Trisomy 1 in a clinically recognized IVF pregnancy.

Most chromosomal trisomies lead to spontaneous abortion. To date, trisomies of all human chromosomes have been observed. Chromosome 1 has been the most elusive, as trisomy 1 was the last aberration to be identified. To date there has been only one case report of a full trisomy 1 in the literature [1997: Am J Med Genet 68:98]. We have identified a second full trisomy 1 from the chromosome analysis of products of conception. We present a patient who conceived by in vitro fertilization (IVF). The cellular divisions of the fertilized egg were carefully monitored prior to transfer. Hormonal changes (increased hCG) indicated that implantation had occurred. Vaginal ultrasound demonstrated a gestational sac. At 42 days postfertilization no fetal heart beat could be detected. Cytogenetic analysis of the chorionic villi isolated from the products of conception found that all of the cells analyzed contained a 47,XY,+1 chromosomal complement.

The effect of a propofol-based sedation technique on cumulative embryo scores, clinical pregnancy rates, and implantation rates in patients undergoing embryo transfers with donor oocytes.

STUDY OBJECTIVE: To determine the effect, if any, of a propofol-based sedation technique on the reproductive outcomes of patients undergoing embryo transfers with donor oocytes. These ova recipients form a unique subgroup, whose clinical outcomes are unrelated to direct anesthetic effects on their reproductive tracts. DESIGN: Retrospective chart review. SETTING: A 1200-bed university medical center. PATIENTS: 117 patients who received fresh embryo transfer cycles between January 1991 and December 1995. MEASUREMENTS AND MAIN RESULTS: The anesthesia records of 106 women who donated ova were reviewed for propofol usage during the transvaginal needle aspiration of the ova. The medical records of the 117 patients who received these donated embryos were reviewed for cumulative embryo scores, clinical pregnancy rates, and implantation rates. Fourteen patients received ova from women who were sedated with fentanyl and midazolam during ovum retrievals, while 103 patients received ova from women who had been given fentanyl, midazolam, and propofol in doses of 1.87 mg/kg to 8 mg/kg. The pregnancy rate among all patients who received ova from women who received propofol (44 of 103 = 42.7%) was 14.1% greater than those whose ovum donors did not receive propofol (4 of 14 = 28.6). 78.6% of both propofol and non propofol-exposed groups had cumulative embryo scores of greater than 50. Among patients who became pregnant, 52.3% of propofol-exposed and 50% of nonpropofol-exposed cases had greater than 20% implantation rates. CONCLUSION: There is no evidence from our data that the administration of propofol during the aspiration of ovarian follicles for oocyte donation had a negative impact on the oocytes as measured by cumulative embryo scores, probability of a clinical pregnancy, or implantation rate.

Perinatal outcome after embryo transfer in ovum recipients. A comparison with standard in vitro fertilization.

OBJECTIVE: To compare perinatal outcome after embryo transfer vs. standard in vitro fertilization (IVF) in ovum recipients. STUDY DESIGN: We reviewed 22 consecutive ovum donor pregnancies delivered at Mount Sinai Hospital between July 1989 and November 1992 and matched them for age, parity and order of gestation to a control group who underwent standard IVF-embryo transfer (ET) during that period. RESULTS: The two groups showed similar rates of maternal complications, including hypertensive disorders, gestational diabetes and puerperal complications. When compared to patients undergoing autologous IVF-ET, ovum recipients had a lower rate of preterm labor (22.7% vs. 54.6%, P < .05), a higher mean gestational age at delivery (38.7 vs. 36.1 weeks, P < .01) and increased mean birth weight of neonates (2,924 vs. 2,374 g, P < .005). Though infants born through traditional IVF-ET were more likely to be preterm, Apgar scores were similar at one and five minutes. Our data support the generally favorable outcome seen in pregnancies conceived through ovum donation despite the fact that many of these patients had prior poor prenatal outcomes, long intervals until conception, and coexisting medical conditions. CONCLUSION: Ovum donation in women of comparable ages has obstetric outcomes equal to or better than patients undergoing traditional IVF-ET. Obstetric and perinatal outcome do not seem to be impaired in patients receiving donated oocytes.

