Ken Dowell

Live birth after polar body array comparative genomic hybridization prediction of embryo ploidy—the future of IVF?

OBJECTIVE To ascertain meiotic aneuploidy of the human egg using array comparative genomic hybridization to evaluate the 23-paired chromosome copy number of first polar body as an objective prognosticator of embryo viability for embryo transfer in the same cycle. DESIGN Case report. SETTING Independent-sector IVF program. PATIENT(S) A 41-year-old woman with a history of 13 failed cycles of IVF. INTERVENTION(S) Polar body biopsy of metaphase II eggs. MAIN OUTCOME MEASURE(S) Birth. RESULT(S) Two of the nine eggs were euploid, and the resulting embryos, although morphologically inferior to sibling embryos, were selected for transfer to the uterus, resulting in the birth of a normal healthy baby. CONCLUSION(S) Selection of euploid eggs, as an objective parameter of subsequent embryo viability and with the opportunity to transfer embryos in the same cycle could maximise the opportunity for live birth after IVF even in cases with poor prognosis.

Severe ovarian hyperstimulation syndrome: is it really preventable by prophylactic intravenous albumin?

OBJECTIVE To evaluate the effectiveness of i.v. albumin in preventing severe ovarian hyperstimulation syndrome (OHSS) in patients at risk. DESIGN Retrospective review and data analysis. SETTING University-based tertiary referral center for assisted reproductive technologies (ART). PATIENT(S) Sixty women at high risk of developing severe OHSS after superovulation for ART. INTERVENTION(S) One liter of albumin (4.5%) administered i.v. during oocyte retrieval and immediately afterward. RESULT(S) Of the 60 women who had prophylactic i.v. albumin, 5 (8%) developed severe OHSS, which led to hospitalization. Eight (13%) developed moderate OHSS. Forty-seven (78%) did not develop any symptoms. Four of the 5 women who developed severe OHSS had ET and 3 of them (75%) were pregnant (1 twin and 2 singletons). CONCLUSION(S) Intravenous albumin administered at oocyte retrieval does not prevent the occurrence of severe OHSS, especially in cases associated with pregnancy. It is important that clinicians are not lured into a false sense of security by the early report, full of promise, on the use of i.v. albumin to prevent severe OHSS.

Predicting the chance of live birth for women undergoing IVF: a novel pretreatment counselling tool

STUDY QUESTION Which pretreatment patient variables have an effect on live birth rates following assisted conception? SUMMARY ANSWER The predictors in the final multivariate logistic regression model found to be significantly associated with reduced chances of IVF/ICSI success were increasing age (particularly above 36 years), tubal factor infertility, unexplained infertility and Asian or Black ethnicity. WHAT IS KNOWN ALREADY The two most widely recognized prediction models for live birth following IVF were developed on data from 1991 to 2007; pre-dating significant changes in clinical practice. These existing IVF outcome prediction models do not incorporate key pretreatment predictors, such as BMI, ethnicity and ovarian reserve, which are readily available now. STUDY DESIGN, SIZE, DURATION In this cohort study a model to predict live birth was derived using data collected from 9915 women who underwent IVF/ICSI treatment at any CARE (Centres for Assisted Reproduction) clinic from 2008 to 2012. Model validation was performed on data collected from 2723 women who underwent treatment in 2013. The primary outcome for the model was live birth, which was defined as any birth event in which at least one baby was born alive and survived for more than 1 month. PARTICIPANTS/MATERIALS, SETTING, METHODS Data were collected from 12 fertility clinics within the CARE consortium in the UK. Multivariable logistic regression was used to develop the model. Discriminatory ability was assessed using the area under receiver operating characteristic (AUROC) curve, and calibration was assessed using calibration-in-the-large and the calibration slope test. MAIN RESULTS AND THE ROLE OF CHANCE The predictors in the final model were female age, BMI, ethnicity, antral follicle count (AFC), previous live birth, previous miscarriage, cause and duration of infertility. Upon assessing predictive ability, the AUROC curve for the final model and validation cohort was (0.62; 95% confidence interval (CI) 0.61-0.63) and (0.62; 95% CI 0.60-0.64) respectively. Calibration-in-the-large showed a systematic over-estimation of the predicted probability of live birth (Intercept (95% CI) = -0.168 (-0.252 to -0.084), P < 0.001). However, the calibration slope test was not significant (slope (95% CI) = 1.129 (0.893-1.365), P = 0.28). Due to the calibration-in-the-large test being significant we recalibrated the final model. The recalibrated model showed a much-improved calibration. LIMITATIONS, REASONS FOR CAUTION Our model is unable to account for factors such as smoking and alcohol that can affect IVF/ICSI outcome and is somewhat restricted to representing the ethnic distribution and outcomes for the UK population only. We were unable to account for socioeconomic status and it may be that by having 75% of the population paying privately for their treatment, the results cannot be generalized to people of all socioeconomic backgrounds. In addition, patients and clinicians should understand this model is designed for use before treatment begins and does not include variables that become available (oocyte, embryo and endometrial) as treatment progresses. Finally, this model is also limited to use prior to first cycle only. WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this is the first study to present a novel, up-to-date model encompassing three readily available prognostic factors; female BMI, ovarian reserve and ethnicity, which have not previously been used in prediction models for IVF outcome. Following geographical validation, the model can be used to build a user-friendly interface to aid decision-making for couples and their clinicians. Thereafter, a feasibility study of its implementation could focus on patient acceptability and quality of decision-making. STUDY FUNDING/COMPETING INTEREST None.

