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Study Question: What are couples' preferences for fresh embryo transfer versus freezing of all embryos followed by frozen embryo transfer and the associated clinical outcomes that may differentiate them?Summary Answer: Couples' preferences are driven by anticipated chances of live birth, miscarriage, neonatal complications, and costs but not by the differences in the treatment process (including delay of embryo transfer linked to frozen embryo transfer and risk of ovarian hyperstimulation syndrome (OHSS) associated with fresh embryo transfer).What Is Known Already: A policy of freezing all embryos followed by transfer of frozen embryos results in livebirth rates which are similar to or higher than those following the transfer of fresh embryos while reducing the risk of OHSS and small for gestational age babies: it can, however, increase the risk of pre-eclampsia and large for gestational age offspring. Hence, the controversy continues over whether to do fresh embryo transfer or freeze all embryos followed by frozen embryo transfer.Study Design, Size, Duration: We used a discrete choice experiment (DCE) technique to survey infertile couples between August 2018 and January 2019.Participants/materials, Setting, Methods: We asked IVF naïve couples attending a tertiary referral centre to independently complete a questionnaire with nine hypothetical choice tasks between fresh and frozen embryo transfer. The alternatives varied across the choice occurrences on several attributes including efficacy (live birth rate), safety (miscarriage rate, neonatal complication rate), and cost of treatment. We assumed that a freeze-all strategy prolonged treatment but reduced the risk of OHSS. An error components mixed logit model was used to estimate the relative value (utility) that couples placed on the alternative treatment approaches and the attributes used to describe them. Willingness to pay and marginal rates of substitution between the non-cost attributes were calculated. A total of 360 individual questionnaires were given to 180 couples who fulfilled the inclusion criteria, of which 212 were completed and returned Our study population included 3 same sex couples (2 females and 1 male) and 101 heterosexual couples. Four questionnaires were filled by one partner only. The response rate was 58.8%.Main Results and the Role Of Chance: Couples preferred both fresh and frozen embryo transfer (odds ratio 27.93 and 28.06, respectively) compared with no IVF treatment, with no strong preference for fresh over frozen. Couples strongly preferred any IVF technique that offered an increase in live birth rates by 5% (P = 0.006) and 15% (P < 0.0001), reduced miscarriage by 18% (P < 0.0001) and diminished neonatal complications by 10% (P < 0.0001). Respondents were willing to pay an additional £2451 (95% CI 604 - 4299) and £761 (95% CI 5056-9265) for a 5 and 15% increase in the chance of live birth, respectively, regardless of whether this involved fresh or frozen embryos. They required compensation of £5230 (95% CI 3320 - 7141) and £13 245 (95% CI 10 110-16 380) to accept a 10 and 25% increase in the risk of neonatal complications, respectively (P < 0.001). Results indicated that couples would be willing to accept a 1.26% (95% CI 1.001 - 1.706) reduction in the live birth rate for a 1% reduction in the risk of neonatal complications per live birth. Older couples appeared to place less emphasis on the risk of neonatal complications than younger couples.Limitations, Reasons For Caution: DCEs can elicit intentions which may not reflect actual behaviour. The external validity of this study is limited by the fact that it was conducted in a single centre with generous public funding for IVF. We cannot rule out the potential for selection or responder bias.Wider Implications Of the Findings: If a strategy of freeze all was to be implemented it would appear to be acceptable to patients, if either success rates can be improved or neonatal complications reduced. Live birth rates, neonatal complication rates, miscarriage rates, and cost are more likely to drive their preferences than a slight delay in the treatment process. The results of this study have important implications for future economic evaluations of IVF, as they suggest that the appropriate balance needs to be struck between success and safety. A holistic approach incorporating patient preferences for expected clinical outcomes and risks should be taken into consideration for individualized care.Study Funding/competing Interest(s): No external funding was sought for this study. A.M. is the chief investigator of the randomized controlled trial 'Freeze all'. S.B. is an Editor in Chief of Human Reproduction Open. The other co-authors have no conflicts of interest to declare. Graham Scotland reports non-financial support from Merck KGaA, Darmstadt, Germany, outside the submitted work.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Are the in vitro procedure, ovarian hyperstimulation or a combination of these two associated with blood pressure (BP) of 9-year-old IVF children born to subfertile couples?Summary Answer: Our study demonstrates that ovarian hyperstimulation and the in vitro procedure are not associated with BP values in 9-year-old children born to subfertile couples.What Is Known Already: Possible long-term effects of IVF on child health and development have been studied relatively little. This is surprising, as it is known that environmental conditions may influence embryonic and foetal development which may result in health related problems in later life. Some studies suggested that IVF is associated with higher BP at pre-school age. Yet, it is unclear whether this may be also true for older children and if so, which component of IVF, i.e. the ovarian hyperstimulation, the embryo culture or a combination of these, attributes to this potentially less favourable BP.Study Design, Size, Duration: The Groningen Assisted Reproductive Technology cohort-study is a prospective assessor-blinded