Yacoub Khalaf

The effect of intramural fibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta-analysis

BACKGROUND The influence of fibroids on fertility is poorly understood. Submucosal and intramural fibroids that distort the endometrial cavity have been associated with decreased pregnancy rates (PRs) following IVF treatment. However, there is uncertainty about the effect of intramural fibroids that do not distort the endometrial cavity on IVF outcomes. METHODS We conducted a systematic review and meta-analysis of studies to evaluate the association between non-cavity-distorting intramural fibroids and IVF outcome. Searches were conducted on MEDLINE, EMBASE, Cochrane Library and Web of Science. Study selection and data extraction were conducted independently by two reviewers. The Newcastle-Ottawa Quality Assessment Scales were used for quality assessment. Meta-analysis was performed if appropriate. RESULTS We identified 19 observational studies comprising 6087 IVF cycles. Meta-analysis of these studies showed a significant decrease in the live birth (RR = 0.79, 95% CI: 0.70-0.88, P < 0.0001) and clinical PRs (RR = 0.85, 95% CI: 0.77-0.94, P = 0.002) in women with non-cavity-distorting intramural fibroids compared with those without fibroids, following IVF treatment. CONCLUSION The presence of non-cavity-distorting intramural fibroids is associated with adverse pregnancy outcomes in women undergoing IVF treatment.

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages

BACKGROUND Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain. METHODS We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation. RESULTS A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events. CONCLUSIONS Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.).

The effect of cryopreservation on the genome of gametes and embryos: principles of cryobiology and critical appraisal of the evidence

BACKGROUND Cryopreservation has been extensively used in assisted reproductive technology, agriculture and conservation programmes for endangered species. The literature reports largely positive results regarding the survival of frozen-thawed cells and clinical outcomes. Nonetheless, it is unclear whether or not cryopreservation of sperm, oocytes and embryos causes any disruption in their genetic integrity. Drawing on the available published evidence, this review paper describes in detail the physical and biochemical factors of cryopreservation that could potentially affect genomic integrity. METHODS A critical review of the published literature using PubMed with particular emphasis on studies which include assessment of genetic stability after cryopreservation of oocyte, sperm and embryos. The search was performed in 2014 and covered the period from the beginning of electronic records until July 2014. No language restrictions were applied. RESULTS Cryopreservation is associated with extensive damage to cell membranes, and results in alteration of the functional and metabolic status of the cells and mitochondria. Some evidence suggests an increase in DNA single-strand breaks, and degree of DNA condensation or fragmentation in sperm after cryopreservation. The extent of these changes may vary between different individuals and different techniques. The addition of antioxidants to the cryopreservation media and the use of well-controlled cooling regimes could potentially improve such outcomes. Limited numbers of studies on oocytes provide controversial results regarding the effect on DNA fragmentation, sister chromatid exchange (SCE) and aneuploidy. The only study on human embryos suggested that vitrification affects DNA integrity to a much lesser extent than slow freezing. Animal studies show increases in mitochondrial DNA mutations in embryos after cryopreservation. The limited numbers of long-term follow-up studies in humans provide reassurance that derives mostly from retrospective studies with some methodological weaknesses. CONCLUSIONS This review provides an overview of studies performed to date on the effect of cryopreservation on the oocyte, sperm and embryos. Controversy of the reported data has highlighted the gaps in our knowledge not only for clinical studies, but also for basic research in human embryos. New perspectives for future research are proposed.

EFFECT OF BLASTOMERE LOSS ON THE OUTCOME OF FROZEN EMBRYO REPLACEMENT CYCLES

OBJECTIVE To assess the impact of survival of cryopreservation and thawing with all blastomeres intact on the outcome of frozen embryo replacement (FER) cycles. DESIGN Prospective observational study. SETTING University-affiliated tertiary referral assisted conception unit. PATIENT(S) The number of intact blastomeres before cryopreservation and after thawing was prospectively recorded in 1,687 cleavage-stage embryos thawed in 377 FER cycles. The cycles were categorized into two groups: group A (n = 184) included cycles in which all embryos transferred survived the cryopreservation and thawing process with all their original blastomeres intact; group B (n = 193) included cycles in which embryos transferred included at least one partially damaged embryo that has lost up to 50% of its original blastomere number. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Pregnancy and embryo implantation rates. RESULT(S) Groups A and B were comparable with respect to mean age at cryopreservation, mean number of oocytes retrieved and fertilized normally in the fresh cycle, and mean age at frozen transfer. No significant difference was found between the two groups with regard to mean number of frozen and thawed embryos per cycle and mean endometrial thickness reached before P supplementation. More embryos were transferred per cycle in group B than group A (2.4 +/- 0.6 vs. 2.1 +/- 0.6, respectively). However, the pregnancy and clinical pregnancy rates per cycle were significantly higher in group A than in group B (39.1% and 28.3% vs. 22.8% and 13.5%, respectively). The implantation rate was also higher in group A than in group B (17.3% vs. 8.1%, respectively). CONCLUSION(S) FER cycles in which all embryos transferred remained fully intact at thawing achieve a better outcome than those with at least one partially damaged embryo.

