Treatment of patients with long-standing unexplained subfertility with in vitro fertilization

OBJECTIVE: To evaluate whether IVF is an effective treatment for long-standing unexplained subfertility. DESIGN: Retrospective cohort study. SETTING: Tertiary care infertility center in a university hospital. PATIENT(S): Two hundred two couples with unexplained subfertility of 2 years' duration or more who attended the center for their first IVF attempt. INTERVENTION(S): Couples were placed on a waiting list for IVF. They received no treatment until IVF was started. MAIN OUTCOME MEASURE(S): Pregnancy rate (PR) while on the waiting list and PR after IVF treatment. RESULT(S): Complete data sets were available for 131 couples. Seventeen of 131 women became pregnant while waiting for IVF treatment (PR 0.9% per exposure cycle), whereas 45 of 119 receiving IVF treatment became pregnant (PR 17% per IVF attempt). CONCLUSION(S): IVF treatment has substantial added value over waiting and is an efficient treatment for long-standing unexplained subfertility.     

Development of brief stress management support groups for couples undergoing in vitro fertilization treatment

OBJECTIVE: To develop and assess the efficacy of couples stress management groups offered concurrently with IVF treatment. DESIGN: Couples in IVF treatment were given the option of participating in a biweekly stress management group. SETTING: The IVF treatment clinic at Wilford Hall Medical Center, San Antonio, Texas. PATIENT(S): One or both members of 17 couples participated in the program in one of four group cycles. INTERVENTION(S): A cognitive behavioral treatment model was used to help couples process their feelings and cognitions about the impact of infertility on their life and explore their expectations about their future options for becoming parents. MAIN OUTCOME MEASURE(S): Couples were asked to anonymously evaluate the efficacy of the group after they had completed their IVF cycle. RESULT(S): Participants reported that the group helped them deal with the stress of infertility and that they valued the social bonds they formed with other group members. CONCLUSION(S): These data suggest that brief focused group therapy, offered while couples are undergoing IVF, is an effective way to help people deal with the stress of infertility treatment.     

In vitro fertilization-intracytoplasmic sperm injection split: an insemination method to prevent fertilization failure

OBJECTIVE: To determine whether the performance of intracytoplasmic sperm injection (ICSI) in cases of unexplained infertility and of borderline semen parameters can prevent fertilization failure. DESIGN: Prospective cohort study. SETTING: Hospital-based assisted reproductive technology program. PATIENT(S): Sixty couples with unexplained infertility (group 1) and 50 couples with borderline semen (group 2). INTERVENTION(S): Conventional IVF and ICSI were performed on sibling oocyte cumulus complexes. MAIN OUTCOME MEASURE(S): Rate of fertilization according to patient diagnosis. RESULT(S): The fertilization rate per oocyte cumulus complex in couples with unexplained infertility (group 1) was significantly higher with ICSI (65.3%) compared with IVF insemination (48.1%). Fertilization rates per OCC in couples with borderline semen (group 2) were not significantly different between ICSI (58.1%) and IVF (56.7%). In group 1, failure of fertilization after IVF insemination occurred in 10 of the 60 couples (16.7%) and in none with ICSI. In group 2, 2 of 50 couples (4.0%) failed fertilization by IVF, and 1 (2.0%) failed with ICSI. No couple in group 2 failed both IVF insemination and ICSI. CONCLUSION(S): In couples with unexplained infertility, a higher fertilization rate was achieved through ICSI compared with conventional IVF. No such benefit could be demonstrated for couples with borderline semen parameters. The use of ICSI rescued 12 of 110 cycles (10.9%) where IVF failed. Adoption of the ICSI-IVF insemination split in cases of unexplained infertility may help eliminate fertilization failures.     