study of children followed from before birth onwards. In total, 170 children were assessed at the age of 9 years. The attrition rate up until the 9-year-old assessment was 21%.Participants/materials, Setting, Methods: We evaluated cardiovascular health, focusing on BP (in mmHg and the internationally recognized percentiles of the US National High BP Education Program), heart rate and anthropometrics of 57 children born following controlled ovarian hyperstimulation-IVF/ICSI (COH-IVF/ICSI); 47 children born after modified natural cycle-IVF/ICSI (MNC-IVF/ICSI); and 66 children who were conceived naturally by subfertile couples (Sub-NC). Cardiovascular parameters were measured multiple times on one day. In addition, anthropometric data, including BMI and skinfold thickness, were collected.Main Results and the Role Of Chance: Systolic BP in mmHg did not differ between the COH-IVF/ICSI (mean 106.9, SD 6.7), MNC-IVF/ICSI (mean 104.8, SD 5.9) and Sub-NC (mean 106.3, SD 5.3) groups. In addition, systolic BP percentiles did not differ between the groups: COH-IVF/ICSI (mean 62.4, SD 20.2); MNC-IVF/ICSI (mean 56.3, SD 19.3); and Sub-NC (mean 62.3, SD17.8). Also, after adjustment for confounders BP in the three groups was similar. Heart rate and anthropometric values in the three groups did not differ. For instance, BMI values in the COH-IVF/ICSI-children were 16.3 (median value, range 13.0-24.7), in MNC-IVF/ICSI-children 16.1 (range 12.7-22.5) and in Sub-NC children 16.3 (range 12.7-24.0).Limitations, Reasons For Caution: The size of our study groups does not allow for pertinent conclusions on the effect of ovarian hyperstimulation and the in vitro procedure. The lack of a fertile control group may be regarded as another limitation.Wider Implications Of the Findings: Our study suggests that ovarian hyperstimulation and in vitro procedures are not associated with cardiovascular health in 9-year-old. Yet, BP percentiles of the three groups were higher than the expected 50th percentile. This might indicate that children of subfertile couples have a higher BP than naturally conceived children.Study Funding/competing Interest(s): The study was financially supported by the University Medical Center Groningen (UMCG), the two graduate schools of the UMCG, BCN, SHARE and the Cornelia Stichting. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does ovarian hyperstimulation, the in vitro procedures required for in vitro fertilization (IVF)/ intracytoplasmic sperm injection or the combination of both, affect the neurological outcome of 4-year-old singletons? SUMMARY ANSWER Ovarian hyperstimulation, the in vitro procedure and the combination of both, were not associated with the worse neurological outcome in 4-year-old singletons. WHAT IS KNOWN ALREADY Assisted reproduction techniques (ARTs) are not associated with neurological dysfunction during the first post-natal years; however, effects on the long-term neurological outcome are still inconclusive. An increased time to pregnancy (TTP, a proxy for the severity of subfertility) has been associated with a less optimal neurological condition at age 2. The present study focuses on the neurodevelopmental outcome of 4-year-old ART-offspring. STUDY DESIGN, SIZE, DURATION Longitudinal, prospective follow-up study. PARTICIPANTS, SETTING, METHODS Four-year-old singletons born to subfertile parents (subfertile group, n = 195), including singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 63), modified natural cycle IVF (MNC-IVF, n = 53) and natural conception (Sub-NC, n = 79). Data on underlying cause of subfertility and TTP were present. In addition, we assessed newly recruited 4-year-old singletons born to fertile parents after natural conception (reference group, n = 98). Neurological development was evaluated with the neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the occurrence of the clinically relevant form of minor neurological dysfunction (complex MND). The primary outcome was the fluency score, as fluency of movements is easily reduced by subtle brain dysfunction. Data were analysed with univariable and multivariable regression analyses, in which special attention was paid to sex differences in the neurological outcome. MAIN RESULTS AND THE ROLE OF CHANCE The fluency score, NOS and the prevalence of complex MND were similar in COH-IVF, MNC-IVF and Sub-NC children. The neurological condition of children born to subfertile parents was similar to that of children of fertile parents and was independent of the underlying cause of subfertility. No statistically significant associations were found between TTP and the fluency score and NOS. However, a positive correlation was found between TTP and the prevalence of complex MND (TTP in years, adjusted odds ratio [OR] [95% confidence interval, CI]: 1.207 [1.038 to 1.404], P = 0.014); a correlation which could be attributed to girls, in whom an evident positive correlation was present (adjusted OR [95% CI]: 1.542 [1.161 to 2.047], P = 0.003). A similar association was absent in boys. LIMITATIONS, REASONS FOR CAUTION The prospective design of our study and small post-natal attrition rate (9.3%) reduced potential selection bias based on the child's development or health. The assessors were blind to the mode of conception, except for the group of children born to fertile parents, which was newly recruited. The study lacks sufficient power to conclude firmly that increased TTP is associated with a higher prevalence of complex MND. WIDER IMPLICATIONS OF THE FINDINGS Our study suggests that the severity of subfertility, rather than its simple presence or components of IVF treatment, affects the neurological outcome. Moreover, girls may be neurologically more vulnerable for the effect of severity of subfertility. The finding that the severity of subfertility may be the decisive factor rather than the presence of a history of subfertility per se corroborates previous reports. Our results cannot be generalized to multiples, as we studied singletons only. STUDY FUNDING/COMPETING ... [ABSTRACT FROM AUTHOR]

