Rescue intracytoplasmic sperm injection (ICSI)-salvaging in vitro fertilization (IVF) cycles after total or near-total fertilization failure.

OBJECTIVE: To evaluate the effectiveness of delayed oocyte reinsemination by ICSI (rescue ICSI) after total or near-total fertilization failure (

An ounce of prevention: outpatient management of the ovarian hyperstimulation syndrome.

OBJECTIVE: To evaluate a protocol of active outpatient management, including outpatient paracentesis and albumin administration, in women at risk for severe ovarian hyperstimulation syndrome (OHSS). DESIGN: Prospective cohort. SETTING: Freestanding IVF program. PATIENT(S): Thirteen women progressing from moderate to severe OHSS. INTERVENTION(S): Bed rest and home monitoring with intermittent outpatient paracentesis and albumin administration. MAIN OUTCOME MEASURE(S): Procedural outcomes and time to resolution of OHSS symptoms. RESULT(S): The initial paracentesis occurred 14.1 +/- 3.3 days after oocyte retrieval, removing 1,735 +/- 506 mL of ascitic fluid. Eleven women required a second paracentesis and five women required a third paracentesis over the next 8 days. Six women received albumin on seven occasions because of hypoalbuminemia. The onset of diuresis occurred 2.8 +/- 1.9 days and recovery occurred 7. 4 +/- 3.0 days after the first paracentesis. There were no hospitalizations for OHSS symptoms and no complications. All 13 women had viable intrauterine pregnancies. CONCLUSION: Active outpatient intervention in the early stages of OHSS, including paracentesis and albumin administration, can avoid hospitalization while minimizing the progression and complications of OHSS.

Withholding gonadotropins ("coasting") to minimize the risk of ovarian hyperstimulation during superovulation and in vitro fertilization-embryo transfer cycles.

OBJECTIVE: To evaluate superovulation (SOV) and IVF-ET cycles in which E2 levels were allowed to decrease to restrain rapid follicular growth and minimize the risk of ovarian hyperstimulation syndrome. DESIGN: Retrospective series. SETTING: Tertiary care infertility practice. PATIENT(S): Women who underwent SOV (n = 51) and IVF-ET (n = 93) treatment and who were at risk for OHSS. INTERVENTION(S): In SOV cycles, hMG was withheld (coasting) for >3 days before hCG administration, until follicular maturity was attained (> or = 3 follicles of > or = 18 mm) and E2 levels decreased. In IVF-ET cycles, either follicular maturity was attained before coasting (n = 63), allowing hCG administration after E2 levels decreased by >25%, or coasting occurred before follicular maturation (n = 30), necessitating the administration of additional hMG after coasting. MAIN OUTCOME MEASURE(S): Estradiol concentrations, follicle size, and pregnancy rates. RESULT(S): Estradiol concentrations usually rose for > or = 1 day after coasting began, then fell by > or = 25% while follicle numbers and mean diameters increased. No spontaneous LH surges occurred, although four SOV cycles were canceled because of excessive follicular development. Of the women who received hCG,11 of 47 (23% per cycle) conceived during SOV and 35 of 93 (37.6% per cycle) conceived during IVF-ET. Severe ovarian hyperstimulation syndrome developed in 1 woman who underwent IVF-ET. CONCLUSION(S): Coasting can safely rescue overstimulated SOV and IVF-ET cycles characterized by an excessive rise in E2 levels and/or numerous incompletely mature follicles.

Use of nafarelin versus placebo after reductive laparoscopic surgery for endometriosis.

