Case Report: Delayed intra-abdominal bleeding following trans-vaginal ultrasonography guided oocyte retrieval for in vitro fertilization in patients at risk for thrombo-embolic events under anticoagulant therapy

Introduction

Nowadays, ultrasonographically guided trans-vaginal ovum pick-up (OPU) is considered an accepted and safe method for oocyte retrieval worldwide. Nevertheless, the multiple punctures of the vaginal vault can injure or tear the vaginal mucosa, ovaries, intra-abdominal organs or blood vessels, resulting in mild to severe internal and external bleeding and other complications^1,2. Clinically significant blood loss after OPU is actually uncommon³, with a reported incidence of severe intra- or retroperitoneal bleeding varying from 0 to 1.3%;².

Intraperitoneal bleeding tends to be severe with acute hemodynamic deterioration, whereas retroperitoneal bleeding usually has a later and more indolent presentation. Intra-abdominal bleeding should be suspected immediately after OPU with the development of signs and symptoms of anemia. While a drop in hemoglobin concentration is an indication for prompt blood transfusion, hemodynamic deterioration dictates surgical intervention with subsequent hemostatis. Most of cases are diagnosed several hours following OPU, with a reported interval between OPU and surgical intervention, ranging from 3 to 18 hours^4,5.

In patients with an underlying coagulopathy, the interval between OPU and the appearance of clinical signs and symptoms of severe intra-abdominal bleeding or surgical intervention, was reported to be longer. While, Battaglia et al.⁶ reported a 3 hour interval between OPU and surgical intervention in a patient with coagulation factor XI deficiency⁶, intervals of 2 and 10 days, were reported in patients suffering from essential thrombocythemia⁷ and factor VIII deficiency⁸, respectively. Notably, none of the aforementioned patients were treated with anticoagulant medications.

The situation is even more complicated for women with known thrombophilia and/or history of a thrombo-embolic event, who use anticoagulant drugs. The hitherto published research regarding this issue is scarce, with only one study reporting on 24 patients treated concomitantly with anticoagulation therapy, who underwent 68 oocyte retrieval procedures⁹. Since IVF treatment was not associated with any medical complication, such as bleeding or thromboembolic complications, Yinon et al. have concluded that among patients considered as high risk for a thromboembolic event, the introduction of low molecular weight heparin (LMWH), as a cycle protective treatment, is safe⁹.

Here, we report two cases of massive delayed intra-abdominalhemorrhage following OPU, in patients at risk for thromboembolic events, who concomitantly used LMWH. These cases aim to direct physicians' attention and keep them alert, while treating this subgroup of at risk patients.

Case report

Two patients were referred to our IVF clinic for egg/embryos collection for surrogacy because of the risk associated with pregnancy. Both were under therapeutic doses of LMWH, which according to a senior haematologist consultant, were co-administered during the controlled ovarian hyperstimulation (COH) for IVF, until 16 h before the oocyte retrieval and resumed 12 h after the procedure. This study was approved by the institutional review board of Sheba Medical Centre.

Discussion

We report herein, to our knowledge, the first 2 cases of massive delayed intra-abdominal hemorrhage following OPU, in patients at risk for thromboembolic event, who concomitantly used therapeutic doses of LMWH. We are not aware of any guidelines that have been published by any professional society, regarding OPU under LMWH. Moreover, since most guidelines relate to patients undergoing surgeries that may apply strict hemostatic measures, which are not available during US guided OPU, our report challenges and calls for re-evaluation of the anticoagulation regimen, provided to this subgroup of at risk patients, during an IVF treatment cycle.

Following OPU, the cessation of bleeding requires the interaction of the injured blood vessel with the circulating platelets and clotting proteins in order to form a stable platelet-fibrin clot. Any abnormalities of these factors may result in clinically significant bleeding. In the present cases, both patients received therapeutic doses of LMWH (enoxaparin, 60mg bid), which were discontinued 16 h prior to OPU and resumed 12 h after the procedure. Moreover, intra abdominal bleeding occurred 2 and 4 days following OPU.

Several plausible mechanisms might be responsible for the aforementioned delayed bleeding: (a) early postoperative use of enoxaparin and unfractionated heparin was reported to be associated with a significant increase in re-exploration for postoperative bleeding, often at a significantly delayed time period after the initial surgery¹⁰. Moreover, this delay was especially common with enoxaparin; (b) while the effect of LMWH and unfractionated heparin on the coagulation cascade is well established, we may wonder whether these substances also affect the fibrin nanostructure, which plays a major role in the mechanical strength and lysis of clots. Yeromonahos et al.¹¹ provided quantitative evidence showing that both LMWH and unfractionated heparin, independent of their other actions on the coagulation cascade, directly alter the nanostructure of fibrin fibers, contributing to improved fibrinolysis.

We therefore believe that the presently accepted anticoagulant co-treatment regimen, including the dose and timing of administration, should be challenged and undergo a critical re-evaluation. For example, delaying and reducing the first dose of LMWH post OPU, with gradual increments might offer some advantages. However, whether this modification will increase the tendency toward thrombosis, should be further investigated. Moreover, since intra abdominal bleeding obviously occurs, and may occur several days following OPU, we recommend that the patient be kept in the ward for observation for at least 2–4 days following OPU.

In the presented cases we also observed a tear of the ovarian capsule and an inadvertent puncture of a blood vessel within the infudibullo-pelvic ligament. Both complications might have been prevented by meticulous follicular aspiration using a small diameter aspiration needle (19G), and preferably under the guide of color Doppler ultrasonography¹², respectively.

In conclusion, massive delayed intra-abdominal hemorrhage may occur following OPU, in patients at risk for thromboembolic event, who concomitantly used LMWH. These case-reports should direct physicians' attention and keep them alert, while conducting an IVF treatment to this subgroup of high risk patients.