An elevated day three follicle-stimulating hormone:luteinizing hormone ratio (FSH:LH) in the presence of a normal day 3 FSH predicts a poor response to controlled ovarian hyperstimulation.

OBJECTIVE: To determine if an elevated FSH:LH ratio predicts response in infertile patients undergoing controlled ovarian hyperstimulation (COH) for IVF-ET. DESIGN: Retrospective study. SETTING: The Division of Reproductive Endocrinology at the Mount Sinai Medical Center, New York, New York. PARTICIPANTS: Seventy-four patients undergoing IVF-ET using similar protocols for COH with day 3 FSH, LH, and E2 testing available for analysis. All patients were < 41 years of age and had day 3 serum FSH < 15 mIU/mL (conversion to SI unit, 1.00). MAIN OUTCOME MEASURES: Follicle-stimulating hormone:LH ratio, day 8 serum E2, peak serum E2, cancellation rate, pregnancy rate, and number and size of follicles. RESULTS: An FSH:LH ratio > or = 3.6 (group I) predicted a poor response to COH (sensitivity 85.7% and specificity 95%). There were no significant differences regarding day 3 serum FSH and ampules of gonadotropins used for COH. Group I (ratio > or = 3.6) patients responded to COH with lower day 8 E2 (97 +/- 18 versus 319 +/- 36 pg/mL; conversion factor to SI unit, 3.671), peak E2 (422 +/- 115 versus 2,368 +/- 183 pg/mL), and fewer follicles > 15 mm (1.3 +/- 0.5 versus 17.1 +/- 1.0). In group I the cycle cancellation rate (12/14) was significantly higher than the group II cycle cancellation rate (2/60) and pregnancy rate in group II (ratio < 3.6) was 25%. CONCLUSIONS: The FSH:LH ratio may increase before a dramatic increase in serum FSH is observed and appears to be a useful marker of ovarian reserve.

The uterus and endometrium.

Transvaginal sonography is useful for the identification of physiologic and pathologic changes within the myometrium and endometrium. Endometrial ultrasonography is simple to learn because of the reliable identification of the uterus. It is useful for monitoring fertility treatment, evaluation of abnormal bleeding and monitoring patients in the menopause.

Early first-trimester ultrasound provides a window through which the chorionicity of twins can be diagnosed in an in vitro fertilization (IVF) population.

PURPOSE: Early and accurate diagnosis of placentation alerts the obstetrician to potential clinical sequelae. The reproductive endocrinologist has a unique opportunity to sonographically evaluate the very early intrauterine pregnancy. We undertook this study to determine whether chorionicity could accurately be predicted using early first-trimester transvaginal ultrasound. RESULTS: Of 47 sets of twins conceived through our IVF-ET program, all underwent detailed transvaginal sonography. These findings were then compared with results of placental pathology examination, after birth. Transvaginal sonography was performed 41 days following embryo transfer. All 3 monochorionic placentas were correctly predicted by ultrasound, while the remaining 44 placentas were dichorionic. CONCLUSIONS: The significance of our findings lies both in our 100% accuracy in diagnosis and in the extremely early gestational age at which we were able to establish correctly the diagnosis of chorionicity. The errors in diagnosis made by previous investigators were often the result of not recognizing single placentae which were later histologically shown to be the result of placental fusion. The infertility specialist has a unique window of opportunity to evaluate placentation and should provide useful information regarding chorionicity to the obstetrical team.

Severe ovarian hyperstimulation despite prophylactic albumin at the time of oocyte retrieval for in vitro fertilization and embryo transfer.