OBJECTIVE: To evaluate the efficacy of the GnRH agonist (GnRH-a) nafarelin compared with placebo administered for 6 months after reductive laparoscopic surgery for symptomatic endometriosis. DESIGN: Randomized, prospective, placebo-controlled, multicenter clinical trial. SETTING: Thirteen clinics including private practice and university centers. PATIENT(S): One hundred nine women aged 18-47 with laparoscopically proven endometriosis and pelvic pain who had undergone reductive laparoscopic surgery for endometriosis. INTERVENTION(S): Patients were randomized to receive either the GnRH-a nafarelin (200 micrograms twice daily) or placebo for 6 months. MAIN OUTCOME MEASURE(S): Time to initiation of alternative treatment (the length of time from beginning study medication to receiving alternative therapy or to deeming that the study drug was ineffective) and patient-reported and physician-assessed pelvic pain scores. RESULT(S): The median time to initiation of alternative treatment was > 24 months in the nafarelin group versus 11.7 months in the placebo group. Fifteen (31%) of 49 nafarelin-treated patients required alternative therapy, compared with 25 (57%) of 44 placebo-treated patients. The patients' pelvic pain scores dropped significantly in the nafarelin and placebo groups after 6 months of treatment. Physician summary ratings showed significant improvement in the nafarelin group and no significant changes in the placebo group after 6 months of treatment. CONCLUSION(S): Compared with placebo, nafarelin administered after reductive laparoscopic surgery for endometriosis significantly delays the return of endometriosis symptoms requiring further treatment.

Retreatment with nafarelin for recurrent endometriosis symptoms: efficacy, safety, and bone mineral density.

OBJECTIVE: To assess the efficacy, safety, and effect on bone mineral density of a 3-month course of retreatment with intranasal nafarelin acetate for recurrent symptoms of endometriosis. DESIGN: Multicenter, open-label, nonrandomized clinical trial. SETTING: Eleven hospital-based and private practices. PATIENT(S): Thirty-six women with endometriosis symptoms recurring after 3 or 6 months of treatment with nafarelin. INTERVENTION(S): Nasal nafarelin 200 micrograms twice daily for 3 months. MAIN OUTCOME MEASURE(S): Assessments for dysmenorrhea, dyspareunia, pelvic pain, tenderness, and induration. Measurement of bone mineral density of the lumbar spine. RESULT(S): Improvements from admission to the end of retreatment were significant for dysmenorrhea, pelvic pain, tenderness, induration, and dyspareunia. Three months after retreatment ended, mean symptom scores for dysmenorrhea and pelvic tenderness, although worse than at the end of retreatment, were still significantly better than scores at admission. Mean bone mineral density 3 months after retreatment was 0.56% lower than before retreatment and 1.94% lower than before initial treatment. CONCLUSION(S): Three-month nafarelin retreatment for recurrent endometriosis symptoms was effective and safe.

A randomized clinical trial of oxidized regenerated cellulose adhesion barrier (Interceed, TC7) alone or in combination with heparin.

OBJECTIVE: To compare the efficacy of heparin-saturated oxidized regenerated cellulose absorbable adhesion barrier, Interceed (TC7; Johnson and Johnson Medical Inc., New Brunswick, NJ) to oxidized regenerated cellulose alone for the prevention of postoperative adhesions. DESIGN: Clinical trial. By random assignment, one ovary was wrapped in oxidized regenerated cellulose, and the contralateral ovary was wrapped in oxidized regenerated cellulose saturated with a heparin solution (1,000 U/mL). PATIENT(S): Forty women with defects on both ovaries due to adhesiolysis and/or ovarian cystectomy. MAIN OUTCOME MEASURE: Adhesion formation and raw ovarian surface area were assessed at second-look laparoscopy 10 days to 16 weeks later. RESULT(S): At the second-look laparascopy-adhesions were present on 52.5% (21/40) of the ovaries treated with oxidized regenerated cellulose plus heparin and in 65% (26/40) of the contralateral ovaries treated with oxidized regenerated cellulose alone. For ovaries treated with oxidized regenerated cellulose plus heparin, the raw surface area was reduced from 9.41 +/- 1.27 cm2 (mean +/- SE) at laparotomy to 1.33 +/- 0.52 cm2 at second-look laparoscopy. The corresponding figures for ovaries treated with oxidized regenerated cellulose alone were from 10.24 +/- 1.08 to 1.92 +/- 0.54 cm2, respectively. The mean difference between the reductions in raw surface area (85.9% for oxidized regenerated cellulose plus heparin; 81.3% for oxidized regenerated cellulose alone) was not significantly different from zero (difference = - 0.24 cm2; 95% confidence interval = -2.56 to 3.04). CONCLUSION(S): Adding heparin did not enhance significantly the adhesion-reducing capacity of oxidized regenerated cellulose adhesion barrier when applied to ovarian surfaces after cystectomy and/or ovariolysis at laparotomy. This conclusion is subject to the possibility of a type II error.

