Bradley T. Miller

Reproductive outcome in patients with diminished ovarian reserve

OBJECTIVE To compare reproductive outcome between women with normal ovarian reserve and women with abnormal ovarian reserve. DESIGN Retrospective. SETTING Tertiary care center. PATIENT(S) Nine thousand eight hundred and two patients who had basal follicle-stimulating hormone (FSH) concentrations measured as part of an infertility evaluation. INTERVENTION(S) Monitoring of early pregnancy. MAIN OUTCOME MEASURE(S) Pregnancy loss rates, live birth rates. RESULT(S) Of 1,034 patients with diminished ovarian reserve (DOR) (FSH > or =14.2 IU/L), 28 (2.7%) conceived. Twenty of these pregnancies (20/28; 71.4%) were lost in the first trimester. Pregnancy loss rates in women with DOR were 57.1% in women <35 years old, 63.5% in women 35-40 years old, and 90.0% in women >40 years old. These rates of pregnancy loss were significantly higher compared to age-matched patients with normal ovarian reserve. CONCLUSIONS(S) Women with DOR have exceedingly high rates of pregnancy loss, regardless of age. Women with diminished ovarian reserve should be counseled that, in addition to a low probability of conception, live birth rates are poor.

Pregnancy rates after embryo transfer depend on the provider at embryo transfer

OBJECTIVE To evaluate the effect of individual providers on pregnancy outcome after embryo transfer. DESIGN Retrospective data analysis. SETTING University-based tertiary-care assisted reproductive technology program with 10 physician-providers. PATIENT(S) Six hundred and seventeen women who underwent 854 fresh embryo transfers between January 1996 and January 1999. INTERVENTION(S) Pregnancies after embryo transfer were recorded for each provider. MAIN OUTCOME MEASURE(S) Establishment of a clinical pregnancy. RESULT(S) Three hundred ninety-three clinical pregnancies resulted from 854 embryo transfers, for an overall clinical pregnancy rate of 46.0% per embryo transfer. Three hundred forty-seven (40.6%) pregnancies were ongoing. The clinical pregnancy rate varied significantly between providers: for example, 17.0% (47 transfers) vs. 54.3% (57 transfers) (P<.05). Similarly, the ratio of high-grade embryos required to produce a gestational sac differed between providers. The number or quality of embryos transferred did not differ significantly. CONCLUSION(S) Significant differences were observed in pregnancy rates after embryo transfer done by different providers, suggesting that embryo transfer technique may influence pregnancy outcome in assisted reproductive technology.

A prospective assessment of the predictive value of basal antral follicles in in vitro fertilization cycles

OBJECTIVE To determine the predictive value and define threshold values for basal antral follicle count in patients undergoing IVF. DESIGN Prospective cohort analysis. Tertiary care center. Two hundred eighty-nine patients. Transvaginal ultrasonography before starting gonadotropin administration. MAIN OUTCOME MEASURES Number of oocytes retrieved, basal hormone levels, and cycle outcomes. RESULTS Pregnant patients had significantly more antral follicles (13.8 +/- 7.5 vs. 12.4 +/- 10.0). Patients in whom cycles were canceled had significantly fewer antral follicles (7.6 +/- 4.8 vs. 13.7 +/- 8.8). Antral follicle count significantly correlated with most prestimulation and poststimulation IVF variables. Threshold analysis demonstrated a lower pregnancy rate (23.5% vs. 57.6%) and a higher cancellation rate (41% vs. 6.4%) associated with having four or fewer antral follicles. CONCLUSION(S) The basal antral follicle count identified patients who responded poorly to IVF stimulation. Having four or fewer antral follicles was associated with a high cancellation rate (41%) and, in patients without a cancelled cycle, a low pregnancy rate (23%). However, no antral follicle count absolutely predicted pregnancy or cycle cancellation.

Controlled ovarian hyperstimulation does not adversely affect endometrial receptivity in in vitro fertilization cycles