Comparison of stimulation with clomiphene citrate in combination with recombinant follicle-stimulating hormone and recombinant luteinizing hormone to stimulation with a gonadotropin-releasing hormone agonist protocol: a prospective,randomized study

OBJECTIVE: To compare IVF-ET outcome with a new stimulation protocol using clomiphene citrate (CC) with recombinant FSH and LH to stimulation with the standard long GnRH-a protocol. DESIGN: Prospective randomized study. SETTING: Outpatient infertility clinic in Vienna, Austria. PATIENT(S): Two hundred ninety-four infertile women undergoing IVF-ET; 154 IVF cycles stimulated with CC + recombinant FSH + recombinant LH (group A) and 140 cycles with long GnRH-a suppression + recombinant FSH (group B). INTERVENTION(S): Controlled ovarian hyperstimulation, egg retrieval, and ET. MAIN OUTCOME MEASURE(S): Cycle parameters (number of oocytes, fertilization, number of embryos) and outcome (pregnancy rate, cancellation rate, ovarian hyperstimulation syndrome [OHSS]). RESULT(S): Pregnancy rate per ET was 42.9% (implantation rate, 21.3%) in group A and 36.6% (17.4%) in group B. Cancellation rates were similar. The OHSS occurred in four cases (3%) in group A and 12 cases (10%) in group B. CONCLUSION(S): Stimulation with CC + recombinant FSH + recombinant LH leads to comparable pregnancy rates vs. the long protocol. With this new stimulation, less gonadotropins are used and there is less need for monitoring (lower cost for patient and clinic). The risk of OHSS is reduced as well. Therefore, this protocol should be regarded as the first-line treatment.     

The case for initial treatment with intrauterine insemination as opposed to in vitro fertilization for idiopathic infertility

The recent questioning of the validity of evidence used by the Royal College of Obstetricians and Gynaecologists in recommending ovarian stimulation with intrauterine insemination (IUI) as an effective treatment for couples with unexplained infertility, has re-ignited the debate on what the initial treatment for idiopathic infertility should be. The current best available evidence is used here with the conclusion that the initial treatment for idiopathic infertility should be IUI as opposed to IVF. This conclusion is reached using the results of randomized controlled trials wherever possible, live birth rates rather than pregnancy rates and taking into account efficacy; complications, especially multiple pregnancy rates; patient compliance and cost efficiency. None of these factors indicate that a change of policy to use IVF as first-line treatment in lieu of IUI for unexplained infertility is justified.     

Present concept of unexplained infertility.

Despite improvements in both diagnostic assessment and treatment of infertile couples, many couples still have no explanation for their infertility. Unexplained infertility (the failure to conceive of a couple in whom no definitive cause for infertility can be found) has an incidence of 10-20% in all infertile couples. The incidence varies with the population studied and with the criteria used. Unexplained infertility is not an absolute condition but rather a relative inability to conceive, and many of these couples may conceive without treatment. The treatment options for unexplained infertility are several and the treatment results are promising. Expectant management can be recommended if the woman is under 28-30 years of age and the infertility duration is less than 2-3 years. In vitro fertilization (IVF) has revolutionized the treatment of infertile couples, as well as profoundly increasing the basic understanding of human reproduction. IVF can be used as both a diagnostic and a therapeutic tool in couples with unexplained infertility. The pregnancy rates with IVF are good, at 40% per treatment cycle. In addition, the outcome of pregnancies among women with unexplained infertility is generally comparable to that of spontaneous and other pregnancies using assisted reproductive technologies.     

Intrauterine insemination with controlled ovarian stimulation for treatment of infertility: an audit of a new IUI programme in a low resource setting.