STUDY QUESTION What causal relationships underlie the associations between ovarian stimulation, the IVF procedure, parental-, fertility- and child characteristics, and blood pressure (BP) and anthropometrics of 4-year-old IVF children? SUMMARY ANSWER Causal models compatible with the data suggest the presence of positive direct effects of controlled ovarian hyperstimulation as applied in IVF (COH-IVF) on systolic blood pressure (SBP) percentiles and subscapular skinfold thickness. WHAT IS KNOWN ALREADY Increasing evidence suggests that IVF is associated with higher blood pressure and altered body fat distribution in offspring, but underlying mechanisms describing the causal relationships between the variables are largely unknown. STUDY DESIGN, SIZE, DURATION In this assessor-blinded follow-up study, 194 children were assessed. The attrition rate until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS We measured blood pressure and anthropometrics of 4-year-old singletons born following COH-IVF (n = 63), or born following modified natural cycle IVF (MNC-IVF, n = 52) or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Primary outcome measures were the SBP and diastolic blood pressure (DBP) percentiles. Anthropometrics included triceps and subscapular skinfold thickness. Causal inference search algorithms and structural equation modeling were applied. MAIN RESULTS AND THE ROLE OF CHANCE Explorative analyses suggested a direct effect of COH on SBP percentiles and on subscapular skinfold thickness. This hypothesis needs confirmation with additional, preferably larger, studies. LIMITATIONS, REASONS FOR CAUTION Search algorithms were used as explorative tools to generate hypotheses on the causal mechanisms underlying fertility treatment, blood pressure, anthropometrics and other variables. More studies using larger groups are needed to draw firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome, but this is the first study suggesting a causal mechanism underlying this association. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo, possibly resulting in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to confirm the role of ovarian stimulation in poorer cardiometabolic outcome and should investigate the underlying mechanisms. Our proposed causal models provide research hypotheses to be tested with new data from preferably larger studies. STUDY FUNDING/COMPETING INTEREST(S) The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does ovarian hyperstimulation, the in vitro procedure, or a combination of these two negatively influence blood pressure (BP) and anthropometrics of 4-year-old children born following IVF? SUMMARY ANSWER Higher systolic blood pressure (SBP) percentiles were found in 4-year-old children born following conventional IVF with ovarian hyperstimulation compared with children born following IVF without ovarian hyperstimulation. WHAT IS KNOWN ALREADY Increasing evidence suggests that IVF, which has an increased incidence of preterm birth and low birthweight, is associated with higher BP and altered body fat distribution in offspring but the underlying mechanisms are largely unknown. STUDY DESIGN, SIZE, DURATION We performed a prospective, assessor-blinded follow-up study in which 194 children were assessed. The attrition rate up until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS We measured BP and anthropometrics of 4-year-old singletons born following conventional IVF with controlled ovarian hyperstimulation (COH-IVF, n = 63), or born following modified natural cycle IV (MNC-IVF, n = 52), or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Both IVF and ICSI were performed. Primary outcome measures were the SBP percentiles and diastolic BP (DBP) percentiles. Anthropometric measures included triceps and subscapular skinfold thickness. Several multivariable regression analyses were applied in order to correct for subsets of confounders. The value ‘B’ is the unstandardized regression coefficient. MAIN RESULTS AND THE ROLE OF CHANCE SBP percentiles were significantly lower in the MNC-IVF group (mean 59, SD 24) than in the COH-IVF (mean 68, SD 22) and Sub-NC groups (mean 70, SD 16). The difference in SBP between COH-IVF and MNC-IVF remained significant after correction for current, early life and parental characteristics (B: 14.09; 95% confidence interval (CI): 5.39–22.79), whereas the difference between MNC-IVF and Sub-NC did not. DBP percentiles did not differ between groups. After correction for early life factors, subscapular skinfold thickness was thicker in the COH-IVF group than in the Sub-NC group (B: 0.28; 95% CI: 0.03–0.53). LIMITATIONS, REASONS FOR CAUTION Larger study groups are necessary to draw firm conclusions. An effect of gender or ICSI could not be properly investigated as stratifying would further reduce the sample size. We corrected for the known differences between MNC-IVF and COH-IVF but it is possible that the groups differ in additional, more subtle parental characteristics. In addition, we measured BP on 1 day only, had no control group of children born to fertile couples (precluding investigating effects of the underlying subfertility) and included singletons only. As COH-IVF is associated with multiple births we may have underestimated cardiometabolic problems after COH-IVF. Finally, multivariable regression analysis does not provide clear insight in the causal mechanisms and we have performed further explorative analyses. WIDER IMPLICATIONS OF THE FINDINGS Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome but this is the first study suggesting that ovarian hyperstimulation, as used in IVF treatments, could be a causative mechanism. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo that result in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to assess further the role of ovarian hyperstimulation in poorer cardiometabolic outcome and investigate the underlying mechanisms. The findings emphasize the importance of cardiometabolic monitoring of the ... [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is there a shift in the timing of nucleolar channel system (NCS) formation following controlled ovarian hyperstimulation (COH)? SUMMARY ANSWER NCSs appear prematurely following COH compared with natural cycles. WHAT IS KNOWN ALREADY During natural cycles, NCSs of endometrial epithelial cell (EEC) nuclei are exclusively present during the window of implantation and are uniformly distributed throughout the upper endometrial cavity. STUDY DESIGN, SIZE, DURATION Prospective two-cohort study. Cohorts I and II each consisted of seven volunteers for the duration of three menstrual study cycles that were separated by at least one wash-out or rest cycle, between December 2008 and May 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were recruited from a pool of healthy oocyte donors. Consecutive endometrial biopsies were obtained during the same luteal phase on cycle days (CD) 16, 20 and 26 for Cohort I, and on CD14, 22 and 24 for Cohort II, following random assignment to a natural cycle group, a COH cycle group (using a GnRH antagonist), or a COH cycle group receiving luteal phase hormonal supplementation (COH + S). The day of oocyte retrieval was designated CD14 in COH cycles and the day of the LH surge was designated CD13 in natural cycles. Prevalence of NCSs in the nuclei of EECs was quantified using indirect immunofluorescence with an antibody directed against a subset of related nuclear pore complex proteins that are major constituents of NCSs. Progesterone and estradiol levels were measured on the day of each endometrial biopsy. MAIN RESULTS AND THE ROLE OF CHANCE The natural cycle group exhibited peak NCS prevalence on CD20 [53.3%; interquartile range (IQR) 28.5–55.8], which rapidly declined on CD22 (11.8%; IQR 6.3–17.6), CD24 (2.5%; IQR 0.0–9.2) and CD26 (0.3%; IQR 0.0–3.5), and no NCSs on CD14 and 16 defining a short NCS window around CD20. In contrast, in COH and COH + S cycles, NCS prevalence was high already on CD16 (40.4%; IQR 22.6–53.4 and 35.6%; IQR 26.4–44.5, respectively; P = 0.001 compared with CD16 of the natural cycle group, Mann–Whitney), whereas no significant difference in NCS prevalence was detected on any of the other five CDs between the three groups (P > 0.05). LIMITATIONS, REASONS FOR CAUTION The cohort size was small (n = 7) but was offset by the all-or-none presence of NCSs on CD16 in natural versus COH and COH + S cycles and the fact that each subject served as her own control. WIDER IMPLICATIONS OF THE FINDINGS Premature appearance of NCSs and hence maturation of the endometrium following COH is consistent with previous studies based on histological dating but contradicts studies based on mRNA expression profiling, which reported a lag in endometrial maturation. However, this is the first study of this kind that is based on consecutive endometrial biopsies within the same cycle and that reports such clear-cut differences: no versus robust NCS presence on CD16. Our observation of advanced endometrial maturation following COH may contribute to the reduced implantation rates seen in fresh compared with frozen and donor IVF-embryo transfer cycles. Therefore, the NCS window could serve as a sensitive guide for timing of embryo transfer in frozen and donor cycles. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the March of Dimes Birth Defects foundation (1-FY09–363 to U.T.M.); Ferring Pharmaceuticals, Parsippany, NJ; East Coast Fertility, Plainview, NY and the CMBG Training Program (T32 GM007491 to M.J.S.). We report no competing interests. [ABSTRACT FROM PUBLISHER]