Therapeutic efficacy and bone mineral density response during and following a three-month re-treatment of endometriosis with nafarelin (Synarel).

OBJECTIVE: Our goal was to determine the effects of a repeated course of the gonadotropin-releasing hormone agonist nafarelin on symptoms and signs of endometriosis and lumbar and distal radius bone mineral density. STUDY DESIGN: Forty-five women previously treated for 6 months with nafarelin, who had recurrent symptoms and signs of endometriosis, received 400 mcg/day of nafarelin intranasally for 3 months. Efficacy was evaluated by changes in severity of symptoms and signs. Lumbar bone mineral density was measured by dual-energy x-ray absorptiometry and distal radius bone mineral density by single-photon absorptiometry. Bone mineral density was also measured in 10 control volunteers. RESULTS: Repeated 3-month treatment significantly alleviated recurrent symptoms and signs of endometriosis. Lumbar bone mineral density decreased significantly by a mean of 2% at the end of treatment; this loss was restored within 3 to 6 months after treatment completion. No bone mineral density decline occurred in the radius. Bone mineral density changes in the control group were statistically insignificant. CONCLUSIONS: A repeated 3-month course of nafarelin treatment significantly relieved recurrent endometriotic symptoms and signs without sustained loss of bone mineral density.

Memory complaints associated with the use of gonadotropin-releasing hormone agonists: a preliminary study.

OBJECTIVES: To study the effect of GnRH agonist (GnRH-a) treatment on memory and to assess the role of psychological factors. DESIGN: A randomized prospective study. SETTING: An academic teaching hospital. PARTICIPANTS: Women with endometriosis and infertility or endometriosis alone. MAIN OUTCOME MEASURES: Memory Observation Questionnaire, Profile of Mood States, Health Concerns scale, a weekly diary of adverse effects. RESULTS: Perceived memory functioning decreased during GnRH-a administration and by the final week of treatment 44% of women reported moderate to marked impairment in comparison to community norms. Prospective memory was most affected and withdrawal of GnRH-a treatment resulted in a return to normal memory functioning. Impairment was not related to excessive health concerns or mood changes and was uncorrelated with other adverse effects. CONCLUSIONS: Memory disruption may be a more common side effect of GnRH-a treatment than currently is recognized. Problems were temporary and more likely a result of rapid estrogen depletion than a consequence of mood, somatic distress, or personality factors.

The pregnancy rates of cohorts of idiopathic infertility couples gives insights into the underlying mechanism of infertility.

OBJECTIVES: To determine causes of "idiopathic" infertility, the IVF-ET experience of three cohorts of couples with this diagnosis was examined. DESIGN: Three cohorts of idiopathic infertility couples undergoing IVF-ET: a "failed IUI" group, three previous controlled ovarian hyperstimulation (COH)-IUI cycles with no pregnancies; a "conversion" group, patients converted during a COH-IUI cycle to IVF-ET because of excess follicle numbers; and a "direct IVF" group, patients proceeding directly to IVF-ET were compared. SETTING: A tertiary referral reproductive medicine unit. PARTICIPANTS: Forty-one idiopathic infertility couples. INTERVENTION: In vitro fertilization-ET. MAIN OUTCOME MEASURES: Number of oocytes retrieved, percent oocytes fertilized, number embryos per ET, implantation rate, percent pregnancy per cycle. RESULTS: The cohorts had similar fertilization rates and mean (+/- SD) number of pre-embryos transferred. The conversion group demonstrated a higher pregnancy rate (PR) per cycle and a higher E2 concentration than the other groups. The PR of 35.0% in the direct IVF group appeared higher than the 16.7% rate observed in the failed IUI group. CONCLUSIONS: Our observation of a lower PR in couples in the failed IUI group (16.7%) than in couples in the direct IVF group (35.0%) suggests pre-embryo developmental problems or implantation problems as likely important etiologies for a large proportion of idiopathic infertility couples. However, as the conversion group demonstrated both a significantly higher E2 concentration ([E2]) and per cycle PR than the other cohorts with similar fertilization and pre-embryo transfer rates. Subjects converted in a COH-IUI cycle to IVF-ET are thus either more likely to produce pre-embryos more genetically capable of continued development to implantation stage (i.e., better oocytes recruited and fertilized) or due to the higher [E2] to have endometrium more receptive to implantation. Neither undiagnosed tubal factors nor fertilization problems appear to be major etiologic contributors.

Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain.

OBJECTIVES: To determine the effectiveness of a 3-month course of nafarelin and, furthermore, to determine the long-term efficacy in patients treated for 3 and 6 months with nafarelin for symptoms associated with endometriosis. DESIGN: Double-blind, prospective, multicenter, clinical trial. SETTING: Fifteen reproductive endocrine clinics throughout the United States. PATIENTS: One hundred seventy-nine women with pelvic pain and endometriosis. INTERVENTIONS: Patients were assigned randomly to 3 months nafarelin followed by 3 months of placebo (n = 91) or to 6 months nafarelin (n = 88) in a prospective, randomized, double-blind multicenter trial. Patients were followed for 12 months after cessation of therapy. MAIN OUTCOME MEASURES: Patient-reported pain scores and physician-reported physical exam findings. RESULTS: Pain scores dropped significantly by the end of treatment in both groups. Symptoms recurred in both groups, and pain scores gradually increased during the follow-up period but always remained below baseline in both groups. No significant difference in efficacy was noted between the groups. A total of 26% of patients in each group underwent retreatment for recurrent symptoms. CONCLUSIONS: A 3-month course of nafarelin provided effective symptom relief for endometriosis. One year follow-up demonstrated continued pain relief but with gradual return of symptoms.

Randomized trial of partial zona dissection for male infertility.

OBJECTIVES: To compare IVF rates using partial zona dissection versus zona intact insemination in couples with male infertility. To analyze pregnancy rates relative to sperm characteristics, fertilization rates, and treatment. DESIGN: Randomized prospective comparison of fertilization in sibling oocytes. Transfer of the three best quality embryos from one or both treatments. SETTING: Department of Gynaecology and Reproductive Medicine, University Hospital, London, Ontario, Canada. PARTICIPANTS: Thirty-two couples undergoing IVF with a principal diagnosis of male infertility. INTERVENTION: Treatment with partial zona dissection. MAIN OUTCOME MEASURES: Fertilization and pregnancy. RESULTS: Fertilization rates were 26% and 9% after partial zona dissection and IVF, respectively. Polyspermy was < 1% in each treatment. There were five singleton pregnancies in 29 completed cycles, three in cycles with fertilization only by partial zona dissection and two in cycles with both partial zona dissection and IVF fertilization. There were no pregnancies after fertilization by IVF only. Stepwise logistic regression analysis indicated that pregnancy was related to partial zona dissection, initial sperm concentration, and total acrosin activity. CONCLUSION: Partial zona dissection was associated with minimal polyspermic fertilization and higher normal fertilization rates than sibling oocytes treated by modified IVF. Pregnancy occurred only after transfer of embryos from partial zona dissection or combined partial zona dissection and IVF.

Confounding variables affecting in vitro fertilization success: a decade of experience.

PURPOSE: To evaluate etiology of infertility, female age, ovarian response and stimulation protocol in affecting in vitro fertilization (IVF) success. METHODS: Retrospective analysis was used. Computer records of all 5209 cycles initiated in 2391 couples from February 1, 1984 to December 31, 1993 were analyzed. RESULTS: There were 644 intrauterine, 24 solely ectopic and 7 heterotopic pregnancies. Pregnancy rates increased with number of embryos transferred with a significant increase still found between transfer of three or four embryos. Multiple gestations also increased in association with an increasing number of embryos transferred. Pregnancy rates per cycle did not decline with repeated cycles. Reduced pregnancy rates were associated with a primary diagnosis of male infertility. Covariates associated with a better pregnancy rate were younger age of the female partner or higher peak preovulatory serum estradiol. Routine administration of GnRH-agonist was associated with a reduced cycle cancellation rate, an increase in oocytes retrieved and an improved pregnancy rate. CONCLUSIONS: Couples with male infertility and increased female age should be counselled regarding the reduced prognosis for success.

Nafarelin acetate for pituitary down-regulation in in vitro fertilization. Comparison of two dosages.

