Late-onset Ovarian Hyperstimulation Syndrome Research Articles

Ovarian hyperstimulation syndrome and pregnancy luteoma mimicking malignant ascites: a rare case report

BackgroundDuring pregnancy, both ovarian hyperstimulation syndrome (OHSS) and pregnancy luteoma could manifest as massive ascites, enlarged ovaries, or elevated serum levels of cancer antigen 125 (CA125), and atypical cells may be found in the ascitic fluid of OHSS patients. Whether this should be treated aggressively as peritoneal carcinomatosis is controversial.Case presentationA 35-year-old G2P1A1 woman with secondary infertility had a successful pregnancy after one cycle of assisted reproductive technology. The patient complained of lower abdominal distension, oliguria, and poor appetite 19 days after embryo transplantation. She was diagnosed with late-onset OHSS. Although the size of the ovaries decreased bilaterally to the normal range at 12 weeks of gestation after prompt medical care, the ascites increased again after an initial decreasing trend. Elevated serum levels of CA125 (191.1 IU/mL), and suspected adenocarcinoma cells were observed in the ascitic fluid. Although further magnetic resonance imaging examination or diagnostic laparoscopy was recommended, the patient was provided with supportive treatment and closely monitored upon her request. Surprisingly, her ascites diminished, and serum level of CA125 started to decline at 19 weeks of gestation. During cesarean section, pathological examination of the solid mass in the right ovary revealed pregnancy luteoma, which was presumably the other cause of the intractable ascites.ConclusionsCaution should be exercised in cases of suspicious malignant ascites during pregnancy. This may due to OHSS or pregnancy luteoma, in which abnormalities usually regress spontaneously.

Clinical characteristics of severe late-onset ovarian hyperstimulation syndrome and its impact on the live birth outcome of IVF-ET

Objective: To investigate the correlation between different clinical features and live birth in patients with severe late-onset ovarian hyperstimulation syndrome (OHSS) after in vitro fertilization-embryo transfer (IVF-ET). Methods: The clinical information of 330 patients who were pregnant after IVF-ET and referred to medical treatments diagnosed as late-onset severe OHSS in Peking University Third Hospital from January 2016 to December 2020 was retrospectively analyzed. The patients were divided into live birth achieved group (n=287) and non-live birth achieved group (n=43) according to pregnancy outcomes, and live birth achieved group was further divided into two subgroups, full-term birth group (n=222) and early-term birth group (n=65) according to gestational week at delivery for better analysis. Single factor and multi-factor analysis were utilized to clarify the influencing factors of both live birth and early-term birth. Results: Among all the patients who received IVF-ET, the incidence of severe OHSS was 0.67% (673/100 758). Among 330 severe late-onset OHSS patients, 42.4% (140/330) had pleural effusion, the incidence of abnormal liver function was 69.4% (229/330), and the live birth rate was 87.0% (287/330). Among the 287 patients who achieved live birth, 55.4% (159/287) had no pleural effusion, 18.5% (53/287) had a small amount of pleural effusion, and 26.1% (75/287) had medium or massive pleural effusion; in the non-live birth achieved group, there were more patients without pleural effusion and less patients with a small amount of pleural effusion; the difference was statistically significant (χ2=6.213, P=0.045). The rate of selective fetal reduction in live birth achieved group was 16.0% (46/287), which was significantly higher than that in the non-live birth achieved group, which was 2.3% (1/43; χ2=5.749, P=0.017). Multivariate logistic regression analysis revealed that moderately abnormal liver function was an independent risk factor for live birth (OR=3.15, 95%CI: 1.60-6.19), while selective fetal reduction was an independent protective factor for live birth (OR=0.13, 95%CI: 0.02-0.96). Additionally, subgroup analysis suggested that twin birth was an independent risk factor for preterm birth (OR=8.54, 95%CI: 4.31-16.91). Conclusions: Moderate hepatic dysfunction may be associated with adverse pregnancy outcomes in patients with severe late-onset OHSS. Selective fetal reduction and singleton pregnancy are recommended to ameliorate live birth rate, full-term delivery rate, also the maternal and neonatal prognosis for patients with multiple pregnancies.

