Reproductive outcomes of women aged 40 and older undergoing IVF with donor sperm.

STUDY QUESTION: Do women ≥40 years old without a male partner who utilize donor sperm have the same reproductive outcomes as those who utilize their partner's sperm? SUMMARY ANSWER: After controlling for relevant confounders, women ≥40 years old using donor sperm for IVF have significantly higher odds of having a live birth compared to those utilizing their partner's sperm. WHAT IS KNOWN ALREADY: Women who are unpartnered or in same-sex relationships are by definition not infertile, but may choose to conceive using donor sperm. It is not known how IVF outcomes are affected with the use of donor sperm compared to women utilizing their partner's sperm, particularly at very advanced maternal ages. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study conducted at a university-affiliated center of women undergoing IVF with fresh embryo transfer between 2008 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were divided into two groups based on the ejaculated sperm source utilized: donor or partner sperm. Live birth rate was the primary outcome. Pregnancy rate was the secondary outcome. Multivariable logistic regression was performed and adjusted for age, the developmental stage of the embryo, and the number of embryos transferred. Unadjusted odds ratio (OR) and adjusted OR (aOR) with 95% CI for pregnancy and live birth were estimated. Statistical significance was denoted by P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 3910 cycles in women ≥40 years old were analyzed, of which 307 utilized donor sperm and 3603 utilized their partner's sperm to conceive. In the univariate analysis, patients utilizing donor sperm were found to have similar pregnancy rates as those utilizing partner sperm (41.0 vs 39.8%, OR: 0.95, 95% CI: 0.75-1.20). After adjusting for age, the number of embryos transferred and the developmental stage of the embryos, the model estimates did not vary (aOR: 1.22, 95% CI: 0.95-1.56). Similarly, the univariate analysis for live birth did not demonstrate a difference between groups (19.2 vs 17.8%, OR: 0.91, 95% CI: 0.67-1.22). However, after a similar adjustment was made for confounders, the use of donor sperm was associated with statistically significant increased odds of live birth (aOR: 1.38, 95% CI: 1.01-1.88). LIMITATIONS, REASONS FOR CAUTION: As with any retrospective study, the potential for residual confounding exists, despite attempts to control for this with regression modeling. WIDER IMPLICATIONS OF THE FINDINGS: Women ≥40 years old who are unpartnered or in same-sex relationships can be counseled that their odds of a live birth are slightly better than women in heterosexual relationships utilizing their partner's sperm. These findings serve to further refine and individualize counseling on the expected IVF outcomes for women in this population. STUDY FUNDING/COMPETING INTEREST(S): No funding was sought for this study. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Histologic characteristics of the endometrium predicts success when utilizing autologous endometrial coculture in patients with IVF failure.

PURPOSE: To analyze the success of autologous endometrial coculture (AECC) in improving embryo quality and pregnancy outcome based on the histologic characteristic of the biopsy. METHODS: Prospective study of 86 consecutive patients undergoing IVF utilizing AECC. RESULTS: The patients were on average 37.4+/-4.0 years with a history of 2.6+/-1.8 failed previous attempts. An overall clinical pregnancy rate of 45.3% per ET was found. The embryos grown in AECC were of an improved quality in comparison to those grown in conventional media. 33.7% (29/86) of the biopsies were out of phase (>3 days). In-phase (IP) and OOP (out of phase) specimens both demonstrated an improvement in embryo quality. However, OOP endometrial biopsies that displayed significant retarded endometrial development (< cycle day 19) did not demonstrate an improvement in embryos grown on AECC as compared to IP endometrial biopsies or OOP endometrial biopsies that demonstrated at least an endometrial development of cycle day 19. CONCLUSIONS: We have demonstrated a significant improvement in embryo quality with AECC. We have also demonstrated that histologic dating of the endometrium is predictive of IVF outcome when utilizing AECC.

Ovarian cancer and fertility medications: a critical appraisal.

Ovarian cancer is the fifth most common cancer in the Western world. Infertility and nulliparity are independent risk factors for this disease. The possible link between fertility drugs and ovarian cancer remains controversial. Despite concern regarding increasing use of fertility therapy, the incidence of ovarian cancer in the Western world has remained stable for several decades. Evaluation of the literature requires assessment of the validity, importance, and applicability of the study to your particular patient. The following article demonstrates how to conduct such an assessment. The data to date do not support a causal relationship between fertility drugs and ovarian cancer. In fact, infertility therapy may confer protection for those patients who conceive. Further prospective, long-term data are needed to further delineate this relationship.

Superovulation strategies for assisted reproductive technologies.

