Outcome of treatment subsequent to the elective cryopreservation of all embryos from women at risk of the ovarian hyperstimulation syndrome.

From 1st June 1989 to 31st May 1991, 78 women with a serum oestradiol level greater than 3500 pg/ml on the day of the ovulatory trigger, following pituitary suppression with buserelin and ovarian stimulation with human menopausal gonadotrophins (HMG), had all their embryos electively cryopreserved at the pronucleate stage to minimize the risk of developing ovarian hyperstimulation syndrome (OHS). Treatment with buserelin was continued in the luteal phase. A median of 19 oocytes (range 7-43) was obtained and 12 embryos (range 1-37) frozen per cycle. Twenty-one (27%) women developed OHS (six severe). Women developing OHS had higher (P less than 0.05) serum oestradiol concentrations on the 7th day after oocyte retrieval, compared to those who did not. No differences were found for any of the following criteria: aetiology of infertility, age, total dose of HMG, number of oocytes, fertilization rate or freeze-thaw survival of embryos. Subsequently, 125 frozen-thawed embryo replacements have been undertaken, using buserelin and hormone replacement therapy (HRT) (n = 93) or natural cycles (n = 32). The overall freeze-thaw survival and implantation rates per embryo were 71.8 and 11.7%, respectively. The pregnancy rates in natural cycles (19%) and buserelin/HRT cycles (29%) were not significantly different.     

Continuation of GnRH agonist administration for 1 week,after hCG injection,prevents ovarian hyperstimulation syndrome following elective cryopreservation of all pronucleate embryos

BACKGROUND: An approach consisting of elective cryopreservation of all embryos has been proposed for patients at risk of ovarian hyperstimulation syndrome (OHSS). Although elective cryopreservation can prevent pregnancy-induced late OHSS, it cannot prevent early OHSS. Early OHSS is reported to have been complicated with thromboembolism. The study was carried out to assess the efficacy with which the continued administration of GnRH agonist for 1 week after 5000 IU of hCG injection could prevent early OHSS. METHODS: This study employed an open controlled clinical trial at three centres for treatment of infertility in Sapporo. A total of 138 patients at risk of OHSS during IVF-embryo transfer from January 1, 1998 to December 31, 1999, were assigned in turn either to a group with elective cryopreservation of all pronucleate embryos (n = 68) or to one with continuation of GnRH agonist administration for 1 week after hCG injection following elective cryopreservation (n = 70). Subsequently, they were transferred in hormone replacement cycles. The development of severe OHSS (ascites, haemoconcentration) was compared between the two groups. RESULTS: A total of 10% of patients developed severe OHSS necessitating hospitalization because of a marked increase in ascites in the upper abdomen and the haemoconcentration in the elective cryopreservation alone group. On the other hand, none developed severe OHSS in the GnRH agonist continuation group. CONCLUSIONS: In our study, continuation of GnRH agonist for 1 week after hCG injection prevented severe early OHSS following elective cryopreservation of all embryos. This treatment is safe and cost-beneficial, and should be performed promptly for patients at risk of OHSS.     

Pregnancy rates after transfer of embryos obtained from different stimulation protocols and frozen at either pronucleate or multicellular stages.