Predictive performance of peritoneal fluid in the pouch of Douglas measured five days after oocyte pick-up in predicting severe late-onset OHSS: A secondary analysis of a randomized trial

ObjectivesTo investigate if the amount of peritoneal fluid (PF) in the Pouch of Douglas at oocyte pick-up (OPU) or OPU + 5 days predict severe late-onset ovarian hyperstimulation syndrome (OHSS) in women undergoing ovarian stimulation for assisted reproductive technology (ART). Study designA secondary analysis of a dual-centre RCT on 1050 women referred for their first ART treatment in two public fertility clinics in Denmark and randomized 1:1 to GnRH-antagonist or GnRH-agonist protocol. All women from the two arms who were examined on day of OPU and OPU + 5 days were included in this study (n = 940). The ability of PF in the pouch of Douglas to predict severe late-onset OHSS was assessed by multivariate logistic regression analyses and receiver operator characteristics (ROC) curve analyses and compared with other known predictors of OHSS. The final models were cross-validated by the leave-one-out method to assess the models’ generalizability. ResultsA total of 28 (3%) women developed severe late-onset OHSS. PF in the pouch of Douglas measured on OPU + 5 days predicted severe late-onset OHSS. The optimal cut-off value was 17.5 mm at OPU + 5 days with a 61% sensitivity and 71% specificity (Area under the curve = 0.70 95% CI 0.61–0.80). PF on the day of OPU was not predictive of late on-set OHSS as the adjusted multivariate logistic regression analyses showed insignificant results. ConclusionAlthough PF in the pouch of Douglas could predict late-onset severe OHSS, the low sensitivity underlines that it is not useful as a sole marker to decide whether to perform blastocyst transfer or to use a freeze-all strategy.

Pregnancy outcomes in patients with late-onset severe OHSS following different methods of ascetic fluid drainage and a comparison with non-OHSS IVF patients.

In this study, we aimed to identify whether there are any differences in pregnancy outcomes in patients with severe ovarian hyperstimulation syndrome (OHSS) following the drainage of ascites by central venous catheter or paracentesis. We also aimed to identify differences in pregnancy outcomes between severe OHSS patients and non-OHSS IVF patients. This was a retrospective cohort analysis carried out in a university-affiliated reproductive center between 2012 and 2019 featuring 359 women with severe OHSS following ascites draining and 345 non-OHSS women (matched by age and the number of oocytes retrieved). We investigated the rates of clinical pregnancy, multiple pregnancies, miscarriage, live birth, and preterm delivery, between the two groups. Within the OHSS group (central venous catheter group vs paracentesis group), we also analyzed the odds ratios and 95% confidence intervals of clinical pregnancy. The rate of biochemical pregnancy loss in non-OHSS patients was significantly higher than that of severe OHSS patients (11.1% vs. 0.6%; P < 0.05). Live birth rate and the rate of multiple pregnancy (twin pregnancy) were much higher in the severe OHSS group than in the non-OHSS group (88.9% vs. 73.5%; 57.6% vs. 28.1%, respectively). There was no significant difference between the rate of singleton and twin preterm delivery, and neonatal birth weight between the OHSS and the non-OHSS groups. Binary logistic regression analysis revealed that multiple pregnancy and the long superovulation protocol had high odds ratios (odds ratio (OR) = 2.53), thus suggesting that these are significant risk factors for severe OHSS. When considering the patients with severe OHSS and the manner in which they underwent ascites drainage, we found that the volume of ascites in the central venous catheter group was significantly higher than that in the abdominal paracentesis group (P < 0.05). There were no significant difference between the two groups with regards to the number of live births and the birth weight of singletons and twins (P>0.05), although the premature birth rate of singletons in abdominal paracentesis group was 9.3% (10/107), compared with 3.75% in the central venous catheter group (P < 0.05). Analysis indicated that for women undergoing in vitro fertilization embryo transfer (IVF-ET), a higher number of antral follicle count, COS long protocol, and multiple pregnancy may be risk factors for late-onset OHSS. Both paracentesis and central venous catheters are effective modalities for the management of ascites in patients with severe OHSS. Catheters represent a safe and effective way to treat patients who need to undergo repeated paracentesis.

Investigation on the risk factors for late-onset OHSS: a retrospective case-control study.