Assisted reproductive technologies (ART) pregnancy rates improve with the replacement of multiple embryos. The specific number of embryos to be transferred (typically between two and four) is based on a patient's age and past history and a morphologic assessment of embryo quality. Superovulation, with the goal of multifollicular recruitment and the harvest of multiple preovulatory oocytes, is therefore an integral aspect of in vitro fertilization and related techniques. Given the considerable interindividual variability in response to superovulation, the selection of an appropriate ovarian stimulation protocol is critical both for the safety and success of ART. Specific superovulation strategies have therefore been developed for treatment of abnormal response patients as well as for patients expected to manifest a "normal" response to ovulation inducing agents.

"Co-Flare" stimulation in the poor responder patient: predictive value of the flare response.

PURPOSE: In this study we review our experience with a day 2 start, "Co-Flare" protocol analyzing the flare response as a predictor of outcome in patients with a history of a poor response. METHODS: This study was conducted at a university based IVF Center. A total of 564 patient cycles over a 2.5-year time frame in patients that had either elevated FSH levels or a previous poor response to conventional leuprolide acetate down-regulated stimulation were retrospectively analyzed. These patients were treated with our co-flare protocol (1.0 mg of leuprolide acetate administered on day 2 and decreased on day 5 to 0.5 mg; gonadotropins initiated on day 3). We analyzed the initial flare response and the outcome for these patients. RESULTS: A total of 564 patients attempted to initiate an IVF cycle. The patients mean age was 39.4+/-3.7 years. Of the 450 cycles that started, the outcomes were as follows: 24% (108/450) cancellation, 20.4% (92/450) clinical pregnancy per initiated cycle, and a 14.0% delivery rate per initiated cycle. Patients with an estradiol flare that doubled were less likely to have cycles cancelled (13.6% vs. 35.6%, P < 0.01), but no differences were noted in pregnancy outcome if the cycle was not cancelled once the patient made it to retrieval. CONCLUSIONS: We have demonstrated an overall 14.0% delivery rate per initiated cycle in these "poor prognosis" patients. While the initial flare response (as indicated by a doubling of the estradiol by the second day of stimulation) was indicative of a better stimulation, no difference in pregnancy outcome was seen if the patient underwent retrieval.

The role of LH in ovarian stimulation: exogenous LH: let's design the future.

Historically, follicular stimulation protocols have included both FSH and LH in an attempt to mimic the physiology of normal human folliculogenesis. However, many recent gonadotrophin administration regimens have completely eliminated LH bioactivity. The importance and the amount of LH necessary for optimal follicular stimulation has been a topic of debate. Several recent studies have added to our understanding of the actions of androgens, oestrogens, gonadotrophins, and insulin on the follicle-oocyte unit, allowing a less speculative approach. Moreover, the availability of human gonadotrophins synthesized by recombinant DNA technology and gonadotrophin-releasing hormone (GnRH) antagonists, should soon permit a precise in-vivo assessment and re-evaluation of the historical 2-cell, two-gonadotrophin hypothesis. These pharmacological tools may also provide essential insights into the physiological roles of FSH and LH in human follicular development and oocyte maturation. The recombinant gonadotrophins give clinicians the unique opportunity to tailor ovarian stimulation regimens according to the patient's medical history, in an effort both to maximize oocyte yield and to improve oocyte quality.

An analysis of the effect of age on implantation rates.

PURPOSE: To evaluate implantation rate as a function of age. METHODS: A total of 1621 consecutive cycles of IVF were evaluated for implantation as a function of age at The New York Hospital/Cornell Medical Center. RESULTS: An overall implantation rate of 23.3% (1328/5691) was found. The implantation rate as a function of age decreased in a nonlinear fashion. Implantation remained constant until the age of 35 and then decreased in a significantly, linear fashion by 2.77% per year (P < 0.001, R2 = 0.975). A formula to predict implantation rates for a given age was developed: Implantation rate = -119.352 + (9.985 x Age - (0.164 x Age2)). CONCLUSIONS: We have demonstrated that implantation rates remain constant until the age of 35 at which time a linear decrease of 2.77% per year is observed.

Antiphospholipid antibodies and in vitro fertilization success: a meta-analysis.