BACKGROUND: The rationale for double insemination is to create the opportunity for a longer fertilization period as follicle rupture may occur over a wide interval (∼22-47 h) after hCG administration in ovarian hyperstimulation (OH) with intrauterine insemination (IUI) cycles. This randomized study evaluates the effectiveness of single versus double IUI in only OH cycles with multi-follicular development. METHODS: We conducted a single center trial, 228 eligible patients were randomized for this study on the day of hCG. Only cycles with multi-follicular development without premature luteinization (progesterone levels >1 ng/ml on the day of hCG), were included in the study. Multi-follicular development has been defined as at least two dominant follicles reaching minimum ⩾15 mm diameter in which one of them is >17 mm. OH cycles with more than five dominant follicles (>15 mm in diameter) were excluded from the study. In the single IUI group (Group 1 = 112 patients) IUI was applied 36 h after the hCG injection and in the double IUI group (Group 2 = 114 patients) the first IUI was performed 18 h after hCG administration and the second IUI was performed 40 h after hCG administration. The primary end-point is to compare live birth rates (LBRs) between single and double IUI arms. RESULTS: LBRs were 10.7% (12/112 patients) in the single IUI group and 12.3% (14/114) in the double IUI group and the difference was not statistically significant (P = 0.835, OR = 1.16, 95% CI: 0.51-2.64). In the unexplained infertility group the LBR was 11.1% (5/45 patients) with single IUI and 18.4% (9/49) with double IUI (P = 0.393). In the mild male factor group this rate was 10.4% (7/67) and 7.7% (5/65) in the single and double IUI groups, respectively (P = 0.764). CONCLUSION: Our study did not find any difference in LBRs between single and double IUI groups in OH cycles with multi-follicular development. To the best of our knowledge this is the first report with this kind of study design. [ABSTRACT FROM AUTHOR]