The pathophysiology of ovarian hyperstimulation syndrome (OHSS) is largely unknown. High ovarian response is acknowledged as a risk factor. However, in our clinical practice, the incidence of OHSS is not necessarily linked to the degree of such response among women. Here, we aimed to screen for potential risk factors other than those associated with ovarian response. A total of 21,222 ovarian stimulation cycles were collected among women undergoing assisted reproductive technology, among which 84 patients with late-onset OHSS were identified as cases; corresponding matched control cases were obtained from the remaining 21,138 cycles. A multivariable logistic regression with the best subset method was performed to screen for significant risk factors. First, control samples were obtained with a case-to-control ratio of 1:4. The matching criteria were mainly ovarian response-related factors including age, body mass index, number of oocytes retrieved, standard or mild ovarian stimulation, and specific ovarian stimulation protocols. After matching the five ovarian response-related factors, 81 cases and 318 controls were obtained. The best model was selected after analysis as above. Basal serum low-density lipoprotein cholesterol (LDL-C), basal total cholesterol (TC), and estradiol (E2) concentrations on the day of triggering ovulation were included in the model, with odds ratios of 0.3410 (95% confidence interval, CI, 0.1618-0.7186), 2.2008 (95% CI 1.1192-4.3275) and 1.0000 (95% CI 1.0000-1.0001), respectively. Basal LDL-C was a risk factor negatively associated with late-onset OHSS, while basal TC and triggeringE2 levels during ovarian stimulation were positive risk factors.

Maternal complications of fetal triploidy: a case report.

A 32-year-old woman underwent a medical termination in the second trimester of a spontaneously conceived triploid pregnancy after developing early-onset preeclampsia with subsequent haemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Placental histology was normal (non-molar) and unusually, she developed ovarian hyperstimulation syndrome (OHSS) 4 weeks later. She was managed conservatively following multidisciplinary team input to exclude malignant pathology. The rarity of late-onset spontaneous OHSS could have resulted in inappropriate surgical management. In the absence of supportive treatment there is also a risk of the condition progressing to a critical stage. Follow-up ultrasonography after termination of pregnancy should be considered for women with evidence of ovarian hyperstimulation, particularly if other risk factors for OHSS are present. Delayed-onset OHSS should be considered in women presenting with bilateral cystic ovarian enlargement after triploid pregnancy.

Late-onset ovarian hyperstimulation syndrome developing during ovarian stimulation in an ectopic pregnancy: a case report

BackgroundOvarian hyperstimulation syndrome is normally induced by ovarian stimulation drugs. Severe cases of ovarian hyperstimulation syndrome involve complications such as renal failure and thrombosis. Evidence has recently been developed for a method to prevent ovarian hyperstimulation syndrome. Most cases of ovarian hyperstimulation syndrome are of an early-onset type, which occurs shortly after injection of human chorionic gonadotropin. However, late-onset ovarian hyperstimulation syndrome, which occurs in a pregnancy cycle, also requires caution. We report our experience in treating a woman who was transported to our hospital with a severe case of ovarian hyperstimulation syndrome occurring during ovarian stimulation and who was determined to have an ectopic pregnancy.Case presentationAssisted reproductive technology was planned for a 29-year-old nulligravida Japanese woman diagnosed with bilateral fallopian tube obstruction and right-sided hydrosalpinx. On day 1 of controlled ovarian stimulation, the result of her human chorionic gonadotropin urine test was negative, and her serum levels of luteinizing hormone, estradiol, and progesterone were normal. On day 11 of controlled ovarian stimulation, the levels of estradiol and progesterone had risen to 9679 pg/ml and 16 ng/ml, respectively, prompting suspension of controlled ovarian stimulation. Eleven days after controlled ovarian stimulation was suspended, the patient demonstrated ascites that did not improve despite administration of cabergoline, and she was transported to our hospital 2 days after. Late-onset ovarian hyperstimulation syndrome suggested that she was pregnant, and her serum human chorionic gonadotropin level was 27,778 IU/ml. She underwent laparoscopic bilateral salpingectomy and was diagnosed with right tubal pregnancy.ConclusionIn an ectopic pregnancy, human chorionic gonadotropin sometimes increases later than in an intrauterine pregnancy. In our patient’s case, endogenous human chorionic gonadotropin following the start of controlled ovarian stimulation may have caused late-onset ovarian hyperstimulation syndrome. The key to early detection of similar cases may be to suspect pregnancy in the event of unexpectedly high progesterone levels during ovarian stimulation.

