of studies have shown changes in coagulation during IVF treatment to be modest [5,6]. Recent data suggest that hyperestrogenism related to ovarian stimulation is not associated with the coagulation abnormalities observed with high estrogen‐content oral contraceptives, and therefore does not significantly increase the potential for thrombus formation. During down‐regulation and luteal support the changes in plasma levels of anticoagulant proteins are virtually negligible. The only coagulation variable that may change considerably during IVF treatment is activated protein C resistance; patients resistant to activated protein C have been shown to be at greater risk of thrombosis during ovarian stimulation. The prothrombotic state appears to be most significant after the administration of human chorionic gonadotropin (hCG). Following hCG administration, levels of fibrinogen and factors II, V, VII, VIII and IX are elevated. In one study, activation of the coagulation cascade system was observed to occur within 2 days after hCG, reaching a maximum approximately 8 days following hCG administration [7]. Activation of these systems was observed to continue for more than 3 weeks when pregnancy was established. The predominant contribution of hCG rather than estradiol in the pathogenesis of VTE after ovarian stimulation is also supported by the clinical observation that in frozen thawed cycles where only estradiol is used, the risk of VTE is comparable to natural conceptions [4].
All patients proceeding to IVF treatment should be individually assessed for their risk of thrombotic complications (Table 8.1) [8].
Thrombotic disorders
Inherited thrombophilia
Fifteen to 25% of Caucasian populations have thrombophilic risk factors. Heritable thrombophilias include deficiencies of the endogenous anticoagulants, antithrombin, protein C and protein S, and genetic mutations in procoagulant factors such as factor V Leiden and prothrombin G20210A, and the thermolabile (C677T) variant of the methylene tetrahydro‐folate reductase (MTHFR) gene. The prevalence of these thrombophilias is variable, with significant ethnic variation. For example, 2–7% of Western European populations are heterozygous for factor V Leiden and prothrombin G20210A compared with less than 1% of Chinese.
Table 8.1 Risk factors for venous thromboembolism (VTE) [8].
| History markers | |
|---|---|
| Previous venous or arterial thromboembolism | |
| Obesity (body mass index ≥30 kg/m2) | |
| Gross varicose veins | |
| Previous/current intravenous drug abuse | |
| Age over 35 years | |
| Parity >=3 | |
| Smoker | |
| Ovarian hyperstimulation syndrome | |
| Dehydration | |
| Immobility | |
| Prolonged bed rest | |
| Prolonged travel | |
| Medical conditions (such as infections, malignancies, cardiac conditions, active systemic lupus erythematosus, inflammatory bowel disease, sickle cell disease, type 1 diabetes with nephropathy, nephrotic syndrome etc.) | |
| Inherited thrombophilia | Odds ratio for VTE (95% confidence interval) |
| Factor V Leiden heterozygous | 9.2 (5.44–12.70) |
| Factor V Leiden homozygous | 34.40 (9.86–120.05) |
| Antithrombin deficiency | 4.69 (1.30–16.96) |
| Protein C deficiency | 4.76 (2.15–10.57) |
| Prothrombin G20210A heterozygous | 6.80 (2.46–19.77) |
| Prothrombin G20210A homozygous | 26.36 (1.24–559.29) |
| Family history of VTE in one or more first degree relatives | 2.7 (1.8–3.8) |
| Acquired thrombophilia | |
| Lupus anticoagulant | |
| Anticardiolipin antibodies | |
Acquired thrombophilia
Antiphospholipid syndrome is the most common acquired thrombophilia associated with an increased risk of recurrent miscarriage and pregnancy morbidity. Antiphospholipid syndrome is present if at least one of the clinical criteria and one of the laboratory criteria shown in Box 8.1 are present [9].
Management options
There is currently little evidence to support universal screening for thrombophilia in pregnancy or prior to IVF for the prevention of VTE [10]. However, screening for thrombophilia should be considered in women with a history of recurrent miscarriage, or personal or family history of VTE. The association between thrombophilia and OHSS is conflicting. According to one study thrombophilia is thought to be associated with a high risk of developing OHSS [11], and this has been proposed as an additional reason for screening for thrombophilia in women with a family or personal history of thrombosis prior to undergoing ovarian stimulation and in women who have developed OHSS. However, another study failed to show an increased prevalence of thrombophilia in women with severe OHSS undergoing ovulation induction. Therefore, the clinical and cost effectiveness for screening in this context could not be demonstrated [12].
Screening for thrombophilias should include the following:
plasma antithrombin
proteins S and C
antiphospholipid antibodies
factor V Leiden mutation
MTHFR C677T
The management of the woman with a single previous VTE has been controversial, but data from studies of pregnancy may guide therapy in the context of IVF. In a woman with a previous VTE that was not related to pregnancy or oral contraceptive use, and in whom no thrombophilia or other additional risk factor is present, thromboprophylaxis probably need not be prescribed [13]. However, in women with a previous VTE and underlying thrombophilia, or where the VTE