After in-vitro fertilization, 2161 supernumerary embryos were frozen with 1,2-propanediol and sucrose as cryoprotectants at either pronucleate or multicellular (2-6 blastomeres) stages. By the end of March 1990, 494 pronucleate stage embryos and 492 multicellular stage embryos had been thawed and 54 and 47% of them, respectively were considered suitable for transfer. Ongoing pregnancy and implantation rates were 17.9 and 10.7%, respectively for embryos frozen at the pronucleate stage and 5.5 and 4.7% for embryos frozen at the multicellular stage. Ovarian stimulation with human menopausal gonadotrophin (HMG) after pharmacological hypophysectomy with a gonadotrophin releasing hormone agonistic analogue (GnRHa) using a long protocol permitted us to freeze significantly more embryos per cycle (7.2 +/- 4.1) than stimulation with HMG and GnRHa in a short protocol (4.7 +/- 3.4) or stimulation with clomiphene citrate (CC) and HMG (2.7 +/- 1.9). Ongoing pregnancy rates after transfer during the stimulated cycles were similar for the three types of treatment (27.1, 27.3 and 32.1%, respectively). However, ongoing pregnancy rates after frozen-thawed embryo transfers were significantly higher when originating from GnRHa + HMG treatments (14.3 and 14.8%, respectively for long and short protocols) than when originating from CC + HMG treatment (5.6%). Embryo cryopreservation has permitted the ongoing pregnancy rate to increase from 28.4 to 36.9% (P less than 0.01) even though more than half of the embryos have not been thawed. We conclude that embryos obtained after stimulation with GnRHa + HMG and frozen at the pronucleate stage are more likely to result in a pregnancy.     

Induction of pre-ovulatory luteinizing hormone surge by gonadotrophin-releasing hormone agonist for women at risk for developing the ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a major risk inpatients undergoing ovulation induction protocols. Withholdinginjection of human chorionic gonadotrophin (HCG) may preventthe development of OHSS, but can also result in failure to ovulateand conceive. We have used a gonadotrophin-releasing hormoneagonist (GnRHa) as an alternative to HCG in women not undergoingin-vitro fertilization in an attempt to prevent OHSS. The studyincluded 12 cycles in 12 women scheduled for ovulation inductionwith human menopausal gonadotrophin (HMG) who were at risk ofdeveloping OHSS (oestradiol>3500 pg/ml, number of follicles>20).GnRHa was injected to induce the pre-ovulatory, luteinizinghormone surge which triggers follicular maturation. Progesteronewas administered for luteal support. Six pregnancies were achieved,and none of the 12 women developed OHSS. Since the pregnancyrate in this study was acceptable, we can recommend the useof GnRHa instead of HCG in any case at risk of developing OHSS     

Ovarian hyperstimulation syndrome and its effect on renal function in a renal transplant patient undergoing IVF treatment: case report

Ovarian hyperstimulation syndrome (OHSS) in a renal transplant patient undergoing assisted conception treatment is reported. A couple with infertility secondary to tubal blockage and pelvic endometriosis received IVF treatment. Ovarian enlargement secondary to OHSS resulted in obstruction in the transplanted kidney and deterioration of renal function. No other systemic manifestations of OHSS were evident. Conservative management was successful and a twin live birth was later achieved by replacement of two frozen-thawed embryos.     

Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups.

In a retrospective analysis of 637 cycles of ovarian stimulation and transvaginal follicular aspiration for various assisted reproductive technologies, severe ovarian hyperstimulation syndrome (SOH) occurred in six (0.94%) cycles. The patients at a high risk of developing SOH in cycles of assisted reproduction were those who had excessive serum oestradiol levels on the day of human chorionic gonadotrophin (HCG) administration (oestradiol greater than 6000 pg/ml; 38% SOH) and a high number of oocytes obtained (greater than 30 oocytes; 23% SOH). In those patients with both oestradiol greater than 6000 pg/ml on the day of HCG administration and greater than 30 eggs retrieved, the chance of developing SOH was 80%. The higher the serum oestradiol levels and the more eggs retrieved, the higher the pregnancy rates observed. High oestradiol level did not appear to have a detrimental effect on pregnancy rates and outcome. Furthermore, our results are not consistent with suggestions that the addition of gonadotrophin-releasing hormone agonist to ovarian stimulation protocols, follicular aspiration and/or luteal support with progesterone may reduce the incidence of ovarian hyperstimulation syndrome.     

