A multicentre randomized controlled trial of expectant management versus IVF in women with Fallopian tube patency.

BACKGROUND: Although observational studies suggest that IVF is more effective than no treatment for women with Fallopian tube patency, this has not been tested rigorously in a randomized controlled trial (RCT). METHODS: Eligible consenting couples planning their first treatment cycle in five Canadian fertility clinics received either IVF, within 90 days of randomization, or a period of 90 days with no treatment. Random allocation was stratified by female age and sperm quality, and administered using numbered, opaque, sealed envelopes. Follow-up assessed live birth and associated morbidity. RESULTS: Sixty-eight couples were randomized to a first cycle of IVF and 71 couples had 3 months without treatment. The live birth rates were 20/68 (29%) and 1/71 (1%), respectively. The single delivery in the untreated group was of twins, as were six of the 20 IVF deliveries (30%). An average of 2.0 embryos were transferred and no triplet pregnancies resulted. The relative likelihood of delivery after allocation to IVF was 20.9-fold higher than after allocation to no treatment [95% confidence interval (CI) 2.8-155]. The presence of abnormal sperm did not reduce this likelihood. Treating four women (95% CI 3-6) with one cycle of IVF is required to achieve a single additional birth. CONCLUSIONS: This study provides a valid and up-to-date comparison for policy makers and patients as they make choices around IVF, accurately measuring and confirming a major benefit from treatment.

Transvaginal ultrasound detection of multifollicular ovaries in non-hirsute ovulatory women.

OBJECTIVES: To characterize ovarian morphology in a group of ovulatory, non-hirsute women with infertility and normal circulating levels of gonadotropins and sex steroids. METHODS: Thirty-three women with normal physical examinations, regular ovulatory menses, and absence of hirsutism (Ferriman-Gallwey score < or = 7) were studied. No woman had thyroid disease, galactorrhea, polycystic ovary syndrome, 21-hydroxylase deficiency or diabetes. Two-dimensional (2D) transvaginal sonography (TVS) was used to measure follicle size and ovarian volume on menstrual cycle day 5. Three-dimensional (3D) TVS images were stored to determine the number of follicles (measuring 2-10 mm in diameter) in the largest sonographic plane. Fasting blood sampling and oral glucose tolerance testing were performed to assess serum gonadotropin and sex steroid levels as well as glucose tolerance. RESULTS: The median ovarian volume by 2D-TVS imaging was 7.2 (range, 2.3-15.8) cm(3) (n = 64 ovaries). No follicles were > 10 mm in diameter. The median number of follicles by 3D-TVS was 4 (range, 2-8) (n = 63 ovaries) in the largest sonographic plane. Fourteen of 63 ovaries (22%) had six or more small follicles in one plane distributed within normal stroma (multifollicular ovary, MFO). No ovary had 10 or more follicles in one plane located within abundant stroma (polycystic ovary). Of 33 women examined, 20 women (61%) had apparently normal ovaries bilaterally, while 13 (39%) had at least one MFO. There were no significant differences between women with and those without MFO in serum gonadotropin and steroid levels or glucose tolerance. CONCLUSIONS: MFO is a common morphological variant in non-hirsute ovulatory women with normal gonadotropin secretion and ovarian steroidogenesis.

Treatment of atypical endometrial hyperplasia with an insulin-sensitizing agent.

Endometrial cancer and hyperplasia have long been associated with diabetes. Hyperinsulinemia may have a direct mitogenic effect on the endometrium and may inhibit the effect of progestogen therapy. This case report describes the treatment of a patient with atypical endometrial hyperplasia with an insulin-sensitizing agent. A 37-year-old patient presented after failed treatment of endometrial hyperplasia with progestogen therapy. One month after initiating metformin therapy the patient's endometrial biopsy demonstrated proliferative endometrium. This patient's atypical endometrial hyperplasia regressed after the initiation of treatment with an insulin-sensitizing agent. This relatively new class of drugs may provide an adjunct to the therapy of endometrial hyperplasia.

IVF births and pregnancies: an exploration of two methods of assessment using life-table analysis.

PURPOSE: Our purpose was to explore two methods of expressing the performance of IVF programs. METHODS: Using life-table methods, hazard and cure rates and a "monthly fecundability rate" were calculated for an Ontario IVF clinic. The rates were evaluated for their meaningfulness as indicators of the clinic's performance. RESULTS AND CONCLUSIONS: While the hazard rate describes monthly fertility among those who will eventually become pregnant, the fecundability rate describes fertility for all patients who enter the program, making it the more appropriate index for program comparisons. However, from a prospective patient's perspective, both methods are valid indices for summarizing a program's performance.

