Evaluation of the clinical efficacy of embryo cryopreservation.

To fully evaluate the advantages of a cryopreservation program a method needs to be established to express the additional patients pregnant from cryopreservation. The patient specific method considers cryopreservation as augmentation only among patients without a pregnancy from the fresh transfer, or from previously transferred frozen material from the same harvest. In an analysis of the pregnancy rate at the Jones Institute between January 1996 and December 1998 we found a fresh pregnancy rate of 40.8% in the good responders and 28.8% in poor responders. The patient specific pregnancy rate in the same cycles was 53.4% in good responders and 32.3% in poor responders. Good responders less than 35 years of age with ten or more mature eggs at retrieval had a fresh pregnancy rate of 40.2% and a patient specific pregnancy rate of 57.9%. It is exceedingly important for the physician and patient to understand and comprehend the potential in cryopreserved material.

Endometrial receptivities after leuprolide suppression and gonadotropin stimulation: histology, steroid receptor concentrations, and implantation rates.

The effect of markedly supraphysiologic levels of E2 and P4 on the endometrium was assessed by examining endometrial histology, E2 and P4 receptor concentrations, and embryo implantation rates in IVF cycles with and without leuprolide use. Results suggest that 1) the high ovarian response common in leuprolide pretreated cycles can advance endometrial histology, but only up to a certain limit, 2) P4 greater than 25ng/ml or E2 greater than 200pg/ml on the day of transfer was associated with non-lagging endometria, 3) implantation rate in high response cycles is not impaired and may be increased, 4) earlier P4 supplementation in low response cycles may be beneficial, 5) extraordinarily high response (E2 greater than 5000pg/ml) may be detrimental to implantation, and 6) the optimal histology for implantation appears to be at least day 16.

Use of gonadotrophin-releasing hormone agonists in controlled ovarian hyperstimulation for in vitro fertilization.

The aim of ovarian hyperstimulation for in vitro fertilization (IVF) is the recruitment of multiple fertilizable healthy oocytes. Transfer of multiple embryos yields a better success rate than single-embryo transfers. Moreover, cryopreservation of excess pre-embryos allows patients an added opportunity to achieve a pregnancy without undergoing a repeat stimulated cycle. In the last 4 years, gonadotrophin-releasing hormone (Gn-RH) agonists have been used widely as adjuncts to gonadotrophins for ovarian hyperstimulation. Advantages of Gn-RH agonist use include prevention of a premature luteinising hormone (LH) surge, suppression of endogenous basal LH levels and recruitment of a larger cohort of follicles. Gn-RH agonists can be used in a long (suppression) or a short (stimulatory, flare-up) protocol. In our clinic, the use of Gn-RH agonist suppression (starting in the mid-luteal phase) prior to ovarian hyperstimulation was demonstrated to be extremely beneficial in intermediate and high responder patients but not in low responders (defined endocrinologically as patients with a basal follicle-stimulating hormone [FSH]: LH ratio of 1:1 and a basal LH:FSH ratio of greater than or equal to 1.5, respectively). We have not been able to demonstrate any beneficial effects from the use of Gn-RH agonist suppression in low responder patients (defined endocrinologically as patients with a basal FSH greater than or equal to 15 mIU/ml). In such low responder patients, the use of a 'flare-up' Gn-RH agonist protocol (Gn-RH agonist starting on day 2 of the cycle, followed by gonadotrophins on day 4 of the cycle), taking advantage of the initial agonistic stimulatory effect of Gn-RH agonists on endogenous FSH and LH secretion, has provided significant improvements in stimulation characteristics and better pregnancy results. It should be emphasised that comparisons of results cannot be attempted due to the selective use of each protocol in different patient populations.

The significance of hydrosalpinx in in vitro fertilization.

