Ronit Beck-Fruchter

GnRH agonist therapy as ovarian protectants in female patients undergoing chemotherapy: a review of the clinical data

BACKGROUND Cancer survival rates in young women are improving due to progress in treatment. This includes aggressive chemotherapy, a treatment that often poses a threat to fertility. GnRH agonists were proposed as ovarian protectors during gonadotoxic therapies. This study was undertaken in order to determine the clinical evidence concerning this issue. METHODS The medical literature was searched for studies that reported on ovarian function after the administration of GnRH agonists concomitant with chemotherapy. Twelve studies met the predetermined selection criteria. RESULTS Data on ovarian function were obtained for 579 women who received chemotherapy. Among 345 women who received GnRH agonist co-treatment, ovarian function was preserved in 91% and 9% had premature ovarian failure. In 234 women who did not receive GnRH agonist co-treatment, ovarian function was preserved in 41% and failed in 59%. Only two of the studies were randomized. The control and the GnRH agonist groups differed in several important characteristics: the follow-up times were not equal, different treatment protocols were utilized and end-points were poorly defined and inconsistent between the studies. CONCLUSIONS The effectiveness of GnRH agonists as fertility-preserving agents is debatable. A thorough literature search has found insufficient evidence to show that GnRH agonist co-treatment is effective in protecting the ovary from the damage of chemotherapy. A large randomized controlled trial with adequate follow-up is needed.

Clinical and ultrasonographic weight estimation in large for gestational age fetus

OBJECTIVE To examine prospectively the effect on pregnancy outcome of a management protocol, that adds ultrasonographic weight estimation in fetuses suspected clinically as large. STUDY DESIGN Prospective follow up study of all singleton deliveries during a 1 year period. All patients underwent routine clinical estimation of fetal weight. When clinical estimation of fetal weight was > or = 3700 g, patients were referred for ultrasonographic estimation of fetal weight. When the latter was > or = 4000 g the patient was informed about the risks of birth trauma. Cesarean section was recommended only when > or = 4500 g. Ultrasonography was repeated every 4 days when possible. Predictive values of clinical and ultrasonographic estimations of fetal weight for diagnosing macrosomia, defined for the purpose of this study as 4000 g or more, and their effect on the rate of cesarean sections. RESULTS Five hundred fifty-five (14.4%) out of 3844 singletons were estimated as 3700 g or more. Only 315 fetuses had ultrasonographic estimation of weight within 3 days of delivery. The sensitivity of clinical and ultrasonographic prediction of macrosomia was 68 and 58%, respectively. Cesarean section rate in newborns weighing 4000 g or more was 22% when macrosomia was clinically suspected compared to 11% when it was not (P<0.05). In fetuses estimated ultrasonographically as 4000 g or larger the cesarean section rate was doubled (50.7% versus 24.9%, P<0.05) compared to those estimated as smaller than 4000 g, although actual weight of 4500 g or more was recorded in 10.6 and 8.5% of these groups, respectively. There were no cases of shoulder dystocia in macrosomic babies when macrosomia was not detected by ultrasound compared to two cases of shoulder dystocia (2.7%) when macrosomia was detected by ultrasound. CONCLUSION Antenatal suspicion of macrosomia increased the cesarean section rate while the associated improvement in pregnancy outcome remains questionable. The contribution of ultrasound, added to routine clinical estimation of fetal weight, was clinically insignificant apart from a further increase in cesarean section rate.

Empty follicle syndrome: successful treatment in a recurrent case and review of the literature

Empty follicle syndrome is a condition in which no oocytes are retrieved after an apparently adequate ovarian response to stimulation and meticulous follicular aspiration. It is a rare condition of obscure etiology. A patient with primary infertility who underwent seven assisted reproductive technique cycles is described. In spite of a satisfactory ovarian response, aspiration yielded no oocytes in four cycles and 1-4 low quality oocytes in three cycles. In the index treatment cycle, ovulation was triggered using GnRH agonist 40 h prior to ovum pickup and hCG was added 6 h after the first trigger. Eighteen oocytes were recovered, of which 16 were mature and were inseminated by ICSI. Two embryos were transferred 48 h after aspiration and nine embryos were cryopreserved. The patient conceived and delivered a healthy boy at 38 weeks of gestation. The literature is reviewed and possible etiologies and treatment options of this enigmatic syndrome are suggested.