A comparison of methods for measuring socio-economic status by occupation or postal area.

Seven methods of estimating socio-economic status (SES) were compared, including four based on data specific to individuals (Blishen, Pineo-Porter, British Registrar General, Hollingshead) and three based on the average characteristics of the postal code area in which people live (income alone, education alone, income and education combined). Data from the files of 151 patients undergoing in vitro fertilization were used. The four individual scales were highly correlated among themselves (Spearman's correlation coefficient between 0.6 and 0.9) but only moderately correlated with the measures based on postal code (Spearman's correlation coefficient between 0.2 and 0.3).

Hysteroscopic endometrial ablation is an effective alternative to hysterectomy in women with menorrhagia and large uteri.

STUDY OBJECTIVES: To examine the feasibility, safety, and outcome of hysteroscopic endometrial ablation, and to determine the volume of fluid absorbed during resection versus rollerball coagulation in women with menorrhagia and large uteri. DESIGN: Retrospective review (Canadian Task Force classification II-2). SETTING: University-affiliated teaching hospital. PATIENTS: Forty-two consecutive patients (mean +/- SD age 45.6 +/- 6 yrs) with uterine size greater than 12 weeks (cavity >12 cm). Intervention. Endometrial ablation; 26 (62%) women were pretreated to thin the endometrium. MEASUREMENTS AND MAIN RESULTS: Resection was performed in 27 patients (65%) and rollerball coagulation in 15 (35%). Ablation was successfully performed in all patients in a day surgery setting. Multiple regression analysis examined the relationship of uterine size, pretreatment, procedure, and duration of surgery to amount of glycine absorbed. Glycine absorption was higher with resection than with coagulation (p = 0.04). Fluid absorption correlated with type of procedure (r = 0.32, p = 0.04) but not with duration of the procedure, uterine size, or pretreatment. One patient with uterine fibroids and one with endometrial adenocarcinoma had hysterectomy. With follow-up of 39 (95%) of 41 women (excluding the one with adenocarcinoma) for 14 +/- 2 months, 38 (93%) were very satisfied. Thirty (73%) had amenorrhea, six (15%) had hypomenorrhea (<3 pads/day), and three (7%) had eumenorrhea (<10 pads/day). CONCLUSION: Hysteroscopic endometrial ablation may be a feasible, safe, and effective alternative to hysterectomy in women with menorrhagia and large uteri.

A tale of two syndromes: ovarian hyperstimulation and abdominal compartment.

Abdominal compartment syndrome complicated severe ovarian hyperstimulation in a 35 year old woman with multiple bowel resections due to Crohn's disease. Pain from ovarian enlargement necessitated hospital admission. Despite intravenous fluid administration and heparin prophylaxis, ilio-femoral deep vein thrombosis developed. Treatment by intravenous heparin was complicated by repeated intra-ovarian bleeding, anaemia and acute renal failure requiring haemodialysis. Intra-abdominal pressures were elevated. After placement of an inferior vena caval filter and discontinuation of heparin, there was slow spontaneous recovery without surgery.

Effect of DHA supplementation on DHA status and sperm motility in asthenozoospermic males.

The effects of supplementation with docosahexaenoic acid (DHA) on DHA levels in serum, seminal plasma, and sperm of asthenozoospermic men as well as on sperm motility were examined in a randomized, double-blind, placebo-controlled manner. Asthenozoospermic men (n = 28; < or =50% motility) were supplemented with 0, 400, or 800 mg DHA/d for 3 mon. Sperm motility and the fatty acid composition of serum, seminal plasma, and sperm phospholipid were determined before and after supplementation. In serum, DHA supplementation resulted in decreases in 22:4n-6 (-30% in the 800-mg DHA group only) and total n-6 (-6 and -12% in the 400- and 800-mg DHA groups, respectively) fatty acids. Increases were noted in DHA (71 and 131% in the 400- and 800-mg DHA groups, respectively), total n-3 fatty acids (42 and 67% in the 400- and 800-mg DHA groups, respectively), and the n-3/n-6 ratio (50 and 93% in the 400- and 800-mg DHA groups, respectively). In seminal plasma, DHA supplementation resulted in a decrease in 22:4n-6 (-31% in the 800-mg DHA group only) and an increase in the ratio of n-3 to n-6 (35 and 33% in the 400- and 800-mg DHA groups, respectively). There were insignificant increases in DHA and total n-3 fatty acids. In sperm, decreases were noted in 22:4n-6 (-37 and -31% in the 400- and 800-mg DHA groups, respectively). There were no other changes. There was no effect of DHA supplementation on sperm motility. The results show that dietary DHA supplementation results in increased serum--and possibly seminal plasma--phospholipid DHA levels, without affecting the incorporation of DHA into the spermatozoa phospholipid in asthenozoospermic men. This inability of DHA to be incorporated into sperm phospholipid is most likely responsible for the observed lack of effect of DHA supplementation on sperm motility.