Computer image sperm selection as a novel approach to subzonal insemination in the human

Utilizing real-time computer image analysis, individual spermatozoa were selected using microaspiration. Selection criteria were based on potential hyperactivation motility characteristics; the amplitude of lateral head displacement > 7.5 microns, curvilinear velocity > 70 microns/s and linearity of < 30%. For this pilot study, 16 patients (eight in each group) were recruited. Using subzonal insemination (SUZI), up to five (mean = 4.4 +/- 0.3) spermatozoa selected using computer-image sperm selection (CISS) were micro-injected, or up to 15 (mean = 12.8 +/- 1.3 SD) unselected spermatozoa. In the group which utilized CISS, 28 out of 49 (57%) oocytes were fertilized compared with 13 out of 52 (25%) utilizing conventional SUZI (P < 0.04); polyspermy was 20% (n = 10) and 2% (n = 1) respectively. CISS with SUZI showed increased efficiency in achieving fertilization and is a novel approach to studying individual sperm function in a sperm egg bioassay where gamete ratios are close to unity.

Investigating the effect of ethnicity on IVF outcome.

Success rates for IVF among women from different ethnic groups have been inconclusive. In this study, the relationship between ethnicity and IVF outcome was investigated. Results of a cohort study analysing 13,473 first cycles were compared with the results of meta-analysed data from 16 published studies. Adjustment was made for age, body-mass index, cause of infertility, duration of infertility, previous live birth, previous spontaneous abortion and number of embryos transferred. Black and South Asian women were found to have lower live birth rates compared with White women: Black versus White (OR 0.42 [0.25 to 0.70]; P = 0.001); South Asian versus White (OR 0.80 [0.65t o 0.99]; P = 0.04). Black women had significantly lower clinical pregnancy rates compared with White women (OR 0.41 [0.25 to 9 0.67]; P < 0.001). The meta-analysed results also showed that Black and South Asian women had statistically significant reduced odds of live birth (OR 0.62 [0.55 to 0.71); P < 0.001 and OR 0.66 [0.52 to 0.85); P = 0.001, respectively). Black and South Asian women seem to have the poorest outcome, which is not explained by the commonly known confounders. Future research needs to investigate the possible explanations for this difference and improve IVF outcome for all women.

