Thrombophilia screening in women with recurrent first trimester miscarriage: is it time to stop testing? – a cohort study and systematic review of the literature

Abstract

ObjectiveThere are numerous studies reporting a disproportionally high prevalence of thrombophilia in women with a history of recurrent miscarriage (RM), which has led to overdiagnosis and treatment without an improvement in clinical outcomes. The objective of our study was to assess the prevalence of inherited and acquired thrombophilia in a large cohort of women with a history of early RM using internationally agreed diagnostic criteria and inclusion parameters and compare it to the meta-analysis results of existing literature.MethodsDesignRetrospective cohort study and systematic review of literature.SettingThis is a retrospective cohort study set-up in two dedicated tertiary centres for women with RM in Southwest London and Surrey. We reviewed all the available literature related to causes of RMs. We ascertained the prevalence of thrombophilia in the study population and compared it with historical and published prevalence in the general population.Participants1155 women between 2012 and 2017. All patients had three or more first trimester miscarriages and a full thrombophilia screen.ResultsThe overall prevalence of thrombophilia in our study population is 9.2% (106/1155) with 8.1% (94/1155) of cases positive for inherited thrombophilia, which is similar to the general population; Factor V Leiden (4.9%; 57/1155) and prothrombin gene mutation (2.9%; 34/1155) were the most common inherited thrombophilias, while only 1% (12/1155) tested positive for acquired thrombophilia. Persistent positive lupus anticoagulant (LA) was found in 0.5% (6/1155) and persistent positive anticardiolipin (ACL) antibodies with a value ≥40 U/mL was found in 0.5% (6/1155) of patients. Tests for LA/ACL were performed a minimum of 12 weeks apart thus meeting the revised Sapporo criteria for a diagnosis of antiphospholipid syndrome.ConclusionThe findings of our study demonstrate that the prevalence of inherited thrombophilia is similar in women with RM to that in the general population. Similarly, the prevalence of acquired thrombophilia, using the revised Sapporo criteria, in the cohort of RMs is similar to that in the general population. Therefore, we do not recommend investigation or treatment of inherited or acquired thrombophilia in women with RM.PROSPERO registration numberCRD42020223554.

A Retrospective Assessment of Thrombophilia in Pregnant Women with First and Second Trimester Pregnancy Loss

“…Empirical testing and treatment for thrombophilia, such as low dose aspirin and low molecular heparin, should not be advised, unless there is unequivocal clinical and laboratory evidence of established disease. This is because the contribution of inherited and acquired thrombophilia in causing early recurrent miscarriage is extremely low; therefore, pregnant women and their clinical practitioners should be aware of this fact [ 38 , 39 ].…”

Antiphospholipid syndrome: advances in diagnosis, pathogenesis, and management

“…28 A recent single center retrospective cohort study and systematic analysis concluded that the prevalence of antiphospholipid antibodies in patients with recurrent early miscarriage is similar to that of the general population. 29 Well designed studies to better define the association between antiphospholipid antibodies and early miscarriage are needed. 30 Catastrophic antiphospholipid syndrome Catastrophic antiphospholipid syndrome is characterized by the rapid onset of thrombosis in multiple vascular beds leading to multiorgan failure and a high risk of mortality.…”

“…A subsequent meta-analysis of studies published before 2014 found that the frequencies of lupus anticoagulant test positivity and anticardiolipin antibodies in patients with recurrent early miscarriage ranged widely from 1.8% to 36.5% and 2% to 88.1%, respectively 28. A recent single center retrospective cohort study and systematic analysis concluded that the prevalence of antiphospholipid antibodies in patients with recurrent early miscarriage is similar to that of the general population 29. Well designed studies to better define the association between antiphospholipid antibodies and early miscarriage are needed 30…”

FIGO Good Practice Recommendations on the use of progesterone in the management of recurrent first‐trimester miscarriage

“…Immune causes are also thought to contribute to miscarriages, namely natural killer cells, cytokines, thyroid and antinuclear antibodies, lupus, and other immune syndromes. Inherited thrombophilia includes causes such as the presence of factor V Leiden (FVL), prothrombin G20210A mutation (PGM), and antithrombin and protein C and S deficiencies, whereas acquired thrombophilia includes the presence of lupus anticoagulant (LA), anticardiolipin (ACL), and anti‐beta 2 glycoprotein antibodies 20 …”

“…Inherited thrombophilia includes causes such as the presence of factor V Leiden (FVL), prothrombin G20210A mutation (PGM), and antithrombin and protein C and S deficiencies, whereas acquired thrombophilia includes the presence of lupus anticoagulant (LA), anticardiolipin (ACL), and anti-beta 2 glycoprotein antibodies. 20…”