Isolated Unilateral Pleural Effusion Without Ascites in Late Onset Ovarian Hyperstimulation Syndrome: A Case Report and Review of Literature

Isolated pleural effusion is a rare presentation of severe OHSS. Two to four percent of women of reproductive age have subclinical hypothyroidism which is an uncommon association of late onset iatrogenic OHSS. This report describes an unusual patient with isolated unilateral pleural effusion and subclinical hypothyroidism as the only manifestation of late onset OHSS in a singleton pregnancy following in vitro fertilization (IVF). We have summarized current literature related to isolated pleural effusion in late OHSS and evaluated its pathophysiology and treatment options. Albumin infusion may be considered as a plasma expander whenever there is a planned third space drainage. Thyroid profile test in asymptomatic patients planning IVF will help to identify subclinical hypothyroidism. OHSS is a self-limiting condition and a timely diagnosis with aggressive management can be lifesaving.

Gonadotropin-releasing hormone agonist triggering with concomitant administration of low doses of human chorionic gonadotropin or a freeze-all strategy in high responders.

Objectives:To compare the live birth rates and moderate/severe ovarian hyperstimulation syndrome (OHSS) rates of 2 different approaches using gonadotropin-releasing hormone (GnRH) agonist triggering in high responder women.Methods:A retrospective cohort study was performed to evaluate intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) outcomes in high responder women who underwent ovulation induction with a GnRH antagonist protocol between April 2011 and March 2015. In group 1 (n=74), GnRH agonist was used for ovulation triggering with the concomitant use of 1500 IU of urinary human chorionic gonadotropin (hCG) immediately after oocyte retrieval followed by fresh ET and standard luteal support. In group 2 (n=48), GnRH agonist was used for triggering after freezing all embryos and subsequent frozen/thawed embryo transfer (FET); this approach is considered the “freeze-all” approach.Results:Baseline characteristics were similar between the groups. The clinical pregnancy rates for group 1 was 45.9% and group 2 was 43.8% (p=0.812, chi-squared test) and live birth rates for group 1 was 40.5% and for group 2 41.7% (p=0.902, chi-squared test) were comparable between groups. In group 1, late-onset OHSS was observed (one severe case and one moderate case) in 2 patients (2.7%). In group 2, none of the patients experienced moderate/severe OHSS.Conclusion:The live birth rate with GnRH agonist triggering and concomitant use of 1500 IU of hCG immediately after oocyte retrieval was similar to that obtained with the freeze-all approach and FET in a subsequent cycle. The administration of a low dose of hCG in GnRH agonist trigger cycles caused moderate/severe OHSS in 2.7% of the patients.

Predictors of Paracentesis in Women with Severe Ovarian Hyperstimulation Syndrome: A Retrospective Cohort Study

Background: To identify predictors of paracentesis in women with severe ovarian hyperstimulation syndrome (OHSS). Methods: In a retrospective cohort study, we assessed patient characteristics and outcome measures of women with severe OHSS Golan grade II/III from 1996 to 2010 using univariate and multivariate analyses with the number of paracenteses as the main outcome. Results: Three hundred ninety four women with OHSS Golan grade II (n = 40) and grade III (n = 354) were included in the study. Paracentesis was performed in 108/394 (27%) of these women. One paracentesis was performed in 63 (16%), 2 paracenteses in 26 (6%), and ≥3 paracenteses 19 (5%) women, respectively. No thrombotic or cerebrovascular morbidity occurred. The mortality of the cohort was 0/394 (0%). In a univariate analysis, late onset OHSS (p = 0.02), pregnancy (p < 0.001), human chorionic gonadotropin use (p = 0.02), ovarian diameter (p = 0.006), and elevated serum levels of alanine aminotransferase (p < 0.001), hematocrit (p < 0.001), leucocytes (p < 0.001), thrombocytes (p < 0.001), and uric acid (p < 0.001) were associated with paracentesis. In a multivariate logistic regression analysis, only alanine aminotransferase (OR 1.006; 95% CI 1.001-1.01) and hematocrit (OR 1.16; 95% CI 1.05-1.27) were independently associated with paracentesis. Conclusion: Alanine aminotransferase and hematocrit at initial presentation are independent predictors of paracentesis.

