Alan S. Penzias

Cumulative Live-Birth Rates after In Vitro Fertilization

BACKGROUND Outcomes of in vitro fertilization (IVF) treatment are traditionally reported as pregnancies per IVF cycle. However, a couples primary concern is the chance of a live birth over an entire treatment course. METHODS We estimated cumulative live-birth rates among patients undergoing their first fresh-embryo, nondonor IVF cycle between 2000 and 2005 at one large center. Couples were followed until either discontinuation of treatment or delivery of a live-born infant. Analyses were stratified according to maternal age and performed with the use of both optimistic and conservative methods. Optimistic methods assumed that patients who did not return for subsequent IVF cycles would have the same chance of a pregnancy resulting in a live birth as patients who continued treatment; conservative methods assumed no live births among patients who did not return. RESULTS Among 6164 patients undergoing 14,248 cycles, the cumulative live-birth rate after 6 cycles was 72% (95% confidence interval [CI], 70 to 74) with the optimistic analysis and 51% (95% CI, 49 to 52) with the conservative analysis. Among patients who were younger than 35 years of age, the corresponding rates after six cycles were 86% (95% CI, 83 to 88) and 65% (95% CI, 64 to 67). Among patients who were 40 years of age or older, the corresponding rates were 42% (95% CI, 37 to 47) and 23% (95% CI, 21 to 25). The cumulative live-birth rate decreased with increasing age, and the age-stratified curves (< 35 vs. > or = 40 years) were significantly different from one another (P<0.001). CONCLUSIONS Our results indicate that IVF may largely overcome infertility in younger women, but it does not reverse the age-dependent decline in fertility.

Luteal phase support

OBJECTIVE To develop a consensus regarding the need for luteal phase support during assisted reproductive technology (ART), and to establish the optimal compound and route of administration for this purpose. DESIGN Review of the published literature on luteal phase support. PATIENT(S) Women undergoing assisted reproductive technologies. INTERVENTION(S) Progesterone was administered orally, vaginally, or by intramuscular (i.m.) injection to supplement the luteal phase after assisted reproductive technology (ART). MAIN OUTCOME MEASURE(S) Pregnancy following ART. RESULT(S); Gonadotropin releasing hormone (GnRH)-agonist protocols necessitate the use of luteal phase support. Progesterone and human chorionic gonadotrophin (hCG) have both been used for this purpose, with comparable outcomes. Progesterone is the product of choice, however, as it is associated with a lower incidence of ovarian hyperstimulation syndrome (OHSS). Its use is indicated up to the serum pregnancy test. Oral, i.m., and vaginal progesterone preparations are available. Intramuscular and vaginal preparations lead to comparable rates of implantation and clinical pregnancy, despite higher serum progesterone levels after i.m. injection. Oral formulations are inferior products for luteal support. Although widely used, i.m. progesterone is uncomfortable and inconvenient for patients. By contrast, the vaginal progesterone gel (Crinone 8%) is more convenient and easier to use. CONCLUSION(S) Progesterone support of the luteal phase in in vitro fertilization (IVF) cycles is indicated, though support beyond the serum pregnancy test may not be needed. The pregnancy rates after vaginal and i.m. progesterone support are comparable, despite higher serum levels after i.m. injection. Patients prefer the vaginal progesterone gel.

The correlation between follicular measurements, oocyte morphology, and fertilization rates in an in vitro fertilization program*

OBJECTIVE To explore the relationship between follicle size and the morphology of the oocyte-cumulus-corona complex with fertilization rates in stimulated cycles of IVF. DESIGN Retrospective comparison of measurements and observations of 2,429 oocytes from 215 patients undergoing 324 stimulated IVF cycles. SETTING A large hospital-based IVF program. MAIN OUTCOME MEASURES Individual follicles were measured by ultrasound before transvaginal aspiration and the size was recorded. The oocyte-cumulus-corona complex from each follicle was examined and classified. The oocytes were checked for evidence of fertilization 17 to 22 hours after insemination. RESULTS The fertilization rate of all oocytes regardless of morphological type revealed a positive linear correlation with increasing follicle diameter. The fertilization rates of type I oocytes was marginally higher than type II oocytes, controlling for follicle diameter; however, this difference did not achieve statistical significance. Oocytes from follicles with a mean diameter > or = 16 mm had significantly higher fertilization rates than did oocytes from follicles with a mean diameter < or = 14 mm. CONCLUSIONS Follicle size is a better predictor of fertilization than is morphological characterization of the oocyte-cumulus-corona complex in IVF.