OBJECTIVE: To review the effects of hydrosalpinx on IVF/ET and the role of salpingectomy. DESIGN: The literature on hydrosalpinx, IVF/ET, embryotoxicity, and salpingectomy for hydrosalpinx was identified through MEDLINE searches and reviewed. RESULT(S): Hydrosalpinx has been associated with poor fertility prognosis. IVF/ET is a better alternative to tubal surgery for those patients with severe distal tubal disease, and it is also more cost effective. However, the presence of hydrosalpinx has a negative effect on IVF/ET by decreasing the pregnancy rates and implantation rates compared with patients undergoing IVF/ET for tubal disease but without hydrosalpinx. The hydrosalpingeal fluid has been demonstrated to be embryotoxic to developing embryos, thus leading to increased early pregnancy losses. Poor endometrial receptivity has also been demonstrated in the presence of hydrosalpinges. Removal of the hydrosalpinges leads to improved IVF/ET rates comparable to those patients without hydrosalpinx. Therefore, salpingectomy has been recommended for patients with hydrosalpinx who will be undergoing IVF/ET. CONCLUSION(S): The presence of hydrosalpinx has a negative effect on IVF/ET because of the suspected embryotoxicity of the hydrosalpingeal fluid. Surgical removal of the hydrosalpinx has been shown to improve IVF/ET rates.

The combination of follicle-stimulating hormone and human menopausal gonadotropin for the induction of multiple follicular maturation for in vitro fertilization.

One hundred fifty-one cycles in 134 consecutive patients were stimulated with 150 IU of human urinary follicle-stimulating hormone (FSH) and 150 IU of human menopausal gonadotropin (hMG) on cycle days 3 and 4 and then with 150 IU of hMG daily for the purpose of multiple follicular development for in vitro fertilization (IVF). Seventy-three patients did not have a prior IVF attempt, and 61 patients in 78 cycles had prior IVF attempts at least once with their previous cycles stimulated with the same method and/or hMG and/or FSH. There was an average of three preovulatory oocytes retrieved per laparoscopy and a pregnancy rate of 27% per transfer cycle. The results were equally favorable in "new" and "old" patient cycles. The pregnancy rate increased with the transfer of two or more conceptuses of preovulatory origin. The multiple pregnancy rate, but not the abortion rate, increased with increased numbers of conceptuses transferred.

Basal follicle-stimulating hormone level and age affect the chance for and outcome of pre-embryo cryopreservation.

All IVF cycles in which subsequent transfers of thawed pre-embryos occurred were studied. Both age and basal (cycle day 3) FSH level are important determinants of the chance for cryopreservation and the performance of cryopreserved pre-embryos. Although there was no age or FSH level above which pregnancy with frozen pre-embryos was not possible, the chances clearly decline. Thus, consideration to transferring larger numbers of pre-embryos fresh should be given to women in the fifth decade and those with basal FSH > 15 IU/L.

Outcome of twin, triplet, and quadruplet in vitro fertilization pregnancies: the Norfolk experience.

OBJECTIVE: To review the maternal morbidity and neonatal morbidity and mortality associated with in vitro fertilization (IVF) multiple pregnancies. DESIGN: Retrospective analysis of data collected from office and hospital records and from questionnaires sent to patients, their obstetricians, and pediatricians. SETTING: Patients (all with private insurance carriers) enrolled in an academic IVF program (The Jones Institute for Reproductive Medicine). PATIENTS, PARTICIPANTS: All IVF pregnancies resulting in one or more gestational sacs on the initial ultrasound at 6 to 7 weeks were reviewed. MAIN OUTCOME MEASURES: The frequency and severity of obstetrical and neonatal complications and the perinatal mortality of IVF twins, triplets, and quadruplets were compared. These were also compared with non-IVF multiple pregnancies. RESULTS: From 1982 to 1990, 629 IVF pregnancies progressed beyond 20 weeks; 115 twins (18.3%), 15 triplets (2.4%), and 4 quadruplets (0.6%). There was a high incidence of antenatal complications such as abortions (30.3%, 42%, and 20%), premature labor (41.5%, 92.3%, and 75%), pregnancy-induced hypertension (17.0%, 38.6%, and 50%), and gestational diabetes mellitus (3.1%, 38.5%, and 25%) for twins, triplets, and quadruplets, respectively. The mean gestational age at delivery was 35.5 +/- 3.7, 31.8 +/- 2.7, and 31.0 +/- 1.7 weeks, respectively. There was also a proportionate progressive increase in neonatal complications. The mean weights were 2,473 +/- 745, 1,666 +/- 441 and 1,414 +/- 368 g, respectively. Twins (22.7%), 64.1% of triplets, and 75% of quadruplets needed admission to the neonatal intensive care unit and remained for an average of 12.0 +/- 2.3, 17.4 +/- 14.0, and 57.8 +/- 17.9 days, respectively. There was no difference in the mean Apgar scores or the incidence of congenital malformations in the three groups. The corrected perinatal mortality rates were 38.5, 0.0, and 0.0 per thousand live births, respectively. CONCLUSION: Triplet and quadruplet IVF pregnancies have increased obstetrical and neonatal complications compared with IVF twins. The perinatal mortality and the incidence of congenital malformations are, however, comparable in all three groups.