OBJECTIVE: To evaluate whether the presence of antiphospholipid antibodies among women undergoing IVF affects the likelihood of IVF success. DESIGN: A meta-analysis of seven eligible studies on antiphospholipid antibodies and IVF outcome. MAIN OUTCOME MEASURE(S): Odds ratios (ORs) and 95% confidence intervals (CIs) of an association between the presence of antiphospholipid antibodies and both clinical pregnancy and live birth from IVF. RESULT(S): There was no significant association between antiphospholipid abnormalities and either clinical pregnancy (OR 0.99; 95% CI 0.64-1.53) or live birth (OR 1.07; 95% CI 0.66-1.75) in IVF patients. CONCLUSION(S): The measurement of antiphospholipid antibodies is not warranted in patients undergoing IVF.

ICSI and its outcome.

Since its introduction in 1992, intracytoplasmic sperm injection (ICSI) has become a popular assisted fertilization technique proved very efficient in treating male factor infertility. Many healthy children have been born worldwide from this procedure, and their physical and mental development appears to be within the normal limits. However, because of the peculiarity of the technique and the poor characteristics of the spermatozoa used, concern about the safety of ICSI still exist. In this article, we analyze the in vivo development of embryos conceived after ICSI as well as the obstetric outcome, occurrence of chromosomal abnormalities, and rate of congenital malformations in neonates born as a result of this treatment. A total of 2435 couples were studied in whom the male partners were presumed to be the cause of repeated failed attempts at in vitro fertilization (IVF) or had semen parameters that were unacceptable for conventional IVF treatment. Pregnancies resulting from 3573 ICSI cycles were analyzed; pregnancy outcome data were obtained from the records of obstetrician-gynecologists and/or pediatricians. The overall clinical pregnancy (fetal heartbeat) rate was 44.8% with a resultant delivery rate of 39.2% per ICSI cycle (n = 1388). In 37 of the 77 miscarriages for which cytogenetic data were available, an autosomal trisomy was found in each and 29 additional pregnancies were terminated because of a chromosomal abnormality revealed by prenatal diagnosis. There was an equal distribution of vaginal deliveries and cesarean sections (n = 682 and n = 658, respectively). Of the 2059 neonates resulting from ICSI treatment, 38 (1.8%) presented with congenital abnormalities (22 major and 16 minor). When the frequency of miscarriages and congenital malformations was analyzed in terms of semen origin, the outcome was no different between ICSI and IVF. The course of pregnancies and occurrence of congenital malformations following treatment by ICSI are within the ranges obtained following conventional IVF.

Gynaecology, forced sterilisation, and asylum in the USA.

PIP: On September 30, 1996, the US Congress enacted a law to grant asylum protection to victims of forced sterilization, forced abortion, and other forms of coerced population control and to opponents of these practices. Before this time, the US Board of Immigration Appeals judged forced sterilization insufficient grounds for political asylum unless it was performed for some discriminatory reason. The authors of this article have examined five women who claimed they were forcibly sterilized in China and were granted political asylum in the US as a result. The average age of these women was 32 years, while the average duration since forced sterilization was 8.6 years. Since asylum applications are not filed according to cause, there are no estimates of the number of women seeking asylum in the US as a result of forced sterilization. The Chinese government claims it does not authorize forced sterilization, but local officials acknowledge it sometimes occurs. In many cases, sterilization is not formally coerced but required as a condition of employment. Consistency between the woman's claim of forced sterilization and medical or psychological reports is essential to the success of asylum applications. US physicians should be prepared to play a documentary role in the evaluation of such requests.^ieng

Oocyte donation: does a previous attempt affect a subsequent attempt?

OBJECTIVE: To analyze the effect of a previous donor oocyte cycle on the outcome of subsequent attempts. DESIGN: Retrospective study. SETTING: Oocyte donation program at The New York Hospital/Cornell Medical Center. PATIENT(S): Two hundred sixty-seven patients undergoing 354 fresh cycles of oocyte donation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical outcomes were divided into groups based on the attempt number of each cycle for each patient. Results were calculated for each recipient cycle. RESULT(S): A clinical pregnancy rate of 56.2% and ongoing pregnancy/delivery rate per retrieval of 50.3% were noted. No statistically significant differences in clinical outcomes were found between the first, second, and third attempts. A significant increase was noted in the ongoing pregnancy/delivery rate per recipient cycle for the second attempt in those patients who had a delivery after the first attempt compared with those who did not. CONCLUSION(S): We demonstrated an overall clinical pregnancy rate of 56.2% and an ongoing pregnancy/delivery rate of 50.3% per retrieval. Outcome for the second attempt was associated with success or failure during an initial attempt at oocyte donation.

Expression of IGFs and their receptors is a potential marker for embryo quality.

