Various hereditary thrombophilias such as activated protein C resistance, the factor V leiden mutation, the prothrombin G20210A mutation, protein S deficiency, hyperhomocysteinemia, or combinations of the above disorders have been linked to pregnancy loss at varying stages of gestation (
Robertson L, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006;132(2):171–96
; Seligsohn U, et al. Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344(16):1222–31
). The literature regarding methylenetetrahydrofolate reductase (MTHFR) mutations is confusing. Much of the evidence supporting a causal relationship between MTHFR mutations and early fetal loss comes from individual case reports with little outcome data. Three recent meta-analyses of thrombophilia in pregnancy concluded that although there may be a trend toward higher risk, the relationship between MTHFR mutations and spontaneous abortions is not truly significant (Robertson L, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006;132(2):171–96
; Nelen WL, et al. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 2000;74(6):1196–9
; Rey E, et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003;361(9361):901–8
). In contrast, a study supporting the role of MTHFR mutations in recurrent unexplained abortions found a 2–3 fold increased risk of early fetal loss among Caucasian females homozygous for the C677T mutation versus normal controls (Nelen WL, et al. Genetic risk factor for unexplained recurrent early pregnancy loss. Lancet 1997;350(9081):861
). We present 5 patients with this genetic defect who presented consecutively to our clinic for decision making for future pregnancies. Each had strong histories of miscarriages after the 8th week of gestation. The clinical features of these patients are reported in the table below.Each woman is Caucasian, and is homozygous for the MTHFR C677T mutation with no other acquired or hereditary thrombophilias. Homocysteine levels were also in normal range for each patient. Our case series of 5 Caucasian women gives support to the theory of a causal relationship between MTHFR mutations and fetal loss. We recommended anticoagulation with low-molecular weight or unfractionated heparin for each patient as a therapeutic intervention to reduce the risk of recurrent abortion in future pregnancies.
