A Brief Review of Stroke associated with Assisted Reproductive Te

Journal of Neurology & Neurophysiology

ISSN - 2155-9562

Review Article - (2017) Volume 8, Issue 2

A Brief Review of Stroke associated with Assisted Reproductive Technology

Mary Angela O'Neal*
Harvard Medical School, Clinical Director of the Neurosciences, Department of Neurology, Brigham and Women's Hospital, USA
*Corresponding Author: Mary Angela O'Neal, Department of Neurology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA, Tel: 617-732-7432, Fax: 617-582-6163 Email:


Strokes related to assisted reproductive technology are rare, but can be devastating. In order to understand how stroke can occur as a complication of assisted reproductive technology, both the normal physiology of ovulation and the hormonal manipulations used to maximize pregnancy will be examined. In particular, the danger of thrombotic complications related to ovarian hyperstimulation syndrome will be reviewed including the pathophysiology, clinical features, risk factors and treatment.

Keywords: Assisted reproductive technology; Stroke; In vitro fertilization; Ovarian hyperstimulation syndrome; Cerebral venous thrombosis

Introduction and Definitions

Assisted reproductive technology (ART) is the generic term referring to the methods used to achieve pregnancy including fertility medication, artificial insemination, in vitro fertilization (IVF) and surrogacy. IVF refers to the procedure where the ovaries are stimulated by fertility medications to produce follicles; the ovocytes are aspirated from the follicles and fertilized in the lab and then transferred to the uterine cavity. The process involves the use of exogenous hormones to achieve cycle control, stimulate the ovaries and support implantation. During this process, supra physiological estradiol levels can result. High estradiol levels alone increase thrombotic risk [1].

One major complication of this intervention, ovarian hyperstimulation syndrome (OHSS) can be associated with significant arterial and venous thrombotic complications [2]. OHSS is a rare iatrogenic complication that occurs when the ovaries are hyper stimulated and enlarged related to fertility treatments. The incidence of OHSS can occur in up to 10% of IVF cycles, but only a small number of these cases are severe [3,4]. It has two clinical forms both of which are related to human chorionic gonadotrophin (HCG). The most common early form occurs in the first eight days after exogenous HCG administration and the late form is related to pregnancy induced HCG production [5,6]. Thrombotic complications related to ART are rare, but neurologists need to understand the risks and pathophysiology.


The incidence of thrombosis varies from 0.2% of all IVF cycles to up to 10% in OHSS [7]. This is a small percentage, but the absolute number of those affected is considerable given the number of women who undergo fertility treatment. Seventy five percent of the thrombotic events are venous including cerebral venous thrombosis; the remainders of events are almost all ischemic strokes [8].

Normal physiology

A normal menstrual cycle is divided into three phases either based on what occurs in the ovary; the follicular phase, ovulation and the luteal phase or the correlating phases in the uterus; proliferative, secretory and menstruation. Follicle stimulating hormone, FSH, released from the pituitary gland stimulates follicular growth. The growing follicles produce estradiol which has a negative effect on the pituitary release of luteinizing hormone, LH and at a threshold causes release of gonadotropin-releasing hormone (GnRH) which stimulates the pituitary release of LH, the LH surge which triggers ovulation. FSH and LH cause the remaining parts of the dominant follicle to transform into the corpus luteum, which produces progesterone [9].

Controlled ovarian stimulation

ART uses hormonal manipulation of this normal physiology to increase the odds of fertilization and pregnancy. Estrogen receptor modulators, such as clomiphene, can stimulate follicular development. They have rarely been associated with OHSS [10]. Most infertility regimens use daily FSH injections for follicular stimulation [11]. FSH is used in conjunction with a low dose of a GnRH analog to prevent the LH surge until the follicles are judged to be mature. Either human chorionic gonadotropin (HCG) or a GnRH agonist can be used to trigger the LH surge and the ovulatory cascade. The oocytes can then be harvested, fertilized and implanted.

Pathophysiology of OHSS

HCG which naturally rises during pregnancy following ovarian stimulation or when it is given for follicular maturation to trigger ovulation appears to be pivotal in the development of the increased vascular permeability which is the core feature of OHSS [12]. High levels of HCG are felt to cause an over expression of vascular endothelial growth factor in the developing follicles leading to a release of vasoactive substances [13,14]. The result is ovarian enlargement as well as capillary hyperpermeability with fluid extravasation causing ascites, pleural and pericardial effusions. The resultant fluid shifts are also responsible for electrolyte disturbances, oliguria, hypovolemia and hemoconcentration [15].