OBJECTIVE To determine whether exposure of developing endometrium to supraphysiologic E2 levels during controlled ovarian hyperstimulation (COH) in IVF cycles inhibits endometrial receptivity. DESIGN Retrospective analysis of IVF-ET and ovum donation data. SETTING Tertiary-care teaching hospital. PATIENT(S) Four hundred ten patients <33 years of age undergoing IVF-ET and 181 anonymous ovum donors (<33 years of age) and their associated ovum recipients. MAIN OUTCOME MEASURE(S) Implantation, pregnancy, and delivery rates. RESULT(S) Ovarian response to COH (duration of stimulation, peak E2 level, area under the curve for E2 exposure, and number of oocytes retrieved) was similar for IVF-ET patients and ovum donors. Donors were younger than IVF-ET patients (mean age, 27.5 +/- 0.2 years vs. 30.4 +/- 0.1 years). A similar number of embryos with similar number of blastomeres were transferred in IVF-ET patients and ovum recipients. The fragmentation rate at time of transfer differed slightly between groups (5.2 +/- 0.2% vs. 4.3 +/- 0.3%). Implantation, pregnancy, and delivery rates did not differ between IVF-ET patients and recipients of donor oocytes. CONCLUSION(S) Exposure of the developing endometrium to controlled ovarian hyperstimulation during IVF cycles does not inhibit embryo implantation or affect pregnancy and delivery rates.

Microdose follicular phase gonadotropin-releasing hormone agonists (GnRH-a) compared with luteal phase GnRH-a for ovarian stimulation at in vitro fertilization

OBJECTIVE To compare an ovarian stimulation protocol using microdose follicular phase GnRH agonist (GnRH-a) and oral contraceptive (OC) pills to a luteal phase GnRH-a protocol. DESIGN Retrospective analysis. SETTING University affiliated IVF program. PATIENT(S) One hundred seventy patients who underwent IVF and ET in 1996. INTERVENTION(S) Patients were assigned to either a midluteal start of leuprolide acetate (LA) 1 mg/d, reduced to 0.5 mg/d after addition of gonadotropins (LUT), or OC pills until cycle day 0 followed by 20 microg of LA every 12 hours on cycle day 3 with addition of gonadotropins on cycle day 5 (MICRO). MAIN OUTCOME MEASURE(S) Number of FSH ampules, days of stimulation, peak E2, and number of oocytes retrieved. RESULT(S) There were no statistically significant differences in the main outcome measures between the two groups using an age-matched ANOVA. Clinical pregnancy rate per cycle start was not statistically different (LUT = 54%, and MICRO = 37%). The cancellation rate was significantly higher in the MICRO group (22.5% vs. 8.2%). CONCLUSION(S) Given the higher cancellation rate in the microdose group, a randomized clinical trial is required to determine the possible benefit of a lower dose of GnRH-a in patients with normal ovarian function.

The predictive value of hysterosalpingography for tubal and peritoneal infertility factors

OBJECTIVE To investigate a practical classification system of hysterosalpingogram (HSG) results that accurately identifies patients with severe pelvic disease or a normal pelvis to allow appropriate patient counseling of therapeutic options. DESIGN Retrospective chart review from university teaching hospital. Hysterosalpingography results were classified as normal, abnormal (bilateral distal tubal obstruction), or suspicious (all others). At surgery, chromopertubation was performed, and pelvic disease was documented. RESULTS From a total of 756 patients, HSGs were confirmed surgically in 96.6% of normals, 63.1% of suspicious, and 95.7% of abnormal. Associated moderate-severe pelvic disease was found in 16.2% of normals, 53.9% of suspicious, and 81.7% of abnormal. CONCLUSION Abnormal HSGs are highly predictive of severe pelvic disease, and counseling of treatment options does not require diagnostic laparoscopy. Patients with suspicious HSGs frequently have normal tubes but also have a significant likelihood of tubal or associated pelvic disease, and they are responsible for the poor predictive value of the HSG. This group of patients requires confirmatory laparoscopy preferably by a physician qualified in pelviscopic surgery. Normal HSGs have a high negative predictive value. Nevertheless, the incidence of associated pelvic disease in the normal HSG group is high enough to warrant diagnostic laparoscopy if nonsurgical treatment is unsuccessful.

Human chorionic gonadotropin levels after blastocyst transfer are highly predictive of pregnancy outcome.

OBJECTIVE To determine the predictive value(s) of beta-hCG serum levels for pregnancy outcome following blastocyst transfer. DESIGN Retrospective review. SETTING University-based assisted reproductive technology (ART) program. PATIENTS All ART patients enrolled from January 1998 to December 1999. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Beta-hCG serum levels and pregnancy outcomes. RESULT(S) Of the 836 ART cycles initiated, 608 embryo transfers met study criteria and were assigned to one of two groups: 248 day 5 blastocyst transfers or 360 day 3 embryo transfers. In the day 5 blastocyst group, 147 pregnancies occurred (59.2%), and day 3 transfers resulted in 165 pregnancies (45.8%). For day 3 and day 5 transfers, mean values of beta-hCG on day 16 post-retrieval of spontaneous abortions were lower than ongoing pregnancies (P< .05). A beta-hCG value on day 16 of >300 mIU/mL predicted an ongoing pregnancy for day 5 transfer group in 97% of pregnancies compared with 92% for day 3 embryo transfers. A multiple gestation was observed in 70% of pregnancies with a beta-hCG level >400 mIU/mL in the day 5 group compared with 63% for the day 3 group. The incidence of higher-order multiple gestations was significantly lower in the day 5 blastocyst group (P< .05). CONCLUSION(S) Beta-hCG serum levels on day 16 post-retrieval were highly predictive of pregnancy outcome after a blastocyst transfer.

