Kate Ryan ( Department of Haematology, Central Middlesex Hospital, London. )
Hannah Cohen ( Department of Haematology, Central Middlesex Hospital, London. )
Tasneem Aslam Tariq ( Department of Obstetrics and Gynaecology, Central Middlesex Hospital, London. )
Normal pregnancy is associated with an increased frequency of venous thromboembolism, a risk which is further aggravated when the woman has additional thrombotic risk factors or when there is a previous history of thromboembolism. The incidence of thromboembolic episodes during pregnancy is approximately 1 per 1000 women and increases to 2 per 1000 during the postnatal period. There is, at present, no real consensus as to the optimal management of anticoagulation in pregnant women at risk of thromboembolism. Both Heparin and Warfarin have disadvantages (see below) and the duration and intensity of anticoagulation remains uncertain. At Central Middlesex Hospital, London, the patients are managed according to local guidelines, devised by haematologists and obstetricians; these guidelines are based on the recent recommendations from the British Society of Haematology1. The investigation of maternal thromboembolic disease is not discussed in this article; the reader is advised to refer to the above guidelines.
Guidelines for anticoagulation Therapy in pregnancy
Anticoagulant drugs (Heparin and Warfarin) during pregnancy may be given for the following reasons:
1. As part of life long treatment in patients with heart valve repacement or other cardiovascular disorders.
2. To treat venous thromboembolism [deep vein thrombosis (DVT) and/or pulmonary embolism (PE)].
3. To prevent venous thromboembolism in women with (a) a previous history of thromboembolism; (b) hereditary or acquired thrombophilia and (c) other risk factors for thromboembolism (see below).
Anticoagulation drugs Heparin must be given by the parenteral route (iv or Sc) and is monitored by plasma KPTT or anti-factor Xa levels. In pregnancy, ani.i-factorXa levels (whenavailable) are probably a more accurate reflection of Heparin levels. Heparin does not cross the placenta and, therefore, does not anticoagulate the fetus. Long term treatment with high doses of Heparin (>20,000 IU daily for >5 months) has been associated with development of osteoporosis in some women2. Heparin requirements increase throughout pregnancy and regular monitoring is required. Heparin may be associated with thrombocytopenia which, in some circumstances, may be severe and associated with thrombosis. All patients receiving Heparin should have their platelet counts monitored at regular intervals (see below). Heparin monitoring should be performed 4 hours post iv infusion and 4-6 hours post sc injection.
Warfann is given orally and requires regular monitoring by the International Normalised Ratio (INR) for each patient. Drug interactions are particularly important in affecting the level of anticoagulation in patients. Warfarin is associated with embiyopathy particularly in the first trimester3. In most cases subcutaneous Heparin must be substituted as soon as possible and before the critical period of 6-12 weeks gestation. Warfarin crosses the placenta and the fetus becomes as and perhaps more anticoagulated than the mother. This increases the risk of haemorrhage, especially cerebral haemorrhage at the time of delivery and all mothers should have their Warfarin changed to Heparin at the end of pregnancy (usually from 36 weeks).
The doctor must ensure that no contraindications exist before prescribing Heparin or Warfarin. Heparin and Warfarin are not secreted in breast milk and mothers taking these drugs can safely breast feed.
Approach to management
The key to optimal management is close liaisonbetween the obstetricians and haematologists.
1. Identify women at risk in the antenatal booking clinic by taking careful and detailed history (patients on Warfarin as soon as pregnancy confirmed). Many of these will have already been counseled at a clinic.
2. All women considered to be at risk should be seen by the consultant obstetrician incharge when seen for the first time at the Antenatal Booking Clinic (ABC). If seen initially by other medical staff, the patient should be referred to the consultant for an opinion.
3. For all women close communication between the obstetricians and haematologists is essential and the patient should be seenpromptly at the anticoagulant clinic. Sister incharge of the ABC should keep a record of all patients referred to the Haemostasis/ Anticoagulant clinic.
4. Each woman requires an individual care plan based on assessed degree of thrombotic risks and previous history of thromboembolism. Planned delivery may be required. This care plan must be fully documented in the antenatal notes.
5. Because of the risks to both mother and foetus, women and their partners should be counselled of these risks and the logistics of treatment so that they can participate in the care plan.
6. Contraception options in the postnatal period should be addressed by the obstetrician and discussed with haematologist and the woman. The combined oral contraceptive pill should be avoided and alevonorgestrel only pill considered.
High risk women
Women on long term anticoagulation with Warfann for recurrent thrombosis. These will include: hereditary thrombophilia with previous thromboembolic events e.g., protein C and protein S deficiencies, women with a thrombotic history but no identifiable thrombophilic abnormality, arterial thromboembolism, antiphospholipid antibodies (lupus anticoagulants and/or anticardiolipin antibodies) with thromboembolic events, cardiac arrhythmias, all ATIII deficient patients. Women in these groups should be aware to present as soon as pregnancy is confirmed. They will require prophylactic anticoagulation throughout pregnancy and postpartum (Table I).