Significance of basal follicle-stimulating hormone levels in women with one ovary in a program of in vitro fertilization.

OBJECTIVE: To understand the impact of having a single ovary on basal follicle-stimulating hormone (FSH) level and its diagnostic and prognostic usefulness in in vitro fertilization (IVF). DESIGN: All IVF cases from July 1987 to June 1990 with known basal FSH (n = 1,272) were divided into those with one and those with two ovaries to compare outcomes based on basal FSH levels. SETTING: Tertiary care academic center with a large IVF practice. MAIN OUTCOME MEASURES: Basal FSH, age, and IVF outcomes including peak estradiol, numbers of follicles aspirated, oocytes retrieved, fertilized, and transferred, and pregnancies (clinical and ongoing). RESULTS: In women with only one ovary, basal FSH was increased, and IVF outcomes were poorer. The rise in FSH was able, in large part, to account for the diminished performance in the single ovary cases. CONCLUSIONS: Women with only one ovary have higher basal FSH levels than those with two ovaries, and this rise can be used to predict their IVF performance.

Progesterone levels on the day of human chorionic gonadotropin do not predict pregnancy outcome from the transfer of fresh or cryopreserved embryos from the same cohort.

OBJECTIVE: To analyze the differences in pregnancy rates (PRs) from the transfer of fresh and cryopreserved embryos from the same cohort of oocytes based on serum P levels on the day of hCG administration and the day after. DESIGN: Retrospective analysis. SETTING: Infertility patients stimulated for IVF-ET in an academic center. PATIENT(S): Three hundred thirty-three patients with fresh transfer and at least one transfer of cryopreserved embryos from the same cohort of recruited oocytes. All stimulations were down-regulated with a GnRH agonist in a long protocol before gonadotropin stimulation. MAIN OUTCOME MEASURE(S): Clinical PR. RESULT(S): The clinical PR in fresh cycles was 24% for the P < or = 0.9 ng/mL group (group A; conversion factor to SI unit, 3.18) and 34% for the P > 0.9 ng/mL group (group B). Group B patients were younger, received fewer ampules of gonadotropins, had higher peak E2 levels, and had more mature oocytes. There were no significant differences in the P levels on the day of hCG between patients who conceived in both fresh and cryopreserved cycles and any other combination of pregnancy outcome sequence. CONCLUSION(S): These findings suggest that serum P level cutoffs, on the day of hCG and the day after, as a means of making clinical decisions with respect to cancelling the fresh transfer and cryopreservation of all embryos for future transfer should be questioned.

The incidence of multiple gestations after in vitro fertilization is dependent on the number of embryos transferred and maternal age.

