James P. Toner

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.

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.

Sperm morphology as diagnosed by strict criteria: probing the impact of teratozoospermia on fertilization rate and pregnancy outcome in a large in vitro fertilization population

OBJECTIVE To investigate the predictive value of sperm morphology assessed by strict criteria on IVF outcome. DESIGN Retrospective analysis of all IVF cycles (January 1987 to December 1992). MAIN OUTCOME MEASURES All patients were assigned to one of three groups based on sperm morphology: P-pattern (< 4% normal forms), G-pattern (4% to 14% normal forms), and N-pattern (> 14% normal forms). Morphology pattern was related to other semen characteristics and IVF outcome. RESULTS Despite corrective measures at oocyte insemination, the fertilization rate was significantly different among the three morphology groups, P < G < N. N-pattern sperm produced a mean fertilization rate over 85% regardless of low motility or concentration. In a cohort study, P-pattern cycles produced a lower implantation rate and lower ongoing pregnancy rate, independent of the lower fertilization rate. CONCLUSIONS Strict morphology is an excellent biomarker of sperm fertilizing capacity, independent of motility and concentration. P-pattern sperm may denote a poorer prognosis for establishing a pregnancy, even after a satisfactory fertilization rate is achieved.

The gonadotropin-releasing hormone agonist stimulation test : a sensitive predictor of performance in the flare-up in vitro fertilization cycle

OBJECTIVE To evaluate the initial versus early pattern of estradiol (E2) change after administration of a gonadotropin-releasing hormone agonist (GnRH-a), i.e., the GnRH-a stimulation test versus E2 pattern, respectively, as predictors of ovarian response and pregnancy in in vitro fertilization (IVF) patients stimulated with a flare-up protocol. DESIGN Prospective study in a consecutive group of patients. SETTING Tertiary care, institutional setting. PATIENTS Two hundred twenty-eight patients entered and completed the study. The only patients excluded from study were those anticipated to have polycystic ovarian disease, those with a single ovary, or those with an ovarian cyst(s). INTERVENTIONS Patients were stimulated with a GnRH-a flare-up protocol beginning on menstrual day 2. MAIN OUTCOME Evaluation of the GnRH-a stimulation test and the E2 pattern as predictors of the number of mature oocytes retrieved and pregnancy. RESULTS The GnRH-a stimulation test but not the E2 pattern was predictive of the number of mature oocytes retrieved (r = 0.53, P less than 1 X 10(-5) and pregnancy (chi 2 = 8.5, P = 0.04). The E2 pattern was predictive of the duration and number of ampules of gonadotropin required for stimulation. CONCLUSION The GnRH-a stimulation test is a sensitive predictor of performance in the flare-up IVF cycle.

Endometrial estrogen and progesterone receptor and pinopode expression in stimulated cycles of oocyte donors

OBJECTIVE To study the effect of controlled ovarian hyperstimulation and the ovarian response on several features of endometrial morphology simultaneously. DESIGN Prospective controlled study. SETTING Academic infertility center. PATIENT(S) Twenty-five oocyte donors undergoing COH and 10 ovulatory controls. INTERVENTION(S) Endometrial biopsies during the luteal phase and measurement of serum E2 and progesterone levels on days 12, 13, and 18-20. MAIN OUTCOME MEASURE(S) Endometrial morphology as judged by histologic dating, pinopode expression, and estrogen and progesterone receptor content. RESULT(S) Controlled ovarian hyperstimulation caused the early expression of endometrial features as judged by histologic dating criteria, estrogen and progesterone receptor expression, and the timing of pinopode expression in many of the subjects. A significant correlation within subjects with regard to their particular result on any one measure (e.g., histologic examination) and the others (e.g., estrogen and progesterone receptors, pinopodes) was observed. Those with higher levels of progesterone the day after hCG administration exhibited the most prematurity of morphologic features. CONCLUSION(S) Many controlled ovarian hyperstimulation cycles are associated with synchronous early expression of the expected pattern of histologic features, estrogen and progesterone receptors, and pinopodes. The most predictive feature of this premature expression was the level of progesterone the day after hCG administration.

