Margo R. Fluker

Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation.

OBJECTIVE To assess the efficacy, safety, and local tolerance of ganirelix acetate for the inhibition of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation (COH). DESIGN Phase III, multicenter, open-label randomized trial. SETTING In vitro fertilization (IVF) centers in North America. PATIENT(S) Healthy female partners (n = 313) in subfertile couples for whom COH and IVF or intracytoplasmic sperm injection were indicated. INTERVENTION(S) Patients were randomized to receive one COH cycle with ganirelix or the reference treatment, a long protocol of leuprolide acetate in conjunction with follitropin-beta for injection. OUTCOME MEASURE(S) Number of oocytes retrieved, pregnancy rates, endocrine variables, and safety variables. RESULT(S) The mean number of oocytes retrieved per attempt was 11.6 in the ganirelix group and 14.1 in the leuprolide group. Fertilization rates were 62.4% and 61.9% in the ganirelix and leuprolide groups, respectively, and implantation rates were 21.1% and 26.1%. Clinical and ongoing pregnancy rates per attempt were 35.4% and 30.8% in the ganirelix group and 38.4% and 36.4% in the leuprolide acetate group. Fewer moderate and severe injection site reactions were reported with ganirelix (11.9% and 0.6%) than with leuprolide (24.4% and 1.1%). CONCLUSION(S) Ganirelix is effective, safe, and well tolerated. Compared with leuprolide acetate, ganirelix therapy has a shorter duration and fewer injections but produces a similar pregnancy rate.

FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure

Premature ovarian failure (POF) is the occurrence of menopause before the age of 40 and affects 1% of the female population. Whereas the etiology of POF is largely unexplained, FMR1 premutation carriers are known to be at increased risk of POF compared with the general population. The FMR1 premutation alleles have 55–200 copies of a CGG repeat in the 5′ untranslated region of the FMR1 gene. However, functional effects on gene expression may occur even for repeat sizes in what has been considered the “normal” range. To evaluate the role of the FMR1 repeat in POF, repeat sizes were examined in 53 women with idiopathic POF, 161 control women from the general population, and 21 women with proven fertility at an advanced maternal age. A significant increase in the number of FMR1 alleles between and including 35 and 54 CGG repeats was found in the POF patient population; 15 of 106 (14.2%) POF alleles were between and including 35 and 54 repeats, whereas only 21 of 322 (6.5%) alleles in the general population (P=0.02) and 2 of 42 (4.8%) alleles from women with proven late fertility (P=0.09) were of this size (P=0.01 versus combined controls). The effect was also significant for comparisons of genotype repeat size (repeat size weighted by the relative activity of the two FMR1 alleles) and biallelic mean (average size of the two alleles). These results are clinically relevant and suggest that the FMR1 gene plays a more significant role in the incidence of POF than has previously been thought.

Perinatal and neonatal outcomes in multiple gestations: Assisted reproduction versus spontaneous conception

OBJECTIVE Our purpose was to test the hypothesis that multiple pregnancies resulting from assisted reproductive therapy have a better outcome than those resulting from spontaneous conception. STUDY DESIGN This was a retrospective cohort study. Cases came from pregnancies from assisted reproductive techniques. Controls were identified from spontaneous multiple pregnancies delivered in the same time period. Matching was done for maternal age, parity, fetal number, and presence of maternal medical problems. A total of 72 cases (56 twins and 16 triplets) and 124 controls (108 twins and 16 triplets) were studied. The primary outcome was perinatal mortality. Secondary outcomes were preterm delivery, birth weight, maternal complications, neonatal morbidity, and length of hospitalization. RESULTS Perinatal mortality is significantly increased in spontaneous twin gestations compared with twins resulting from assisted reproductive techniques (24 vs 2, P =.003). No difference is seen in the perinatal mortality in triplets. Mean gestational age at diagnosis was lower for twins and triplets resulting from assisted reproductive techniques (9.4 vs 13.3; P <.001 and 8.8 vs 15. 8; P <.001, respectively). Rate of cerclage and number of prenatal visits was higher for triplets in the assisted reproductive techniques group (P =.05 and.02, respectively). Mean gestational age at delivery, birth weight, rate of preterm labor, preterm premature rupture of membranes, pregnancy-induced hypertension, and incidence of gestational diabetes were not significantly different between the groups. No significant differences in neonatal morbidity were detected. CONCLUSIONS Assisted reproductive techniques-associated twins have lower perinatal mortality than spontaneously conceived twins. Perinatal and neonatal morbidity, gestational age at delivery, and birth weight are not affected by assisted reproductive techniques, even with closer surveillance and earlier gestational age at diagnosis in this group. Differences may be due to a higher frequency of monochorionic placentation in the spontaneously conceived group.