In a prospective randomized study, we analysed 125 patients at risk of ovarian hyperstimulation syndrome (OHSS), selected in the period between January 1996 and July 1997. All the patients had blood oestradiol concentration 1500 pg/ml on the day of human chorionic gonadotrophin (HCG) administration and 15 oocytes were collected. The patients were matched in two groups: group A, control group (n = 67), had fresh embryo transfers; group B (n = 58) had cryopreservation of all obtained pronucleate embryos. Pregnancy, live birth rates and the incidence of OHSS were compared between the two groups. There were no significant differences in terms of pregnancies per patient (46.3 versus 48.3%) and live birth rates (38.8 versus 39.6%). No cases of OHSS occurred in group B, while four patients developed the syndrome in group A. The implantation rate was slightly but not significantly lower in group B (χ2 = 1.03). These results suggest that elective cryopreservation of all zygotes might prevent the risk of OHSS in patients undergoing IVF treatment. In contrast to what has been reported by other authors, our results show that the elective cryopreservation of zygotes does not affect pregnancy and live birth rates. [ABSTRACT FROM PUBLISHER]

The administration of human serum albumin has been reported to prevent severe ovarian hyperstimulation syndrome (OHSS) in patients considered at risk of developing OHSS while undergoing ovarian stimulation protocols for in-vitro fertilization (IVF). This prospective, randomized study investigated the effectiveness of a single dose of human serum albumin (20 g) administered i.v. immediately after oocyte retrieval. Women enrolled in the IVF programme were treated with the long gonadotrophin-releasing hormone agonist, triptorelin, and an individually-adjusted human menopausal gonadotrophin protocol. The criteria for inclusion in the study were young age, nonobesity, oestradiol concentration >9200 pmol/l on the day of human chorionic gonadotrophin administration and >20 follicles >14 mm diameter as observed by transvaginal sonography. The treatment group ( = 22) received albumin while the control group ( = 18) did not. Patients were followed-up using ultrasound every 3 days. There was a significantly higher number of severe OHSS cases in the control group ( = 4) than in the treatment group ( = 0) ( = 0.035). Where the data base was restricted to patients with an oestradiol concentration >15 000 pmol/l, the difference between control and treatment groups was highly significant ( = 0.008). These findings support the use of i.v. albumin in preventing severe OHSS during IVF treatment. [ABSTRACT FROM PUBLISHER]