PROBLEM: Insulin-like growth factors (IGFs) and insulin have been demonstrated to stimulate oocyte maturation and embryo development. Therefore, the expression of IGFs and their receptors may be an important intrinsic factor for embryo growth and may be a potential marker for embryo quality. METHOD OF STUDY: Thirty donated day 3 embryos were cultured in vitro for an additional 3 days to observe their developmental potential and were semiquantitatively analyzed for the expression of IGF-I, IGF-II, IGF-IR, IGF-IIR, and insulin-R. RESULTS: Our results show that the activity of these gene expressions correlates well with the morphological assessment and that high and more gene expressions were often associated with embryos of high growth potential. CONCLUSION: The IGF system may indeed play an important role in human embryogenesis; IGF gene expressions can be a good indicator of embryonic developmental stage and/or growth potential; finally, the IGF system can serve as a marker for embryo quality.

Dual suppression with oral contraceptives and gonadotrophin releasing-hormone agonists improves in-vitro fertilization outcome in high responder patients.

Certain patients have a tendency for high response to gonadotrophin therapy which is often not ameliorated with prior gonadotrophin-releasing hormone agonist (GnRHa) suppression. As a result, these patients are frequently cancelled and often experience ovarian hyperstimulation syndrome (OHSS) episodes during in-vitro fertilization (IVF)-embryo transfer cycles. Patients with polycystic ovarian syndrome (PCOS) have been noted to be particularly sensitive to exogenous gonadotrophin therapy. We have developed a protocol which is effective in improving IVF outcome in high responder patients, including those with PCOS. Oral contraceptive pills (OCP) are taken for 25 days followed by s.c. leuprolide acetate, 1 mg/day, which is overlapped with the final 5 days of oral contraceptive administration. Low-dose gonadotrophin stimulation is then initiated on the third day of withdrawal bleeding in the form of either human menopausal gonadotrophins or purified urinary follicle-stimulating hormone at a dosage of 150 IU/day. Over a 5 year period, we reviewed our experience utilizing this dual method of suppression in 99 cycles obtained in 73 high responder patients. There were only 13 cancellations prior to embryo transfer (13.1%). The clinical and ongoing pregnancy rates per initiated cycle were 46.5 and 40.4% respectively. Only eight patients experienced mild-moderate OHSS following treatment. For those patients who had undergone previous IVF-embryo transfer cycles at our centre, significant improvements were noted in oocyte fertilization rates, embryo implantation rates and clinical/ongoing pregnancy rates with this protocol. Hormonal analyses revealed that the chief mechanism may be through an improved luteinizing hormone/follicle-stimulating hormone ratio following dual suppression. An additional feature of this dual method of suppression is significantly lower serum androgen concentrations, particularly dehydroepiandrosterone sulphate.

PIP: Presented is a protocol that is effective in improving in vitro fertilization (IVF) outcome in women with a tendency for a high response to gonadotrophin therapy. High responders to exogenous gonadotrophin therapy show recruitment of large numbers of follicles, rapid estradiol responses, and a significant cycle cancellation rate due to the potential risk of hyperstimulation during IVF-embryo transfer attempts. Women with polycystic ovarian syndrome are especially sensitive to exogenous gonadotrophin therapy. The protocol entails 25 days of oral contraceptive (OC) use, followed by 1 mg/day of subcutaneous leuprolide acetate overlapped with the final 5 days of OC therapy. On the third day of withdrawal bleeding, gonadotrophin stimulation is initiated through either human menopausal gonadotrophins or purified urinary follicle-stimulating hormone (150 IU/day). This approach permits normalization of the luteinizing hormone/follicle-stimulating hormone ratio and reduces ovarian androgen concentrations, while circumventing the initial gonadotrophin flare response. This protocol was tested in a retrospective review (1990-94) of 99 cycles from 73 high-responder women treated at a US infertility center. There were only 13 cancellations (13.1%) prior to embryo transfer. The clinical and ongoing pregnancy rates per initiated cycle were 46.5% and 40.4%, respectively. Only 8 women experienced ovarian hyperstimulation syndrome after treatment. Among women who had undergone previous IVF embryo transfer cycles at the center, the present regimen was associated with significant improvements in oocyte fertilization rates, embryo implantation rates, and pregnancy rates.

Delay of gonadotropin stimulation in patients receiving gonadotropin-releasing hormone agonist (GnRH-a) therapy permits increased clinic efficiency and may enhance in vitro fertilization (IVF) pregnancy rates.

