Abstract
Ovarian hyperstimulation syndrome is a rare, but potentially life-threatening iatrogenic disorder arising from ovulation induction or ovarian hyperstimulation for assisted reproduction techniques. We report a case of a 26-year-old multiparous woman, an anonymous egg donor, who died a few hours after undergoing a procedure to donate eggs at an in vitro fertilization clinic. Her husband alleged that medical negligence had led to her death. The autopsy confirmed death due to ovarian hyperstimulation syndrome. We know of no previous descriptions of fatal ovarian hyperstimulation syndrome in an anonymous egg donor in medico-legal literature.
Introduction
Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication that results from uncontrolled ovarian stimulation due to exogenous means of ovulation induction. This complication is unique to the treatment of infertility. 1 The pathophysiology of OHSS has remained unexplained. However, it is believed that in hyperstimulated ovaries, increased production of vasoactive substances belonging to rennin–angiotensin system, cytokines, including the interleukins, tumour necrosis factor alpha, endothelin-1 and vascular endothelial factor leads to a sudden increase in vascular permeability resulting in massive extravascular exudates which accumulates in spaces such as the peritoneal cavity, pleural cavity and pericardial cavity. 2 These cavities may be referred to as “the third space”.
The signs and symptoms of OHSS include ovarian enlargement and fragility, extravascular fluid accumulation and intravascular fluid depletion. An OHSS is graded according to the severity. Grade 1 (mild) is characterized by fluid accumulation in the third space, as evidenced by weight gain, abdominal distension and discomfort. Ultrasonography shows enlarged ovaries with a mean diameter between 5 and 8 cm. Grade 2 (moderate) is associated with development of nausea, vomiting, more discomfort, dyspnoea, greater abdominal distension and ovarian enlargement with the mean diameter between 8 and 12 cm. Grade 3 (severe) is a life-threatening condition, with clinical evidence of reduced intravascular volume (subnormal central venous pressure and reduced cardiac output), severe expansion of third space (tense ascites, pleural and pericardial effusion), severe haemoconcentration and development of hepatorenal failure. 3 Important risk factors for OHSS include the presence of polycystic ovaries, young age of the patient (<35 years), high serum oestradiol (>2500 pg/ml) and human chorionic gonadotropin (hCG) supplementation. 4
A distinction between early and late onset OHSS has been described. Early OHSS occurs within days after the ovulation triggering injection of hCG and is associated with higher serum oestradiol levels and larger number of follicles. It has been proposed that early OHSS may result from ovarian stimulation by the exogenous hCG given to trigger ovulation. In contrast, patients with late OHSS present 10 days after administration of hCG and it may be more closely linked to the endogenous hCG, produced when pregnancy occurs. 5,6
A World Health Organization report in 2002 estimated the overall incidence of severe OHSS was 0.2%–1% of all assisted reproduction cycles with an estimated 1:45,000–1:50,000 mortality in women receiving gonadotropin. 7 The European database from all the reported in vitro fertilization (IVF) cycles in 2004 calculated 2858 cases of OHSS out of 295,069 cycles, and an incidence of 0.97%. There were four deaths reported during these 295,069 cycles, a rate of about 0.001%, although the cause was not described. Mild OHSS probably occurs in 8%–23% of stimulated cycles, moderate OHSS in 1%–7% of stimulated cycles and severe form in about 0.5% of stimulated cycles. The incidence of severe OHSS has increased over the years. 8
In OHSS, the patient usually presents with abdominal pain, distension, rapid weight gain and breathlessness. Diagnosis is generally made by the clinicians on the basis of history, clinical examination and laboratory investigation. Death due to OHSS is very rare. Only a few autopsy cases are reported in the scientific literature.
Case report
Clinical history
A 26-year-old multiparous woman went to an assisted reproduction technique clinic to donate her eggs for an unknown recipient. She started the procedure with 0.5 ml injections of triptorelin acetate (gonadotropin releasing hormone (GnRH) agonist). Triggering was done through 500 µg subcutaneous injection of choriogonadotropin alpha (recombinant hCG (r-hCG)). On the next day, under general anaesthesia, transvaginal ultrasound aspiration was done, which lasted for about 5 to 7 min. After the procedure, she gained consciousness and was moved to the recovery room with normal vital recordings. After about 1 h of gaining consciousness, she started feeling uncomfortable and again became unconscious. She was given cardiopulmonary resuscitation and was referred to a private hospital. She was declared dead there two hours later.