A retrospective study was conducted to evaluate the possible role of endothelial and extracellular factors in the pathophysiology of ovarian hyperstimulation syndrome (OHSS). Plasma changes in von Willebrand—Jürgen factor were correlated with the clinical condition of hyperstimulated patients, since the rise of capillary permeability is the central event in all subsequent morbidity. The corresponding oestradiol levels and ultrasound parameters were assessed. In-vitro fertilization patients designated as ‘high responders’ and with oestradiol values >2500 pg/ml and >8 pre-ovulatory follicles at the time of human chorionic gonadotrophin (HCG) injection were assessed. Among 62 patients, 37 fulfilled these criteria and 18 developed OHSS, indicating the low predictive ability of ultrasound and oestradiol values alone. The remaining 19 patients served as control group. von Willebrand factor-associated antigen in plasma was measured using enzyme-linked immunosorbent assay and ristocetin co-factor activity by an aggregatometric test. Basal values of the two groups of patients did not differ but there were large inter-individual variations. A slight increase occurred in the control group until the day of HCG although individual cycles showed ‘no change of pattern’ or a ‘decreasing tendency’ from the start. Some patients allocated to the non-hyperstimulated type showed a steep increase of values followed by a decline. A consistent increase in the OHSS group lasted after embryo transfer even to the late corpus luteum phase. These subtle changes of capillary permeability or damage always preceded the clinical signs, such as ascites, haemoconcentration, hypoproteinaemia and pleural effusion. Mean values differed in the two groups from the day preceding ovum retrieval. This test may therefore provide an additional ‘prognostic marker’ for early recognition and monitoring of OHSS. [ABSTRACT FROM PUBLISHER]