OBJECTIVE: To promote an even temporal distribution of patients starting IVF cycles at our center, patients undergoing GnRH agonist (GnRH-a) suppression frequently delay the start of gonadotropin stimulation. Our objective was to analyze the effect that the delay of initiation of gonadotropin stimulation has on outcome parameters in this population. DESIGN: Retrospective analysis. SETTING: A tertiary referral reproductive medicine unit. PATIENT(S): Patients undergoing IVF cycles on long GnRH-a protocols. INTERVENTION(S): Patients were treated with either a "standard-dose" or "low-dose" leuprolide acetate protocol initiated in the mid-luteal phase. MAIN OUTCOME MEASURE(S): Delay time, clinical pregnancy rate, ongoing pregnancy rate, cancellation rate. RESULT(S): Analysis of the overall group revealed associations between stimulation delay and decreases in stimulation duration and the number of gonadotropin ampules administered. Weighted linear regression analyzes revealed statistically positive relationships between delay time and both clinical pregnancy rates and ongoing pregnancy rates, despite a positive relationship between delay time and cancellation rates. Analysis of the standard-dose and low-dose subgroups revealed that the enhancement of pregnancy rates was attributable primarily to patients in the standard-dose protocol. CONCLUSION(S): Delay of gonadotropin stimulation while patients are receiving GnRH-a therapy allows for increased clinic efficiency. There appears to be an enhancement of clinical and ongoing pregnancy rates for the standard-dose leuprolide acetate protocol that is associated with stimulation delay.

Evolution of pregnancies and initial follow-up of newborns delivered after intracytoplasmic sperm injection.

OBJECTIVE: To analyze the in vivo development of embryos conceived after intracytoplasmic sperm injection (ICSI), as well as obstetric outcome, occurrence of chromosomal abnormalities, and rate of congenital malformations in neonates born as a result of this treatment. DESIGN: Retrospective study. SETTING: University-based in vitro fertilization (IVF) clinic. PATIENTS: A total of 751 couples in whom the male partners were presumed to be the cause of repeated failed IVF attempts or whose semen parameters were unacceptable for conventional IVF treatment. INTERVENTIONS: Analysis of pregnancies resulting from 987 ICSI cycles; pregnancy outcome data were obtained from the records of obstetrician-gynecologists and/or pediatricians. MAIN OUTCOME MEASURES: Pregnancy rates, obstetric outcome, and frequency of chromosomal abnormalities and congenital malformations. RESULTS: The overall clinical pregnancy (fetal heartbeat) rate was 44.3%, with a resultant delivery rate per ICSI cycle of 38.7% (n=382). In 8 of 11 miscarriages for which cytogenetic data were available, an autosomal trisomy was found, and 7 additional pregnancies were terminated because of a chromosomal abnormality after prenatal diagnosis. There was an equal distribution of vaginal vs cesarean deliveries (n=192 and n=190, respectively). Of the 578 neonates resulting from treatment by ICSI, 15 (2.6%) presented with congenital abnormalities (9 major and 6 minor abnormalities). However, this frequency of malformations is lower than that observed in offspring born after standard IVF at our institution. Furthermore, when pregnancy outcome of ICSI vs IVF was analyzed in terms of semen origin, no differences were found in the frequency of miscarriages or in the rate of congenital malformations. CONCLUSIONS: The evolution of pregnancies and occurrence of congenital malformations following treatment by ICSI were within the range observed with standard in vitro fertilization.

Twin gestation occupying separate horns of a bicornuate uterus after in-vitro fertilization and embryo transfer.

The detection of congenital uterine anomalies has increased because of heightened physician awareness and improved diagnostic modalities. The occurrence of a twin pregnancy occupying separate horns of a bicornuate uterus has been reported only sporadically in the literature. This is the first reported case resulting after in-vitro fertilization and embryo transfer.

The role of maternal age in assisted reproduction.

There is a significant decline in human fecundity with advancing age. A significant decrement in success rates is also seen in older women undergoing assisted reproduction, including in-vitro fertilization. We have observed a drop in the ongoing pregnancy rate per embryo transfer, from 48.8% in women aged < 30 years to 13.6% in women aged > or = 42 years. Embryo implantation rates also decline in a linear fashion, from 29% in women < 34 years to approximately 5% at age 42. We observed that the impaired implantation efficiency seen in older women is apparently independent of the magnitude of their stimulation response. Oocyte factors are felt to be primarily responsible; however, some available data suggest that uterine factors, e.g. diminished endometrial receptivity, may also play a role. There are presently no treatment strategies apart from oocyte donation, which have been shown to significantly improve implantation efficiency in older women. However, recent efforts have focused on the continued development of improved stimulation protocols, facilitation of embryo implantation by zona pellucida micromanipulation, and the possibility of screening preimplantation embryos for aneuploidy.