This study is an audit of a new intrauterine insemination (IUI) programme in a low resource private fertility practice in southeast Nigeria. IUI was performed using a Wallace flexible catheter 1 day before or on the day of ovulation after ovarian stimulation with clomiphene citrate. The 18 couples treated had either male (16) or unexplained (2) infertility. The women were between 25 and 49 years and 13 (72.2%) of the couples had primary infertility while the duration of infertility ranged from 3 to 15 years. All the women had tubal patency confirmed by laparoscopy and dye test before undergoing IUI. The pregnancy rates per couple and per insemination cycle and the effect of maternal age and source of semen (partner or donor) were determined. The 18 couples had a total of 48 treatment cycles and five became pregnant (confirmed by early ultrasound scan) giving a pregnancy rate of 27.8% per couple or 10.4% per treatment cycle. The pregnancy rate was 41.7% per couple, 15.6% per treatment cycle for the donor group and 0% for the partner group (p<0.01). Poor sperm quality was responsible for the poor pregnancy outcome in the partner group. The pregnancy rate per couple was 36.5% in women<35 years compared with 14.3% in those>or=35 years (p=0.02). Similarly, the cycle pregnancy rate was significantly higher in women<35 years (16.0% vs 4.4%; p<0.02). There was one (20%) case of twin pregnancy and no miscarriage. Four of the women had a live birth (80%) at term and one had an intrauterine death following severe pre-eclampsia at 29 weeks' gestation. In conclusion, the overall couple and cycle pregnancy rates at our centre is comparable with the rates in many centres. Younger age and good quality semen are good indicators of a successful outcome. Infertile couples should therefore be evaluated early and recommended for this treatment option before advanced female age.     

The predictive value of idiopathic failure to fertilize on the first in vitro fertilization attempt

OBJECTIVE: To investigate the subsequent performance of patients with idiopathic fertilization failure on the first in vitro fertilization (IVF) cycle. DESIGN: A retrospective study of 2,322 consecutive patients undergoing their initial IVF cycle. SETTING: Advanced infertility treatment in an IVF/general infertility clinic. PATIENTS: In 5 years, 94 couples with unexplained failed oocyte fertilization had 270 cycles of treatment. Each couple's performance was tracked through subsequent cycles of treatment. INTERVENTIONS: In vitro fertilization with husband and donor sperm. MAIN OUTCOME MEASURE(S): Investigated retrospectively after 5 years of data collection. RESULTS: Sixty-five couples of the original 94 had a second IVF attempt. Fifty of these successfully fertilized oocytes with husband's sperm and 4 with donor sperm. Nineteen of the 65 couples who continued treatment achieved a pregnancy, and only one couple had continuing fertilization failure. CONCLUSIONS: The prognosis in the study group was surprisingly favorable despite the initial failed IVF treatment cycle.     

Confounding variables affectingin 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.Presented at the 50th Annual Meeting of the American Fertility Society, San Antonio, Texas, November 5–10, 1994.     

A randomized controlled trial of tubal flushing with lipiodol for unexplained infertility.

OBJECTIVE: To test the hypothesis that, in couples with unexplained infertility, tubal flushing with an oil-soluble media (lipiodol) would increase the pregnancy rate within 6 months compared with expectant management. DESIGN: A prospective, randomized, controlled study in which couples were allocated to either a single treatment with lipiodol or no further action. SETTING: Two tertiary referral centers for assisted reproduction. PATIENT(S): Couples with a diagnosis of primary or secondary unexplained infertility based on a normal semen analysis according to World Health Organization criteria, patent fallopian tubes at hysterosalpingography or laparoscopy, and ovulatory menstrual cycles based on midluteal phase progesterone levels or ultrasonic follicle tracking. INTERVENTION(S): In those patients randomized to lipiodol, a single treatment was performed. MAIN OUTCOME MEASURE(S): Biochemical (i.e., positive pregnancy test) and clinical (i.e., fetal heart on ultrasound scan) pregnancy rates. RESULT(S): Seventeen couples were randomized to lipiodol and 17 to expectant treatment. The higher pregnancy rate after lipiodol was statistically significant. There were no complications after lipiodol treatment. CONCLUSION(S): There was a statistically significantly higher pregnancy rate in couples with unexplained infertility randomized to a single tubal flush with lipiodol compared with no treatment.     

Cost-effectiveness of IVF in women 38 years and older.