Rescue intracytoplasmic sperm injection: a systematic review

OBJECTIVE To assess the feasibility, efficacy, and safety of rescue intracytoplasmic sperm injection (ICSI) in cases of fertilization failure, using a scientific literature search. DESIGN Systematic review. SETTING Centers for reproductive care. PATIENT(S) Infertility patients with total or partial fertilization failure during an IVF cycle. INTERVENTION(S) An electronic literature search was performed in PubMed from 1992 through May 2013. The search was then expanded by using listed references from selected articles. MAIN OUTCOME MEASURE(S) Pregnancy rate. The secondary outcome measures were fertilization rate, normal fertilization rate, cleavage rate, birth rate, and malformation rate. RESULT(S) Thirty-eight studies including 1,863 patients were included. The pooled pregnancy rate was 14.4%; 194 babies were delivered. CONCLUSION(S) Rescue ICSI can result in the delivery of a healthy newborn, although the pregnancy rates are low. The clinical evidence did not indicate an elevated rate of malformations, although the data are limited and incomplete.

Clinical benefit using sperm hyaluronic acid binding technique in ICSI cycles: a systematic review and meta-analysis

The human oocyte is surrounded by hyaluronic acid, which acts as a natural selector of spermatozoa. Human sperm that express hyaluronic acid receptors and bind to hyaluronic acid have normal shape, minimal DNA fragmentation and low frequency of chromosomal aneuploidies. Use of hyaluronic acid binding assays in intracytoplasmic sperm injection (ICSI) cycles to improve clinical outcomes has been studied, although none of these studies had sufficient statistical power. In this systematic review and meta-analysis, electronic databases were searched up to June 2015 to identify studies of ICSI cycles in which spermatozoa able to bind hyaluronic acid was selected. The main outcomes were fertilization rate and clinical pregnancy rate. Secondary outcomes included cleavage rate, embryo quality, implantation rate, spontaneous abortion and live birth rate. Seven studies and 1437 cycles were included. Use of hyaluronic acid binding sperm selection technique yielded no improvement in fertilization and pregnancy rates. A meta-analysis of all available studies showed an improvement in embryo quality and implantation rate; an analysis of prospective studies only showed an improvement in embryo quality. Evidence does not support routine use of hyaluronic acid binding assays in all ICSI cycles. Identification of patients that might benefit from this technique needs further study.

Thrombophilia and stillbirth: possible connection by intrauterine growth restriction

Objective  To define the association between thrombophilia and unexplained stillbirth.

Ectopic pregnancy risk factors for ART patients undergoing the GnRH antagonist protocol: a retrospective study

BackgroundIn-vitro fertilization is a known risk factor for ectopic pregnancies. We sought to establish the risk factors for ectopic pregnancy in GnRH antagonist cycles examining patient and stimulation parameters with an emphasis on ovulation trigger.MethodsWe conducted a retrospective, cohort study of 343 patients undergoing 380 assisted reproductive technology (ART) cycles with the GnRH antagonist protocol and achieving a clinical pregnancy from November 2010 through December 2015.ResultsSignificant risk factors for ectopic pregnancy in the univariate analysis included prior Cesarean section (CS), endometriosis, mechanical factor infertility, longer stimulation, elevated estradiol and progesterone levels, GnRH agonist trigger, higher number of oocytes aspirated, and insemination technique. Independent risk factors for ectopic pregnancy in the multivariate analysis included GnRH agonist trigger, higher number of oocytes aspirated, insemination technique, and prior Cesarean section.ConclusionExcessive ovarian response, IVF (as opposed to ICSI), prior Cesarean section and GnRH agonist trigger were found to be independent risk factors for ectopic pregnancy. Caution should be exercised before incorporating the GnRH agonist trigger for indications other than preventing OHSS. When excessive ovarian response leads to utilization of GnRH agonist trigger, strategies for preventing ectopic pregnancy, such as a freeze all policy or blastocyst transfer, should be considered. Further studies should elucidate whether adjusting the luteal support can reduce the ectopic pregnancy risk.