OBJECTIVE: To report two cases of severe ovarian hyperstimulation syndrome (OHSS) despite the administration of 50 g IV albumin at the time of oocyte retrieval. Two previous published series failed to observe OHSS in patients receiving prophylactic IV albumin. DESIGN: Case reports of two women undergoing controlled ovarian hyperstimulation with E2 > 4,500 pg/mL (conversion factor to SI unit, 3.671) on the day of hCG administration who developed OHSS despite prophylactic albumin administration. SETTING: The division of reproductive endocrinology at the Mount Sinai Medical Center. INTERVENTIONS: Fifty grams IV albumin (200 mL of a 25% albumin solution) were administered over 30 minutes at the time of oocyte retrieval. MAIN OUTCOME MEASURES: Prevention of interstitial fluid accumulation such as ascites, pleural effusions, and generalized edema. The other goals of albumin administration included avoiding hemoconcentration, renal insufficiency, and thrombotic complications. RESULTS: The patients developed sequelae of severe OHSS requiring hospitalization, despite administration of IV albumin. CONCLUSION: Albumin is a promising agent in the prevention of OHSS. However, until the basic pathophysiology of this disorder can be elucidated, the mechanism of its action will remain elusive. Attempts to quantify and report clinical outcomes and the ultimate completion of a prospective randomized study will assist in the prevention and management of this enigmatic disorder.

Cumulative number and morphological score of embryos resulting in success: realistic expectations from in vitro fertilization-embryo transfer.

OBJECTIVE: To define statistical thresholds for the number and morphological score of embryos transferred that would be predictive of reproductive success in an IVF program. DESIGN: A retrospective review of patient records. SETTING: The Mount Sinai Medical Center Assisted Reproductive Technologies Program. PARTICIPANTS: One hundred women who underwent IVF-ET for a diagnosis of tubal occlusion and later delivered viable infants. RESULTS: The mean number of embryos transferred before achieving live birth was 10.7 +/- 7.9 (mean +/- SD), with one half of patients achieving success within the first seven embryos transferred, and 95% achieving success within 25 embryos. For high quality embryos, the numbers were 7.5 +/- 6.3, 5, and 17, respectively, and, for the cumulative embryo score, a measure of both embryo morphology and metabolic activity, were 114.2 +/- 86.0, 83, and 280, respectively. Greater than 50% of live births occurred within the first two ET attempts. CONCLUSIONS: Although more than half of patients achieved reproductive success within the first two ETs and the first five high quality embryos transferred, after this threshold, fecundity declined rapidly. The calculation of cumulative embryo scores offered additional prognostic information. While all prior attempts to define IVF-ET failure have done so by including patients who did not become pregnant, we have found an analysis of our successes to be a useful adjunct in counseling patients.

Failed fertilization in vitro: second day micromanipulation of oocytes versus reinsemination.

OBJECTIVE: To compare routine reinsemination with 2nd day micromanipulation in patients with poor day 1 fertilization. DESIGN: A retrospective review of patient records. SETTING: The Mount Sinai Medical Center Assisted Reproductive Technologies Program. PARTICIPANTS: Patients undergoing IVF-ET who had poor fertilization (< 35%) with standard insemination and underwent second day reinsemination of oocytes (group I, n = 84) compared with patients who underwent 2nd day micromanipulation with subzonal insemination (group II, n = 12). MAIN OUTCOME MEASURES: Fertilization rate, cleavage rate, number of embryo transfers, and pregnancy rate. RESULTS: Fertilization rate and cleavage rate were significantly higher in group II patients. Pregnancies per transfer were similar between groups I (3/21, 14.3%) and II (0/9, 0%). Second day fertilization was possible in 9 of 12 group II patients, and fertilization rate was higher than day 1 in all nine, however, only 50% achieved cleavage, and none achieved pregnancy. CONCLUSIONS: Although micromanipulating oocytes that fail to fertilize may identify occult male factor infertility, may help the clinician plan future cycles, and may result in fertilization and even transfer of embryos in some cycles, there were no pregnancies in our series, and, for now, the clinical efficacy of this procedure remains in question.

The significance of endometrial filling defects detected on routine transvaginal sonography.