Prolonged high-dose cabergoline administration in a case of late-onset ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is a serious complication of controlled ovarian hyperstimulation which could be life-threatening. The present case is a patient at low risk for developing OHSS. She underwent a flexible antagonist protocol, followed by embryo transfer on day 3. She developed symptoms of abdominal pain, distension, and discomfort on the 7 th day after embryo transfer. She was diagnosed as moderate OHSS. Cabergoline 0.5 mg daily was started in addition to the standard treatment protocol for management of OHSS. On day 14 after embryo transfer, symptoms worsened following a positive pregnancy test. After this, cabergoline was stepped up to 1 mg/day. She was discharged, following complete resolution of her symptoms at 7 weeks of gestation. Cabergoline was withdrawn at discharge. Thus, in addition to the standard management protocol, prolonged high-dose cabergoline was required to help patient tide over OHSS and recover from it.

Spontaneous Late Onset OHSS in Singleton Pregnancy in 2nd Trimester: A Rare Case.

Ovarian hyperstimulation syndrome (OHSS) is a potentially life‐threatening complication of pharmacological ovarian stimulation. It is seen in approximately 2 % of all IVF cycles. The prevalence of moderate to severe OHSS ranges from 1 to 10 % in major IVF programs. Severe forms complicate 1 % of IVF cycles and are characterized by massive ovarian enlargement together with a fluid shift into extravascular compartments responsible for the development of ascites, sometimes pleural and/or pericardial effusion, hypovolemia, oliguria, and hydroelectrolytic disorders. In the most marked cases, thromboembolic phenomena may occur as a result of hemoconcentration and coagulation disturbances (Hollemaert et al. [1]). Spontaneous ovarian hyperstimulation (spontaneous OHSS) is extremely rare in naturally conceived pregnancies. OHSS in the absence of exogenous gonadotropins is very rare, and only a few cases have been reported in the literature. Spontaneous OHSS likely to occur at 8–14 weeks of gestation, while iatrogenic OHSS usually occurs earlier at 3–8 weeks of gestation [2]. Human chorionic gonadotropin (hCG) is thought to play a crucial role in the development of the syndrome. Severe forms are indeed restricted to cycles with exogenous hCG to induce ovulation or as luteal phase support or with endogenous pregnancy‐derived hCG (Delbaere et al. [3]). Here, we report a rare case of spontaneous 2nd trimester OHSS in 22-year-old primigravida.

GnRH agonist triggers and their use in assisted reproductive technology: the past, the present and the future.

Gonadotropin releasing hormone agonist triggers are very effective in eliminating early-onset ovarian hyperstimulation syndrome (OHSS). However, in most studies they result in inferior pregnancy rates compared to hCG triggers in fresh autologous transfers. This is not due to an effect on embryo quality but rather due to inadequate corpus luteum formation and a defective luteal phase causing poor implantation. Intensive and adjusted steroid support or low-dose hCG may correct this. Late-onset OHSS is eliminated by using a freeze-all strategy. Pregnancy rates after transfer of thawed vitrified embryos are consistently high. A strategy combining a gonadotropin releasing hormone agonist trigger with vitrification of all embryos has been proposed as a means of achieving a truly OHSS-free clinic.

Déclenchement de l’ovulation par agonistes du GnRH en FIV et soutien de la phase lutéale chez les femmes à risque d’hyperstimulation ovarienne

ObjectiveTo evaluate the efficacy and safety of ovulation triggering by agonists in antagonists IVF cycles with fresh embryo transfer in modulating low HCG dose for luteal phase support in patients at risk of ovarian hyperstimulation syndrome (OHSS). Patients and methodsIn an observational study from September 2011 to March 2013, we triggered with agonist 107 cycles with OHSS risk, we initially triggered 39 cycles with 2 doses of Triptorelin 0.1mg. Injection of 1500IU HCG was performed one hour after the pick up and a second injection of 1500IU was made 5 days later (group 1) combined with 400mg of natural progesterone vaginally. In the following 68 cycles we removed the second HCG injection and increased to 600mg vaginal progesterone associated with E2 4mg orally (group 2). ResultsGroup 1: the ongoing pregnancy rate and birth rate in fresh cycle is respectively 37.1% and 34.3% and the cumulative ongoing pregnancy rate and birth rate per patient is 43.6% and 41%. We recorded three late onset OHSS in pregnant women. Group 2: ongoing pregnancy rate in fresh cycle is 39.6%, the current cumulative ongoing pregnancy rate per patient was 45.6%. We observed a case of early onset OHSS. Discussion and conclusionTriggering with agonist and administering an injection of 1500 IU of HCG the day of the pick up appears to be effective in women at risk of OHSS. The exclusion of all OHSS is still not reached. The search for the best protocol and its indications should continue.

GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients

Does a GnRH agonist (GnRHa) trigger followed by a bolus of 1.500 IU hCG in a group of patients at risk of ovarian hyperstimulation syndrome (OHSS) reduce the OHSS incidence compared with hCG trigger? A GnRHa trigger followed by early luteal hCG support with one bolus of 1.500 IU hCG appears to reduce OHSS in patients at risk of OHSS; however, in a low-risk group a second bolus of 1.500 IU hCG induced two cases of late onset OHSS. A GnRHa trigger is an alternative to hCG in GnRH antagonist co-treated cycles. Two RCTs were performed in four Danish IVF units. A total of 446 patients were assessed for eligibility and 390 patients were enrolled in the study from January 2009 until December 2011. The primary outcome of the study was OHSS incidence in the group at risk of OHSS. Patients received a fixed dose of recombinant human FSH for the first 4 days. On the day of triggering, patients were assessed for their risk of OHSS based on the total number of follicles ≥11 mm diameter, and were classified as being at risk of OHSS when the total number of follicles ≥11 mm was between 15 and 25 and at low risk of OHSS when the total number of follicles ≥11 mm was ≤14. Two separate randomization lists were used for each of the OHSS risk groups. Women at risk of OHSS were allocated (RCT 1) to either: Group A (n = 60), ovulation triggering with a bolus of 0.5 mg buserelin (GnRHa) s.c. followed by a single bolus of 1.500 IU hCG s.c. after the oocyte retrieval-or: Group B (n = 58): 5.000 IU hCG. Similarly, women at low risk of OHSS were allocated (RCT 2) to receive either: Group C (n = 125), a bolus of 0.5 mg buserelin s.c., followed by a bolus of 1.500 IU hCG s.c. after oocyte retrieval and a second bolus of 1.500 IU hCG on the day of oocyte retrieval +5-or: Group D (n = 141), 5.000 IU hCG. Groups C and D were included in order to obtain preliminary data. In women at risk of OHSS (RCT 1) (15-25 follicles) no OHSS case was seen in Group A (GnRHa trigger and one bolus of 1.500 IU hCG), whereas two cases of moderate late-onset OHSS occurred in group B (3.4%), (P = 0.24). In contrast, in women at a low risk of OHSS (RCT 2) (≤14 follicles) two cases of late-onset OHSS occurred in Group C (GnRHa trigger and two boluses of 1.500 IU hCG), whereas no OHSS case was encountered in Group D (P = 0.22). Although the first RCT was powered to include 168 patients at risk of OHSS (15-25 follicles ≥11 mm) randomized to either GnRHa trigger or hCG trigger, the trial was prematurely discontinued when a total of 118 patients at risk of OHSS were randomized. In addition the second RCT in the OHSS low-risk group was designed as a feasibility study to assess the incidence of OHSS after GnRHa trigger and dual hCG administration versus 5.000 IU hCG. No power calculation was performed for this trial. In addition, there was a lack of blinding in the RCTs. Although a non-significant result, one bolus of 1.500 IU hCG after GnRHa trigger tended to reduce the OHSS rate in patients with 15-25 follicles ≥11 mm as well as secure the ongoing pregnancy rate. In contrast, in patients at low risk of OHSS the administration of two boluses of 1.500 IU hCG after GnRHa trigger should be avoided as it may induce OHSS.