The effect of embryo quality on subsequent pregnancy rates after in vitro fertilization

OBJECTIVE To determine if a simple morphological classification of embryos was predictive of subsequent pregnancy. DESIGN Prospective case series. SETTING University-based in vitro fertilization (IVF) program. PATIENTS, PARTICIPANTS Consecutive embryo transfer (ET) cycles (n = 206). INTERVENTIONS Embryos were classified into three grades: (1) equal-size blastomeres with no fragmentation; (2) unequal-size blastomeres; and (3) evidence of fragmentation. MAIN OUTCOME MEASURES Embryo quality, age, indication for IVF, and stimulation protocol were evaluated for their effect on pregnancy rates (PRs). RESULTS In cycles in which the best embryo transferred was grade 3, 2, or 1, the clinical PRs per ET were 0% (0/11 cycles), 12.8% (6/47 cycles, P less than 0.05), and 21.8% (32/148 cycles, P less than 0.05), respectively. When one, two, or three or more grade 1 embryos were replaced, the clinical PRs per ET were 15.6%, 16.3%, and 40% (P less than 0.05), respectively. Using logistic regression, embryo quality (P = 0.0011) and patients age (P = 0.0044) were the only variables that affected PRs. CONCLUSION The transfer of more than two good quality embryos had a positive effect, patients age had a negative effect on PRs after IVF-ET.

Withholding gonadotropins (“coasting”) to minimize the risk of ovarian hyperstimulation during superovulation and in vitro fertilization–embryo transfer cycles

OBJECTIVE To evaluate superovulation (SOV) and IVF-ET cycles in which E2 levels were allowed to decrease to restrain rapid follicular growth and minimize the risk of ovarian hyperstimulation syndrome. DESIGN Retrospective series. SETTING Tertiary care infertility practice. PATIENT(S) Women who underwent SOV (n = 51) and IVF-ET (n = 93) treatment and who were at risk for OHSS. INTERVENTION(S) In SOV cycles, hMG was withheld (coasting) for >3 days before hCG administration, until follicular maturity was attained (> or = 3 follicles of > or = 18 mm) and E2 levels decreased. In IVF-ET cycles, either follicular maturity was attained before coasting (n = 63), allowing hCG administration after E2 levels decreased by >25%, or coasting occurred before follicular maturation (n = 30), necessitating the administration of additional hMG after coasting. MAIN OUTCOME MEASURE(S) Estradiol concentrations, follicle size, and pregnancy rates. RESULT(S) Estradiol concentrations usually rose for > or = 1 day after coasting began, then fell by > or = 25% while follicle numbers and mean diameters increased. No spontaneous LH surges occurred, although four SOV cycles were canceled because of excessive follicular development. Of the women who received hCG,11 of 47 (23% per cycle) conceived during SOV and 35 of 93 (37.6% per cycle) conceived during IVF-ET. Severe ovarian hyperstimulation syndrome developed in 1 woman who underwent IVF-ET. CONCLUSION(S) Coasting can safely rescue overstimulated SOV and IVF-ET cycles characterized by an excessive rise in E2 levels and/or numerous incompletely mature follicles.

Rescue intracytoplasmic sperm injection (ICSI)-salvaging in vitro fertilization (IVF) cycles after total or near-total fertilization failure

OBJECTIVE To evaluate the effectiveness of delayed oocyte reinsemination by ICSI (rescue ICSI) after total or near-total fertilization failure (</=25%) in IVF. DESIGN A retrospective clinical study. SETTING Non-hospital-based IVF program. PATIENT(S) Thirty IVF cycles with total fertilization failure and two cycles with </=25% initial fertilization. MAIN OUTCOME MEASURE(S) Fertilization and pregnancy rates after rescue ICSI. INTERVENTION(S) Rescue ICSI 19-22 hours after initial oocyte insemination. RESULT(S) A fertilization rate of 60.2% was achieved with rescue ICSI (141 of 234 oocytes, 29 of 32 patients). Of 30 patients with total fertilization failure, 27 had fresh transfers with rescue ICSI embryos. Two additional patients with </=25% initial fertilization had subsequent replacement of frozen-thawed rescue ICSI embryos. Six pregnancies resulted, including three singleton, one twin, one missed abortion, and one ectopic pregnancy (20.7%). One of the singleton pregnancies resulted from replacement of four frozen-thawed embryos and is the first known pregnancy achieved from cryopreserved rescue ICSI embryos. CONCLUSION(S) Rescue ICSI should be considered in the presence of total or near-total fertilization failure in IVF. Early application of rescue ICSI (19-22 hours after insemination) may be critical for establishing fertilization within an optimal window and producing viable embryos and pregnancies.

Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial

OBJECTIVE To evaluate the effect of intravenous immunoglobulin (IVIG) on pregnancy outcome in couples with repeated unexplained in vitro fertilization (IVF) failure. DESIGN Prospective, randomized, double blind, placebo-controlled clinical trial. SETTING A university-based and a free-standing IVF program. PATIENT(S) Fifty-one couples with a history of repeated unexplained IVF failure who were preparing for another fresh IVF cycle or replacement of cryopreserved embryos. INTERVENTION(S) Eligible women underwent a standard IVF stimulation using a long luteal phase GnRH analog protocol. Cryopreserved embryos were replaced after endometrial preparation with oral micronized estradiol and subsequent vaginal progesterone. The women were randomly selected to receive IVIG (500 mg/kg) or an equivalent volume of normal saline. The first infusion was given on the day of embryo transfer or during the preceding 72 hours. The second infusion was given 4 weeks later if a clinical pregnancy was confirmed by ultrasound. MAIN OUTCOME MEASURE(S) Live-birth rates. RESULT(S) Overall, the live-birth rates were 4/26 (15%) for the IVIG group and 3/25 (12%) for the placebo group (P=0. 52). There were 39 fresh IVF cycles, which yielded a clinical pregnancy rate of 28%, with live-birth rates of 4/21 (19%) for the IVIG group and 3/18 (17%) for the placebo group (P=0.59). CONCLUSION(S) In this randomized clinical trial, IVIG did not improve the live-birth rate in couples with repeated unexplained IVF failure, stringently defined by known determinants of IVF outcome.

Guidelines for the Number of Embryos toTransfer Following In Vitro Fertilization

OBJECTIVE To review the effect of the number of embryos transferred on the outcome of in vitro fertilization (IVF), to provide guidelines on the number of embryos to transfer in IVF-embryo transfer (ET) in order to optimize healthy live births and minimize multiple pregnancies. OPTIONS Rates of live birth, clinical pregnancy, and multiple pregnancy or birth by number of embryos transferred are compared. OUTCOMES Clinical pregnancy, multiple pregnancy, and live birth rates. EVIDENCE The Cochrane Library and MEDLINE were searched for English language articles from 1990 to April 2006. Search terms included embryo transfer (ET), assisted reproduction, in vitro fertilization (IVF), ntracytoplasmic sperm injection (ICSI), multiple pregnancy, and multiple gestation. Additional references were identified through hand searches of bibliographies of identified articles. VALUES Available evidence was reviewed by the Reproductive Endocrinology and Infertility Committee and the Maternal-Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada and the Board of the Canadian Fertility and Andrology Society, and was qualified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force on the Periodic Health Exam. BENEFITS, HARMS, AND COSTS This guideline is intended to minimize the occurrence of multifetal gestation, particularly high-order multiples (HOM), while maintaining acceptable overall pregnancy and live birth rates following IVF-ET.

Telomere length and reproductive aging

BACKGROUND Rate of reproductive aging may be related to rate of biological aging. Thus, indicators of aging, such as short telomere length, may be more frequent in women with a history suggestive of premature reproductive senescence. METHODS Telomere-specific quantitative PCR was used to assess telomere length in two groups of women with evidence of reproductive aging: (i) patients with idiopathic premature ovarian failure (POF, N = 34) and (ii) women with a history of recurrent miscarriage (RM, N = 95); and two control groups: (1) women from the general population (C1, N = 108) and (2) women who had a healthy pregnancy after 37 years of age (C2, N = 46). RESULTS The RM group had shorter age-adjusted mean telomere length than controls (8.46 versus 8.92 kb in C1 and 9.11 kb in C2, P = 0.0004 and P = 0.02 for C1 and C2, respectively), although short telomeres were not confined to subsets of this group known to have experienced single or multiple trisomic pregnancies. Although sample size is limited, mean telomere length in the POF group was significantly longer than that in C1 (9.58 versus 8.92 kb, P = 0.01). CONCLUSIONS Women experiencing RM may have shorter telomeres as a consequence of a more rapid rate of aging, or as a reflection of an increased level of cellular stress. Longer telomere length in the POF group may be explained by abnormal hormone exposure, slow cell division rates or autoimmunity in these women. Despite small sample sizes, these results suggest that different manifestations of reproductive aging are likely influenced by distinct physiological factors.

The outcome of in vitro fertilization and embryo transfer in women with polycystic ovary syndrome failing to conceive after ovulation induction with exogenous gonadotropins

OBJECTIVE To assess the outcome of in vitro fertilization and embryo transfer (IVF-ET) in women with refractory polycystic ovarian syndrome (PCOS). DESIGN Retrospective case series with an age-matched control group. SETTING Ovulation induction and IVF programs in a tertiary referral center. PATIENTS AND INTERVENTIONS Nine patients with PCOS who failed standard ovulation induction treatment (clomiphene citrate plus greater than or equal to 6 ovulatory human menopausal gonadotropin [hMG] cycles) underwent 19 cycles of IVF-ET. Forty age-matched tubal factor patients who completed 40 cycles of IVF-ET served as a control group. OUTCOME MEASURES Demographic features and IVF-ET cycle characteristics were compared using Students t-test and Fishers exact test. RESULTS Cycles of IVF-ET in patients with PCOS were associated with higher estradiol levels (5,222 versus 4,009 pmol/L), lower hMG requirements (15.8 versus 19.6 vials), greater numbers of oocytes (7.6 versus 5.6), and lower fertilization rates (56% versus 75%) compared with tubal factor cycles (P less than 0.05). However, the number of embryos transferred (3.9 versus 4.0) and the clinical pregnancy rate per embryo transfer (24% versus 25%) did not differ significantly between the two groups. CONCLUSION These results suggest that conception failure after six or more ovulatory hMG cycles in patients with PCOS does not adversely affect subsequent IVF performance.