ATIH deficiency: Prophylactic Heparin is needed throughout pregnancy even in asymptomatic patients. Higher anti-Xa levels may be needed. Cover delivery and immediate postpartum period with ATIII concentrates. Regime to be decided by haematologist. This may require planned induction. Continue anticoagulation with Heparin/Warfarin until 3/12 postpartum.
Antiphospholipid antibodies: These women may also need aspirin. The regime should be decided by haematologist.
Medium risk women
Women not on Warfarin but with established risk factors: proven or highly likely DVT/PE in previous pregnancy or outside of pregnancy; asymptomatic protein C or S deficiency, sickle cell disease will need prophylactic anticoagulation in later pregnancy and in postpartum period (Table II).
Timing of initiation of anticoagulation and duration depends on individual assessment.
Prosthetic cardiac valves
These women require therapeutic anticoagulation throughout pregnancy and postpartum period. Details of management are given in Table III.
Other women at possible risk
The risks not well defmed and are associated with conditions of pregnancy. Risk factors often occur in conjunction and decision to anticoagulate will be based on clinical judgement. Risk factors include operative delivery, prolonged bed rest, obesity, age/parity, strong family history of thromboembolism. Short term anticoagulation is required in this case.
Operative delivery: TED stocking and Heparin 5000 IU scbd immediately postLSCS and postpartumuntilfully mobile. No monitoring required.
Immobilisation or other risk factors: TED stocking and in individual cases 5000 IU sc bd (discuss with obstetrician/haematologist). No monitoring required.
Epidural anaesthesia in women taking anticoagulant
Contraindicated in women on therapeutic anticaogulation. Other cases are controversial. If anticoagulation has been stopped or reduced and a full clotting screen (PT, KPTF, TI’) and FBC are normal, it is probably safe to proceed1,4 but discuss with anaesthetist/obstetric consultant/haematologist. The plan should be made before hand after discussion with consultants and documented in notes. NB: Epidurals should not be used in women receiving low molecular weight Heparin because clotting studies do not reflect degree of anticoagulation.
Suspected DVT/PE during pregnancy
Maintain a high index of suspicion if symptoms of calf or acute chest pain, swollen leg etc. It is important to confirm objectively by ultrasound and/or venography as the diagnosis will have implications for future management. Diagnostic procedures should be discussed with Radiologist/Obstetrician. If pulmonaiy embolism is suspected, do CXR, ECG, blood gas, V:Q scan and consult medical specialist regarding management. Details of therapeutic anticoagulation for acute venous thromboembolism are given in Table IV.
Surgical intervention may be required for life threatening pulmonary embolism or massive ileofemoral thrombosis. Women with thromboembolic disease in pregnancy may be considered for further investigations for inherited thrombophilia, particularly if there is a significant past or family history. These tests are ideally performed in the non-pregnant state and should be performed after discussion with the haematologist.
Reversal of Warfarin
If a woman on Warfann goes into premature labour delivery by Caesarean section should be considered to protect the fetus. Emergency LSCS may require some reversal of anticoagulation. Discuss all cases with consultant obstetrician/haematologist and proceed along the guidelines outlined in Table V.
Remember that epidural anaesthesia is contraindicated.
Reversal of Heparin
Heparin is rapidly cleared from the blood. It is usually sufficient to stop Heparin as most surgical procedures can be carried out without the risk of bleeding in the presence of low dose Heparin. If the patient is bleeding or emergency surgery is necessary, check full clotting screen and consult consultant obstetrician/haematologist if KPTT ratio is >1.5. Protamine sulphate neutralisation may be required for those women on iv Heparinorwithin 2 hours following bolus Heparin. Protaminc sulphate dose in mg is calculated as follows:
Dose given as bolus or amount given in last hour by infusion 100
Maximum dose of protarnine sulphate that should be prescribed is 50 mg.
1. The British Society ofHaematology. Guidelines on theprevention, investigation and management of thrombosis associated with pregnancy. J. Clin. Pathol., 1993;46:489-96.
2. Hirsh, J. Heparin. N. tngi. J. Med, 1991;324:1565-14.
3. Iturbe-Alessio, I., Fonesca, M. C., Mutchinik, 0. et at. Risks of anticoagulant therapy in pregnant women with artificial heart valves. N. Engl. J. Med., 1986;315:1390-3.
4. Letsky, E. A. Haemostasis and Epidural anaesthesia. Int. J. Obstet. Anaesth., 1991;1:51-4.