THROMBOPHILIAS AND ADVERSE PREGNANCY OUTCOME
Said JM, Higgins JR, Walker SP, Monagle PA, Brennecke SP
Royal Women’s Hospital
Melbourne
Over the past decade, a number of inherited and acquired conditions (Box 1) have been
identified which predispose particular groups of patients to an increased risk of thrombosis. The
identification of these conditions, collectively referred to as thrombophilias, has greatly altered
the investigation and counselling of patients presenting with venous thromboembolism. Venous
thromboembolism has long been recognised as a major cause of maternal morbidity and
mortality. Pregnancy itself has been recognised as a procoagulant state and the additional
impact of a thrombophilia may well tip the balance towards thrombosis in an otherwise healthy
pregnant woman. Despite the extreme seriousness of venous thromboembolism in pregnancy,
the condition remains relatively rare occurring in approximately 1 per 1000 pregnancies. 1 By
contrast, pregnancy complications such as recurrent miscarriages, pre-eclampsia, fetal growth
restriction, placental abruption and stillbirth are far more common and affect up to 10% of
pregnancies. These conditions have significant implications not only on maternal and perinatal
morbidity and mortality but also on long term adult outcomes of affected fetuses.
Excessive uteroplacental thrombosis has been proposed as the pathogenic mechanism leading
to these obstetric complications. Histopathologic assessment of placentas from pre-eclamptic
pregnancies and pregnancies complicated by fetal growth restriction and unexplained stillbirth
have demonstrated the presence of mural thrombi within both the maternal and fetal
circulations2. In addition, activation of the coagulation cascade in the uteroplacental circulation
of preeclamptic patients has been demonstrated.3 The various pregnancy related changes in
the uteroplacental circulation make this region of the vascular system vulnerable to the
development of intravascular thrombosis in patients who may have an additional risk factor
predisposing them to thrombosis.
The association between inherited thrombophilias and adverse pregnancy outcome has been
debated over the past decade. Since the earliest reports, including those by Dekker and
colleagues of an increased rate of thrombophilia in patients with severe pre-eclampsia,4 there
have been numerous case control studies which both affirm5-7 and refute this association.8-10
Systematic reviews11, 12 on the topic continue to be constrained by the different study
populations used (differing clinical definitions), range of thrombophilias tested, ethnic differences
and publication bias, which can all contribute to skewed results which may not necessarily be
applicable to all populations and all patients with adverse pregnancy outcomes. Despite this, a
recent meta-analysis has once again confirmed an association between thrombophilias and
adverse pregnancy outcomes including early and late pregnancy loss, pre-eclampsia, placental
abruption, and fetal growth restriction.13 Furthermore, there is growing evidence that the
presence of thrombophilic defects is associated with a greater severity of obstetric
complications including earlier onset disease and more severe adverse perinatal outcomes.14, 15
However, despite these apparent associations, we still have very little information on which to
base therapeutic interventions. The early trials of combinations of aspirin and heparin in patients
with the antiphospholipid syndrome demonstrated significant improvements in the live-birth
rate.16 Whether it is safe to translate these findings to populations with inherited thrombophilias
remains uncertain since the antiphospholipid syndrome is thought to exert its effects at least in
part through immune mechanisms which are yet to be fully defined. In addition, heparins may be
exerting their beneficial effects through these immunologic pathways rather than via a purely
anticoagulant effect. While the combination of heparin and aspirin does appear to increase the
chances of a live birth in patients with the antiphospholipid syndrome, uncertainty persists
regarding the benefits beyond the first trimester, in particular with regard to a reduction in rates
of pre-eclampsia, fetal growth restriction, placental abruption, stillbirth and prematurity.
The comparative safety of low molecular weight heparins (LMWH) has seen a trend towards
their use in women with adverse pregnancy outcomes and inherited thrombophilias. Gris et al
demonstrated a significant improvement in the livebirth rate in thrombophilic patients with a
history of a single fetal loss beyond 10 weeks who received Enoxaparin in a subsequent
pregnancy compared to those who received only Aspirin.17 This study, together with other small
studies reporting improvements in pregnancy outcomes in patients receiving LMWH has
prompted what may be somewhat premature recommendations for all thrombophilic patients
with adverse pregnancy outcomes to receive LMWH prophylaxis in future pregnancies. 18 This
treatment modality must be subjected to the scrutiny of well conducted double blind randomized
control trials before it becomes established practice.19
As the topic of thrombophilias and adverse pregnancy outcomes is so broad and controversial,
this presentation will primarily be limited to the association between the inherited thrombophilias
and pre-eclampsia20. Pre-eclampsia remains a challenging condition for the obstetrician with the
precise aetiology remaining elusive and definitive therapy ultimately limited to timely delivery.
Consequences for the neonate of premature delivery must be carefully balanced against the
maternal consequences of delaying delivery which include neurologic sequelae, pulmonary
oedema, DIC, and even death. A genetic predisposition to pre-eclampsia is currently under
investigation21 and thrombophilic polymorphisms represent potential candidates in the
pathogenesis of pre-eclampsia. The findings of current studies must be confirmed and further
assessed in a prospective manner in both asymptomatic cohorts as well as in patients who have
previously experienced pre-eclampsia to determine whether therapeutic interventions such as
LMWH may alter the development or course of pre-eclampsia.
Box 1
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Activated Protein C Resistance / Factor V Leiden
Prothrombin Gene Mutation
Hyperhomocysteinaemia
Anticardiolipin Antibodies
Lupus Anticoagulant
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