Combination of aspirin and heparin in unexplained recurrent miscarriages - "Empirical or evidence based".

Sir,

Recurrent miscarriage is defined as three or more miscarriages before 20 weeks of gestation. Only 1% couples are affected by this problem which increases to 5% if couples with two miscarriages are included. Many causes have been implicated including chromosomal abnormalities, uterine structural anomalies, leuteal phase defects, thrombophilias, and immunological and endocrinological causes. Even after evaluating the cause, in over 50% of cases it remains unexplained. How to treat such patients is a difficult situation for the physicians.

A combination of low-molecular-weight heparin and aspirin in recurrent miscarriage with antiphospholipid antibodies has become a routine practice. This treatment is being commonly used for unexplained miscarriages in clinical practice without proper evidence. The possible mechanism of unexplained miscarriages guiding the use of this regime is that it is a prothromobotic phenotype. Moreover, not only the thrombosis in the decidual vessels but also the adverse effect of coagulation cascade activation on developing trophoblasts may result in a miscarriage.[1]

Recently, the Anticoagulant for Living Fetus (ALIFE) study, a large randomized trial by Kaandorp et al., has given significant insights on the use of this regime in unexplained recurrent miscarriages. This trial included 364 patients with two or more recurrent abortion, who were attempting to conceive or had pregnancy of less than 6 weeks. They were randomized into three subgroups of aspirin and LMWH (nadroparin 2850 IU subcutaneously), aspirin only and placebo groups. Aspirin was started as soon as patient was randomized and LMWH was started at 6 weeks after confirming viability. They concluded that the live birth rates among the three groups were almost similar and there was no advantage of treatment over placebo. The proportion of women who gave birth to a live infant was 54.5% in the group receiving aspirin plus nadroparin (combination therapy group), 50.8% in the aspirin-only group, and 57.0% in the placebo group (absolute difference in live birth rate: Combination therapy versus placebo, –2.6 percentage points; 95% confidence interval [CI], –15.0 to 9.9; aspirin only versus placebo, –6.2 percentage points; 95% CI, –18.8 to 6.4). Among 299 women who became pregnant, the live birth rate was 69.1% in the combination therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live birth rate: Combination therapy versus placebo, 2.1 percentage points; 95% CI, –10.8 to 15.0; aspirin alone versus placebo –5.4 percentage points; 95% CI, –18.6 to 7.8).[2] In conclusion, neither aspirin combined with nadroparin nor aspirin alone improved the live birth rate, as compared with placebo, among women with unexplained recurrent miscarriages. According to the authors, a study reports that in thrombodulin-deficient mice, aspirin and heparin did not reverse the defective trophoblastic differentiation or embryonic growth defect. This supports their study that all unexplained miscarriages cannot be attributed to thrombosis. Similar results were produced by the Scottish Pregnancy Intervention Study in which there was no benefit of LMWH (enoxaparin 40 mg) plus aspirin with surveillance over only surveillance in live birth rates among patients with two or more miscarriages.[3]

Reviewing various trials, heparin plus low-dose aspirin is only recommended in diagnosed antiphospholipid antibody syndrome and not in unexplained miscarriages.[4] The Green Top RCOG Guidelines revised recently have also included that women with unexplained recurrent miscarriages have an excellent prognosis for the future pregnancy outcome without pharmacological intervention. Based on these two randomized trials, they have suggested that the use of empirical treatment in women with unexplained recurrent miscarriages is unnecessary and should be resisted.[5] Therefore, the usual practice of prescribing this should be seriously looked into as this regime unnecessarily increases the cost. Moreover, it is troublesome to take injections daily, and often, bruise or swelling and itching are noted at the injection site.

Further research is warranted in this field. Only LMWH without aspirin trials are in progress. Further researches should also include newer treatment options based on different mechanisms such as TNF-alpha inhibitors and granulocyte colony-stimulating factor.[6]