The correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome

Background  

To evaluate the relationship between endometrial thickness on day of human chorionic gonadotrophin administration (hCG) and pregnancy outcome in a large number of consecutive in vitro fertilization and embryo transfer (IVF-ET) cycles.     

In vitro fertilization and embryo transfer: a brief overview

The in vitro fertilization process breaks down into three essential components: induction of ovulation, fertilization of the oocyte, and development of embryos that are transferred into the uterus. Problems may arise resulting in failure at any one of these junctions. In 1984, the World Congress on In Vitro Fertilization was held, looking at 9,641 laparoscopies yielding 1,101 clinical pregnancies, with an overall pregnancy rate of 11 percent--clearly indicating that in vitro fertilization/embryo transfer (IVF/ET) was an idea whose time had come. Ovulation induction is monitored by both the use of ultrasound and daily estradiol levels, ultrasound indicating the number of oocytes that will be available for capture, and estradiol indicating in an indirect way the quality of those oocytes. It is a major aim in each patient to obtain at least four embryos, since this optimizes success rates. Ovulation induction at Yale is carried out with a high-dose human menopausal gonadotropin (HMG)/human chorionic gonadotropin (HCG) regimen. This regimen has insured us a success rate of 17 percent clinical pregnancies per laparoscopy. In the future, modification will occur in the process with cryopreservation of oocytes and embryos, and gamete manipulation. The modifications will be effected primarily to increase pregnancy rates. Research will continue mainly to delineate better biochemical markers for oocyte quality, but also to further explain the mystery of implantation.     

Indications for in vitro fertilization and embryo transfer

The main indications of IVF-ET, i.e. tubal sterility, idiopathic infertility and male infertility are critically discussed. Tubal sterility is in our opinion the only clear clinical indication. The IVF-ET application in cases of idiopathic infertility can be considered as an empirical therapeutic approach. According to our own results and those of other authors, male infertility is the most questionable indication to IVF-ET.     

Endometrial thickness, Caucasian ethnicity, and age predict clinical pregnancy following fresh blastocyst embryo transfer: a retrospective cohort

Background  

In-vitro fertilization (IVF) with blastocyst as opposed to cleavage stage embryos has been advocated to improve success rates. Limited information exists on which to predict which patients undergoing blastocyst embryo transfer (BET) will achieve pregnancy. This study's objective was to evaluate the predictive value of patient and cycle characteristics for clinical pregnancy following fresh BET.     

In vitro fertilization and human embryo transfer: biological problems

Optimal results in in-vitro fertilisation procedures can only be achieved using both meiotic competent, mature oocytes and spermatozoa with a high fertilization potential. This situation is not verified in the overwhelming number of couples submitting to IVF-ET. Many of the steps in the gametes maturation processes need to be urgently clarified in order to reach optimal fertilization rates.     

In vitro fertilization and embryo transfer in the rhesus monkey

Twenty-three rhesus monkeys were subjected to 9 days of ovarian hyperstimulation with sequential exposure to human follicle-stimulating hormone (hFSH) and then human luteinizing hormone (hLH) + hFSH. Six animals (26%) did not exhibit sustained, elevated levels of circulating estradiol, primarily due to the occurrence of a premature surge of endogenous LH (n = 4). Seventeen animals (74%) responded with supraphysiologic levels of circulating estradiol (peak value: means = 4480 pg/ml) and received human chorionic gonadotropin (hCG) on Day 10. Oocytes were collected 26 h later by aspiration of large antral follicles. Oocyte quantity (means = 18/animal) and quality (63% mature) were evaluated by in vitro fertilization (IVF), embryonic development, and embryo transfer to foster mothers. Modified conditions for the successful fertilization of oocytes used a Tyrode's augmented (TALP) medium supplemented with 0.3% bovine serum albumin (BSA). Oocytes were inseminated at the metaphase II stage with ejaculated, washed sperm (50 100 x 10(3)/ml) preexposed at ambient temperature to caffeine and dibutyryl cyclic adenosine 3'5'-monophosphate. Successful fertilization ranged from 26% to 75%. In one experiment, 5 of 11 embryos produced by IVF developed in vitro to hatched blastocysts. Embryo freezing employed a propanediol-based protocol and was applied to early cleavage-stage embryos with 100% (5 of 5) post-thaw survival. Two frozen-thawed embryos were transferred transtubally on 3 occasions into rhesus monkeys during the early luteal phase of spontaneous menstrual cycles. One pregnancy resulted, which proceeded normally to the unassisted delivery of a male offspring 170 days after the LH surge. We conclude that this sequential regimen of human gonadotropins provides a cohort of oocytes from rhesus monkeys that will complete meiotic maturation and fertilize in vitro, with embryonic development proceeding in vitro and in vivo. The production of putative antibodies to human gonadotropins, assessed by the presence of Protein A-precipitated hCG binding components in sera, limits the repeated use of monkeys in the hyperstimulation protocol. Nevertheless, this model system should facilitate further studies on oocyte maturation, fertilization, and early embryogenesis in primates.     