Expression of brx proto-oncogene in normal ovary and in epithelial ovarian neoplasms☆☆☆★

OBJECTIVE We previously identified a protein, Brx, that interacted with estrogen receptor alpha. Sequence analysis determined that Brx is a novel member of the Dbl family of oncoproteins involved in signaling pathways that regulate cell growth. Because the Brx protein was found to be highly expressed in hormoneresponsive breast epithelium, the objective of this study was to determine whether Brx was expressed in both normal and neoplastic ovarian tissues. STUDY DESIGN A polyclonal antiserum directed against the Brx protein was used to perform immunolocalization on sections from 5 normal ovaries and 20 ovarian neoplasms. Chromosomal localization of the brx gene was accomplished by means of fluorescence in situ hybridization. Northern and Western blot analyses were performed on extracts prepared from human ovaries. RESULTS Brx protein was localized to the cytoplasm of granulosa cells from mature graafian follicles, the corpus luteum, and islands of hilar cells in normal ovaries. In tumors with low malignant potential and ovarian carcinomas the neoplastic epithelium stained strongly for Brx protein. Northern and Western blot analyses, respectively, confirmed expression of Brx messenger ribonucleic acid and protein in normal ovary. Finally, the brx gene was localized to 15q25. CONCLUSION The proto-oncogene brx is expressed in specific normal human ovarian tissues and is also present in ovarian epithelial neoplasms.

Adjuvant therapy enhances endometrial receptivity in patients undergoing assisted reproduction

Adjuvant therapies are often used to enhance endometrial thickness during IVF. This retrospective cohort analysis investigated if women undergoing oocyte donation cycles with sonographic evidence of endometrial insufficiency benefit from adjuvant medicaltherapy. Infertile patients received 503 mock cycles followed by 503 anonymous oocyte donation cycles. One hundred and twenty-three patients received adjuvant therapy during a donor oocyte cycle. Patients who had a mock endometrial thickness > or = 8 mm experienced a significant decrease in endometrial thickness with the donor oocyte cycle regardless of the use of adjuvant therapy (P < 0.001). In contrast, those patients with a mock endometrial thickness < 8 mm experienced a significant increase in donor oocyte cycle endometrial thickness regardless of adjuvant therapy use (P < 0.001). The patients with a mock endometrial thickness < 8 mm experienced a significant improvement in pregnancy rates when taking adjuvant therapy (87.7 versus 73.5%, P < 0.05). Adjuvant therapy significantly improved both pregnancy (87.8 versus 76.8%, P < 0.01) and live birth rates (74.8 versus 63.7%, P < 0.05) in the entire patient population. While the use of adjuvant therapy did not significantly improve ultrasonographic endometrial thickness, it did improve outcome rates.

Intracytoplasmic Sperm Injection Increases Embryo Fragmentation Without Affecting Clinical Outcome

AbstractPurpose: To examine the effect of intracytoplasmic sperminjection (ICSI) on embryo fragmentation and implantationrates in those embryos chosen for transfer compared toconventional in vitro fertilization (IVF). Methods: We compared 253 infertility patients (71 ICSI and182 IVF) with respect to age, semen analysis, number ofembryos transferred, embryo fragmentation, implantationrate, and pregnancy rate. Embryo fragmentation wasdetermined by one observer at the same laboratory over the entirestudy period. Results: A statistically significant difference was observedin mean embryo grade between IVF (2.2 ± 0.84) and ICSI(2.5 ± 0.77), P = 0.01. Additionally, the IVF patients hadsignificantly more nonfragmented (grade I) embryoscompared to the ICSI group, P < 0.01. Conclusions: These data suggest that ICSI, irrespective ofsemen parameters, may increase embryo fragmentation andproduce fewer nonfragmented grade I embryos while maintaining implantation and pregnancy rates similar toconventional IVF.