Recurrent IVF failure: other factors

IVF failure is a problem for a couple in the singular but can be a tragedy in the plural. Recurrent IVF failure has multiple known causes but many which are not routinely considered as part of the posttreatment analysis. The reason is there are several causes associated with lifestyle and other causes related to pre-existing conditions that have only a tenuous or no apparent connection to fertility. This article examines the impact of obesity, cigarette smoke, uterine anatomy, body mass index, thyroid dysfunction, immune factors, the hereditary and acquired thrombophilias, and embryo transfer technique on recurrent IVF failure.

Administration of progesterone before oocyte retrieval negatively affects the implantation rate

OBJECTIVE To compare the efficacy of two clinically accepted methods of progesterone supplementation during IVF. DESIGN Prospective randomized trial. SETTING A university-based IVF program. PATIENT(S) Three hundred fourteen stimulated IVF cycles between January 1993 and October 1994. INTERVENTION(S) Patients were assigned to one of two luteal phase progesterone regimens by a random permuted block design. In protocol A, 12.5 mg of IM progesterone was given 12 hours before oocyte retrieval; in protocol B, 25 mg of IM progesterone was given on the day of oocyte retrieval. MAIN OUTCOME MEASURE(S) Clinical pregnancy. RESULT(S) Patient demographic characteristics, including age, diagnosis, number of oocytes retrieved and fertilized, and number of embryos transferred, were not different between the two groups. There was no difference in the rate of cycle cancellation between the groups. One hundred forty ETs were performed in patients assigned to protocol A and 142 in patients assigned to protocol B. The clinical pregnancy rate in group A was 12.9% compared with 24.6% in group B. CONCLUSION(S) The administration of progesterone before oocyte retrieval is associated with a lower pregnancy rate than the administration of progesterone after oocyte retrieval.

Cumulative live-birth rates after assisted reproductive technology.

Purpose of review Despite the promising success rates of IVF, many couples have to undergo several cycles before achieving live birth. In counseling patients faced with subfertility, it is important to provide cumulative live-birth rates. This review evaluates the current knowledge on cumulative rates, summarizing recently published evidence. Recent findings Existing data have been mostly presented in the form of live-birth rates per IVF cycle as a function of maternal age or reason for subfertility. Recent publications have been reporting IVF success rates in terms of cumulative live-birth rate (CLBR) per woman, thus providing a more realistic estimate that becomes applicable to individual couples. In general, CLBR following IVF has been reported between 45 and 55%. Maternal age has been shown to significantly reduce these rates, as has preimplantation genetic diagnosis. On the contrary, techniques mostly used to decrease the chance of multiple births, such as elective single embryo transfer and natural cycle IVF, do not affect CLBR while achieving a significant reduction in the rates of multiples. Summary Couples should be counseled that CLBR following IVF lies mostly around 50% and that maternal age as well as genetics of transferred embryos remain factors that influence success.

Age-related variations in follicular apolipoproteins may influence human oocyte maturation and fertility potential

OBJECTIVE To investigate involvement of specific apolipoproteins in the process of human oocyte maturation and age-related infertility as molecular constituents of follicular fluid. DESIGN Laboratory-based observational study. SETTING Basic science laboratory at a large academic institution. PATIENT(S) Follicular fluid obtained from healthy women aged 18 to 45 years undergoing in vitro fertilization for unexplained infertility, ovulatory dysfunction, tubal disease, male factor infertility, or oocyte donation. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Specific concentration of apolipoproteins and content of lipoprotein particles in follicular fluid and blood plasma as related to reproductive aging. RESULT(S) We registered a decline of follicular apolipoprotein A1 (Apo A1) and apolipoprotein CII (Apo CII) and an increase of the apolipoprotein E (Apo E) with age, which parallels a lower number of retrieved mature oocytes in older women. Follicular apolipoprotein A1, apolipoprotein B (Apo B), apolipoprotein E, and apolipoprotein C II are present in diverse heterogeneous complexes including very-low-density lipoproteins (VLDL), intermediate-low-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) that vary with patient age and differ from the blood plasma lipoprotein complexes. CONCLUSION(S) Age-related variation in follicular apolipoprotein content and distribution in the cholesterol particles may be associated with the decrease in production of mature oocytes and the age-related decline in fertility potential.