The objective of this study was to compare endometrial filling defects detected on transvaginal sonography performed without distending media with findings on hysterosalpingography. Forty-three infertile patients were studied in the follicular phrase. Of these, 17 patients had endometrial contour abnormalities detected on vaginal sonogram and 26 patients had no filling defects on ultrasonography. Ultrasonography of the endometrium and hysterosalpingography were performed on all patients as part of a routine workup for infertility. Patients with contour abnormalities detected on either hysterosalpingography or transvaginal ultrasonography underwent hysteroscopy. When a contour abnormality was detected on vaginal sonogram, hysterosalpingography confirmed a defect in 94% of the cases and hysteroscopy in 100% of the cases. Seven of 26 subjects (27%) with normal vaginal ultrasonograms had abnormal hysterosalpingograms; however, only two patients with a normal sonogram had abnormal hysteroscopic findings. Filling defects seen on hysterosalpingography that were not detected on sonography include synechiae, and cornual polyps. This study indicates that vaginal ultrasonography is an accurate tool in the identification of submucous fibroids and polyps. If the examination is performed in the follicular phase, use of distending medium is not necessary to detect major abnormalities of the endometrium. Synechiae are not, however, visible without distention of the endometrial cavity.

Infertile couples with normal counts who require subzonal sperm insertion possess a fertility defect that affects zona pellucida penetration.

The results of subzonal sperm insertion (SUZI) have been retrospectively analysed in a subset of patients with normal sperm counts who were found to require SUZI because of poor or absent fertilization of zona-intact oocytes. This patient group is of particular interest because male factor-related infertility cannot be due to insufficient numbers of spermatozoa reaching the oocytes. Thus, failed fertilization can be attributed to deficiencies in one or more steps in the fertilization process, and SUZI provides a method of distinguishing defects of zona pellucida penetration from gamete fusion. A total of 26 such patients were treated identically to and concurrently with a much larger group of SUZI candidates who typically suffered from oligozoospermia, and fertilization results were compared. Fertilization rates after SUZI were higher in patients with normal counts than in oligozoospermic patients (51 and 26% respectively), indicating that the proportion of spermatozoa capable of fusing with the oocyte is the same or higher in the group with normal counts. In addition, nearly all SUZI procedures led to fertilization (23/26), with two out of three failed fertilizations occurring in cases where two or less oocytes were manipulated, results which further indicate that failed fertilization in these patients is not due to a defect at the level of gamete fusion. These findings suggest that infertility in these patients is based upon the inability of the spermatozoa to reach the oolemma and thus, that their fertility defect resides at the step of zona penetration.

Urinary follicle-stimulating hormone as a biological marker of ovarian toxicity.

Reproductive senescence has not been adequately explored as a possible end point for assessing toxicity to the reproductive system. We propose that urinary FSH be used as a biologic marker of ovarian function in women. A urinary marker would facilitate the incorporation of this measure into epidemiologic studies of reproductive toxicity. Although there is some evidence that FSH in serum is a good biologic marker of ovarian reserve, the relationship between serum FSH and urinary FSH has not been adequately explored. We found that urinary FSH and serum FSH were closely correlated in 50 consecutive women seen in clinical practice.

Ovarian hyperstimulation and follicular aspiration. Effect on ovulatory function.

The return of normal function of the reproductive axis immediately after hyperstimulation and follicular aspiration is of both physiologic and clinical interest. These cycles may be utilized for the replacement of cryopreserved embryos, for repeated ovarian stimulation or for any alternative treatment that relies upon normal ovulatory function. Thirty-five women were randomly assigned to be monitored in the first (n = 11), second (n = 13) or third (n = 11) menstrual cycle after in vitro fertilization (IVF). Five of 35 patients (14.3%) failed to ovulate, 2 in each of the first and second menstrual cycles and 1 in the third cycle after IVF. Six (20%) ovulatory cycles demonstrated luteal phase deficiencies. The defective luteal phases were evenly distributed between cycles immediately after IVF and those more remote in time from the procedure.

