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Effect of letrozole on moderate and severe early-onset ovarian hyperstimulation syndrome in high-risk women: a prospective randomized trial

  • Author Footnotes
    1 These authors contributed equally to this article.
    Qingyun Mai
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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  • Author Footnotes
    1 These authors contributed equally to this article.
    Xiaokun Hu
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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  • Gang Yang
    Affiliations
    Department of Obstetrics and Gynecology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, China
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  • Yingyi Luo
    Affiliations
    Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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  • Kejun Huang
    Affiliations
    Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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  • Yuan Yuan
    Affiliations
    Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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  • Canquan Zhou
    Correspondence
    Corresponding author: Canquan Zhou, MD.
    Affiliations
    Center for Reproductive Medicine and Department of Gynecology and Obstetrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this article.
Published:August 21, 2016DOI:https://doi.org/10.1016/j.ajog.2016.08.018

      Background

      Ovarian hyperstimulation syndrome is an iatrogenic complication of controlled ovarian stimulation. Early ovarian hyperstimulation syndrome occurs during luteal phase of controlled ovarian stimulation within 9 days after human chorionic gonadotropin trigger and reflects an acute consequence of this hormone on the ovaries. Late ovarian hyperstimulation syndrome occurs 10 or more days after human chorionic gonadotropin trigger and reflects increased endogenous human chorionic gonadotropin levels following pregnancy. Human chorionic gonadotropin stimulates granulosa-lutein cells to produce vascular endothelial growth factor messenger RNAs, which in turn raises serum vascular endothelial growth factor concentration and increases vascular permeability in women with ovarian hyperstimulation syndrome. Efforts to reduce the incidence and severity of ovarian hyperstimulation syndrome after oocyte retrieval, and in particular primary prevention efforts, are vital to prevent thrombogenesis and other serious complications.

      Objective

      The objective of the study was to compare the efficacy of letrozole, an aromatase inhibitor, with aspirin in primary prevention of early ovarian hyperstimulation syndrome and to compare vascular endothelial growth factor levels between groups.

      Study Design

      Participants in this prospective randomized trial included 238 participants undergoing cryopreservation of the whole embryos after oocyte retrieval with at least 1 of the following high-risk factors for ovarian hyperstimulation syndrome: oocyte retrieval ≥25; estradiol level ≥5000 pg/mL on the day of human chorionic gonadotropin administration; and clinical or ultrasonographic evidence of ovarian hyperstimulation syndrome on the day of oocyte retrieval, such as ultrasonographic evidence of ascites. After human chorionic gonadotropin triggering, experimental (119 cases) and control (119 cases) groups received letrozole and aspirin, respectively, for 5 days. The 5 categories of ovarian hyperstimulation syndrome include no, yes-mild, yes-moderate, yes-severe, and yes-critical. The primary outcome was the incidence and severity of early ovarian hyperstimulation syndrome. The secondary outcome included vascular endothelial growth factor level both on the second and seventh day after the human chorionic gonadotropin trigger, and clinical and laboratory features of ovarian hyperstimulation syndrome symptoms.

      Results

      The incidence of ovarian hyperstimulation syndrome was significantly higher in women receiving aspirin, compared with letrozole (90.2% vs 80.4%, P = .044). Moderate and severe ovarian hyperstimulation syndrome was also higher in the aspirin group, 45.1%, compared with the letrozole group, 25.0% (P = .002). Moreover, the duration of luteal phase was shortened in letrozole group compared with aspirin group (8.1 ± 1.1 days vs 10.5 ± 1.9 days, P < .001). The vascular endothelial growth factor level was significantly higher in the letrozole-treated group than aspirin-treated group (0.49 ± 0.26 vs 0.42 ± 0.22, P = .029).

      Conclusion

      Letrozole was more effective than aspirin in decreasing the incidence of moderate and severe early-onset ovarian hyperstimulation syndrome. Our results indicate that ovarian hyperstimulation syndrome might be caused through a luteolytic effect rather than through modulation of vascular endothelial growth factor, racing by a decline in estradiol and termination of early-onset ovarian hyperstimulation syndrome in advance in high-risk women with cryopreservation of the whole embryos.

      Key words

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