Toward a more meaningful in vitro fertilization success rate.

PURPOSE: The objective was to explore the variability in in vitro fertilization (IVF) success rates. METHODS: Published success rates from IVF clinics in North America were investigated to establish types of biases and potential inaccuracies. RESULTS: Success rates reported by IVF clinics vary with regard to the indices and patient populations used to compute them. Selection bias and misunderstood statistics are major factors contributing to the inappropriateness of certain rates. CONCLUSIONS: The influence of privatization and market forces also may contribute to the need to oversimplify IVF statistics.

Fatty acid analysis of blood serum, seminal plasma, and spermatozoa of normozoospermic vs. asthenozoospermic males.

Docosahexaenoic acid (DHA; 22:6n-3) is found in extremely high levels in human ejaculate with the majority occurring in the spermatozoa. However, the relative concentration of DHA and other fatty acids, in blood serum, seminal plasma, and spermatozoa of asthenozoospermic vs. normozoospermic individuals is not known. We analyzed the phospholipid fatty acid composition of blood serum, seminal plasma, and spermatozoa of normozoospermic men and asthenozoospermic men in order to determine if DHA levels, as well as the levels of other fatty acids, differed. The serum phospholipid DHA levels were similar in the two groups, suggesting similar intakes of dietary DHA. On the other hand, seminal plasma levels of DHA (3.0 vs. 3.7%) and total polyunsaturated fatty acids (PUFA) (11.8 vs. 13.5%) were significantly lower in asthenozoospermic vs. normozoospermic men, respectively, while 18:1 (19.0 vs. 16.8%) and monounsaturated fatty acids (MUFA) (24.2 vs. 21.7%) were significantly higher in the asthenozoospermic vs. the normozoospermic men. Spermatozoa from asthenozoospermic men had higher levels of 18:1, 20:0, 22:0, 22:1, and 24:0 than sperm from normozoospermic men, and lower levels of 18:0 and DHA (8.2 vs. 13.8%). Furthermore, total MUFA (19.3 vs. 16.5%) was higher and total PUFA (19.0 vs. 24.0%), n-3 fatty acids (9.3 vs. 14.6%), and the ratio of n-3 to n-6 fatty acids (1.0 vs. 1.6) were lower in the asthenozoospermic men. Therefore, in asthenozoospermic individuals, lower levels of DHA in the seminal plasma, but not in the blood serum, mimic the decreased concentrations of DHA in the spermatozoa. This suggests that the lower concentrations of spermatozoon DHA in these individuals are due not to dietary differences but to some type of metabolic difference in the asthenozoospermic men.

Precision and method bias of two assays for oestradiol: consequences for decisions in assisted reproduction.

Oestradiol monitoring in assisted reproduction is empirical, with no proof of benefit. Precise oestradiol estimation will be an essential pre-requisite for high quality evaluation of possible differences between combined and ultrasound-only monitoring. Objectives of the present trial were independent method comparison and bias estimation of chemiluminescent immunoassay (CLIA) versus radioimmunoassay for oestradiol. In a prospective comparison, 505 consecutive samples were split and assayed concurrently. Precision (reproducibility), relative bias and logistics were analysed and compared to manufacturers' findings. Correlation between CLIA and radioimmunoassay was excellent. Positive bias with CLIA necessitated altering decision points for therapy. Precision (reproducibility) was superior with CLIA, making it an appropriate candidate method for future randomized trials of the effectiveness of combined oestradiol/ultrasound monitoring for assisted reproduction.

Does withholding gonadotrophin administration prevent severe ovarian hyperstimulation syndrome?

Withholding gonadotrophin administration (coasting) may prevent severe ovarian hyperstimulation syndrome (OHSS). To ascertain the effectiveness of this protection a cohort of 252 consecutive in-vitro fertilization (IVF) or IVF with intracytoplasmic sperm injection (ICSI) cycles was studied. Twenty women with exaggerated response were treated with coasting. Despite coasting, four patients developed severe OHSS requiring hospitalization. Two of these four patients also required paracentesis. Multiple regression analysis in coasting cycles revealed severe OHSS was related to youth, number of oocytes retrieved and serum oestradiol prior to human chorionic gonadotrophin (HCG). Risk of developing severe OHSS was multifactorial and not necessarily prevented by withholding gonadotrophin.

Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis.

OBJECTIVE: To evaluate the efficacy of superovulation and IUI versus no treatment for infertility associated with minimal or mild endometriosis. DESIGN: Randomized trial. SETTING(S): London Health Sciences Centre, University Campus, The University of Western Ontario, London, Ontario; and Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada. PATIENT(S): Three hundred eleven cycles in 103 couples in whom minimal or mild endometriosis was the sole identified subfertility factor. INTERVENTION(S): Superovulation with FSH and IUI. MAIN OUTCOME MEASURE(S): Live birth. RESULT(S): Live birth followed 14 of 127 (11%) superovulation and IUI cycles and 4 of 184 (2%) no-treatment cycles. The odds ratio was 5.6 (95% confidence interval 1.8 to 17.4) in favor of superovulation and IUI. CONCLUSION(S): Treatment with superovulation and IUI was associated with superior outcome both by crude live-birth rates and proportional hazard analysis.

Future in vitro fertilization pregnancy potential of women with variably elevated day 3 follicle-stimulating hormone levels.

OBJECTIVE: To determine the IVF-ET pregnancy potential of women with variably elevated day 3 FSH. DESIGN: Cohort evaluation of 1,868 consecutive IVF-ET cycles January 1991 to December 1994. SETTING: University hospital infertility unit. PATIENTS: Four cohorts of couples were defined based on day 3 FSH determinations with an arbitrary threshold of 20 mIU/mL, only > or = 20 mIU/mL, always < 20 mIU/mL, current < 20 mIU/mL but one previous > or = 20 mIU/mL, and current < 20 mIU/mL but two or more previous > or = 20 mIU/mL (conversion factor to SI unit, 1.00). INTERVENTION: In vitro fertilization-embryo transfer. MAIN OUTCOME MEASURE: Fetal heart activity on luteal day 40 transvaginal ultrasound. RESULTS: No pregnancies occurred in 53 cycles with day 3 FSH only > or = 20 mIU/mL. In 1,750 women whose day 3 FSH levels were always < 20 mIU/mL, the pregnancy rate (PR) per cycle was 16.5%. In 54 cycles in which day 3 FSH was > or = 20 one time only, but < 20 mIU/mL during the treatment cycle, the PR was 5.6%. In 11 cycles where two or more previous FSH determinations were > or = 20 mIU/mL but with a current day 3 FSH < 20 mIU/mL, no pregnancies occurred. CONCLUSION: Our data leads us to the conclusion that day 3 FSH determination precede every IVF cycle and that cycles with FSH > or = 20 mIU/mL be canceled. It also suggests that women with two previous elevations of day 3 FSH be discouraged from future IVF cycles. The 5.6% pregnancy per cycle with one previously elevated FSH warrants extreme pessimism in discussion of further cycles.

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.

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.

Cumulative pregnancy rates and pregnancy outcome after in-vitro fertilization: > 5000 cycles at one centre.

Cumulative pregnancy rates and pregnancy outcome analysis are useful methods for advising an infertile couple of the probability of in-vitro fertilization (IVF) success. All 5209 IVF cycles in 2391 couples at University Hospital, London, Ontario, Canada, over 10 years were studied. Cumulative pregnancy rates were estimated using life table analysis. The Cox proportional hazards model was used to estimate the influence of covariates. Oocyte retrieval and embryo transfer were achieved in 84 and 64% of cycles initiated respectively. There were 644 intra-uterine and 24 ectopic pregnancies (13%/cycle initiated, 15%/oocyte retrieval and 20%/embryo transfer). Cumulative pregnancy rates following six cycles were: tubal 55%, idiopathic 65%, endometriosis 60%, multifactorial 63% and male 40%. There were 68 spontaneous abortions (10.6%) and three induced abortions for congenital anomalies. The multiple gestation rate was 22%. Caesarean section and preterm delivery rates were 35 and 20% respectively, due in part to the high proportion of multiple gestations. Of 15 deliveries which resulted in stillbirths and/or neonatal deaths, 12 were multiple gestations; 18 pregnancies (3.3%) were complicated by congenital malformations. No increases in congenital malformations or spontaneous abortions were identified. Cumulative pregnancy rates were lower in cases of male infertility. Success rates did not decline with successive IVF cycles. IVF is an evolving infertility treatment.