Cessation of gonadotropin-releasing hormone agonist therapy combined with high-dose gonadotropin stimulation yields favorable pregnancy results in low responders

OBJECTIVE To evaluate the pregnancy results of an ovarian hyperstimulation protocol for IVF-ET that combines GnRH agonist down-regulation, cessation of GnRH agonist therapy with the onset of menstruation, and high-dose gonadotropin administration in low responders. DESIGN Prospective analysis. SETTING Academic IVF program. PATIENT(S) One hundred eighty-two low responders undergoing 224 IVF-ET cycles. INTERVENTION(S) Down-regulation was obtained with the administration of leuprolide acetate beginning in the midluteal phase and ending with the onset of menses. Daily administration of 6 ampules of FSH alone or in combination with hMG was initiated on cycle day 3. MAIN OUTCOME MEASURE(S) Stimulation characteristics and pregnancy rates (PRs) were compared between fresh cycles in which pure FSH alone was used and 35 cycles in which a combination of FSH and hMG was administered. RESULT(S) The clinical PR per transfer, the ongoing PR per transfer, and the implantation rate were 32%, 24%, and 9%, respectively. No differences were noted between cycles in which pure FSH alone was used in comparison with cycles in which a combination of FSH and hMG was administered. CONCLUSION(S) Short-term ovarian suppression begun in the luteal phase and discontinued with the onset of menses followed by high-dose stimulation with gonadotropins yields favorable pregnancy results in low responders.

Intracytoplasmic sperm injection: achievement of high pregnancy rates in couples with severe male factor infertility is dependent primarily upon female and not male factors

OBJECTIVE To determine the efficacy and factors affecting outcome of intracytoplasmic sperm injection (ICSI) in patients with severe male factor infertility. DESIGN Prospectively designed clinical trial of patients selected to participate in the study based upon the following inclusion criteria: previous total failed fertilization or unsuitable sperm parameters for conventional IVF. SETTING Tertiary care academic center. PATIENTS Ninety-two consecutive couples undergoing IVF therapy augmented with ICSI during April through December 1994 were studied. MAIN OUTCOME MEASURES Fertilization and ongoing implantation and pregnancy rates (PRs). RESULTS A total of 1,163 preovulatory oocytes were manipulated, yielding a diploid fertilization rate of 60.9%; the oocyte damage rate was 13.2%. The transfer rate was 95% with 43.1% of cycles having excess embryos that were cryopreserved. Overall, the clinical and ongoing PRs per transfer were 31.9% and 26.8%, respectively. None of the sperm parameters of the original semen analysis correlated with ICSI outcome. Female age did not affect fertilization results but had a significant impact on PR (< 34 years: 48.9%; 35 to 39 years: 22.9%; > or = 40 years: 5.9% clinical PR per transfer). CONCLUSIONS Intracytoplasmic sperm injection offers a new and powerful therapeutic option to treat couples with severe male factor infertility associated with a variety of sperm abnormalities. An adequate female age is a pivotal factor determining a successful outcome.

Evaluation of outpatient hysteroscopy, saline infusion hysterosonography, and hysterosalpingography in infertile women: a prospective, randomized study ☆