Elevated estrogen levels alone cause a hypercoaguable state. In studies of oral contraceptives or hormone replacement therapy, high estrogen levels are associated with an increased risk of both arterial and venous thrombosis [16]. In a study of seven women undergoing ovarian stimulation, endogenous estrogen levels (other hormonal changes were not investigated) and the associated changes in coagulation parameters were evaluated. These women showed a predictable rise in fibrinogen which correlated with the marked rise in estrogen during the cycle, thus producing a prothrombotic state [17]. This thrombotic risk is magnified in OHSS. In addition to high estradiol levels, hypercoaguability is worsened by the hypovolemia and hemoconcentration both which result from the increased capillary permeability [18]. Ascites and increased ovarian size promote venous stasis further exacerbating the hypercoaguable state [19].

Clinical features

The clinical signs and symptoms of OHSS are varied. The increase in ovarian size can cause abdominal pain, nausea and vomiting. Increased vascular permeability occurs leading to a shift of fluid from the intravascular to extravascular space resulting in third spacing with subsequent hypotension, edema, ascites, pericardial and pleural effusions. A complex cascade ensues which may include hypotension, hemoconcentration, tachycardia and hypercoaguability. The latter problem results in thrombotic complications. These events (especially venous thrombosis) have been reported to occur even weeks after OHSS has resolved. Thrombotic complications are primarily venous, 66% [19]. The venous complications related to OHSS have been reported in axillary, mesenteric, jugular, subclavian and cerebral venous sinuses. In fact, venous thromboembolic complications preferentially occur in the neck and upper limbs in particular the internal jugular and subclavian veins [20,21]. The arterial events are almost always ischemic stroke [18].

Risk factors

A number of risk factors for thrombotic complications from ART have been defined. The risk is particularly prominent in women who are more likely to develop OHSS. The defined primary risk factors include young age, history of polycystic ovary syndrome, PCOS, a prior history of OHSS and any underlying thrombophilia [22]. Younger patients are more likely to have a robust response to ovarian stimulation increasing the risk for complications and development of OHSS. A prior history of OHSS as well as a history of PCOS also increases the risk of OHSS [22,23]. Women with PCOS are also more likely to suffer this complication as they tend to produce more follicles.

The secondary risk factors include features related to treatment response including absolute estradiol level as well as the number and size of follicles produced. If pregnancy follows this exuberant response to IVF, that will also increase the risk of OHSS due to the stimulation of HCG.


Prevention and recognition of OHSS are the key elements to patient safety as no direct treatment exists. One strategy would be to identify women at risk for OHSS and in these high risk individuals to carefully follow the ovaries response to stimulation using both estrogen levels and ultrasounds. Additionally, cancelling the IVF cycle if there is concern for OHSS is prudent [13,23,24]. Currently, there is a movement away from using HCG as an ovulatory trigger as it seems to be important in the pathogenesis of OHSS. For women with PCOS the use of metformin during controlled ovarian hyperstimulation has been shown to decrease the relative risk of OHSS by O.2; 95% CI without changes the clinical outcomes of implantation rate, pregnancy or live birth rate [25].

The key features of treatment once OHSS has occurred are supportive. These measures include fluid replacement, pain control, avoiding non-steroidal anti-inflammatory medications (as these may worsen renal function) and maintenance of adequate blood pressure. Women with severe OHSS require hospitalization to manage hypotension, poor renal function, pain and ascites. In patients with severe OHSS, an antithrombotic medication should be initiated [26,27]. Those women with neurologic complaints require an expeditious consultation. Neurologists need to be aware of the propensity of thrombotic complications both venous and arterial in this group of otherwise healthy women in order to rapidly assess, utilize appropriate imaging and treat.