High-resolution endovaginal ultrasonography of the endometrium: a noninvasive test for endometrial adequacy.

Endovaginal sonography of the endometrium demonstrates characteristic findings throughout the menstrual cycle. To correlate these findings with histologic criteria for normal endometrial development, we compared endometrial biopsies with ultrasonographic findings. Nineteen cycles were monitored in 18 women with ovarian failure whose endometrial cycles were induced exogenously by sequential transdermal 17 beta-estradiol (E2) and intramuscular progesterone. These subjects underwent ultrasonography of the endometrium prior to the day of progesterone initiation (luteal day +1) and continuing throughout the mid-secretory phase. On luteal day +1, ultrasonography characteristically demonstrated a multilayered endometrium consisting of a hyperechoic perimeter (endometrial-myometrial interface), a hypoechoic inner layer, and a hyperechoic midline (luminal interface). By luteal day +7, a gradual increase in echogenicity of the inner layer was detected, while the inner myometrium remained hypoechoic. Eleven of 19 cycles demonstrated a completely hyperechoic endometrium on luteal day +7 and also demonstrated normal stromal development on endometrial biopsies. Three patients who had endometrial biopsies consistent with their chronological development failed to demonstrate a hyperechoic endometrium by luteal day +7. All five biopsies that were histologically out of phase were detected by ultrasonography. Thus, ultrasonography demonstrated a sensitivity of 100% and a specificity of 62% for the detection of histologically normal endometrial development. Endometrial thickness could not be used to discriminate between biopsies that were normal (13 +/- 1.0 mm) and those out of phase (13.8 +/- 1.8 mm). Endometrial histology demonstrated asynchrony of glands and stroma in nine cases in which ultrasonography correlated with stromal, but not with glandular dating, suggesting that the increased echogenicity may reflect stromal edema.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of female antisperm antibodies on in vitro fertilization, early embryonic development, and pregnancy outcome.

STUDY OBJECTIVE: To evaluate the extent to which human in vitro fertilization-embryo transfer (IVF-ET) alleviates immunological infertility. DESIGN: Retrospective. SETTING: In vitro fertilization program. PATIENTS: Thirty-three patients with positive antisperm antibodies undergoing 50 cycles of IVF-ET in which maternal serum was replaced by 5 mg/mL of bovine serum albumin (BSA) comprised the study group. Seventy-one patients with tubal infertility served as controls. In 50 of these, medium was supplemented with 7.5% maternal serum, and 21 were assigned to BSA substitution. RESULTS: Percentage of fertilization in the study group was significantly lower (41 +/- 31; mean +/- SD) than that of controls with maternal serum (77 +/- 15) and BSA (76 +/- 22). Early embryonic quality, as assessed by percentage of cleavage and morphological grading, was found to be inferior in patients with antisperm antibodies. The percentage of advanced embryos (greater than or equal to 4 blastomeres) at the time of transfer was 42 +/- 39 in the study group, compared with 65 +/- 23 and 75 +/- 35 for maternal serum and BSA controls, respectively. Percentage of morphologically favorable embryos (grades 1 and 2 in a 1 to 5 grading system) was 49 +/- 31 in the study group, compared with 78 +/- 35 and 74 +/- 23 for the controls. Percentage of clinical pregnancy was somewhat lower in the study group (12.5%) than in controls with either maternal serum (18%) or BSA (19%). CONCLUSIONS: Antisperm antibodies may have an adverse effect on fertilization and early embryonic development. Female immunological infertility may not be completely alleviated by IVF-ET.

Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility.