OBJECTIVE: To determine if the incidence of multiple gestations after IVF differs significantly depending on the number of embryos transferred and maternal age. DESIGN: Retrospective analysis of IVF database. SETTING: Tertiary care academic center. PATIENTS: One thousand eight hundred sixty-seven patients undergoing IVF with up to four embryos transferred during 1986 through 1993. MAIN OUTCOME MEASURES: The rate of singleton and multiple gestations > 20 weeks estimated gestational age (EGA). RESULTS: The incidence of triplet gestations > 20 weeks EGA among patients < or = 34 years of age with three versus four embryos transferred was 0.3% (1/335) versus 2.4% (15/662), respectively. The incidence of twin gestations > 20 weeks EGA among patients < or = 34 years of age with two versus four embryos transferred was 1.3% (3/234) versus 7.4% (46/622), respectively. Also among patients < or = 34 years of age, the incidence of singleton gestations > 20 weeks EGA with two versus three embryos transferred was 12.8% (30/234) versus 15.8% (53/335); with two versus four embryos was 12.8% (30/234) versus 17.2% (107/622); and with three versus four embryos was 15.8% (53/335) versus 17.2% (107/622), respectively. CONCLUSIONS: In women < or = 34 years of age undergoing IVF-ET, the transfer of four versus three and four versus two embryos significantly increased the incidence of triplet and twin gestations, respectively, without significantly improving the chance of singleton conception. This implies that a policy of transferring only three embryos should be considered in this age group (realizing that such a policy may merit modulation if pretransfer embryo selection is used.).

Experience with diethylstilbestrol-exposed infertile women in a program of in vitro fertilization.

Twenty infertile women with a history of diethylstilbestrol exposure in utero were seen in Norfolk for the purpose of in vitro fertilization. Seventeen patients had undergone 25 stimulated cycles with harvest of oocytes by laparoscopy. The serum estradiol response to stimulation in these patients and the number and quality of oocytes retrieved did not differ significantly from those of patients with infertility due to blocked fallopian tubes. There were four pregnancies in 17 patients after 21 cycles of embryo transfers, for a pregnancy rate of 23.5% per patient, or 19% per embryo transfer. Two of the pregnant patients have had a term delivery, one has had a preclinical abortion, and one has a single intrauterine gestation in progress.

Intercycle variability of day 3 follicle-stimulating hormone levels and its effect on stimulation quality in in vitro fertilization.

Prior studies have demonstrated that gonadotropin stimulation quality and pregnancy rates are better in in vitro fertilization (IVF) patients with low basal cycle day 3 follicle-stimulating hormone (FSH) levels. The records of 81 patients who had undergone three or more IVF attempts during a 2-year period were studied to determine the degree and potential impact of intercycle variability in basal FSH concentrations. The mean of the individual standard deviations for all 81 patients was 4.2 +/- 0.4 mIU/mL. However, the patients with a mean basal FSH of less than 15 mIU/mL had a mean deviation of only 2.6 +/- 0.2 mIU/mL, whereas those with a mean basal FSH of greater than or equal to 15 mIU/mL had a mean deviation of 7.3 +/- 0.7 mIU/mL. Intercycle variability in basal FSH values did not predict changes in ovarian response to gonadotropin stimulation and thus may not be used to select an optimal cycle in which to stimulate an individual patient. Furthermore, patients with large intercycle variation responded poorly to gonadotropin stimulation independent of their basal FSH concentration. This information allows more precise counseling of patients regarding their appropriateness for assisted reproduction.

Wedge metroplasty for the septate uterus: an update.

Twenty-one patients with septate uteri and 2 patients with a T-shaped uterine anomaly and recurrent abortions underwent wedge metroplasty during the period from September 1978 to August 1983. Thirteen patients had a characteristic history of one or more abortions associated with the septate uterus and absence of other metabolic and endocrine abnormalities. Ten other patients, including the two with a T-shaped uterine anomaly, either had one or more abortions of an uncharacteristic nature with absence of other abnormalities or had one or more characteristic abortions in addition to the presence of other metabolic, endocrine, or surgically correctable disease. The application of wedge metroplasty for the surgical reconstruction of the uterus yielded equally gratifying results in both groups with approximately two thirds of the patients having a term delivery or carrying a pregnancy in the third trimester.

Follicular atresia associated with concurrent initiation of gonadotropin-releasing hormone agonist and follicle-stimulating hormone for oocyte recruitment.