Hysteroscopy prior to the first IVF cycle: A systematic review and meta-analysis

This systematic review and meta-analysis investigated the use of routine hysteroscopy prior to starting the first IVF cycle on treatment outcome in asymptomatic women. Searches were conducted on MEDLINE, EMBASE, Cochrane Library, National Research Register and ISI Conference Proceedings. The main outcome measures were clinical pregnancy and live birth rates achieved in the index IVF cycle. One randomized and five non-randomized controlled studies including a total of 3179 participants were included comparing hysteroscopy with no intervention in the cycle preceding the first IVF cycle. There was a significantly higher clinical pregnancy rate (relative risk, RR, 1.44, 95% CI 1.08-1.92, P=0.01) and LBR (RR 1.30, 95% CI 1.00-1.67, P=0.05) in the subsequent IVF cycle in the hysteroscopy group. The number needed to treat after hysteroscopy to achieve one additional clinical pregnancy was 10 (95% CI 7-14) and live birth was 11 (95% CI 7-16). Hysteroscopy in asymptomatic woman prior to their first IVF cycle could improve treatment outcome when performed just before commencing the IVF cycle. Robust and high-quality randomized trials to confirm this finding are warranted. Currently, there is evidence that performing hysteroscopy (camera examination of the womb cavity) before starting IVF treatment could increase the chance of pregnancy in the subsequent IVF cycle in women who had one or more failed IVF cycles. However, recommendations regarding the efficacy of routine use of hysteroscopy prior to starting the first IVF treatment cycle are lacking. We reviewed systematically the trials related to the impact of hysteroscopy prior to starting the first IVF cycle on treatment outcomes of pregnancy rate and live birth rate in asymptomatic women. Literature searches were conducted in all major database and all randomized and non-randomized controlled trials were included in our study (up to March 2013). The main outcome measures were the clinical pregnancy rate and live birth rate. The secondary outcome measure was the procedure related complication rate. A total of 3179 women, of which 1277 had hysteroscopy and 1902 did not have a hysteroscopy prior to first IVF treatment, were included in six controlled studies. Hysteroscopy in asymptomatic woman prior to their first IVF cycle was found to be associated with improved chance of achieving a pregnancy and live birth when performed just before commencing the IVF cycle. The procedure was safe. Larger studies are still required to confirm our findings.

Meta-analysis of GnRH antagonist protocols: do they reduce the risk of OHSS in PCOS?

This systematic review and meta-analysis investigated whether gonadotrophin-releasing hormone (GnRH) antagonist protocols reduce the risk of ovarian hyperstimulation syndrome (OHSS) in women with polycystic ovary syndrome undergoing IVF compared with the long agonist protocol. Searches were conducted on MEDLINE, EMBASE, Cochrane Library, National Research Register and ISI Conference Proceedings. Primary outcome was OHSS incidence. Secondary outcomes were total duration and dose of gonadotrophin, number of oocytes retrieved and clinical pregnancy and miscarriage rates. A total of 966 women were included in nine randomized controlled trials. There was inconsistency in definition, classification of severity and reporting of the OHSS rate. There was no difference in the incidence of severe OHSS in the antagonist group compared with the long agonist group (relative risk 0.61; 95% CI 0.23 to 1.64). However, when all moderate and severe OHSS cases were pooled, the antagonist protocol was associated with significantly lower risk of OHSS (relative risk 0.60; 95% CI 0.48-0.76; P<0.0001). A possible reduction in the incidence of severe OHSS with the GnRH antagonist protocol should be viewed with caution since the data is inconclusive. Larger randomized trials with adequate sample size and standardized definition, classification and diagnosis of OHSS remain necessary.

Increased risk of preterm birth and low birthweight with very high number of oocytes following IVF: an analysis of 65 868 singleton live birth outcomes

