Preston F E, Rosendaal F R, Walker I D, Briët E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, van der Meer F J
Royal Hallamshire Hospital, Sheffield, UK.
Lancet. 1996 Oct 5;348(9032):913-6. doi: 10.1016/s0140-6736(96)04125-6.
A successful outcome of pregnancy requires an efficient uteroplacental vascular system. Since this system may be compromised by disorders of haemostasis associated with a prothrombotic state, we postulated that maternal thrombophilia might be a risk factor for fetal loss. We studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women with factor V Leiden or deficiency of antithrombin, protein C, or protein S.
We studied 1384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). Of 843 women with thrombophilia 571 had 1524 pregnancies; of 541 control women 395 had 1019 pregnancies. The controls were partners of male members of the EPCOT cohort or acquaintances of cases. We analysed the frequencies of miscarriage (fetal loss at or before 28 weeks of gestation) and stillbirth (fetal loss after 28 weeks of gestation) jointly and separately.
The risk of fetal loss was increased in women with thrombophilia (168/571 vs 93/395; odds ratio 1.35 [95% Cl 1.01-1.82]). The odds ratio was higher for stillbirth than for miscarriage (3.6 [1.4-9.4] vs 1.27 [0.94-1.71]). The highest odds ratio for stillbirth was in women with combined defects (14.3 [2.4-86.0]) compared with 5.2 (1.5-18.1) in antithrombin deficiency, 2.3 (0.6-8.3) in protein-C deficiency, 3.3 (1.0-11.3) in protein-S deficiency, and 2.0 (0.5-7.7) with factor V Leiden. The corresponding odds ratios for miscarriage in these subgroups were 0.8 (0.2-3.6), 1.7 (1.0-2.8), 1.4 (0.9-2.2), 1.2 (0.7-1.9), and 0.9 (0.5-1.5). Significantly more pregnancy terminations had been done in women with thrombophilia than in controls (odds ratio 2.9 [1.8-4.8]); this discrepancy was apparent in nine of 11 participating centres and for all thrombophilia subgroups.
Women with familial thrombophilia, especially those with combined defects or antithrombin deficiency, have an increased risk of fetal loss, particularly stillbirth. Our findings have important implications for therapy and provide a rationale for clinical trials of thromboprophylaxis for affected women with recurrent fetal loss.
成功妊娠需要高效的子宫胎盘血管系统。由于该系统可能因与血栓形成前状态相关的止血障碍而受损，我们推测母体血栓形成倾向可能是胎儿丢失的一个危险因素。我们在一组患有因子V莱顿突变或抗凝血酶、蛋白C或蛋白S缺乏的女性队列中研究了遗传性血栓形成倾向缺陷与胎儿丢失之间的关系。
我们研究了纳入欧洲血栓形成倾向前瞻性队列（EPCOT）的1384名女性。在843名患有血栓形成倾向的女性中，571名有1524次妊娠；在541名对照女性中，395名有1019次妊娠。对照组为EPCOT队列男性成员的伴侣或病例的熟人。我们联合并分别分析了流产（妊娠28周及以前的胎儿丢失）和死产（妊娠28周以后的胎儿丢失）的发生率。
患有血栓形成倾向的女性胎儿丢失风险增加（168/571对93/395；比值比1.35[95%可信区间1.01 - 1.82]）。死产的比值比高于流产（3.6[1.4 - 9.4]对1.27[0.94 - 1.71]）。合并缺陷的女性死产的比值比最高（14.3[2.4 - 86.0]），相比之下，抗凝血酶缺乏者为5.2（1.5 - 18.1），蛋白C缺乏者为2.3（0.6 - 8.3），蛋白S缺乏者为3.3（1.0 - 11.3），因子V莱顿突变者为2.0（0.5 - 7.7）。这些亚组中流产的相应比值比分别为0.8（0.2 - 3.6）、1.7（1.0 - 2.8）、1.4（0.9 - 2.2）、1.2（0.7 - 1.9）和0.9（0.5 - 1.5）。患有血栓形成倾向的女性终止妊娠的次数显著多于对照组（比值比2.9[1.8 - 4.8]）；这种差异在11个参与中心中的9个以及所有血栓形成倾向亚组中都很明显。
患有家族性血栓形成倾向者，尤其是那些合并缺陷或抗凝血酶缺乏者，胎儿丢失风险增加，尤其是死产风险。我们的研究结果对治疗具有重要意义，并为对反复发生胎儿丢失的受影响女性进行血栓预防的临床试验提供了理论依据。