Subzonal insemination and zona breaching techniques for assisting conception in vitro

The following comments can be made with regard to zona breaching procedures (PZD) and SUZI. First and foremost, it is important to establish that fertilization cannot occur with microdrop IVF or conventional IVF before proceeding with microassisted fertilization technology. PZD increases the rate of polyspermy, and this is significantly higher than when utilizing SUZI. SUZI increases the incidence of implantation in cases exhibiting severe teratozoospermia. SUZI increases the fertilization rate per patient and per oocyte in cases where IVF has previously failed on more than one occasion. SUZI increases the incidence of fertilization when very few motile sperm are available, and there is an increase in the incidence of cytoplasmic fragmentation with SUZI, which might be alleviated by improving methods of penetrating the zona pellucida, for example by using the Sonic Sword or utilizing a thinner, sharper injection needle alone or in addition to increasing the perivitelline space by dehydrating the oocyte (Yang et al, 1988). Morphology is an important parameter in predicting the outcome of IVF and therefore in guiding patients on the relevance of microinjection technology.

Assisted Reproduction Techniques for Managing Infertility

Artificial Insemination using donor sperm (AID or DI) This treatment is offered to couples where the male partner is azoospermic and involves the placement of donor sperm at the cervix or of washed donor sperm directly into the uterine cavity. Donor sperm can also be used if there is a serious risk of the male partner passing on an inherited disorder. The procedure is continued for several months and up to 50% of couples attending for DI can be successful after 6 months of treatment. Donor insemination requires careful consideration and couples are offered counselling to discuss all the implications of treatment detailed in the Code of Practice of the Human Fertilisation and Embryology Authority (HFEA). In accordance with the guidelines of the 32%

Optimal endometrial thickness to maximize live births and minimize pregnancy losses: Analysis of 25,767 fresh embryo transfers

RESEARCH QUESTION What is the association of endometrial thickness with pregnancy losses and live births in IVF treatment and the optimal threshold that optimizes the IVF outcome? DESIGN Data were analysed from 25,767 IVF cycles from centres of the CARE Fertility Group in the UK between 2007 and 2016. Transvaginal ultrasound was conducted to measure the maximum endometrial thickness during gonadotrophin stimulation. Live birth rates were per embryo transfer. Pregnancy loss rates included the combination of biochemical and clinical pregnancy losses. RESULTS The live birth rate was 15.6% with 5 mm or less endometrial thickness and gradually increased to 33.1% with an endometrial thickness of 10 mm. On the other hand, the pregnancy loss rate was 41.7% with 5 mm or less endometrial thickness and gradually decreased to 26.5% with an endometrial thickness of 10 mm. Statistical modelling for optimal endometrial thickness threshold found 10 mm or more maximized live births and minimized pregnancy losses. This association was independent after adjusting for confounders such as age, oocyte number, number of transferred embryos, ovarian stimulation protocol and embryo quality for live births (crude RR 1.27; 95% CI 1.21 to 1.33; Adjusted RR 1.18; 95% CI 1.12 to 1.23) and pregnancy losses (crude RR 0.83; 95% CI 0.77 to 0.89; adjusted RR 0.86; 95% CI 0.8 to 0.92). CONCLUSIONS Endometrial thickness is strongly associated with pregnancy losses and live births in IVF, and the optimal endometrial thickness threshold of 10 mm or more maximized live births and minimized pregnancy losses.

A new era of PGS for IVF - will it yield the anticipated improved efficiency?

At the outset it is necessary to establish the acronyms that geographically have a different meaning. In the UK and elsewhere it is customary to separate out the screening of chromosomes (Preimplantation Genetic Screening - PGS) from diagnosing a single gene disorder - Preimplantation Genetic Diagnosis (PGD). In some regions, notably the US, both processes PGS and PGD are often included in the over-arching term, PGD. This short article deals only with PGS (perhaps better described as Chromosome Screening). However, it should be noted that with some platforms it is becoming increasingly easier to deliver information on not only the full complement of chromosome information, including a translocation, but also the diagnosis of a monogenic diseased state as well as HLA matching, from a single cell [1] - an exciting prospect indeed.