CASE REPORT: Severe ovarian hyperstimulation syndrome, selective embryo reduction and heterotopic pregnancy

Ovarian hyperstimulation syndrome is common (21.4%) in patientswith polycystic ovarian disease, treated by gonadotrophins.It is much frequent (50%) in conceptual cycles. We report acase associated with a quadruplet pregnancy that underwent selectiveembryo reduction at 8 weeks' gestation to a twin pregnancy andwas subsequently found to have an unruptured ectopic pregnancyat 11 weeks' gestation. After laparotomy and partial salpingectomya successful twin pregnancy ensued.     

Dopamine treatment for severe ovarian hyperstimulation syndrome.

Seven oliguric patients with severe ovarian hyperstimulation syndrome following gonadotrophin treatment for in-vitro fertilization or gamete intra-Fallopian transfer, were treated with low doses of dopamine by peripheral infusion. Five patients were pregnant. The rationale for this therapeutic approach was to increase renal blood flow and glomerular filtration. In addition to dopamine, fluid intake was restricted to 500 ml/day and a protein and salt-rich diet was provided in order to increase serum osmolarity. Within 24-48 h from the beginning of the dopamine treatment, the syndrome started to regress in all cases. No adverse maternal or fetal effects occurred. We conclude that dopamine therapy may constitute a major advance towards the management of severe ovarian hyperstimulation syndrome.     

Metabolic characteristics of women who developed ovarian hyperstimulation syndrome

BACKGROUND: The aim of this study was to investigate whether a higher incidence of hyperinsulinism is found in women who have suffered from ovarian hyperstimulation syndrome (OHSS) as compared with other IVF patients. Additionally, we also assessed whether any abnormalities in the haemostatic system were more frequent in women with a past history of OHSS. METHODS: A pilot study was carried out involving OHSS patients and matched IVF patients. Homeostasis model assessment (HOMA) of insulin sensitivity was calculated. The main outcome measures were: insulin sensitivity, coagulation anomalies, factor V Leiden mutations, methylene tetrahydrofolate reductase (MTHFR) polymorphism and prothrombin gene mutation, protein C and protein S deficiency. RESULTS: No increased incidence in hyperinsulism nor in abnormalities of the haemostatic system were observed. CONCLUSIONS: This pilot study does not provide evidence for an increased prevalence of hyperinsulinism among women who have developed OHSS in the past.     

In-vitro fertilization and the ovarian hyperstimulation syndrome.

Eight patients who developed severe ovarian hyperstimulation syndrome (OHSS) were identified among 1302 patients undergoing in-vitro fertilization (IVF) over a 1 year period (prevalence of 0.6%); 63% had ultrasonically diagnosed polycystic ovaries (PCO) and 75% were undergoing their first attempt at IVF. Pretreatment with a superactive luteinizing hormone-releasing hormone (LHRH) analogue significantly increased the prevalence of severe OHSS (1.1% versus 0.2%, P less than 0.05) compared with ovarian stimulation with clomiphene citrate and human menopausal gonadotrophin (HMG). The mean serum oestradiol concentration on the day of human chorionic gonadotrophin (HCG) administration was 8200 +/- 2300 pmol/l. A mean of 19.6 +/- 6.8 follicles had been aspirated and 13.1 +/- 7.7 oocytes recovered at transvaginal ultrasound-directed oocyte recovery. All patients had an embryo transfer and luteal support in the form of HCG. The clinical pregnancy rate was 88%, multiple pregnancy rate 71% and implantation rate 63.5 +/- 41.3%. In a group of seven patients who were hospitalized for moderate OHSS during the same period, peak oestradiol levels were significantly lower than in those with severe OHSS (P less than 0.05). Of the group with moderate OHSS, 57% had PCO, the clinical pregnancy rate was 100% and multiple pregnancy rate 43%. Patients with ultrasound-diagnosed PCO have an increased risk of developing OHSS and the dose of HMG administered to them should be minimized. In patients at risk of developing OHSS, progesterone instead of HCG should be used for luteal support. Transfer of a maximum of two embryos or freezing all embryos for transfer in a subsequent cycle may reduce the likelihood of multiple pregnancy.     

