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Please cite this paper as: Korteweg F, Folkeringa N, Brouwer J, Erwich J, Holm J, van der Meer J, Veeger N. Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study. BJOG 2012;119:422–430. Objective To assess the absolute risk of fetal loss associated with hereditary deficiencies of antithrombin (AT), protein C (PC) and protein S (PS), and the contribution of additional thrombophilic defects to this risk. Design A retrospective family cohort study. Setting A tertiary referral teaching hospital. Population Women from families with hereditary deficiencies of AT, PC and PS, and their non-deficient relatives. Methods We assessed the absolute risk of fetal loss, comparing deficient women with non-deficient female relatives. Main outcome measures Early, late and total fetal loss rates; odds ratios of fetal loss. Results We evaluated 289 women, who had 860 pregnancies. The total fetal loss rates were 23% (AT deficient), 26% (PC deficient), 11% (type-I PS deficient) and 15% (type-III PS deficient), compared with 11, 18, 12 and 13% in non-deficient women, respectively. Odds ratios were 2.3 (95% CI 0.9–6.1), 2.1 (95% CI 0.9–4.7), 0.7 (95% CI 0.2–1.8) and 1.1 (95% CI 0.6–2.0), none of which reached statistical significance. Differences were mainly the result of higher late fetal loss rates in women deficient in AT (OR 11.3, 95% CI 3.0–42.0) and PC (OR 4.7, 95% CI 1.3–17.4). The concomitance of factor-V Leiden and prothrombin G20210A was observed in 19% of women, and did not increase the risk of fetal loss. Conclusions Although absolute risks of fetal loss were high, odds ratios of total fetal loss were not statistically significant in deficient versus non-deficient women. However the higher absolute risks appeared to reflect higher late fetal loss rates as opposed to early fetal loss rates. An additional effect of concomitance of factor-V Leiden and prothrombin G20210A was not demonstrated, which may result from the exclusion of women at highest risk of venous thromboembolism, or from the small numbers sampled in the study.