OBJECTIVE: To compare the cost per delivery in women younger than 38 years with women equal to or older than 38 years of age attempting IVF. METHODS: All couples undergoing IVF treatment between October 1991 and September 1998 were enrolled in this study. A standard protocol of controlled ovarian hyperstimulation was employed throughout the study. Four hundred and seven cases were allocated to two groups - group I composed of patients younger than 38 years of age and group II of patient equal to or older than 38 years of age. The total cost of each successful outcome was the goal of our study. RESULTS: A total of 407 women underwent 722 stimulated cycles for IVF of which 122 cycles (16.89%) did not proceed to oocyte retrieval. We found statistically significant differences in the cancellation rate, the number of hMG ampoules, the number of oocytes retrieved, the number of oocytes fertilized, the number of embryos transferred, the clinical pregnancy rate, the rate of multiple pregnancy, the delivery per initiated cycle and the cost per delivery between the two groups (P<0.05, significant). The cost per delivery in group II was approximately 3.6 times that of group I. CONCLUSIONS: Women age 38 years or more have less chance of a successful outcome from IVF treatment. Couples contemplating IVF should be provided with accurate information about prognosis for the pregnancy and the financial costs.     

Successive pregnancies with delivery of two healthy infants in a couple who was discordant for human immunodeficiency virus infection

OBJECTIVE: To describe two successive pregnancies resulting in two healthy infants in an HIV-discordant couple who underwent IVF-ICSI. DESIGN: Case report. SETTING: University-based infertility clinic. PATIENT(S): A couple seeking fertility treatment in which the male partner was seropositive for HIV-1. INTERVENTION(S): Controlled ovarian hyperstimulation and IVF-ET with ICSI. MAIN OUTCOME MEASURE(S): Pregnancy outcome and HIV-1 seroconversion. RESULT(S): The couple delivered two healthy infants on successive pregnancies with use of IVF-ET with ICSI. CONCLUSION(S): For HIV-discordant couples in which the male partner is seropositive for HIV-1, IVF with ICSI is a viable option.     

The case for initial treatment with intrauterine insemination as opposed to in vitro fertilization for idiopathic infertility

The recent questioning of the validity of evidence used by the Royal College of Obstetricians and Gynaecologists in recommending ovarian stimulation with intrauterine insemination (IUI) as an effective treatment for couples with unexplained infertility, has re-ignited the debate on what the initial treatment for idiopathic infertility should be. The current best available evidence is used here with the conclusion that the initial treatment for idiopathic infertility should be IUI as opposed to IVF. This conclusion is reached using the results of randomized controlled trials wherever possible, live birth rates rather than pregnacy rates and taking into account efficacy; complications, especially multiple pregnancy rates; patient compliance and cost efficiency. None of these factors indicate that a change of policy to use IVF as first-line treatment in lieu of IUI for unexplained infertility is justified.     

Isolated teratozoospermia and intrauterine insemination

OBJECTIVE: This study tests the hypothesis that IUI treatment in cases with isolated teratozoospermia (<10% normal forms using strict criteria, normal motility and normal count), results in a lower cumulative live birth rate compared to cases with normozoospermia. DESIGN: A retrospective cohort study. SETTING: An academic fertility center. PATIENT(S): Eight hundred seventy-two IUI cycles in 440 couples were analyzed. INTERVENTION(S): Couples (n = 440) were classified in three groups: normozoospermia (n = 213), isolated teratozoospermia (n = 104), and male factor infertility (n = 123). MAIN OUTCOME MEASURE(S): Live birth rate per cycle and cumulative live birth rate (CLBR). RESULT(S): The three groups were similar with regard to female age, female infertility factors, and ovarian response after hormonal stimulation. The overall CLBR after four cycles was 41.5%, and was significantly increased in the normozoospermic group (52.8%) when compared to the isolated teratozoospermia group (33.4%) and the male factor infertility group (31.4%). CONCLUSION(S): This study documents for the first time that the CLBR after four IUI cycles is significantly and similarly reduced in couples with isolated teratozoospermia as in couples with other sperm defects, when compared to couples with normozoospermia. As with couples with male factor infertility, couples with isolated teratozoospermia should be counseled about other treatment options such as IVF, as the CLBR after three IVF cycles is 70%-80% in our program.     