Autopsy findings
An autopsy was performed two and a half days after death. The body was that of a 26-year-old woman of average build. Bluish discoloration of all finger nails (cyanosis) was present. A subcutaneous injection mark, encircled and annotated 5:30 with a blue pen, devoid of any redness or swelling suggestive of test dose, was present over the ventral aspect of right forearm. Multiple injection marks were present over the back of both hands. There were two injection marks present over the left anterior chest wall in the third intercostal space suggestive of resuscitation procedures. Dissection and internal examination of the thorax revealed about 200 ml of blood mixed fluids in the pleural cavities (pleural effusion), about 30 ml of blood mixed fluid in the pericardial sac (pericardial effusion). The lungs were bilaterally congested and oedematous with weight of left and right lung being 423 and 741 g, respectively. There was no evidence of pulmonary infarction or pulmonary emboli. The coronary arteries were patent. The brain, liver, spleen and kidneys were congested. The uterovesical pouch contained about 50 cc of blood clot (Figure 1(a)). The ovaries were bilaterally enlarged and congested (Figure 1(b)). The right and left ovaries measured 10.5 and 10 cm and weighed 110 and 167 g, respectively. The uterus was enlarged and weighed 120 g. Toxicological analysis of viscera, urine sample and samples from injection sites did not show the presence of any poison or drugs.
(a) Haematoma in uterovesical pouch and (b) enlarged ovaries and uterus.
Histopathological examination
Microscopic examination of both ovaries revealed multiple ovarian follicles in different stages of maturation with marked vascular congestion and focal haemorrhage (black arrows; Figure 2(a)). There was the presence of luteinized theca cells (black arrows) lining some larger follicles (Figure 2(b)). Diffuse and marked oedema was seen in the ovarian stroma (Figure 2(c)). The uterus showed early secretory endometrium. The myometrium was unremarkable. Section from the liver exhibited congestion of sinusoids, portal vein and microvesicular steatosis. Both kidneys showed autolytic changes with congestion of peritubular capillaries in the medulla. Sections from both lungs revealed diffuse and marked oedema, congestion of blood vessels and capillaries of intra-alveolar septae and focal intra-alveolar haemorrhage (Figure 2(d)). No evidence of pulmonary infarction, vascular or microvascular thrombosis was seen. Sections from the spleen, heart and brain were histologically unremarkable.
(a) Section from the ovary shows ovarian follicle with marked vascular congestion and focal haemorrhage (black arrows) (H&E, 100×). (b) Luteinized theca cells (black arrows) are seen in the wall of the follicle (H&E, 200×). (c) Ovarian stroma shows diffuse and marked oedema (H&E, 100×). (d) Section from lung shows marked oedema, congestion of intraalveolar septae, and intra-alveolar haemorrhage (H&E, 100×).
Cause of death was attributed to the diffuse and severe pulmonary oedema consequent to ovarian hyper stimulation syndrome.
Discussion
OHSS is a potentially life-threatening medical complication following superovulation therapy for assisted conception procedures, including both IVF and oocyte donation. 1 The reported cases are mostly mild and moderate form (Grades 1 and 2) and successfully managed by clinicians. Deaths have been reported in Grade 3 OHSS undergoing IVF due to cerebrovascular thrombosis, renal failure or cardiac tamponade resulting from pericardial effusion.3,9 However, only a few autopsy cases are reported in the literature.10–12
In our case, the victim was an anonymous donor. Ovarian stimulation was done by GnRH agonist followed by triggering with r-hCG. The procedure of egg retrieval was through transvaginal ultrasound aspiration under general anaesthesia. The victim died about 36 h after triggering with r-hCG and approximately 7 h after completion of the procedure. The presence of a blood clot in uterovesical pouch suggested the transvaginal vaginal approach and injury to a blood vessel. The findings were suggestive of OHSS. Although the pathophysiology of OHSS has not been completely elucidated, an increased vascular permeability in our case led to the development of the syndrome. r-hCG is known to produce OHSS. 13 Development of the syndrome about 36 h after injection of r-hCG can be considered as early onset OHSS. The onset of OHSS soon after r-hCG administration or oocyte retrieval is associated with an increased risk for progression to severe disease. 3 The victim was under 35 years of age, which is also a risk factor for developing the syndrome. The role of trauma due to the procedure to the already hyperstimulated ovaries for the production of OHSS is not known. Saha et al., 14 however, reported that caution should be taken with pelvic examinations to minimize the risk of trauma to enlarged ovaries.
The reported incidence of OHSS is about 1% of egg donation cycles. 15 To date, no fatal case of OHSS in an anonymous egg donor has been reported in forensic literature. In the lay press, the death of a teenager was reported in Mumbai in 2010, two days after egg donation. 16
In India, with more and more childless couples seeking the help of fertility clinics, egg donation for money has been on the rise. Fatal OHSS in an egg donor can be avoided by the judicious use of gonadotropin and careful monitoring of stimulation agents. The other risk factors for developing the syndromes such as polycystic ovarian disorder, high serum oestradiol, etc. must be assessed and precautions should be taken. During the procedure, caution should also be taken not to injure the enlarged ovaries. The prospective oocyte donors should be adequately counselled about the risks related to egg donation. The guidelines issued by the Indian Council of Medical Research for artificial reproduction techniques, including egg donation and IVF, should be strictly followed. 17
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.