The effects of 'coasting' on follicular fluid concentrations of vascular endothelial growth factor in women at risk of developing ovarian hyperstimulation syndrome

BACKGROUND: The aim of this study was to assess the effect of withholding gonadotrophins (coasting) during controlled ovarian stimulation (COS) on individual follicle concentrations of follicular fluid vascular endothelial growth factor (VEGF) in women at high risk of developing ovarian hyperstimulation syndrome (OHSS). METHODS: Twenty-two women who had been coasted and 26 optimally responding women (control group) undergoing COS for IVF were studied. At the time of oocyte retrieval, the follicular fluid from four to six individual follicles of different sizes was collected for VEGF analysis. RESULTS: A total of 118 follicles was analysed in the coasted group and 137 in the control group. A negative correlation was observed between the follicle size and VEGF concentration (r = -0.18, P = 0.03) in the control group, which was not seen in the coasted group. Similarly, the correlation between oestradiol (E(2)) and VEGF (r = 0.4, P < 0.0001) observed in the control group was not apparent in the coasted group. Significantly lower concentrations of VEGF were seen in the follicular fluid of the coasted patients. CONCLUSIONS: It is clear that there are differences in follicular fluid VEGF concentrations between the two groups. It is possible that coasting alters the capacity of the granulosa cells to produce VEGF and/or their response to hCG and in this way acts to reduce the severity and incidence of severe OHSS.     

Severe ovarian hyperstimulation syndrome following salvage of empty follicle syndrome.

We report a case of severe ovarian hyperstimulation syndrome (OHSS) following a rescue of empty follicle syndrome (EFS). This suggests that the risk of developing OHSS remains unaltered even in the presence of EFS. The case supports the possibility of obtaining oocytes that fertilize and cleave normally after a second dose of human chorionic gonadotrophin (HCG) and a repeat oocyte retrieval. It supports the suggestion that the follicles are not necessarily empty in EFS. It demonstrates further that OHSS cannot be prevented by aspiration of follicular fluid and patients with large numbers of follicles and EFS must be warned of this potential complication.     

CLINICAL REPORT: The use of intravenous albumin in patients at high risk for severe ovarian hyperstimulation syndrome

Previous experiences in subjects with other forms of third spacefluid accumulation have shown that albumin is efficacious inpreventing and correcting haemodynamic instability. Using asimilar approach in an effort to increase the serum oncoticpressure and to reverse the leakage of fluids from the intravascularspace, high risk subjects for severe ovarian hyperstimulationsyndrome (SOHS) were treated with albumin. In a recent largestudy two high risk factors were identified, i.e. the numberof oocytes and levels of serum oestradiol. Thirty-six womenundergoing assisted reproductive techniques who presented boththese factors, received intravenous albumin at a dose of 5%in Ringers lactate in doses of 500 ml during oocyte retrievaland 500 ml immediately thereafter in the recovery room. Dailymeasurements of urine output, serum and urine electrolytes,weight, abdominal girth, and haematocrit prior to and afteroocyte retrieval revealed normal serum and urine electrolytelevels, and no signs of haemoconcentration. No patient in thisstudy developed SOHS, and of course none had to be hospitalized.Vaginal ultrasound performed in the majority of the subjectsrevealed 100 ml of peritoneal fluid 48–72 h after oocyteretrieval. The only complication from the use of intravenousalbumin was the appearance of a ‘flu-like condition’(low grade temperature, nausea and muscle pains) developed by12 women between days 3 and 5 after oocyte collection. Intravenousalbumin had thus prevented the development of severe ovarianhyperstimulation syndrome in an assisted reproduction programme.Its use could allow the maintenance of treatment in patientsthat otherwise would have been cancelled due to their high riskof developing this condition. The proposed mechanisms of actioninclude increase in plasma oncotic pressure, and in the sexsteroid binding capacity of the plasma. Both factors could preventleakage of fluid from the intravascular space into the peritonealcavity.     