Factors predicting patient use of the emergency department: a retrospective cohort study

Background:

Many studies have shown the tendency for people without a regular care provider or primary physician to make greater use of emergency departments. We sought to determine the effects of three aspects of care provided by primary physicians (physician specialty, continuity of care and comprehensiveness of care) on their patients’ use of the emergency department.

Methods:

Using provincial administrative databases, we created a cohort of 367 315 adults aged 18 years and older. Participants were residents of urban areas of Quebec. Affiliation with a primary physician, the specialty of this physician (i.e., family physician v. specialist), continuity of care (as measured using the Usual Provider Continuity index) and comprehensiveness of care (i.e., number of complete annual examinations) were measured among participants (n = 311 701) who had visited a physician three or more times during a two-year baseline period. We used multivariable negative binomial regression to investigate the relationships between measures of care and the number of visits to emergency departments during a 12-month follow-up period.

Results:

Among participants under 65 years of age, emergency department use was higher for those not affiliated than for those affiliated with a family physician (incidence rate ratio [IRR] 1.11, 95% confidence interval [CI] 1.05–1.16) or a specialist (IRR 1.10, 95% CI 1.04–1.17). Among patients aged 65 years and older, having a specialist primary physician, as opposed to a family physician, predicted increased use of the emergency department (IRR 1.13, 95% CI 1.09–1.17). Greater continuity of care with a family physician predicted less use of the emergency department only among participants who made 25 or more visits to a physician during the baseline period. Greater continuity of care with a specialist predicted less use of the emergency department overall, particularly among participants with intermediate numbers of multimorbidities and admissions to hospital. Greater comprehensiveness of care by family physicians predicted less use of the emergency department.

Interpretation:

Efforts to increase the proportion of adults affiliated with a family physician should target older adults, people who visit physicians more frequently and people with multiple comorbidities and admissions to hospital.Reforming primary care in Canada has been stimulated in part by increased crowding of emergency departments and evidence that their use, particularly for nonurgent care, may be related to inadequate primary care in the community.^1,2 Restructuring efforts, such as encouraging family physicians to work in multidisciplinary group practices with 24-hour access, are challenged by a relative shortage of family physicians.³ These issues are of particular importance in Quebec; despite relatively high numbers of family physicians per capita, in comparison with other provinces, residents of Quebec have the lowest rates of affiliation with a family physician and have one of the highest rates of seeing specialists.^4,5 In addition, residents of Quebec have among the highest rates of visits to emergency departments in international comparative studies.^6–8Research is needed into the effect that affiliation with a specialist rather than a family physician has on patients’ use of the emergency department, as is research into the continuity and comprehensiveness of care provided by the primary physician, regardless of specialty.Many studies have shown the tendency for people without a regular care provider to use the emergency department more often than people who have a primary physician.^1,9,10 Greater continuity of care with a primary physician has also been associated with fewer visits to the emergency department, but much of this research is cross-sectional, making causal interpretation difficult.¹¹ Furthermore, the distinction between continuity with a family physician versus a specialist primary physician has not been made, although one American study reported that having a specialist primary physician was associated with increased use of emergency departments.⁹We sought to determine whether certain factors predicted patients’ subsequent use of emergency departments, such as the specialty of their primary physician, the continuity of care with that physician and the comprehensiveness of care provided by that physician. To determine whether certain subgroups of the population may derive greater benefit from a particular type of care, we examined the potentially modifying effects of demographic factors, health status and previous use of health services. We restricted our study to residents of urban areas of Quebec for three reasons: rural residents visit the emergency department for primary care more often than residents of urban areas;¹² most specialist care is provided in urban areas; and primary care services in rural areas are more likely to be provided by salaried physicians, whose information is not available in the billing database.     

The cytology of vaginal, cervical and endometrial smears obtained at the time of embryo transfer during in vitro fertilization

Seventy-four women enrolled in an in vitro fertilization (IVF) program had cytologic smears of the vagina, cervix and endometrium obtained at the time of embryo transfer (ET). Of these, 68 vaginal, 46 cervical and 25 endometrial smears were available for cytologic examination. Of the 68 vaginal smears, 4% showed a proliferative pattern, 40% were early secretory and 56% were advanced secretory. The 46 cervical smears demonstrated a delayed hormonal effect, with 70% showing a proliferative pattern, 23% early secretory and 7% advanced secretory cytology. Endometrial cells were obtained only when the Jones catheter, which has a side opening, was used. Twenty-two patients had both vaginal smears and suitable endometrial smears. Of these, 8 of the 9 patients with early secretory vaginal cytology had secretory endometrium while 10 of the 12 patients with mid-secretory vaginal cytology had secretory endometrium. The value of endometrial cytology in predicting conception following IVF-ET is unknown. It seems, however, that a good correlation exists between endometrial and vaginal cytology and that the latter may be of value as an additional, noninvasive tool for the evaluation of endometrial development.     