The ability of gonadotropin-releasing hormone agonist (GnRHa) to cause an initial stimulation of serum gonadotropins was used for follicular recruitment for in vitro fertilization (IVF) in 12 patients with a history of low estradiol (E2) response to conventional gonadotropin stimulation. Stimulation was initiated on cycle day 3 with concurrent administration of leuprolide (1 mg/day subcutaneously) and follicle stimulating hormone (FSH, 4 ampules/day intramuscularly). An 8-fold increase in basal serum luteinizing hormone (LH) and a 4-fold increase in basal serum FSH was seen on cycle day 4. Serum progesterone levels rose significantly by day 6. When compared to prior IVF attempts in these patients, the mean day of human chorionic gonadotropin administration and corresponding E2 levels were not significantly different. More atretic oocytes and fewer preovulatory oocytes were retrieved using GnRHa, and no increase was seen in total oocytes retrieved. One patient was canceled for poor E2 response, and one patient conceived, with a current viable pregnancy. It is concluded that concurrent initiation of leuprolide and FSH stimulation on cycle day 3 in patients with prior low response does not improve oocyte recruitment, and the high LH environment generated from initial stimulation of the agonist may be detrimental to normal oocyte development.

Timing of oocyte retrieval in cycles with a spontaneous luteinizing hormone surge in a large in vitro fertilization program.

Forty-four cycles with a spontaneous luteinizing hormone (LH) surge among 377 in vitro fertilization (IVF) patients were studied for outcome with different timing of oocyte retrieval. Mean number of preovulatory oocytes per retrieval and per transfer was significantly less in these cycles than in controls. Mean number of preovulatory oocytes per retrieval and per transfer was significantly higher when the human chorionic gonadotropin (hCG)-retrieval interval was greater than 35 hours, compared with less than 24 hours. In cycles with an hCG-retrieval interval of less than 24 hours, percentage of preovulatory oocytes was higher when serum estradiol (E2) decreased by greater than 15% on the morning after hCG administration compared with a plateau or an increase in serum E2. Timing oocyte retrieval after spontaneous LH surge should consider the hCG-retrieval interval and changes in E2 levels after hCG administration; this may avoid cancellation for many patients.

Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome.

Cycle day 3 basal levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were measured in 441 patients in 758 consecutive cycles to determine their predictive value for stimulation quality and pregnancy rates in vitro fertilization (IVF). Patients with low basal FSH levels (less than 15 mIU/ml) had higher pregnancy rates per attempt than those with moderate levels (15 to 24.9 mIU/ml), both of which were higher than those with high FSH levels (greater than 25 mIU/ml). Basal LH and E2 values did not improve the predictive value beyond that provided by FSH. Ongoing pregnancy rates per attempt in the low, moderate, and high FSH groups were 17.0%, 9.3%, and 3.6%, respectively (P less than 0.01). The three groups differed significantly in the percentage of patients having two ovaries, the mean number of follicles aspirated per retrieval, the mean number of preovulatory oocytes obtained, and peak E2 values (P less than 0.01). Cycle day 3 FSH levels are predictive of pregnancy outcome and stimulation characteristics in IVF, and may be useful in counseling patients.

Delaying the initiation of progesterone supplementation results in decreased pregnancy rates after in vitro fertilization: a randomized, prospective study.

OBJECTIVE: To compare IVF outcome between two protocols for luteal phase supplementation, one beginning on day 3 after oocyte retrieval and the other beginning on day 6 after retrieval. DESIGN: Prospective, randomized study. SETTING: University-based assisted reproductive technology center. PATIENT(S): One hundred twenty-six consecutive patients undergoing IVF between January and July 2000. INTERVENTION(S): Patients were randomized to begin luteal phase support using vaginal progesterone beginning either on day 3 after oocyte retrieval or on day 6 after oocyte retrieval. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates and implantation rates. RESULT(S): All patients randomized underwent transfer. There were no differences in age, oocytes retrieved, or embryos transferred between the two groups. Those patients receiving luteal phase support with progesterone beginning on day 6 after retrieval had a significantly lower clinical pregnancy rate per transfer compared with those beginning support on day 3 after retrieval (44.8% vs. 61.0%, respectively). This difference in pregnancy rates was greater in those patients undergoing a luteal gonadotropin releasing hormone (GnRH) agonist down-regulation protocol (47.5% vs. 71.4%, day 6 vs. day 3, respectively). Beginning support on day 6 also significantly decreased implantation rates in the GnRH agonist group (21.0% vs. 34.0%, day 6 vs. day 3, respectively). CONCLUSION(S): Pregnancy rates are significantly decreased by initiating luteal-phase progesterone supplementation on day 6 after oocyte retrieval during in vitro fertilization cycles.