OBJECTIVE To compare the diagnostic accuracy, pain scores, and procedure length of outpatient hysteroscopy (OHS), hysterosalpingography (HSG), and saline infusion hysterosonography (SIS) for evaluation of the uterine cavity of infertile women. DESIGN Prospective, randomized, investigator-blind study. SETTING Tertiary infertility clinic. PATIENT(S) Forty-six consecutive infertile women. INTERVENTION(S) Outpatient HSG, OHS, and SIS, followed by operative hysteroscopy (HS). MAIN OUTCOME MEASURE(S) Uterine abnormalities, procedure length, and subjective pain. RESULT(S) Fifty-nine percent of infertile subjects were found to have an abnormality on at least one of three outpatient uterine evaluations. When compared with the case of definitive operative HS, 60% of abnormalities were correctly classified by HSG, 72% by OHS, and 52% by SIS (P: NS). When comparing all combinations of 2 outpatient screening tests to operative hysteroscopy, 68% were correctly classified by HSG/OHS, 58% by HSG/SIS, and 64% by OHS/SIS (P: NS). The average time length for the OHS was 9.1 min., which was significantly greater than for both HSG (average, 5.3 min) and SIS (average, 6.1 min.) (P<.0001 for both). HSG and SIS were not statistically different regarding procedure time length. The average pain score (0-10) for SIS was 2.7, compared with 5.8 and 5.3 for HSG and OHS, respectively. Both HSG and OHS mean pain scores were significantly greater than the SIS mean. CONCLUSION(S) OHS, SIS, and HSG were statistically equivalent regarding evaluation of uterine cavity pathology in infertile women.

Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience, 1996-1998

OBJECTIVE To evaluate the role of recipient age on the outcome of donor egg cycles. DESIGN Retrospective cohort study of aggregated national cycles of donor egg therapy that are collected by Society for Assisted Reproductive Technology and the Centers for Disease Control and Prevention. SETTING Assisted reproductive technology centers in the United States that report their results to the Centers for Disease Control and Prevention by way of the Society for Assisted Reproductive Technology. PATIENT(S) Recipients of embryos (17,339 cycles) derived from donated eggs between 1996 and 1998. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Rates of implantation, clinical intrauterine pregnancy, pregnancy loss, and delivery based on the age of the recipient. RESULT(S) Success of donor egg therapy was remarkably constant among recipients aged 25 years through those in their late forties. At higher ages, declining rates of implantation, clinical pregnancy, and delivery were seen, along with small increases of pregnancy loss. During the course of the 3 years studied, fewer embryos were transferred and higher rates of implantation were observed. CONCLUSION(S) The success of donor egg therapy is unaffected by recipient age up to the later 40s, after which they begin to decline. Although recipient age per se is likely to be the major cause of this effect, other factors may contribute to this observation.

Salpingectomy improves the pregnancy rate in in-vitro fertilization patients with hydrosalpinx

The objective of this study was to assess the impact on pregnancy outcome of excising hydrosalpinx(ges) in patients with repeated in-vitro fertilization (IVF) failures. A group of 15 patients who had previously undergone failed IVF attempts and had unilateral or bilateral hydrosalpinx was subjected to an operative laparoscopy with excision of the affected tube(s). Of these, 10 patients underwent a unilateral salpingectomy and five had a bilateral salpingectomy. Stimulated cycles of IVF and/or cryo-thaw cycles were then carried out post-salpingectomy and the results were compared to those of pre-salpingectomy cycles. There was no statistically significant difference between the number of mature eggs retrieved, peak oestradiol concentrations, number of days to human chorionic gonadotrophin administration, or number of pre-zygotes frozen in the stimulated cycles pre- versus post-salpingectomy. Pre-salpingectomy, 15 patients underwent 38 stimulated cycles and eight patients underwent 14 cycles with cryopreserved-thawed embryos, achieving one pregnancy from a fresh transfer that resulted in a miscarriage. Post-salpingectomy, eight patients underwent 12 stimulated cycles, achieving five clinical pregnancies (two miscarriages and three ongoing pregnancies, i.e. either delivered or a pregnancy > or = 20 weeks), and nine patients underwent 10 cycles with cryopreserved-thawed embryos, achieving four clinical pregnancies (one miscarriage and three ongoing). We conclude that excision of hydrosalpinx(ges) improves the pregnancy potential after IVF, and that new and repeat IVF patients should be counselled accordingly.