Ahmed M. Abou-Setta

Slow freezing, vitrification and ultra-rapid freezing of human embryos: a systematic review and meta-analysis

Embryo cryopreservation is an important aspect of assisted reproduction. Many methods have been described, but they have been poorly investigated in randomized trials, highlighting the need for a systematic review of the literature. Meticulous electronic/hand searches were performed to locate randomized trials (RCT) comparing embryo cryopreservation methods. Primary outcomes were clinical pregnancy rate (CPR) and incidence of congenital abnormalities. Secondary outcomes included live-birth (LBR), ongoing pregnancy (OPR), implantation (IR), and miscarriage (MR) rates. Data were extracted to allow for an intention-to-treat analysis and analysed using a random-effects model. Literature search revealed 11 RCT, of which five were excluded. The quality of the included studies was variable, but generally poor. There was a significantly higher CPR, OPR and IR with vitrification compared with slow freezing (odds ratio (OR)=1.55, 95% confidence interval (CI)=1.03-2.32, OR=1.82, 95% CI=1.04-3.20 and OR=1.49, 95% CI=1.03-2.15, respectively). In addition, there was a significantly lower CPR and OPR with embryo ultra-rapid freezing compared with slow freezing (OR=0.35, 95% CI=0.16-0.76 and OR=0.37, 95% CI=0.17-0.81, respectively). Vitrification is superior to slow freezing, which in turn is superior to ultra-rapid freezing. However, more well-designed and powered studies are needed to further corroborate these findings.

Efficacy and safety of human menopausal gonadotrophins versus recombinant FSH: a meta-analysis

LH activity has been proposed to influence treatment response and outcome. In order to assess its clinical profile and efficacy, human menopausal gonadotrophin (HMG) was compared with recombinant FSH (r-FSH) in IVF/intracytoplasmic sperm injection (ICSI) cycles. Computerized and hand searches were conducted for relevant citations. Primary outcome measures were live-birth and OHSS rates. Secondary outcomes were clinical pregnancy, multiple pregnancy, miscarriage rates and cycle characteristics. The live-birth rate was significantly higher with HMG [odds ratio (OR) = 1.20, 95% CI = 1.01-1.42] versus r-FSH, but OHSS rates (OR = 1.21, 95% CI = 0.78-1.86) were not significantly different. As for the secondary outcomes, there was statistical significance with regard to the clinical pregnancy rate also in favour of the HMG group. Even so, there were significantly fewer treatment days, total dose and embryos produced in the r-FSH group compared with the HMG group. The other secondary outcomes were not different between the two groups. In conclusion, HMG has been demonstrated to be superior to r-FSH with regard to the clinical outcomes, with equivalent patient safety during assisted reproduction.

Paternal age and outcome of intracytoplasmic sperm injection.

In a retrospective study, the outcome of intracytoplasmic sperm injection (ICSI) in two age groups of men was studied. Couples with male partners aged 50 years and over (group A) (n = 227) with mean age of 53 +/- 5 years were compared with couples with younger age-group male partners (group B) (n = 227) with a mean age of 38.4 +/- 5.8 years. The control group of younger men was selected so that the womens age matched between the two groups. There was no significant difference in pregnancy rate between the two groups (37.9 versus 36.6%; OR = 1.06, 95% CI = 0.72-1.55). There was also no significant difference in the pregnancy rate between men aged 60 years and over as compared with men aged 50 to 59 years (OR = 1.00, 95% CI 0.74-1.37). However, the long-term outcome of these pregnancies needs further investigation. Semen analysis showed significantly lower motility in group A (37.4 +/- 20.4) versus group B (46.4 +/- 15.5; P < 0.0001). There was a significantly higher fertilization rate in younger men (P < 0.0001; OR = 1.36, 95% CI = 1.19-1.55), but this did not affect the pregnancy rate. In conclusion, it appears that paternal age has no effect on the pregnancy rate after ICSI.

Removal of cervical mucus prior to embryo transfer improves pregnancy rates in women undergoing assisted reproduction

The removal of cervical mucus during embryo transfer has been postulated to increase the pregnancy and implantation rates by not interfering with embryo implantation. Even so, this is a time-consuming procedure that may increase the incidence of difficult transfers by removing the naturally lubricant mucus. In addition, any cervical manipulations at the time of embryo transfer may cause unwarranted uterine contractions. In this prospective, controlled study, 286 women undergoing embryo transfer between January and May 2006 were divided into two groups according to whether the cervical mucus was scheduled to be aspirated (group A) or not (group B). The two groups were similar with regards to the demographics, cause of infertility, characteristics of ovarian stimulation and embryos transferred. Even so, the clinical pregnancy rate was significantly higher in group (A) than group (B) (OR = 2.18, 95% CI = 1.32-3.58), although there were easier transfers in group (B) than group (A) (OR = 3.00, 95% CI = 1.05-8.55). This demonstrates that even though embryo transfers were easier to perform when the cervical mucus was left in place, aspiration resulted in an increased chance of clinical pregnancy.

