI greater than 30) should be considered for thromboprophylaxis with LMWH for 7 days after delivery||Australia [Australian Government National Health and Medical Research Council. For the prevention of venous thromboembolism in patients admitted to Australian Hospitals: Clinical practice guideline. 2009.]|
|All women with asymptomatic heritable or acquired thrombophilia should be considered for LMWH for at least 7 days following delivery, even if they were not receiving antenatal thromboprophylaxis. This could be extended to 6 weeks if there is a family history or other risk factors present||Europe|
|Women with VTE before the current pregnancy should be offered LMWH for 6 weeks following delivery||Australia and New Zealand|
|Women receiving LMWH antenatally should usually continue prophylactic doses of LMWH until 6 weeks postpartum but a postnatal risk assessment should be made. If they are receiving long-term anticoagulation with warfarin, this can be started when the risk of haemorrhage is low||United States|
|Women should be repeatedly assessed for risk factors for VTE if they develop intercurrent problems or require surgery or readmission in the puerperium||Australia and New Zealand|
|In women who have additional persistent (lasting more than 7 days postpartum) risk factors, such as prolonged admission or wound infection, thromboprophylaxis should be extended for up to 6 weeks or until the additional risk factors are no longer present|
|Pre-existing||Previous venous thromboembolism|
|Heritable – antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden, prothrombin gene G20210A|
|Acquired (antiphospholipid syndrome) – persistent lupus anticoagulant, persistent moderate/high-titre anticardiolipin antibodies or ß2 glycoprotein 1 antibodies|
|e.g. Systemic lupus erythematosus, cancer, heart or lung disease, inflammatory conditions (inflammatory bowel disease or inflammatory polyarthropathy), nephrotic syndrome (proteinuria >3 g/day), sickle cell disease, intravenous drug user|
|Age >35 years|
|Obesity (body mass index >30 kg/m2) prepregnancy or early pregnancy|
|Gross varicose veins|
|Obstetric||Multiple pregnancy, assisted reproductive therapy|
|Prolonged labour, mid-cavity rotational operative delivery|
|Postpartum haemorrhage (>1 L) requiring transfusion|
|New-onset/transient/potentially reversible||Surgical procedure in pregnancy or puerperium|
|e.g. Evacuation of retained products of conception, appendicectomy, postpartum sterilization|
|Hospital admission or immobility (>3 days’ bed rest) e.g. symphysis pubis dysfunction restriction mobility|
|Systemic infection (requiring antibiotics or admission to hospital)|
|e.g. Pneumonia, pyelonephritis, postpartum wound infection|
|Long-distance travel (>4 h)|
In the US, for women with thrombophilia (other than homozygous factor V Leiden and prothrombin 20210A), no prophylaxis is recommended. In those with homozygous factor V Leiden and prothrombin 20210A, antepartum vigilance and 6-week postpartum anticoagulaition are recommended. Patients with severe ovarian hyperstimulation syndrome (OHSS) are advised to have thromboprophylaxis for 3 months after OHSS resolution.
The Australia and New Zealand Working Party guideline in 2007 suggests that women undergoing CS should receive thromboprophylaxis provided there are no contraindications for anticoagulant therapy  . A primary postpartum haemorrhage (PPH) of >1000 mL is considered a contraindication for anticoagulation in a separate guideline from the Australian National Health and Medical Research Council in 2009. This contradicts the RCOG guideline, in which PPH >1000 mL is a risk factor for VTE and prophylaxis is advocated. The recommendations endorsed by Councils of the Society of Obstetric Medicine of Australia and New Zealand and the Australasian Society of Thrombosis and Haemostasis are comparable to those of the RCOG.
The French recommendations are similar to those from RCOG, except patients with >3 risk factors would not be considered for antenatal thromboprophylaxis, but for postnatal prophylaxis only. In Spain, the postnatal intermediate risk group is advised to have 3–5 days of anticoagulation rather than 7 days as in the UK. The Italian guidelines recommend antenatal and postnatal prophylaxis in those with previous VTE regardless of thrombophilia or family history status except for those related to temporary factors  . In all women with thrombophilia, they recommend postnatal prophylaxis for 6 weeks.
The Swedish guideline uses a weighted risk score based on major factors associated with a 5-fold increased risk or its multiples  . For example, women with risk score 1 are at 5-fold increased risk, risk score 2 (2 variables with 1 point or 1 variable with 2 points) are at a 25-fold increased risk, and risk score 3 have a 125-fold increased risk, and so on. The score also determines the timing and duration of anticoagulation.
The German guideline and European international consensus statement are both similar to those from RCOG.
As VTE in pregnancy remains a major but potentially preventable cause of maternal death and morbidity, it is entirely understandable and appropriate that VTE prevention should be a focus of positive national policy. RCOG and NICE guidelines are largely based on case-control studies and expert opinions with limited or no evidence from randomised controlled trials or meta-analyses. It is worth noting that the RCOG guideline highlighted the low grade of evidence for many of its recommendations. There is also a statement recognising the need for individualised treatment in some women, particularly in discussion with the woman concerned and with input from a local expert. Though there has been a decline in the number of deaths for VTE 2006–2008 coinciding with the 2004 publication of RCOG guidelines on LMWH prophylaxis, the reason for this remains unknown: whether it represents cyclical variation; improved diagnosis and management of VTE or prophylaxis itself.
The LMWH prophylaxis policy has been implemented with no apparent health economic or clinical risk benefit analysis. Even notwithstanding this, according to generally accepted principles for introducing a therapeutic intervention, there should be some form of organised national follow-up of complications and to determine unintended consequences of such a policy. To our knowledge, no such surveillance is planned.
Whether the incidence of complications will actually increase in this population with the introduction of more stringent LMWH prophylaxis remains to be seen. Nevertheless, there is a risk that the widespread use of LMWH in the pregnant population will result in rising pharmacotherapy costs and increased demand on resources due to more haematological, neurological and medical complications.
There is an unarguable urgent need for large-scale, well-designed studies with adequate power in order to establish the clinical effectiveness of thromboprophylaxis in pregnancy and puerperium and direct true evidence-based practice. Until the policy for routine thromboprophylaxis is aligned with the basic principles of introducing new treatments to a population, we urge that the policy is reconsidered for all women except those with the highest level of prior risk.
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a The Ian Donald Fetal Medicine Unit, Southern General Hospital, Greater Glasgow and Clyde NHS Trust, Glasgow G51 4TF, United Kingdom
b Department of Anaesthesia, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
c Heart of England NHS Foundation Trust, Birmingham B9 5SS, United Kingdom
d Department of Development and Regeneration, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium, B-3000
e Department of Fetal-Maternal Medicine, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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