Lag time from ovulation trigger to oocyte aspiration and oocyte maturity in assisted reproductive technology cycles: a retrospective study

OBJECTIVE To study the correlation between the lag time from ovulation trigger to oocyte aspiration and the proportion of metaphase II (MII) mature oocytes aspirated. DESIGN Retrospective study. SETTING Fertility and IVF center in an academic regional hospital. PATIENT(S) A total of 511 women undergoing IVF-intracytoplasmic sperm injection at our center, with at least one oocyte available for maturity determination. INTERVENTION(S) Data were retrieved from patient electronic databases and files. Demographic data, hormone treatments and ovarian response, and the time of ovulation trigger and oocyte aspiration were recorded. MAIN OUTCOME MEASURE(S) The primary outcome was the proportion of MII mature oocytes relative to the total number of oocytes aspirated and allocated to intracytoplasmic sperm injection. Pregnancy rates and clinical pregnancy rates were secondary outcomes. RESULT(S) There were fewer MII mature oocytes when the lag time between oocyte trigger and aspiration was between 33.45 hours and 34.45 hours. The proportion of MII oocytes seems to increase up to a 35-hour lag time and then stabilizes up to 38 hours. Pregnancy and clinical pregnancy rates did not differ among the different time groups studied. CONCLUSION(S) Oocyte aspiration should be scheduled at least 35 hours after ovulation trigger. Oocytes can be aspirated in a 3-hour window of time between 35 and 38 hours without compromising results. Further research should elucidate whether even longer lag times will improve the proportion of MII mature oocytes.

A randomized trial comparing time intervals from HCG trigger to intrauterine insemination for cycles utilizing GnRH antagonists

Abstract Intrauterine insemination (IUI) during ovarian stimulation cycles is typically performed 36 hours after human chorionic gonadotropin (hCG) injection. We hypothesized that adjusting the time interval to IUI to better coincide with ovulation may increase pregnancy rates. Patients undergoing induction of ovulation utilizing gonadotropins and gonadotropin releasing hormone (GnRH) antagonists and IUI were divided to three groups based on the time from hCG injection to IUI: 36, 42, and 48 hours. Primary outcome was defined as the clinical pregnancy rate. Secondary outcomes comprised additional parameters including multifetal pregnancy rate. A total of 92 patients completed the study. Baseline parameters were similar between the groups. The clinical pregnancy rate in the three groups was 20%, 38%, and 24%, respectively. While the 42 hour time interval had a higher numerical pregnancy rate, the pregnancy rates did not differ statistically among the study groups. The multifetal pregnancy rate did not differ among the three groups as well. A larger study is necessary to ascertain if a 42 hour time interval can indeed improve pregnancy rates.

Haptoglobin phenotypes and in vitro fertilization treatment outcomes

The haptoglobin (Hp) protein has been implicated in various aspects of reproduction. One possible mechanism is through its effect on angiogenesis. Angiogenesis plays a major role in follicle production. The Hp insertion polymorphism results in the production of Hp proteins denoted Hp 1-1, 2-1, and 2-2, with markedly different angiogenic activities. We sought to determine if the number of oocytes aspirated during in vitro fertilization is related to the Hp type and to compare clinical data and treatment outcomes. We conducted a prospective non-interventional study in an academic in vitro fertilization center serving northern Israel. All patients undergoing in vitro fertilization who agreed to have their haptoglobin phenotype and clinical data evaluated anonymously were included. The main outcome measure was the number of oocytes harvested from each aspiration. The groups did not differ regarding ethnicity or BMI, though women with the Hp1-1 phenotype had a longer duration of infertility (p = 0.037) and a higher gonadotropin requirement (p = 0.024) to achieve the same treatment outcome. Women with mechanical factor infertility were more likely (p = 0.042) to have the Hp 1-1/2-1 phenotypes than the Hp2-2 phenotype. There were no differences in the number of oocytes aspirated or the pregnancy rate. In summary, we could not establish a correlation between Hp phenotype and oocyte number or IVF outcomes though the Hp2-2 phenotype may be protective against mechanical factor infertility. Further studies with a larger sample size, particularly concerning the Hp1-1 phenotype, are required in order to extend these results.