Inhibition of endometrial fundocervical wave by phloroglucinol and the outcome of in vitro fertilization

One hundred thirty-five infertile patients were enrolled to investigate the efficacy of phloroglucinol-induced inhibition of the endometrial fundocervical wave and its effect on in vitro fertilization (IVF). We found that phloroglucinol significantly inhibited (P < 0.05) peristaltic fundocervical wave, suggesting a feasible way of application of phloroglucinol to suppress endometrial waves during IVF.     

Cancer in children born after frozen-thawed embryo transfer: A cohort study

BackgroundThe aim was to investigate whether children born after assisted reproduction technology (ART), particularly after frozen-thawed embryo transfer (FET), are at higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception.Methods and findingsWe performed a registry-based cohort study using data from the 4 Nordic countries: Denmark, Finland, Norway, and Sweden. The study included 7,944,248 children, out of whom 171,774 children were born after use of ART (2.2%) and 7,772,474 children were born after spontaneous conception, representing all children born between the years 1994 to 2014 in Denmark, 1990 to 2014 in Finland, 1984 to 2015 in Norway, and 1985 to 2015 in Sweden. Rates for any cancer and specific cancer groups in children born after each conception method were determined by cross-linking national ART registry data with national cancer and health data registries and population registries. We used Cox proportional hazards models to estimate the risk of any cancer, with age as the time scale.After a mean follow-up of 9.9 and 12.5 years, the incidence rate (IR) of cancer before age 18 years was 19.3/100,000 person-years for children born after ART (329 cases) and 16.7/100,000 person-years for children born after spontaneous conception (16,184 cases). Adjusted hazard ratio (aHR) was 1.08, 95% confidence interval (CI) 0.96 to 1.21, p = 0.18. Adjustment was performed for sex, plurality, year of birth, country of birth, maternal age at birth, and parity. Children born after FET had a higher risk of cancer (48 cases; IR 30.1/100,000 person-years) compared to both fresh embryo transfer (IR 18.8/100,000 person-years), aHR 1.59, 95% CI 1.15 to 2.20, p = 0.005, and spontaneous conception, aHR 1.65, 95% CI 1.24 to 2.19, p = 0.001. Adjustment either for macrosomia, birth weight, or major birth defects attenuated the association marginally. Higher risks of epithelial tumors and melanoma after any assisted reproductive method and of leukemia after FET were observed.The main limitation of this study is the small number of children with cancer in the FET group.ConclusionsChildren born after FET had a higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception. The results should be interpreted cautiously based on the small number of children with cancer, but the findings raise concerns considering the increasing use of FET, in particular freeze-all strategies without clear medical indications.Trial registrationTrial registration number: ISRCTN 11780826.

Nona Sargisian and colleagues investigate the risk of childhood cancer in children born after Frozen-Thawed Embryo Transfer in Denmark, Finland, Norway, and Sweden.     

Asymmetrical dimethylarginine levels on the implantation success of in vitro fertilization and embryo transfer

The aim of this study was to evaluate the level of asymmetrical dimethylarginine (ADMA) levels before gonadotrophine treatment and on the day of oocytes retrieval in order to determine whether ADMA can be used as a predictive marker for implantation success in in vitro fertilization (IVF) cycles. Forty-four unexplained infertile patients were included in the study. Controlled ovarian hyperstimulation was performed using the recombinant follicle-stimulating hormone (FSH) with the standard long protocol for all patients. ADMA and E2 were measured at the beginning of the ovulation induction and on oocyte retrieval day. The primary outcome was the difference in ADMA levels in implantation positive and implantation negative women. At the beginning of the ovulation induction, the mean ADMA levels were 1553 μmol/L and 1.464 μmol/L in the implantation positive and negative groups, respectively. There was no statistically significant difference between groups (p: 0.90). On the day of oocyte retrieval, the mean ADMA levels were 1173 μmol/L and 1170 μmol/L in the implantation positive and negative groups, respectively. There was no statistically significant difference between groups (p: 0.97). In conclusion, ADMA levels before gonadotrophine treatment and the day of oocytes retrieval cannot be used as a predictive marker for implantation success in IVF cycles.