Subclavian vein thrombosis: a late complication of ovarian hyperstimulation syndrome.

Two cases of subclavian vein thrombosis following ovarian stimulation for in-vitro fertilization and subsequent ovarian hyperstimulation syndrome (OHSS) are described. Both occurred several weeks after complete resolution of the OHSS. The site of the lesions and their timing suggest that there is a generalized disturbance of coagulation associated with OHSS, which persists beyond the duration of the clinical syndrome.     

Liver abnormality in ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a potentially fatal condition associated with the therapeutic induction of ovulation in infertility. Liver function abnormality has been previously reported in four patients, one of whom had ultrastructural abnormalities on liver biopsy. This paper describes a patient presenting with severe OHSS 16 days after ovulation had been induced. Liver function abnormality was apparent 11 days later, with a sustained rise in alkaline phosphatase and aspartate aminotransferase (AST) which lasted up to 2 months. A liver biopsy performed during the second month of her protracted hospital admission showed marked zonal fatty change (acinar zone 1) and associated inflammation, with mitochondrial crystalline inclusions and rough endoplasmic reticulum dilatation on electron microscopy. This report discusses the clinical features and possible aetiological factors.     

Dual renin-angiotensin blockade therapy in patients at high risk of early ovarian hyperstimulation syndrome receiving IVF and elective embryo cryopreservation: a case series

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an important and dangerous aspect of assisted reproduction techniques. Although elective cryopreservation of all embryos can prevent pregnancy-induced late OHSS, it cannot prevent early OHSS, which is induced by hCG administration. METHODS: We undertook this trial to assess the efficacy with which the combined oral administration of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) could prevent early OHSS in IVF patients at very high risk for this syndrome. Four women, who had serum estradiol concentration > or =8000 pg/ml on the day of hCG injection, were treated with the combination of the ACEI alacepril and the ARB candesartan cilexetil for 8 days starting the day after oocyte retrieval. Embryos were cryopreserved and embryo transfer was postponed until later cycles. RESULTS: Despite the extremely enlarged ovaries, no ascites was accumulated in any of the cases. Haematocrit (34.1 +/- 1.0) and serum albumin concentration (4.1 +/- 0.2 g/dl) were normal throughout the treatment period. These patients showed elevated plasma renin and angiotensin II concentration before the treatment. CONCLUSIONS: The dual renin-angiotensin blockade therapy used here would be worth exploring further in a study with more patients and a prospective, randomized design.     

Elective cryopreservation of all pronuclear oocytes after GnRH agonist triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, observational proof-of-concept study

BACKGROUND: A bolus dose of GnRH agonist can substitute for hCG as a trigger for the resumption of meiosis in ovarian stimulation with GnRH antagonists, which has been suggested to reduce the risk of ovarian hyperstimulation syndrome (OHSS). As the efficacy of this measure in fresh embryo transfer (ET) cycles is unclear, we evaluated a new clinical concept of GnRH-agonist triggering. METHODS: In this prospective, observational proof-of-concept study, 20 patients considered at increased risk of developing OHSS (> or = 20 follicles > or = 10 mm or estradiol > or = 4000 pg/ml, or a history of cycle cancellation due to OHSS risk or the development of severe OHSS in a previous cycle) after ovarian stimulation and concomitant GnRH-antagonist administration had final oocyte maturation triggered with 0.2 mg triptorelin s.c. All two pronucleate (2 PN) oocytes were cryopreserved by vitrification, and frozen-thawed ETs (FT-ETs) were performed in an artificial cycle. Main outcome measures were the cumulative ongoing pregnancy rate per patient and the ongoing pregnancy rate per first ET. Secondary outcomes included the incidence of moderate-to-severe OHSS. RESULTS: Of the 20 patients triggered with GnRH agonist, 19 patients underwent 24 FT-ETs in the observational period. The cumulative ongoing pregnancy rate was 36.8% (95% confidence interval: 19.1-59.0%). The ongoing pregnancy rate per first FT-ET was 31.6% (15.4-54.0%). No cases of moderate or severe OHSS were observed. CONCLUSIONS: The present study is the proof of the concept that GnRH-agonist triggering of final oocyte maturation in combination with elective cryopreservation of 2 PN oocytes offers OHSS risk patients a good chance of pregnancy achievement, while reducing the risk of moderate and severe OHSS.     

