Thrombophilia and early pregnancy loss
Definition
Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis (e.g. deep vein thrombosis and pulmonary embolism) (94). There are two types of thrombophilias: inherited and acquired.
Thrombophilias are thought to cause pregnancy loss due to thrombosis in the uteroplacental circulation leading to placental insufficiency and inflammation (95).Inherited thrombophilia
This group includes factor V Leiden, prothrombin G20210A gene mutation, protein S and protein C deficiency, and antithrombin III deficiency.
The correlation between inherited thrombophilia and pregnancy loss is debatable, with some previous studies showing an association of as high as 50-60% (96, 97)—although the majority of first- trimester miscarriage is due to a chromosomal abnormality (98).
Acquired thrombophilia
• APS: this is the most recognised acquired thrombophilia; it is characterised by obstetric complications (e.g. recurrent miscarriages, fetal growth restriction, and early-onset PET) and/or thromboembolic events, in association with antiphospholipid antibodies (99, 100). In one study, APS, the only thrombophilia that has been shown to have a direct adverse effect on miscarriages, was found in 15% of women with recurrent miscarriages (7); however, when revised diagnostic criteria are applied, this figure is much lower and recent evidence suggests figures of around 2% (2).
• Acquired activated protein C resistance (APCR): acquired APCR is associated with lupus anticoagulant and elevated coagulation factor VIII. It is a well-documented risk factor for recurrent miscarriages (101), and studies have shown a higher association with acquired rather than inherited protein C resistance (102). There is also an increased incidence of thromboembolism with acquired APCR (103).
Recurrent miscarriages
The European Society for Human Reproduction and Embryology defines recurrent miscarriage as three or more consecutive pregnancy losses before 20 weeks gestation (104).
About 15% of pregnancies will end in a miscarriage, and the incidence of recurrent miscarriage is 1% in the general population. A careful history and examination is important to highlight other causes of recurrent miscarriage, however, in over 50% of cases the cause is unexplained (105). Different protocols have been proposed in the management of couples with recurrent miscarriage, many of them with unproven efficacy (106, 107). An evidence-based approach is recommended to avoid prescribing unnecessary medications in pregnancy.Thrombophilia and recurrent miscarriages
There is much debate about the association between inherited thrombophilia and recurrent miscarriage. A positive result, even after a recent miscarriage, has not been shown to have an effect on future pregnancy outcome (108). The benefit of screening is questionable given that the prevalence of inherited thrombophilia in women of reproductive age is 20% (109), which is similar to the background risk of miscarriage. Nonetheless, most centres routinely offer screening for thrombophilia following recurrent miscarriage and offer anticoagulation if the result is positive (110). Conversely, there is a proven association between APS and recurrent miscarriage.
Treatment of inherited thrombophilia and recurrent miscarriages
A variety of treatment protocols have been used in patients with inherited thrombophilia and recurrent miscarriages, mostly adapted from treatment protocols for patients with APS.
Various studies have shown different efficacies with aspirin monotherapy versus combination therapy with aspirin and heparin (111113). Many of the studies supporting the use of anticoagulation have significant flaws and limitations, and results from larger studies have shown no difference in outcomes (114), and in fact, higher live births in patients managed expectantly (115).
Treatment of APS and recurrent miscarriage
APS is an established, curable cause of recurrent miscarriages (116).
Without treatment, some studies have shown a poor pregnancy outcome with a miscarriage rate as high as 90% (117).Several treatment protocols have been suggested: aspirin alone, aspirin and LMWH, and aspirin and unfractionated heparin. Similar outcomes were found when comparing aspirin alone and aspirin in combination with LMWH (118, 119). Some studies have questioned the benefit of heparin use, but until more robust research data are available, current guidelines advocate the addition of heparin if the patient had previously miscarried with aspirin monotherapy (12, 120, 121).
A Cochrane review of treatment of APS patients with corticosteroids has not shown improved efficacy compared to placebo in improving live birth rates (122). The incidence of gestational diabetes and hypertension was significantly higher in patients treated with corticosteroids (123); hence, steroids are not used for APS in miscarriages.
The role of IVIG in APS and recurrent miscarriage has been reviewed in a number of studies (124). There was no substantial evidence to support the use of IVIG and recent consensus is to limit its use to research trials.