Beta-human chorionic gonadotropin as a monitor of pregnancy outcome in in vitro fertilization-embryo transfer patients.

Serum human chorionic gonadotropin (hCG) was studied to test its predictability of pregnancy outcome in in vitro fertilization (IVF) patients. The mean +/- standard deviation of serum hCG concentration related to the day complete clearance of exogenous hCG was derived from 47 single term pregnancies as a normal range. This range can be used to predict spontaneous abortion (77%), multiple pregnancy (60%), and abortion in multiple-sac pregnancies terminating in the birth of fewer infants than the initial number of sacs (80%). The results also showed that our stimulation protocol did not affect the clearance rate and doubling time of endogenous hCG or implantation time as suggested by the time of endogenous hCG detection and that spontaneous abortion may be due to late implantation.

Effects of the severity of tubo-ovarian disease and previous tubal surgery on the results of in vitro fertilization and embryo transfer.

The purpose of this study was to evaluate the ovarian response and in vitro fertilization/embryo transfer (IVF-ET) results in patients with tubal infertility and two ovaries, according to (1) the degree and extent of pelvic disease (isolated tubal or tubo-ovarian) and (2) previous adnexal surgical procedures. A total of 549 patients who underwent 1031 IVF-ET cycles were evaluated. Significant findings were as follows: (1) No differences were found in the number of preovulatory oocytes, fertilization rates, or serum estradiol levels in the follicular phase between any classes of tubo-ovarian disease. (2) Patients with a "frozen pelvis" had significantly fewer follicles aspirated than those in any other category, although they had equivalent numbers of preovulatory oocytes retrieved and pregnancy rates. (3) Patients with previous bilateral tubal ligation had higher pregnancy rates than patients with severe tubo-ovarian disease. (4) The type of prior pelvic surgical procedure had no effect on IVF-ET outcome. Although patients with no cause of infertility other than tubal ligation had better results, these patients had previously proven fertility. We conclude that neither the stage of tubo-ovarian disease nor any history of pelvic adhesions or tubal surgery has a significant impact on the efficiency of IVF-ET.

The incidence of transient hyperprolactinemia in gonadotropin-stimulated cycles for in vitro fertilization and its effect on pregnancy outcome.

The incidence of transient hyperprolactinemia and its impact on in vitro fertilization (IVF) were determined in 151 euprolactinemic women with tubal infertility undergoing an identical gonadotropin stimulation for IVF. Prolactin (PRL) levels were measured on the morning of cycle day 3, days of human chorionic gonadotropin (hCG) administration, and peak estradiol (E2), and in the midluteal phase. Women were divided into high (H: peak E2 greater than 1,000 pg/mL, n = 51), intermediate (I:peak E2: 500 to 800 pg/mL, n = 50), or low (L:peak E2 less than 400 pg/mL, n = 50) E2 response groups. There was no difference in the incidence of hyperprolactinemia on cycle day 3 between the response groups (H:16%, I: 12%, and L:8%). However, high responders had a higher incidence of hyperprolactinemia than intermediate or low responders on all other study days. The incidence of hyperprolactinemia was greater than baseline (cycle day 3) only in the high responders on the day of peak E2. Serum prolactin was strongly correlated with peak E2 (r = 0.41). There were no differences in the number of preovulatory oocytes retrieved or fertilized or the pregnancy rates between hyperprolactinemic and euprolactinemic patients in each response group or when all hyperprolactinemic and euprolactinemic patients, regardless of E2 response, were compared. Transient hyperprolactinemia during gonadotropin stimulation for IVF occurs and correlates with E2 response but has no impact on IVF outcome.