Thrombophilia and Ovarian Hyperstimulation Syndrome: A Case Report

Abstract

Background

Ovarian Hyperstimulation syndrome (OHSS) is one of the most serious complications of controlled ovarian hyperstimulation. Recent prospective data revealed possible increased prevalence of thrombophilia markers in women who develop severe ovarian hyperstimulation syndrome (OHSS).

Case

A 26-year-old nulliparous woman underwent ovarian stimulation for in vitro fertilization with recombinant follicle stimulating hormone and developed severe OHSS. She was screened for hereditary and inherited thrombophilia markers and was found to be homozygous for MTHFR mutation and had decreased antithrombin levels.

Conclusion

This case adds to the limited information that there may be an association between women who develop severe ovarian hyperstimulation syndrome and an increased prevalence of underlying thrombophilia markers. If further research demonstrates a cost effective strategy, screening for those markers may identify women who are at a higher risk for development of severe ovarian hyperstimulation syndrome.

Introduction

Ovarian hyperstimulation syndrome (OHSS) is one of the most serious complications of controlled ovarian hyperstimulation. It is classified on a scale of severity based on clinical and laboratory parameters. Mild OHSS is characterized by enlarged ovaries, abdominal distension and possibly nausea and emesis. This can progress to severe or critical OHSS, which is characterized by clinical evidence of ascites, hemoconcentration, potential renal insufficiency and thromboembolic phenomenon.¹ The incidence of this syndrome is variable. Schenker et al. reported that mild OHSS is thought to occur in up to 10% of ovulation induction cycles and severe OHSS can complicate up to 1% of patients.² There are numerous factors that predispose a patient to the development of OHSS. Age <35, polycystic ovarian syndrome and an initial high antral follicle count are all risk factors for development of OHSS.³ The pathophysiology of OHSS is not clearly understood. The majority of clinical findings are related to intravascular volume depletion. Vascular endothelial growth factor (VEGF) is responsible for the increased capillary permeability seen in OHSS and this permeability leads to transudation of fluid from the hypervascular ovary, causing ascites. Consequently, hemoconcentration develops and there are numerous reports in the literature documenting thromboembolic events. Numerous authors have examined what additional factors may predispose a patient undergoing ovulation induction and hyperstimulation to develop OHSS.

Dolitzky et al. is the only study in the literature that we are aware of that evaluates the incidence of thrombophilia in patients with severe OHSS. They demonstrated an increased incidence of thrombophilia markers (85%) in patients who developed severe OHSS versus controls (26.8%).⁴ We present another case which may guide future investigation in the direction of whether or not thrombophilia carriers are at a higher risk for developing OHSS with ovarian hypersitmulation and whether underlying thrombophilia markers are associated with development of severe OHSS.

Case Presentation

A 24-year-old gravida zero and her partner presented with infertility secondary to severe oligoathenospermia. Her past medical history was otherwise unremarkable. Her gynecologic review of systems documented normal monthly cycles with molimina. Ovarian reserve testing documented normal day 3 follicle stimulating hormone levels of 5.7 mIU/ml. Her ovarian stimulation was initiated with recombinant follicle stimulating hormone 300 units daily. She had a total of 10 days of stimulation and GnRH antagonist was used to prevent premature ovulation. She developed forty-three follicles and her peak estradiol level on the day of hCG administration was 1469 pg/ml after receiving a total dose of 17 international units of recombinant follicle stimulating hormone. Intramuscular hCG was administered when her lead follicles measured eighteen millimeters. She underwent uncomplicated transvaginal oocyte retrieval. Thirty four oocytes were retrieved and intracytoplasmic sperm injection (ICSI) performed on 32 oocytes resulting in 16 embryos. Seven embryos reached the blastocyst stage of development and were cryopreserved.

Three days after oocyte retrieval the patient presented to the clinic with nausea, vomiting abdominal pain and distention. Physical examination revealed sinus tachycardia in the 120s beats per minute and her abdominal exam revealed moderate distension and clinical ascites. A transvaginal sonogram was performed which documented enlarged ovaries measuring eight centimeters each and four centimeters of free fluid in the pelvis. Laboratory evaluation at that time demonstrated hemoconcentration with a hematocrit of 45%. She was consequently admitted for inpatient management of severe OHSS. Embryo transfer was not performed and all suitable embryos were cryopreserved.

Her management consisted of intravenous fluid administration with normal saline, deep venous thrombosis prophylaxis with low molecular weight heparin and pain management. By hospital day six, her clinical status improved and she did not require paracentesis secondary to her improvement with conservative management. Laboratory parameters normalized and she was discharged home in stable condition.

Based on Dolitzky's et al. findings a decision was made to screen this patient for hereditary and acquired thrombophilia markers. We obtained laboratory analysis for evaluation of protein C and protein S deficiencies, Factor V Leiden mutation, antithrombin III deficiency, prothrombin gene (20210G>A) mutation, methyltetrahydroflate reductase (MTHFR) gene mutations, anticardiolipin antibodies and the lupus anticoagulant.

Her results demonstrated that she was homozygous for the common MTHFR polymorphism (677C>T), a genotype where hyperhomocystinemia is common. In addition she demonstrated laboratory evidence of antithrombin III deficiency with 76% activity.

Discussion

Currently the prevalence of thrombophilia markers in women with severe hyperstimulation syndrome has only been examined once. Additionally, two case reports of women who presented with acute thromboembolic events in context of OHSS and were found to be carriers of thrombophilia have been described.^5,6 However, measuring thrombophilia marker activity levels during acute disease states is usually unreliable and may provide a false positive results as those levels may fluctuate. Consequently, future studies may consider screening women undergoing controlled ovarian hyperstimulation for thrombophilia and prospectively following them to monitor development of OHSS to evaluate if there is further association between thrombophilia markers and development of severe OHSS.

This case report supports Dolitzky's et al. findings that the prevalence of thrombophillia markers may be increased in patients who develop severe OHSS after controlled ovarian hyperstimulation with gonadotropins. Specifically, similar to their findings, our patient demonstrated decreased antithrombin levels and homozygosity for MTHFR 677T. In their study, patients who developed severe OHSS were found to have significantly lower antithrombin levels compared to controls. Similarly, they found that homozygosity for MTHFR 677T was found to be associated with a fivefold increased risk for severe OHSS, a mutation of which our patient was a carrier. Although several thrombophilia markers are not reliable in pregnancy and during acute disease states such as the pathophysiologic changes that occur with OHSS, such as AT III levels, the homozygous MTHFR genotype may be associated with development of OHSS. It is unclear why patients with underlying thrombopilia markers may be at higher risk of OHSS. Kodama et al. reported on decreased Antithrombin III levels in ART cycles that developed OHSS and numerous other papers demonstrated changes in hematologic parameters with ovarian stimulation. Thus it is plausible that patients with underlying hematologic pathology may be at risk for OHSS.

Further prospective studies evaluating underlying thrombophilia markers and severe OHSS are needed. This case report adds to the current limited data regarding underlying thrombophillia markers and a possible association with development of severe OHSS with controlled ovarian hyperstimulation with gonadotropins. The authors acknowledge the fact that undertaking future prospective trials to evaluate for this association may not be cost effective, but may shed light on the underlying etiology of OHSS.

In addition, based on our and Dolitzky's et al. findings homozygosity for MTHFR 677T may potentially be used as a screening tool for patients who may be at high risk for severe OHSS syndrome based on other risk factors.