Embryo freezing for preventing ovarian hyperstimulation syndrome: a Cochrane review

This paper is based on a Cochrane review published in The Cochrane Library, issue 3, 2002 (see www.CochraneLibrary.net for information) with permission from The Cochrane Collaboration and Update Software. Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the review. BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic condition resulting from an excessive ovarian response to superovulation medication. The objective of this review was to evaluate the effectiveness of cryopreservation (embryo freezing) when compared with human i.v. albumin infusion and with fresh embryo transfer for the prevention of OHSS. METHODS: This was based on a Cochrane Review. Randomized controlled trials in which either human i.v. albumin or cryopreservation of all embryos was used as a therapeutic approach to OHSS were included. The participants were women down-regulated by GnRH agonist, undergoing superovulation in IVF/ICSI cycles. The interventions compared were cryopreservation versus i.v. human albumin administration and elective cryopreservation of all embryos versus fresh embryo transfer. The primary outcomes were: incidence of moderate and severe OHSS versus nil/mild OHSS, and clinical pregnancies/woman. Statistical analysis was performed in accordance with the Cochrane Menstrual Disorders and Subfertility Group guidelines. RESULTS: Seventeen studies were identified, two of which met our inclusion criteria. One study was included where cryopreservation was compared with i.v. human albumin administration and another where elective cryopreservation of all embryos was compared with fresh embryo transfer. In both interventions no difference was found in all the outcomes examined between the two groups. CONCLUSIONS: This review has shown that there is insufficient evidence to support routine cryopreservation and insufficient evidence for the relative merits of i.v. albumin versus cryopreservation.     

Decreased incidence of severe ovarian hyperstimulation syndrome in high risk in-vitro fertilization patients receiving intravenous albumin: a prospective study

The administration of human serum albumin has been reportedto prevent severe ovarian hyperstimulation syndrome (OHSS) inpatients considered at risk of developing OHSS while undergoingovarian stimulation protocols for in-vitro fertilization (IVF).This prospective, randomized study investigated the effectivenessof a single dose of human serum albumin (20 g) administeredi.v. immediately after oocyte retrieval. Women enrolled in theIVF programme were treated with the long gonadotrophin-releasinghormone agonist, triptorelin, and an individually-adjusted humanmenopausal gonadotrophin protocol. The criteria for inclusionin the study were young age, nonobesity, oestradiol concentration>9200 pmol/l on the day of human chorionic gonadotrophinadministration and >20 follicles >14 mm diameter as observedby transvaginal sonography. The treatment group (n = 22) receivedalbumin while the control group (n = 18) did not. Patients werefollowed-up using ultrasound every 3 days. There was a significantlyhigher number of severe OHSS cases in the control group (n =4) than in the treatment group (n = 0) (P = 0.035). Where thedata base was restricted to patients with an oestradiol concentration>15 000 pmol/l, the difference between control and treatmentgroups was highly significant (P = 0.008). These findings supportthe use of i.v. albumin in preventing severe OHSS during IVFtreatment.     

Recurrent cholestasis following ovarian hyperstimulation syndrome: case report.

This is a case report illustrating a patient who developed recurrent cholestasis during a twin pregnancy following in-vitro fertilization (IVF) treatment. On the first occasion cholestasis developed unusually in the first trimester, and on the second occasion, it presented in the way that obstetric cholestasis (OC) is commonly seen in the third trimester.