Does anovulation induced by oral contraceptives favor pregnancy during the following two menstrual cycles?

OBJECTIVE: To compare IVF and pregnancy outcomes before and after anovulation induced by oral contraceptives.Design: Observational clinical study. SETTING: Infertility clinic. PATIENT(s): Forty women with two intact ovaries (32 of 40 couples with male factor infertility and 8 with unknown causes of infertility) underwent 190 IVF treatment cycles (55 natural cycles and 135 clomiphene citrate-stimulated cycles). INTERVENTION(s): If the women failed to conceive after 2-4 IVF treatment cycles, oral contraceptives were used to induce anovulation for 1 month before IVF was performed in two consecutive cycles. MAIN OUTCOME MEASURE(s): Rates of oocyte retrieval, fertilization, cleavage, preembryo formation, pregnancy, and implantation were compared before and after a period of anovulation. RESULT(s): The pregnancy rate per cycle of the first and second cycle combined (23%) and that of the second cycle alone (30%) after a period of anovulation were significantly higher than that observed before a period of anovulation (9%). CONCLUSION(s): Anovulation induced by oral contraceptives, showing bilateral ovarian quiescence, enhances pregnancy rates in the following two menstrual cycles of IVF treatment.     

Present concept of unexplained infertility

Despite improvements in both diagnostic assessment and treatment of infertile couples, many couples still have no explanation for their infertility. Unexplained infertility (the failure to conceive of a couple in whom no definitive cause for infertility can be found) has an incidence of 10–20% in all infertile couples. The incidence varies with the population studied and with the criteria used. Unexplained infertility is not an absolute condition but rather a relative inability to conceive, and many of these couples may conceive without treatment. The treatment options for unexplained infertility are several and the treatment results are promising. Expectant management can be recommended if the woman is under 28–30 years of age and the infertility duration is less than 2–3 years. In vitro fertilization (IVF) has revolutionized the treatment of infertile couples, as well as profoundly increasing the basic understanding of human reproduction. IVF can be used as both a diagnostic and a therapeutic tool in couples with unexplained infertility. The pregnancy rates with IVF are good, at 40% per treatment cycle. In addition, the outcome of pregnancies among women with unexplained infertility is generally comparable to that of spontaneous and other pregnancies using assisted reproductive technologies.     

Establishment of a successful donor embryo program: medical, ethical, and policy issues

OBJECTIVE: To determine how couples prefer to dispose of their extra embryos and to establish a donor embryo program for the treatment of infertile couples. DESIGN: Cohort study. SETTING: University-based IVF program. PATIENT(S): Patients (n = 365) with cryopreserved embryos in storage for >2 years and eight patients who desired donated embryos for transfer. INTERVENTION(S): An IVF ethics committee was formed to discuss the ethical and policy issues involved in starting an embryo donation program and to establish program guidelines. Couples with embryos cryopreserved for > or = 2 years were contacted to determine their desires for disposition of embryos. Potential recipients of donated embryos were identified in our clinic, and donated embryos were transferred to these patients. MAIN OUTCOME MEASURE(S): Desires for embryo disposition and pregnancy rates. RESULT(S): Most couples elected either to continue storage of their embryos for future use (44%) or to discard their embryos (34%). A minority elected to donate their embryos either to infertile couples (11%) or for research (10%). Eight couples have had donated embryos transferred, and four have conceived ongoing pregnancies. CONCLUSION(S): Although only a small percentage of couples are willing to donate their embryos, the resulting number of embryos for use is substantial. Transfer of donated embryos results in a high pregnancy rate and is a cost-effective treatment of infertility.     

