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Thrombophilia and early pregnancy loss

https://doi.org/10.1016/j.bpobgyn.2011.10.002Get rights and content

Early pregnancy loss is the most common pregnancy complication. About 15% of pregnancies result in pregnancy loss and 1% of women experience recurrent miscarriage (more than three consecutive miscarriages). The influence of thrombophilia in pregnancy is a popular research topic in recurrent miscarriage. Both acquired and inherited thrombophilia are associated with a risk of pregnancy failure. Antiphospholipid syndrome is the only thrombophilia known to have a direct adverse effect on pregnancy. Historically, clinical research studying thrombophilia treatment in recurrent miscarriage has been of limited value owing to small participant numbers, poor study design and heterogeneity. The debate on the efficacy of aspirin and heparin has advanced with recently published randomised-controlled trials. Multi-centre collaboration is required to ascertain the effect of thrombophilia on early pregnancy loss and to establish an evidence-based treatment protocol.

Section snippets

Thrombophilia and early pregnancy loss

Thrombophilia are a diverse group of coagulation disorders associated with a predisposition for thrombotic events (e.g. deep vein thrombosis and pulmonary embolism).1 Inherited factors associated with thrombophilia include Factor V Leiden (FVL), prothrombin G20210A gene mutation, deficiencies in protein C and protein S as well, as antithrombin. The most established acquired thrombophilia in early pregnancy loss is antiphospholipid syndrome (APS). Antiphospholipid syndrome is a non-inflammatory

Inherited thrombophilia

Inherited thrombophilia can interfere with the natural coagulation system or alter levels of certain coagulation factors. Factor V Leiden mutation results from a replacement of adenine by guanine at the 1691 gene position. As a consequence, factor V becomes resistant to the action of activated protein C. The 677C → T mutation of the MTHFR gene results in an alanine to valine substitution. This in turn reduces the conversion of homocysteine to methionine. Hyperhomocysteinaemia impairs

Antiphospholipid syndrome

Antiphospholipid syndrome (APS) was first described in the early 1980s as a unique form of autoantibody-induced thrombophilia and pregnancy complications. The antibodies involved promote activation of the endothelial cells, monocytes and platelets. As a consequence, tissue factor and thromboxane A2 are overproduced.42 The most common obstetric manifestation is recurrent miscarriage; however, other features include pre-eclampsia and placental insufficiency prompting delivery.43 A concise list of

Pregnancy and miscarriage

Pregnancy promotes an increase in particular coagulation factors and reduces levels of anticoagulant proteins and fibrinolysis. Factor VIII, von Willibrand Factor, ristocetin cofactor, Factor X and Factor XII increase during pregnancy.54 The risk of suffering a VTE is four to five times higher than in women who are not pregnant.55 Thrombophilia in combination with pregnancy further enhances this risk. The pathogenesis of VTE remains diversified with interaction of genetic predisposition and

Diagnosing thrombophilia in women who have had recurrent miscarriages

When screening for thrombophilia, a discrepancy exists between recommended inclusion criteria and investigation protocols. Established guidelines and individual protocols are in practice*58, *63; however, debate surrounds laboratory disparity in specific tests for APS and also inconsistencies when screening for heritable thrombophilia. Even after a pregnancy loss, inherited thrombophilia has apparently no effect on the outcome of the next pregnancy.21 Analysis leads to an increasing number of

Treatments for thrombophilia in recurrent miscarriage

Research on recurrent miscarriage and treatments for thrombophilia has been diverse. A variety of treatments have been tried in isolation or in combination. These include the following: low-dose aspirin (75 mg); low-dose low-molecular-weight heparin (LMWH); unfractionated heparin (UFH); corticosteroids; and intravenous immunoglobulin (IVIG).

Anticoagulant treatment for inherited thrombophilia and recurrent miscarriage

Debate over the treatment for inherited thrombophilia is ongoing. Given that the prevalence of abnormal results in the obstetric population is 20%,69 the question arises whether screening for inheritable thrombophilia among women who have had recurrent miscarriages is advantageous. The treatment decision has, in part, been extrapolated from the treatment of APS, where low-dose aspirin and heparin are frequently prescribed.