Previous experiences in subjects with other forms of third space fluid accumulation have shown that albumin is efficacious in preventing and correcting haemodynamic instability. Using a similar approach in an effort to increase the serum oncotic pressure and to reverse the leakage of fluids from the intravascular space, high risk subjects for severe ovarian hyperstimulation syndrome (SOHS) were treated with albumin. In a recent large study two high risk factors were identified, i.e. the number of oocytes and levels of serum oestradiol. Thirty-six women undergoing assisted reproductive techniques who presented both these factors, received intravenous albumin at a dose of 5% in Ringers lactate in doses of 500 ml during oocyte retrieval and 500 ml immediately thereafter in the recovery room. Daily measurements of urine output, serum and urine electrolytes, weight, abdominal girth, and haematocrit prior to and after oocyte retrieval revealed normal serum and urine electrolyte levels, and no signs of haemoconcentration. No patient in this study developed SOHS, and of course none had to be hospitalized. Vaginal ultrasound performed in the majority of the subjects revealed ≤100 ml of peritoneal fluid 48–72 h after oocyte retrieval. The only complication from the use of intravenous albumin was the appearance of a ‘flu-like condition’ (low grade temperature, nausea and muscle pains) developed by 12 women between days 3 and 5 after oocyte collection. Intravenous albumin had thus prevented the development of severe ovarian hyperstimulation syndrome in an assisted reproduction programme. Its use could allow the maintenance of treatment in patients that otherwise would have been cancelled due to their high risk of developing this condition. The proposed mechanisms of action include increase in plasma oncotic pressure, and in the sex steroid binding capacity of the plasma. Both factors could prevent leakage of fluid from the intravascular space into the peritoneal cavity. [ABSTRACT FROM PUBLISHER]

Concentrations of inhibin, total and free oestradiol and progesterone were determined in preovulatory follicular fluid from 15 women undergoing in-vitro fertilization and embryo transfer treatment. The women underwent ovarian stimulation using clomiphene citrate and human menopausal gonadotrophin (HMG) (69 follicular fluid samples) in one cycle, and gonadotrophin-releasing hormone agonist (GnRHa) and HMG stimulation in the next treatment cycle (64 follicular fluid samples). The women thereby served as their own control. Inhibin, total oestradiol and progesterone were measured by radioimmunoassay. Concentrations of free steroid were calculated after quantitation of the steroid binding proteins, i.e. sex-hormone binding globulin (SHBG), cortisol binding protein (CBP) and albumin. Levels of inhibin and free and total progesterone were significantly higher in follicular fluids collected after stimulation with the GnRHa compared to the clomiphene regime ( < 0.05, < 0.001, < 0.001, respectively). In contrast, levels of total and free oestradiol in follicular fluid were significantly lower after stimulation with GnRHa than after clomiphene stimulation ( < 0.001). These results indicate that the follicles have achieved a more optimal maturation during the GnRHa regime than during the clomiphene regime. It is suggested that the concentration of free biologically active steroids in follicular fluid, released into the peritoneal cavity during ovulation, may be physiologically important in stimulating the oviduct and the uterus in connection with ovulation, pre-embryo development and implantation. [ABSTRACT FROM PUBLISHER]

In a prospective study, 15 patients with normal menstrual cycles were treated with pulsatile gonadotrophin-releasing hormone (GnRH) for one to four cycles. These cycles were compared to unstimulated cycles of 14 volunteers. There was a surprisingly stable number of large (≥ 14 mm diameter) follicles per patient. The number of Large follicles in induction cycles was significantly greater than in controls (2.4 versus 1.07). This was due to signifcantly higher follicle stimulating hormone levels during the first days of treatment. Our data provide a rationale for the use of pulsatile GnRH for a safe and mild form of stimulation in assisted reproductive therapies. [ABSTRACT FROM PUBLISHER]

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 pronucteate 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 11MG 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% ( <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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM PUBLISHER]

Ovarian hyperstimulation syndrome (OHSS) is a major risk in patients undergoing ovulation induction protocols. Withholding injection of human chorionic gonadotrophin (HCG) may prevent the development of OHSS, but can also result in failure to ovulate and conceive. We have used a gonadotrophin-releasing hormone agonist (GnRHa) as an alternative to HCG in women not undergoing in-vitro fertilization in an attempt to prevent OHSS. The study included 12 cycles in 12 women scheduled for ovulation induction with human menopausal gonadotrophin (HMG) who were at risk of developing OHSS (oestradiol > 3500 pg/ml, number of follicles > 20). GnRHa was injected to induce the pre-ovulatory, luteinizing hormone surge which triggers follicular maturation. Progesterone was administered for luteal support. Six pregnancies were achieved, and none of the 12 women developed OHSS. Since the pregnancy rate in this study was acceptable, we can recommend the use of GnRHa instead of HCG in any case at risk of developing OHSS. [ABSTRACT FROM AUTHOR]