  1. Inman WH, Vessey MP, Westerholm B, Engelund A (1970) Thromboembolic disease and the steroidal content of oral contraceptives. A report to the Committee on Safety of Drugs. Br Med J 2: 203-209.
  2. Stewart JA, Hamilton PJ, MurdochAP (1997) Thromboembolic disease associated with ovarian Stimulation and assisted conception techniques. Hum Reprod 12: 2167–2173.
  3. Brinsden PR, Wada I, Tan SL, Balen A, Jacobs HS (1995) Diagnosis, prevention and management of ovarian hyperstimulation syndrome. Br J Obstet Gynaecol 102: 767-772.
  4. Roest J, Mous HVH, Zeilmaker GH, Verhoeff A (1996) The incidence of major clinical complications in a Dutch transport IVF programme. Hum Reprod Update 2: 345–353.
  5. Delvigne A, Rozenberg S (2002) Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): A review. Hum Reprod Update 8: 559-577.
  6. Bettendorf G, Lindner C (1987) The ovarian hyperstimulation syndrome. Horm Metab Res 19: 519-522.
  7. Kasum M, Danolic D, Oreskovic S, Jezek D, Beketic-Oreskovic L, et al. (2014) Thrombosis following ovarian hyperstimulation syndrome. Gynecol Endocrinol 30: 764-768.
  8. Chan WS, Ginsberg JS (2006) A review of upper extremity deep vein thrombosis in pregnancy: Unmasking the 'ART' behind the clot. J Thromb Haemost 4: 1673-1677.
  9. Gougeon A (1986) Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod 1: 81-87.
  10. Kistner RW (1965) Induction of ovulation with clomiphene citrate (clomid). Obstet Gynecol Surv 20: 873-900.
  11. Pouwer AW, Farquhar C, Kremer JA (2015) Long-acting FSH versus daily FSH for women undergoing assisted reproduction. Cochrane Database Syst Rev 14: CD00957.
  12. Rizk B, Smitz J (1992) Ovarian hyperstimulation syndrome after superovulation using GnRH agonists for IVF and related procedures. Hum Reprod 7: 320-327.
  13. Kumar P, Sait SF, Sharma A, Kumar M (2011) Ovarian hyperstimulation syndrome. J Hum Reprod Sci 4: 70-75.
  14. Cerrillo M, Pacheco A, Rodríguez S, Gómez R, Delgado F, et al. (2011) Effect of GnRH agonist and hCG treatment on VEGF, angiopoietin-2 and VE-cadherin: trying to explain the link to ovarian hyperstimulation syndrome. Fertil Steril 95: 2517-2519.
  15. Bartkova A, Sanak D, Dostal J, Herzig R, Otruba P, et al. (2008) Acute ischemic stroke in pregnancy: a severe complication of ovarian hyperstimulation syndrome. Neurol Sci 29: 463–466.
  16. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP (2002) Female hormones and thrombosis. Arterioscler Thromb Vasc Biol 22: 201-210.
  17. Kim HC, Kemmann E, Shelden RM, Saidi P (1981) Response of blood coagulation parameters to elevated endogenous 17ß-estradiol levels induced by human menopausal gonadotropins. Am J Obstet Gynecol 140: 807-810.
  18. Alatri A, Tribout B, Gencer B, Calanca L, Mazzolai L (2011) Thrombotic risk in assisted reproductive technology. Rev Med Suisse 7: 357-360.
  19. Rogolino A, Coccia ME, Fedi S, Gori AM, Cellai AP, et al. (2003) Hypercoagulability, high tissue factor and low tissue factor pathway inhibitor levels in severe ovarian hyperstimulation syndrome: Possible association with clinical outcome. Blood Coagul Fibrinolysis 14: 277–282.
  20. Chan WS, Ginsberg JS (2006) A review of upper extremity deep vein thrombosis in pregnancy: Unmasking the 'ART' behind the clot. J Thromb Haemost 4: 1673-1677.
  21. Mor YS, Schenker JG (2014) Ovarian hyperstimulation syndrome and thrombotic events. Am J Reprod Immunol 72: 541-548.
  22. Lamazou F, Legouez A, Letouzey V, Grynberg M, Deffieux X, et al. (2011) Ovarian hyperstimulation syndrome: pathophysiology, risk factors, prevention, diagnosis and treatment. J Gynecol Obstet Biol Reprod 40: 593–611.
  23. Delvigne A, Rozenberg S (2002) Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): A review. Hum Reprod Update 8: 559-577.
  24. Delvigne A (2009) Symposium: Update on prediction and management of OHSS. Epidemiology of OHSS. Reprod Biomed Online 19: 8-13.
  25. Palomba S1, Falbo A, Carrillo L, Villani MT, Orio F, et al. (2011) Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonadotropin-stimulated in vitro fertilization cycles: A randomized, controlled trial. Fertil Steril 96: 1384-1390.
  26. Delvigne A, Rozenberg S (2003) Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS). Hum Reprod Update 9: 77-96.
  27. Shmorgun D, Claman P, Gysler M, Hemmings R, Cheung AP, et al. (2011) The diagnosis and management of ovarian hyperstimulation syndrome. J Obstet Gynaecol Can 33: 1156-1162.
Citation: O’Neal MA (2017) A Brief Review of Stroke associated with Assisted Reproductive Technology. J Neurol Neurophysiol 8:418.

Copyright: © 2017 O’Neal MA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.