Low-dose hCG supplementation after GnRH agonist triggering: don't be too quick on the trigger

Induction of final oocyte maturation using a GnRH agonist was first described in the early nineties, though with the advent of the GnRH antagonist era it has gained ever increasing attention some two decades later (Humaidan et al., 2011). The primary motive for substituting the ‘classical’ hCG trigger is the complete elimination of clinically significant ovarian hyperstimulation syndrome (OHSS). When used alone (or with steroid-only luteal support) GnRH agonist triggering is undoubtedly themost efficient and powerfulwayof (secondary)OHSSprevention. So far there is no confirmedOHSS case in the literature that proves the opposite (Kol and Humaidan, 2012). This prevention occurs due to a massive, rapid and irreversible luteolysis leading to a practical, total elimination of clinically significant moderate/severeOHSS (Kol, 2004). Consequently when fresh embryo transfer is not planned this strategy has established itself as the first choice option in oocyte donor/fertility preservation cycles and before total freezing of oocytes or embryos (Bodri et al., 2010; Griesinger et al., 2011). However, if the primary goal is performing fresh embryo transfer then the challenge is to save the severely impaired luteal phase without increasing the risk of early/late-onset OHSS. After the discouraging results of initial trials only a few dedicated research groups have made further efforts to undertake research in this area (Humaidan et al., 2006; Engmann et al., 2008; Castillo et al., 2010; Papanikolaou et al., 2011b). Humaidan et al. developed the concept of a modified luteal support aimed at rescuing the impaired luteal phase by administering small boluses of luteotropic substances. This hypothesis was first tested in pilot studies, both in normal and high responders (Humaidan et al., 2006 Humaidan, 2009) and later in a randomized clinical trial (Humaidan et al., 2010). The first randomized trial (mainly involving normal responders) suggested that the reproductive outcome can be improved to the level of control patients with a single, low-dose (1500 IU) hCG bolus administered at the time of oocyte retrieval, without increasing the risk of OHSS (Humaidan et al., 2010). These encouraging results were also reproduced in a retrospective study by an Australian group (Radesic and Tremellen, 2011). Although Radesic and Tremellen used the aforementioned strategy with a fairly high OHSS risk population (without a pre-established upper limit of ovarian response) they were cautious enough to only perform mandatory single embryo transfer to reduce the risk of any late-onset OHSS. In the current issue of Human Reproduction the case series by Seyhan et al., report the combined experience from two geographically distant centres in Canada and Turkey with IVF patients at high risk of OHSS, who received the low-dose hCG rescue protocol. Despite using co-interventions (such as coasting and cabergoline administration) the authors reported a worryingly high rate (22%) of early onset severe OHSS requiring hospitalization. Although the presented retrospective case series is fairly small, the authors felt that it was important to highlight that early onset OHSS can still occur after applying the low-dose hCG rescue protocol. At first sight their findings are in blunt disagreement with most previously published studies that have also used low-dose hCG luteal support (single or multiple-bolus) following GnRH agonist trigger (Table I). However, at closer look notable differences can be observed. Among the four studies that were conducted in high OHSS risk patients Seyhan et al.’s 23 patients represent the highest ovarian response category with extremes of 49 and 65 oocytes retrieved. Moreover, although in one of the participating centres total freeze was considered in 33% of the cases, in the other fresh transfer was performed only transferring two to three embryos. Taken altogether these factors considerably influence the risk of early and late-onset OHSS. Although it was based on a very limited number of cases (5 versus 18) Seyhan et al. also suggested a threshold (≥18 follicles) based on the number of intermediate-sized (10–14 mm) follicles above which embryo/oocyte freezing is strongly recommended. This threshold (which was the only significant finding in this series) was based on the number of intermediate follicles and might be less practical for everyday clinical use than the total follicular count (Papanikolaou et al., 2006). Interestingly, in the design of a more recent randomized trial by Humaidan et al. on low-dose hCG support, patients with .25 follicles .11 mm were judged to be at too high risk and excluded from participation (www.clinicaltrials.gov: NCT00627406).

Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study

BackgroundConventional luteal support packages are inadequate to facilitate a fresh transfer after GnRH agonist (GnRHa) trigger in patients at high risk of developing ovarian hyperstimulation syndrome (OHSS). By providing intensive luteal-phase support with oestradiol and progesterone satisfactory implantation rates can be sustained. The objective of this study was to assess the live-birth rate and incidence of OHSS after GnRHa trigger and intensive luteal steroid support compared to traditional hCG trigger and conventional luteal support in OHSS high risk Asian patients.MethodsWe conducted a retrospective cohort study of 363 women exposed to GnRHa triggering with intensive luteal support compared with 257 women exposed to conventional hCG triggering. Women at risk of OHSS were defined by ovarian response ≥15 follicles ≥12 mm on the day of the trigger.ResultsLive-birth rates were similar in both groups GnRHa vs hCG; 29.8% vs 29.2% (p = 0.69). One late onset severe OHSS case was observed in the GnRHa trigger group (0.3%) compared to 18 cases (7%) after hCG trigger.ConclusionsGnRHa trigger combined with intensive luteal steroid support in this group of OHSS high risk Asian patients can facilitate fresh embryo transfer, however, in contrast to previous reports the occurrence of late onset OHSS was not completely eliminated.