Female fertility declines with advancing age. To establish whether this age-related reproductive failure results from diminished oocyte quality or uterine/endometrial inadequacy we investigated ovum donation in 35 infertile women, aged 40 years or older (mean 42.7 [SE 0.3]) who had failed at attempts at conception with their own (self) oocytes. Oocytes were donated by 29 young individuals (mean age 33.4 [0.7]) undergoing in-vitro fertilisation (IVF). 8 (5.3%) pregnancies were achieved in 150 cycles of ovulation induction with self-oocytes and 2 (3.3%) in 60 such cycles by in-vitro fertilisation (IVF), but none attained viability. By contrast in 50 cycles with donated oocytes 28 (56%) pregnancies and 15 (30%) deliveries were realised (p less than 0.005). The rate of implantation per embryo transferred was higher (14.7%) with donated oocytes than that with self-oocytes (3.3%) (p less than 0.01). To further elucidate the contribution of age to reproductive outcome, pregnancy results were compared between the young donors and older recipients. Both donors and recipients shared oocytes from the same induced cohort. Rates for clinical pregnancy and delivery did not differ between donors (33% and 23%) and recipients (40% and 30%). Our data suggest that the age-related decline in female fertility is attributable to oocyte quality and is correctable by ovum donation. The uterus can adequately sustain pregnancies even when reproductive potential is artificially prolonged into the late 40s.

An insight into early reproductive processes through the in vivo model of ovum donation.

To gain insight into early reproductive processes we have prospectively designed ovum donation protocols to elucidate several phenomena relating to embryo implantation and pregnancy sustenance. Artificial endometrial cycles with variable follicular phases were induced in 60 recipients by sequential estrogen and progesterone. A total of 964 oocytes were retrieved throughout 43 ovum donation attempts, for an average of 22.4 (range, 16-41) eggs/retrieval. The overall delivery rate per egg retrieval (donors and recipients combined) was 72.1% (31 of 43). The shortest estrogen stimulation (short follicular phase) resulting in ongoing pregnancies was 5 days in duration, while the longest (long follicular phase) was 35 days in duration before progesterone initiation. Utilization of variable length follicular phases, artificially extended the stage of endometrial receptivity to over 4 weeks. To assess the window of implantation, same age embryos were transferred onto endometrium of different maturational stages. Pregnancies were documented with embryo transfers between luteal day 1 (day 15) to luteal day 6 (day 20), extending the window of implantation in the human to at least 6 consecutive days. To evaluate the relative contribution of oocyte quality and endometrial receptivity to pregnancy outcome, common source ova were transferred onto endometrium with variable hormonal exposure. Despite the drastically different follicular phase estradiol levels and periods of exposure, similar delivery rates were attained in donor cycles (29.4%) and recipient cycles during short follicular phases (29.6%). Slightly higher delivery rates (39.4%) were observed with long follicular phases. The comparable pregnancy rates in donors and recipients are attributed to the common source oocytes regardless of endometrial stimulation.

Clinical evaluation of three approaches to micromanipulation-assisted fertilization.

Three different micromanipulation procedures were used to assist human fertilization in cases of severe male factor infertility. Zona drilling was performed either with acid Tyrode's solution, mechanically following zona softening with chymotrypsin, or by partial zona dissection. The fertilization rate was lowest in the zona drilling/acid Tyrode's group (7/40; 17.5%), although no differences between groups (zona drilling/chymotrypsin: 21/84, 25%; partial zona dissection: 31/143, 21.7%) were significant. The fertilization rate was significantly increased relative to untreated eggs from the same patients only in the partial zona dissection group (31/143, 21.7% versus 4/102, 3.9%). Oocyte damage occurred at a high rate as a result of zona drilling with acid Tyrode's solution (13/41, 37%). Embryonic development was compromised after zona drilling with chymotrypsin: only 7/12 (58.3%) of the fertilized oocytes cleaved, and the morphology of many of the cleaved embryos was abnormal. Although only 61% (16/26) of the diploid embryos resulting from partial zona dissection cleaved, the embryonic morphology of these embryos was comparable with controls. No pregnancies resulted from the transfer of manipulated embryos. We conclude that although zona manipulation increases the fertilization rate, losses due to oocyte trauma, low rates of diploid fertilization, low rates of cleavage, and a high frequency of abnormal cleavage reduce the number of embryos available for transfer.