STUDY QUESTION Is there a relation between the number of oocytes retrieved following ovarian stimulation and obstetric outcomes of preterm birth (PTB) and low birthweight (LBW) following IVF treatment? SUMMARY ANSWER There is an increased risk of PTB (<37 weeks gestation) and LBW (<2500 g) following IVF in women with a high number (>20) of oocytes retrieved. WHAT IS KNOWN ALREADY Pregnancies resulting from assisted reproductive treatments (ART) are associated with a higher risk of pregnancy complications compared with spontaneously conceived pregnancies. Whether ovarian ageing in women with poor ovarian response is associated with an increased risk of adverse obstetric outcomes is debated. It is also unclear if an excessive response and high egg numbers following ovarian stimulation have an association with adverse obstetric outcomes. STUDY DESIGN, SIZE, DURATION Observational study using anonymized data on all IVF cycles performed in the UK from August 1991 to June 2008. Data from 402 185 IVF cycles and 65 868 singleton live birth outcomes were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on all women undergoing a stimulated fresh IVF cycle with at least one oocyte retrieved between 1991 and June 2008 were analysed for birth outcomes. Logistic regression analysis of the association between ovarian response (quantified as number of oocytes retrieved) and outcomes of PTB and LBW was performed. MAIN RESULTS AND THE ROLE OF CHANCE There was a significantly higher risk of adverse obstetric outcomes of PTB and LBW among women with an excessive response (>20 oocytes) compared with women with a normal response (10-15 oocytes): adjusted odds ratio (OR) 1.15, 95% confidence interval (CI) 1.03-1.28 for PTB, adjusted OR 1.17, 95% CI 1.05-1.30 for LBW, respectively. There was no increased risk of the adverse outcomes among women with a poor ovarian response (≤3 oocytes) compared with women with a normal response: adjusted OR 0.88, 95% CI 0.76-1.01 for PTB, adjusted OR 0.92, 95% CI 0.79-1.06 for LBW, respectively. LIMITATIONS, REASONS FOR CAUTION Although the analysis was adjusted for a number of potential confounders, the dataset had no information on other important confounders such as smoking, BMI and the medical history of women during pregnancy. Furthermore, the dataset did not allow specific identification of women with PCOS and its anonymized nature did not make it permissible to analyse one cycle per woman. WIDER IMPLICATIONS OF THE FINDINGS Analysis of this large dataset suggests that a high oocyte number (>20) following IVF is associated with a higher risk of PTB and LBW. These findings lead to speculation whether ovarian dysfunction and/or an altered endometrial milieu resulting from supraphysiological steroid levels underlie the unfavourable outcomes and warrant further research. Ovarian stimulation regimens should optimize the number of oocytes retrieved to avoid the risk of adverse outcomes associated with very high numbers of oocytes. STUDY FUNDING/COMPETING INTERESTS No funding was obtained. There are no competing interests to declare.

Early embryo development is an indicator of implantation potential

To maximize the chances of pregnancy during assisted reproduction treatment, it is important to be able to identify embryos with high implantation potential. Embryos which divide more quickly following insemination have been shown to produce higher pregnancy and implantation rates than those which divide later. The aim of this study was to compare the developmental potential of early cleaving embryos with those in which the pronuclear membranes had broken down at the time of scoring. Normally fertilized zygotes (n = 2447) were assessed 25-27 h post-insemination and categorized according to developmental stage (pronuclei visible, no pronuclei, or early cleavage to two cells). Pregnancy and implantation rates were assessed in cycles where embryos selected for transfer were at an equivalent stage 25-27 h post-insemination. A significantly higher implantation rate was achieved following transfer of either early cleavage embryos or those which had no pronuclei compared with embryos with intact pronuclei when assessed 25-27 h post-insemination/microinjection. The correlation between early cleavage and an improved pregnancy and implantation rate was confirmed. Scoring for the presence of early cleavage or status of pronuclei is quick and objective and provides information that may be used to discriminate between morphologically equivalent embryos at a later stage in development.

Low serum estradiol concentrations after five days of controlled ovarian hyperstimulation for in vitro fertilization are associated with poor outcome

OBJECTIVE To evaluate the prognostic significance of low serum E2 concentrations in controlled ovarian hyperstimulation (COH) cycles for IVF. DESIGN Retrospective study. SETTING Assisted conception unit of a university hospital. PATIENT(S) One thousand four hundred and forty patients undergoing COH for IVF. INTERVENTION(S) COH, serum E2 measurement, ultrasonographic scanning of ovarian follicles, oocyte retrieval, and ET. MAIN OUTCOME MEASURE(S) Cancellation and pregnancy rates. RESULT(S) Patients were classified into four groups according to serum E2 levels on the sixth day of COH: group A (E2 level < 50 pg/mL [114 cycles]), group B (E2 level 51-100 pg/mL [189 cycles]), group C (E2 level 101-200 pg/mL [320 cycles]), and group D (E2 level >200 pg/mL [817 cycles]). Group A experienced the highest cancellation rates (65.1%) and lowest pregnancy rates (7.8%) despite requiring significantly more hMG ampules (47.8+/-1.7). The cancellation rate was higher (75.1%) and no pregnancy occurred in a subset of group A in whom COH was initiated with > or =3 ampules (225 IU) of gonadotropins. CONCLUSION(S) In COH cycles using luteal phase buserelin, low initial serum E2 concentrations are associated with poor outcome.

Three hundred and thirty cycles of preimplantation genetic diagnosis for serious genetic disease : clinical considerations affecting outcome

Objective  To report on our experience with preimplantation genetic diagnosis (PGD) cycles performed for serious genetic disease in relation to the clinical factors affecting outcome.