The objective of this study was to evaluate the efficacy of intranasal (IN) nafarelin acetate (NA), 400 micrograms/d and 600 micrograms/d, in a luteal-phase-start, long protocol in women undergoing their first in vitro fertilization (IVF) cycle. A sequential comparison of 200 consecutive first IVF cycles, the study was performed in the Department of Gynaecology and Reproductive Medicine, University Hospital, London, Ontario, Canada. The participants were 200 first-cycle IVF patients who were regularly cycling--100 NA 400 micrograms IN followed by 100 NA 600 micrograms IN. Eighty-two percent of the NA 400 micrograms group were adequately suppressed after 11 days of treatment (serum estradiol < or = 150 pmol/L) as compared to 87% with NA 600 micrograms/d. These results compare favorably with those in a historical control group of 179 subjects receiving daily leuprolide acetate (LA), 0.5 mg subcutaneously, in their first cycle of IVF. The amount of human menopausal gonadotropin required for optimal follicular development was similar for the two NA groups. Clinical pregnancy rates were 13% per cycle and 21.7% per embryo transfer (ET) for NA 400 micrograms od and 19% per cycle and 30.1%/ET for NA 600 micrograms od (normal standard dose). No spontaneous luteinizing hormone (LH) surges occurred in any subject. Patient counseling and instruction time for NA use, which required nursing time, averaged five minutes per patient and an additional five minutes of video-viewing time. NA, 400 micrograms and 600 micrograms per day, appear to be acceptable alternate choices for pituitary down-regulation in a luteal-phase-start, long down-regulation protocol for IVF.(ABSTRACT TRUNCATED AT 250 WORDS)

Nafarelin therapy in endometriosis: long-term effects on bone mineral density.

OBJECTIVE: The study intent was to examine long-term effects on bone mass of 3 or 6 months of nafarelin therapy for endometriosis. STUDY DESIGN: Women with established endometriosis (N = 173) were randomized to receive nafarelin (200 micrograms intranasally twice a day) for either 3 or 6 months in a double-blind fashion. Bone mineral density was measured by dual energy x-ray absorptiometry at lumbar spine and proximal femoral sites for 18 months. RESULTS: Bone mineral density declined at spinal and femoral sites similarly in both 3- and 6-month treatment groups. There was a partial, but incomplete, return to baseline levels after 12 to 15 months of follow-up. The recovery of bone mass was more complete in subjects with higher dietary calcium intakes. CONCLUSION: Nafarelin therapy for endometriosis results in a sustained loss of spinal and femoral bone density, particularly in women with lower calcium intakes.

Direct antisperm antibodies using enzyme immunoassay or immunobeads. A prospective cohort comparison.

An enzyme immunoassay for detecting antisperm antibodies directly on sperm was compared to immunobeads in a prospective cohort design. In a series of 112 divided ejaculates evaluated for assisted reproductive technologies, there was moderate overall agreement (kappa = .64) between the methods. All ejaculates positive by immunobeads were also positive by enzyme immunoassay. The enzyme immunoassay could be performed even on oligospermic specimens. When both assays could be employed, the enzyme immunoassay was positive more often (P = .001). Positive specimens by enzyme immunoassay often bound IgA-class antibodies alone, without IgG. Enzyme immunoassay results may represent false-positive results or a new, lower threshold for antibody detection.

Transferring more embryos increases risk of heterotopic pregnancy.

OBJECTIVES: To analyze symptoms and signs that may distinguish heterotopic pregnancy from solely ectopic pregnancy (EP) after IVF. To determine if the number of embryos transferred is a risk factor for heterotopic compared with solely EP. DESIGN: Retrospective cohort of 587 IVF pregnancies, 328 with distorted tubal anatomy. SETTING: University Hospital, London, a referral center for Ontario provincial government-supported assisted reproductive technologies. PARTICIPANTS: Couples undergoing IVF. INTERVENTION: None. MAIN OUTCOME MEASURES: Heterotopic pregnancy, solely EP, intrauterine pregnancy, and distorted pelvic anatomy. RESULTS: Of 587 pregnancies, 7 were heterotopic pregnancies and 24 were solely EP, all in the subset of 328 women with distorted tubal anatomy. Symptoms, signs and time of diagnosis were not different between heterotopic and solely ectopic gestations. Compared with solely EP, heterotopic pregnancies were associated with transfer of more embryos. With four or more embryos transferred, the odds ratio for development of heterotopic versus solely ectopic gestation was 10.0. CONCLUSION: Heterotopic pregnancy occurred in 2% of gestations after IVF, all in women with distorted tubal anatomy. Transfer of four or more embryos was a risk factor for heterotopic pregnancy.