Preliminary clinical outcome of novel strategy for the maximization of cumulative pregnancy rates per retrieval in normal responders.

ObjectiveWe devised a novel strategy, a GnRH antagonist protocol with a GnRH agonist trigger followed by frozen-thawed blastocyst transfers with long zona dissection (LZD). The purpose of this study was to investigate the clinical outcomes of this new strategy according to age.MethodsNinety women aged less than 35 (group A) and 32 women aged 35 to 39 (group B) underwent the GnRH antagonist protocol with a GnRH agonist trigger in order to obtain many oocytes and prevent early-onset ovarian hyperstimulation syndrome (OHSS). All oocytes were cultured to the blastocyst stage and all blastocysts grade 3BB or better were cryopreserved. Embryo transfers were only performed in freeze-thaw cycles to prevent late-onset OHSS and to overcome embryo-endometrium dyssynchrony. LZD was performed just after thawing to improve hatching and implantation rates.ResultsThe average numbers of retrieved oocytes and blastocysts grade 3BB or better were 12.8±5.5 and 4.4±2.6 in group A and 10.9±7.4 and 2.5±2.2 in group B, respectively, and OHSS did not occur in any of the women. Implantation rates were 46.7% in group A and 39.3% in group B. Cumulative clinical pregnancy rates per retrieval were 77.8% in group A and 62.5% in group B. Cumulative ongoing pregnancy rates per retrieval were 71.1% in group A and 53.1% in group B.ConclusionGnRH antagonist protocol with GnRH agonist trigger followed by frozen-thawed blastocyst transfers with LZD can generate many blastocysts without OHSS and maximize cumulative pregnancy rates per retrieval. This strategy is more effective in young women aged less than 35 than in women aged 35 to 39.

Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support

The aim of this study in patients at risk of ovarian hyperstimulation syndrome (OHSS) was to determine the efficacy and safety of luteal support using human chorionic gonadotrophin (HCG) after triggering ovulation with gonadotrophin-releasing hormone (GnRH) agonist in IVF/intracytoplasmic sperm injection antagonist cycles. A total of 192 OHSS-risk patients, following a GnRH antagonist protocol (0.25mg/day cetrorelix) during recombinant FSH stimulation, were triggered with 1.5mg s.c. leuproreline for ovulation. A total of three boluses of HCG were used for luteal support, 1000IU (group A, n=44), 500IU (group B, n=115) or 250IU (group C, n=33) every third day, starting the day after oocyte retrieval. For the reproductive outcome, main variables were biochemical and clinical pregnancy rates, and for OHSS, the variables were the numbers of moderate and severe OHSS cases. Overall pregnancy rate was 51.8% and clinical pregnancy rate was 43.4%. This study observed eight cases of moderate (4.2%) and seven of severe OHSS (3.6%). Six out of the seven (85.7%) severe cases were late-onset OHSS, related to pregnancy. In conclusion, GnRH agonist single dose for triggering ovulation and low doses of HCG used as luteal-phase support seem to secure a normal pregnancy outcome without increasing the OHSS risk.

Pregnant patients with ovarian hyperstimulation syndrome have lower human chorionic gonadotropin levels and doubling time

OBJECTIVE: Ovarian hyperstimulation syndrome (OHSS) is accompanied by hemoconcentration. In late-onset OHSS, human chorionic gonadotropin (hCG) levels used to assess normal intrauterine pregnancy (IUP) may be altered by hemoconcentration and misinterpreted by both patients and clinicians. Only one prior study of 9 patients with OHSS reported a 33% slower rise for hCG in patients with OHSS. Therefore, our aim was to quantify hCG levels and rise in patients with OHSS and a singleton IUP compared to control patients without OHSS.