Support for the use of antithrombotic prophylaxis was first published by

Anticoagulant treatment for antiphospholipid syndrome and recurrent miscarriage

Antiphospholipid syndrome is now recognised to be the most important treatable cause of recurrent miscarriage.78 The pregnancy outcome for untreated women with APS is significantly poor, as described in a prospective, highly selected observational study.79 The miscarriage rate of women positive for APS was 90% with no pharmacological intervention compared with 40% in a control group. Guidelines are in place for the treatment of positively diagnosed APS with thromboprophylactic treatment.*58, 66

Aspirin versus placebo

It is believed that aspirin improves vasodilation, prostacyclin production and reduces levels of thromboxane A2.81 Aspirin is commonly used to treat women with thrombophilia who have had recurrent miscarriages, who are also deemed idiopathic. Two RCTs compared aspirin with placebo or supportive care in women with APS.81, 82 No significant difference was found in the defined outcomes. These results were further supported as part of a meta-analysis conducted in 2005.83

Aspirin alone versus aspirin with heparin

Recent studies have challenged the efficacy of low-dose aspirin and heparin in women positive for APS who have had recurrent miscarriages.5 The hepASA trial5 included an RCT of 88 pregnant women positive for APS over 4 years. Participants were randomised to treatment with aspirin and LMWH or aspirin alone. Live birth rates were achieved in 35 out of 45 women (78%) and 34 out of 43 (79%), respectively. The trial was stopped prematurely, as no difference was found in primary outcome. Also, women

Unfractionated heparin versus low-molecular-weight heparin

Low-molecular-weight heparin is favoured clinically because of its once-daily injection regimen. Currently, no RCT has compared UFH and LMWH for APS in women who have had recurrent miscarriages. Stephenson et al.85 conducted a pilot trial with women diagnosed with APS and were treated with dalteparin (LMWH) or UFH. A successful pregnancy occurred in nine out of 13 women (69%) prescribed dalteparin compared with four out of 13 (31%) prescribed UFH.

In 2005, a US study assigned women positive for

Adverse effects associated with aspirin and heparin

Aspirin in frequently prescribed to women who have had recurrent miscarriages; however, caution is advocated, as side-effects (maternal and fetal bleeding) can occur, albeit rare. Cases of major congenital abnormalities including gastroschisis have been linked with the use of aspirin during pregnancy. A 22-study meta-analysis quoted a two- to three-fold increase in gastroschisis if aspirin was taken in the first trimester.87

Heparin has been a cause of concern when assessing its effect on bone

Antiphospholipid syndrome and corticosteroids

Moderate-to-high doses of prednisolone were initially prescribed for APS purely as an autoimmune disorder, manifesting as recurrent fetal loss. In the early 1990s, two small trials in women positive for APS demonstrated no benefit with the treatment of prednisolone in pregnancy.91, 92 Laskin et al.93 studied the efficacy of prednisone and aspirin in women with APS who had experienced previous miscarriages, looking specifically at maternal morbidity and fetal survival. This study was part of a

Antiphospholipid syndrome and intravenous immunoglobulin treatment

The theory of immunologic aberrations in association with recurrent miscarriages has been extensively considered. Defects in cytokines and growth factors at a trophoblastic level have been postulated; however, experimental models of miscarriage have shown that pregnancy survival depends on the inhibition of local inflammatory mediators.95 IVIG is a fractionated blood product made from human plasma. It is expensive and limited in quantity. Side-effects include anaphylaxis, fever, muscle pains,

Conclusion

Much research has been invested into the role of thrombophilia in recurrent miscarriage. It is acknowledged that APS is the only thrombophilia known to have a direct influence on pregnancy loss. When treated, the prognosis of a subsequent pregnancy is good. A retrospective cohort study involving 693 women who had had recurrent miscarriages found that the live birth rate for women with APS was comparable to those deemed idiopathic (69% and 63%, respectively). The live birth rate was 79% (53/67)

Conflict of interest statement

None declared.

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