Sperm motility in the semen analysis affects the outcome of superovulation intrauterine insemination in the treatment of infertile Asian couples with male factor infertility

Objective To ascertain the relationship between the initial and unprocessed sperm parameters and pregnancy rates in SOIUI, for Asian couples with male factor infertility
Design Retrospective study.
Setting A large government tertiary-care women's hospital with 15,000 deliveries per year
Population One thousand four hundred and seventy nine couples undergoing 2846 cycles of SOIUI
Methods All couples enrolled in the SOIUI programme were analysed, comparing initial sperm parameters and the post-processed total motile sperm, against pregnancy rates per cycle
Main outcome measures Pregnancy rates in relation to initial sperm parameters and post-processed total motile sperm
Results Ninety-three percent of the couples had male factor infertility. The average normal forms for these men was 14.7%. Overall pregnancy rate was 12.1% per completed SOIUI cycle. We found a significant drop in pregnancy rates if the percentage of motile sperms in the unprocessed sperm sample fell below 30%. We also found that insemination of at least 1 million motile sperm resulted in a significant increase in pregnancy rates
Conclusions We recommend SOIUI as an effective treatment of suitable couples with male infertility, before embarking on IVF. However, if the initial percentage of motile sperm fell below 30%, or if after processing, the total motile sperm count was fewer than 1 million, these couples should consider in vitro fertilisation     

Pregnancy outcomes using donor sperm insemination after failed in vitro fertilization with intracytoplasmic sperm injection cycles in couples with complex infertility disorders

OBJECTIVE: To evaluate alternatives for couples with severe male factor infertility who fail to conceive with IVF-intracytoplasmic sperm injection (ICSI). DESIGN: Outcomes of couples using artificial insemination with donor sperm (AID) after failed IVF-ICSI, assessing multiple risk factors affecting prognosis. SETTING: University infertility service. PATIENT(S): Nineteen patients with complex infertility disorders who failed IVF-ICSI and subsequently used AID (1 to 7 cycles). INTERVENTION(S): Artificial insemination with donor sperm was performed 36 hours after detection of an LH surge or hCG injection. MAIN OUTCOME MEASURE(S): Pregnancy outcomes were determined. RESULT(S): Seventeen pregnancies occurred in 16 women associated with AID for a pregnancy rate per cycle of 27.9% within a mean of 3.2 +/- 18 cycles. Live birth rate per cycle was 24.6%. CONCLUSION(S): A high pregnancy rate was achieved with AID in women who failed IVF-ICSI. Given the low cost and effectiveness of AID in this series, consideration of AID is a reasonable and effective option even in couples with poor prognosis who fail to conceive with IVF-ICSI.     

Obstetric outcome

Pregnancy outcome after in vitro fertilization (IVF) is influenced by many factors, some specific to IVF pregnancies and others shared with the general obstetric population. These factors include the characteristics of infertile couples and their underlying causes of infertility, the criteria used by IVF programmes for selecting couples for treatment, the techniques of fertilization and embryo transfer, the management of the early stages of pregnancy and the high incidence of multiple pregnancy. In comparing outcomes in different IVF programmes or with naturally conceived pregnancies, careful attention must be given to definitions and to the methods used to diagnose pregnancies. Very few studies of pregnancy outcome after IVF have been published so far. The incidence of ectopic pregnancy and spontaneous abortion seems higher than in natural pregnancies. Multiple pregnancy is common in those programmes electing to transfer more than one embryo into the uterus. In one study, preterm birth and low birthweight were about three times more common than in population-based figures. As a result, higher perinatal mortality would also be expected, but no studies are yet available. The sex ratio and the incidence of major congenital malformations appear similar to natural pregnancies, but there are insufficient data to determine whether the risks of chromosomal abnormalities are altered in IVF pregnancies. Further studies are needed to confirm these preliminary results, to obtain better information about the occurrence of chromosomal abnormalities in spontaneous abortions, and to assess fetal growth. Comparisons of results would be enhanced by international agreement on terminology and definitions for pregnancy losses, particularly those occurring in the early stages of pregnancy. Couples considering in vitro fertilization as an option for treatment of their infertility should be counselled about their overall chances of achieving a pregnancy and live births, as well as about the outcome of these pregnancies.