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Thromboprophylaxis in Labour and Delivery
Introduction
Pregnancy is a significant risk factor for venous thromboembolism (VTE), which remains a leading direct cause of maternal death in developed countries. There is good evidence that thromboprophylaxis reduces the incidence of VTE in at-risk groups. Heparin, a naturally occurring anticoagulant produced by basophils and mast cells, and its low molecular weight derivatives are the most commonly used anticoagulants and are effective in preventing deep vein thromboses and pulmonary emboli in people at risk. Discovered almost by accident by then medical student McLean in 1916 (during World War I the scientific community were rather more focused on the development of pro- than anti-coagulant substances), it was 1933 before Charles and Scott produced pure crystalline heparin suitable for use in humans. The first documented indication for heparin use was in fact for thromboprophylaxis in surgical patients.
Investigation of uses for heparin in pregnancy began in the early 1950s, with an increasing focus over the last 20 years on the role of anticoagulants not only for VTE thromboprophylaxis, but also, and perhaps more controversially, to prevent serious obstetric complications including pre-eclampsia, fetal growth restriction and stillbirth.
Incidence
Women who are pregnant or postpartum have a four- to five-fold increased risk of VTE compared with age-matched nonpregnant controls. This risk is greatest in the 3 weeks immediately following delivery and persists for up to 12 weeks postpartum. Both unfractionated (UFH) and low molecular weight heparins (LMWH) reduce the incidence of VTE in at-risk groups. Dosing, timing and duration of treatment depends on an individualised risk assessment and local/national guidance. Significant international variation is observed in the number of women deemed to be in an ‘at-risk’ category and thus requiring antenatal and/or postnatal thromboprophylaxis. Research on obstetric VTE is challenging because of a relatively low incidence, despite its prominence in maternal morbidity data. Overall, VTE, manifest as pulmonary embolism (PE) or deep vein thrombosis (DVT), complicates just 0.5–2.2 deliveries per 1000, depending on the population studied. There is evidence from sequential Confidential Enquiries that a more vigilant approach to risk factor identification and increased use of thromboprophylaxis can be effective in reducing maternal mortality from VTE, with a significant fall in the maternal mortality rate from PE from 1.56 per 100,000 maternities in 2003–2005 to 0.70 per 100,000 maternities in 2006–2008.
Anticoagulation Medications in Pregnancy
The agents of choice for thromboprophylaxis are LMWHs. They are considered as effective and safer when compared with UFH when used to prevent VTE during pregnancy. Doses are subcutaneous and based on maternal weight. In general, two dosing regimes are used, a lower ‘thromboprophylactic’ dose and a higher ‘therapeutic’ dose depending on the clinical circumstances. Most women who require VTE prophylaxis receive a weight-adjusted prophylactic dose of LMWH in the antepartum and/or postpartum period. A small proportion of women (such as those with antithrombin deficiency, antiphospholipid syndrome or recurrent VTE) may require higher therapeutic doses of LMWH. The monitoring of anti-Xa levels is not necessary when thromboprophylactic doses of LMWH are used ; indeed, even at higher therapeutic levels there is insufficient evidence to recommend routine monitoring of anti-Xa levels to guide dosing.
There are instances, however, when the use of UFH is preferred, for example, in women who present with VTE at term, or at the time of labour and delivery in women at very high risk of thrombosis where there is an increased risk of haemorrhage. The half-life of UFH is shorter than LMWH, and reversal of its anticoagulant properties is possible with protamine sulphate. LMWHs are eliminated primarily by renal excretion and as such may accumulate in patients with significant renal dysfunction. Consequently, UFH should be used instead of LMWH in patients with glomerular filtration rate (GFR) less than 30 mL/min. When UFH is preferred, it can be given either subcutaneously or intravenously in 12-hourly doses adjusted according to a 6-hour activated partial thromboplastin time (aPTT) into a therapeutic range, although it is recognised that aPTT monitoring is less reliable in pregnancy.
A particular circumstance arises when a pregnant woman is intolerant of heparin (usually because of complications such as thrombocytopenia or allergic skin reactions) but requires thromboprophylaxis. In these circumstances, alternatives must be used. Danaparoid is a heparinoid that is mostly used in patients intolerant of heparin. Fondaparinux is a synthetic pentasaccharide that acts through inhibition of factor Xa via antithrombin. Although no adverse fetal effects have been attributed to either, long-term safety data are limited, and their use should be restricted to those circumstances where heparin cannot be used. Importantly for labour and delivery management, both have longer half-lives than LMWH or UFH; use in conjunction with a haematologist or thrombosis specialist with expertise in haemostasis and pregnancy is recommended.
Warfarin is a vitamin K antagonist commonly used for anticoagulation, particularly in the longer term, outside of pregnancy. It is associated with clearly described adverse fetal effects, especially with first trimester exposure. It is still considered for use in particular high-risk circumstances, such as for women with mechanical heart valves, because of the high risk of thrombosis even with heparin anticoagulation therapy. Warfarin is safe for use following delivery and in breastfeeding but monitoring is required. Higher rates of postpartum haemorrhage and perineal haematoma formation when compared with LMWH are described.
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