Results of a double-blind, placebo-controlled clinical trial program of single-dose ceftizoxime versus multiple-dose cefoxitin as prophylaxis for patients undergoing vaginal and abdominal hysterectomy.

In a series of three double-blind, controlled, clinical studies, the efficacy and safety of a single 1 gram dose of ceftizoxime were compared with those of a standard regimen, three 2 gram doses of cefoxitin, for prophylaxis of perioperative infection in women undergoing abdominal or vaginal hysterectomy. Two hundred and twenty-seven patients received ceftizoxime prophylaxis and 234 patients received cefoxitin prophylaxis. Study 1 entered 110 patients in Dallas, Texas and Los Angeles, California. Study 2 entered 242 patients in Canada. Study 3 entered 109 patients in Denver, Colorado. Within studies, the distribution of surgical procedures was comparable between antibiotic groups. The groups were similar for demographic and medical factors at each center and overall. Analyses were performed within and across studies, applying consistent criteria to the selection of evaluable patients and to the definitions of prophylactic success and primary and secondary prophylactic failure. Three hundred and sixteen patients were evaluable, 160 who received ceftizoxime and 156 who received cefoxitin. Overall, complete prophylactic success occurred in 138 of 160 evaluable patients (86.3 percent) receiving ceftizoxime and 128 of 156 evaluable patients (82.1 percent) receiving cefoxitin. Prophylactic success rates differed by study as well as by type of hysterectomy. In studies 1 and 2, prophylactic success rates for ceftizoxime were 95.1 and 87.6 percent, respectively, versus 93.1 and 87.8 percent for cefoxitin. In study 3, success rates were lowest, 70.0 percent for ceftizoxime and 59.5 percent for cefoxitin. Among evaluable patients overall, prophylactic success rates after vaginal hysterectomy were 91.0 percent for those receiving ceftizoxime and 85.1 percent for those receiving cefoxitin. After abdominal hysterectomy, success rates were 78.3 percent for both groups. Febrile morbidity rates and duration of hospitalization were comparable for both groups across all studies and within individual studies. Ceftizoxime and cefoxitin were safe and well tolerated. The results of these controlled studies indicate that single-dose ceftizoxime is as effective and safe as multiple-dose cefoxitin when used as adjunctive chemoprophylaxis in patients at risk of postoperative infection after vaginal or abdominal hysterectomy.

Risk of repeated spontaneous luteinizing hormone surges in ovarian stimulation for in vitro fertilization.

Although spontaneous luteinizing hormone (LH) surges are preventable with gonadotropin releasing hormone agonist (GnRH-a) inclusion in ovarian stimulation protocols, GnRH-a-containing protocols are more expensive and associated with an increased risk of ovarian hyper-stimulation syndrome. The present study assessed whether spontaneous LH surges occur in predictable patterns, allowing GnRH-a to be utilized selectively. We assessed 1,103 patients receiving clomiphene citrate/human menopausal gonadotropin (CC/hMG) without GnRH-a for their first in vitro fertilization (IVF) cycle and observed spontaneous LH surges in 30.4%. When patients who demonstrated a spontaneous LH surge received a second CC/hMG stimulation protocol, 45.9% surged again. Of those patients who did not demonstrate a spontaneous LH surge in their initial CC/hMG cycle, only 23.0%, significantly less (P < .001), surged in their second cycle. Of those patients who did not surge in their first two cycles, only 15.7% had an LH surge in their third cycle (P < .001). Thus, if all patients received CC/hMG without GnRH-a as their first IVF stimulation protocol, GnRH-a could be reserved for patients who have demonstrated a spontaneous LH surge. By tailoring the treatment plan, the pregnancy rate would be optimized while decreasing cycle cancellations due to spontaneous LH surges in those patients susceptible to LH surges and limiting costs and inconvenience for patients unlikely to surge spontaneously.