The effect of follicular aspiration and oocyte retrieval on hormonal parameters was examined in women undergoing ovarian stimulation for in-vitro fertilization (IVF) compared to induced ovulation in women undergoing ovarian stimulation for intrauterine insemination (IUI). Blood samples were collected immediately before and 1 h after oocyte retrieval and 48 h later on the day of embryo transfer in 25 IVF patients and before the insemination and 48 h later in 20 IUI patients. A highly significant fall in serum levels of oestradiol (E2), progesterone (P) and human chorionic gonadotrophin (HCG), (P less than 0.001) was observed in the IVF group 1 h after follicular aspiration. The decline in serum E2 levels was maintained at 48 h. In contrast, there was no significant change in serum E2 levels in the IUI group during 48 h. The immediate decline in E2 levels after follicular aspiration might play a role in preventing ovarian hyperstimulation syndrome. [ABSTRACT FROM AUTHOR]

We have combined intrauterine insemination (IUI) and controlled ovarian hyperstimulation (COH), for the treatment of infertility due to different aetiologies, prior to performing GUT. To date, we have treated 186 patients over a total of 489 cycles. The mean age of the patients was 34.1 ± 4 years and the mean duration of infertility was 4.8 ± 2.8 years. Follicular development was induced with human menopausal gonatrophin (HMG). Patients were monitored using serum oestradiol determinations and ovarian ultrasound. Two intrauterine inseminations were performed 12 and 36 h after HCG injection. Semen samples were prepared utilizing one of two techniques, swim-up or Percoll gradient. A total of 33 pregnancies have occurred, the gross pregnancy rate being 17.7% per patient and 6.7% per cycle. The cumulative pregnancy rate was 30%. Thirty-one pregnancies (94%) occurred within the first four cycles of treatment. During the same period of time, the pregnancy rate per cycle in patients treated with gamete intra-Fallopian transfer (GIFT) was 32.9%. Our data suggest that IUI combined with COH can result in pregnancy in a significant proportion of patients, but that the efficiency per cycle of the technique is significantly lower than GIFT. [ABSTRACT FROM PUBLISHER]

The relationship between various measures of oestradiol (E) secretion and the total number of oocytes retrieved (OR) and cleaved embryos (CE) was characterized in normal ovulatory women stimulated with pure follicle-stimulating hormone (FSH) in a programme for in-vitro fertilization and embryo transfer (IVF—ET). Patients in this study included women with tubal factor as their only cause for infertility. Cycles were monitored with serum E concentration and ultrasonography. Human chorionic gonadotrophin (HCG) was administered when two follicles had a maximum diameter >15mm. The variables used to characterize the E secretory response included: (i) the difference between the highest and lowest E concentration during stimulation; (ii) the ratio of terminal to initial E concentration; (iii) E concentration on the day of HCG administration; and (iv) the slope of the E curve. These measures of E secretion each correlated with both the number of OR and the number of CE. When all E variables were considered simultaneously in a stepwise multivariate regression procedure, variations in the number of OR ( = 0.84) or CE ( = 0.77) could be explained by variation in the E secretory profile. Equations derived from these E variables may help to identify and improve problem areas within IVF—ET programmes when actual results differ from expected. [ABSTRACT FROM PUBLISHER]

Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy is exceedingly rare. We report a case of ovarian hyperstimulation presenting as bilateral ovarian masses in association with spontaneous pregnancy, occurring in a woman with disturbed liver function. A possible mechanism is discussed. [ABSTRACT FROM AUTHOR]

Ovarian hyperstimulation syndrome may be a serious complication of ovulation induction usually manifested by ovarian enlargement and ascites. In its severe form, haemoconcentration, oliguria and hydrothorax may ensue. As evident from this case report, the usual sequence of events does not necessarily occur in all cases. Unilateral hydrothorax may be the only extra-ovarian manifestation of ovarian hyperstimulation syndrome. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

A patient who suffered from polycystic ovarian disease and anovulation, was treated with pure follicle stimulating hormone for induction of ovulation. The treatment was stopped and human chorionic gonadotrophin was not administered because of high serum oestradiol levels and multiple follicular development. Ovulation occurred 11 days after pure follicle stimulating hormone was discontinued, the patient developed third-degree ovarian hyperstimulation syndrome and conceived with a quintuplet pregnancy. [ABSTRACT FROM PUBLISHER]