Laparoscopic diagnosis and methotrexate treatment of an ovarian pregnancy : a case report

This report suggests an alternative for dealing with the diagnostic dilemma of differentiating an ovarian pregnancy from a ruptured CL cyst and suggests a conservative management approach that will possibly minimize adhesion formation and optimize future fertility. This new approach is based on a single case reported here, and therefore needs further verification. However, use of this revised set of diagnostic criteria, combined with the judicious use of MTX, may be an alternative therapy for selected ovarian pregnancies.

Assessment of day-3 morphology and euploidy for individual chromosomes in embryos that develop to the blastocyst stage.

OBJECTIVE To examine the relationship between day-3 morphology and euploidy for individual chromosomes in embryos that develop to the blastocyst stage by day 5. DESIGN Retrospective cohort study. SETTING Boston IVF, a large university-affiliated reproductive medicine practice. PATIENT(S) Ninety-nine patients undergoing their first preimplantation genetic screening (PGS) cycle between January 1 and December 31, 2006. INTERVENTION(S) In vitro fertilization (IVF) and preimplantation genetic screening (PGS). MAIN OUTCOME MEASURE(S) Prevalence of euploidy for chromosomes X, Y, 8, 13, 14, 15, 16, 17, 18, 20, 21, and 22 in day-3 high implantation potential (HIP) versus non-HIP embryos that grew to day-5 blastocysts. RESULT(S) Seven hundred three embryos from 99 cycles in 99 patients underwent PGS. Three hundred sixty-four (52%) embryos from 88 cycles in 88 patients developed to the blastocyst stage by day 5. High implantation potential embryos were more likely to be euploid for chromosomes X/Y, 8, 15, 16, 18, and 22 compared with non-HIP embryos, with similar trends for chromosomes 14 and 17. There were no statistically significant differences between HIP and non-HIP embryos in euploidy prevalence for chromosomes 13, 20, and 21. CONCLUSION(S) Our data suggest that PGS may detect potentially viable but detrimental chromosomal abnormalities that are not detected by embryo morphology alone.

Clomiphene citrate and intrauterine insemination: analysis of more than 4100 cycles

OBJECTIVE To evaluate the outcomes of a large cohort of patients undergoing fertility treatment with clomiphene citrate and intrauterine insemination. DESIGN A retrospective cohort study. SETTING Boston IVF, a large university-affiliated reproductive medicine practice. PATIENT(S) A total of 4,199 cycles performed in 1,738 infertility patients between September 2002 and July 2007. INTERVENTION(S) All patients received oral clomiphene citrate, and patients with completed cycles had intrauterine insemination performed. MAIN OUTCOME MEASURE(S) Cumulative and per cycle pregnancy rates achieved among subsets of patients defined by age, completed cycles, and intention to treat (ITT). RESULT(S) For women under age 35 years, 2,351 cycles were initiated in 983 patients. A total of 238 pregnancies ensued, yielding a pregnancy rate (PR) per completed cycle of 11.5% and 10.1% per cycle initiated with ITT. In women aged 35-37 years, 947 cycles in 422 women lead to a PR per completed cycle and ITT of 9.2% and 8.2%, respectively. For patients aged 38-40 years, 614 cycles in 265 women lead to a PR per completed cycle and ITT of 7.3% and 6.5%, respectively. In women aged 41-42 years, 166 cycles in 81 patients lead to a PR per completed cycle and ITT of 4.3% and 3.6%, respectively. For women above age 42 years, 120 cycles in 55 patients lead to a PR per completed cycle and ITT of 1.0% and 0.8%, respectively. On a per-patient treated basis, cumulative PRs were 24.2% under age 35, 18.5% ages 35-37, and 15.1% ages 38-40, whereas only 7.4% ages 41-42 and 1.8% above 42 became pregnant (one pregnancy in 55 patients). CONCLUSION(S) As anticipated, younger patients have a higher PR per cycle than older patients. The PR per cycle for patients who initiate only one or only two treatment cycles is notably higher than the corresponding per cycle rates for cycles 3 through 9. The drop in success per patient among 41- and 42-year-olds is sharp, but the exceptionally low success rate above age 42 suggests that CC with IUI has virtually no place in their treatment.