Highly purified hMG achieves better pregnancy rates in IVF cycles but not ICSI cycles compared with recombinant FSH: a meta-analysis

Objective. Human menopausal gonadotropin (hMG) was demonstrated to be superior to recombinant FSH (rFSH) regarding clinical outcomes. It is not clear whether this change in the evidence was due to the introduction of highly purified (HP) hMG. Design. Systematic review of properly randomised trials comparing HP-hMG vs. rFSH in women undergoing in vitro fertilisation (IVF) and/or intracytoplasmic sperm injection (ICSI). A meticulous search was performed using electronic databases and hand searches of the literature. Results. Six trials (2371 participants) were included. Pooling of the trials demonstrated that the probability of clinical pregnancy following HP-hMG administration was higher than rFSH and reached borderline significance (odd ratio (O.R) = 1.21, 95% confidence interval (CI) = 1.00 to 1.45), but the ongoing pregnancy/live-birth rate was not statistically different between the two drugs, although it showed strong trends towards improvement with HP-hMG (O.R = 1.19, 95% CI = 0.98 to 1.44). Subgroup analysis comparing both drugs in IVF cycles demonstrated a statistically significant better ongoing pregnancy/live-birth rate in favour of HP-hMG (O.R = 1.31, 95% CI = 1.02 to 1.68). On the other hand, there was almost an equal ongoing pregnancy/live-birth rate in ICSI cycles (OR = 0.98, 95% CI = 0.7 to 1.36). Conclusions. HP-hMG should be preferred over rFSH in women undergoing assisted reproduction, especially if IVF is the intended method of fertilisation.

Ultrasound guidance during embryo transfer: a prospective, single-operator, randomized, controlled trial

OBJECTIVE To determine whether the implementation of ultrasound (US) guidance will improve the clinical outcomes of ET compared with the standard clinical touch method of embryo catheter placement. DESIGN Prospective, single-operator, randomized, controlled trial. SETTING Saudi Center for Assisted Reproduction. PATIENT(S) Three hundred seventy-three women. INTERVENTION(S) Transcervical, intrauterine ET with or without US guidance. MAIN OUTCOME MEASURE(S) Primary outcomes were the live-birth/ongoing pregnancy and clinical pregnancy rates per randomized woman. Secondary outcomes were the incidences of difficult transfers, blood and/or mucus on the catheter tip, spontaneous miscarriages, and ectopic pregnancies. RESULT(S) Demographics and cycle characteristics were not different between the two groups. The live-birth/ongoing pregnancy rate was significantly higher in the US ET group (68 of 183, 40.98%) than in the clinical touch ET group (50 of 190, 28.42%) (odds ratio = 1.66, 95% confidence interval 1.07-2.57). In addition, there was a significantly higher number of clinical pregnancies in the US ET group (75 of 183, 40.98%) than in the clinical touch ET group (54 of 190, 28.42%) (odds ratio = 1.75, 95% confidence interval 1.14-2.69). Secondary outcomes were not significantly different between the two groups. CONCLUSION(S) Ultrasound-guided ET significantly increases ongoing pregnancy/live-birth and clinical pregnancy rates compared with the clinical touch method.

Firm embryo transfer catheters for assisted reproduction: a systematic review and meta-analysis using direct and adjusted indirect comparisons

A systematic review of published evidence on firm embryo transfer catheters is presented. Extensive searches were conducted for full-text manuscripts, abstracts, ongoing and unpublished trials. Direct and adjusted indirect comparisons were undertaken, where appropriate. Twenty-six randomized controlled trials comparing embryo transfer catheters were identified. Only two trials (314 transfers) compared different firm embryo catheters. Using direct comparison, both the Tom Cat and Tefcat catheters demonstrated statistically significant increased chances of clinical pregnancy compared with the Tight Difficult Transfer (TDT) catheter (P=0.007; OR=3.67, 95% CI=1.48-9.10 and P<0.0001; OR=4.71, 95% CI=2.34-9.48 respectively). The implantation rates were also higher with the Tom Cat and Tefcat catheters than the TDT catheter (P=0.005; OR=3.67, 95% CI=1.48-9.10 and P<0.00001; OR=4.29, 95% CI=2.45-7.50 respectively). Using adjusted indirect comparison, Tom Cat and Tefcat catheters were compared, and shown to have similar pregnancy and implantation rates (OR=0.99; 95% CI=-0.87-1.79 and OR=0.86; 95% CI=-0.77-1.35). In conclusion, both Tom Cat and Tefcat catheters give better outcomes than the TDT catheter, but are similar to each other.

What is the best site for embryo deposition? A systematic review and meta-analysis using direct and adjusted indirect comparisons

The site of embryo replacement has been postulated as being important to the success of IVF/ICSI. In order to determine the best site for embryo deposition during embryo transfer, a meta-analysis of randomized trials comparing different uterine deposition sites was undertaken. Electronic (e.g. PubMed, EMBASE, Cochrane Library, LILACS) and hand searches were performed to locate trials. Outcomes measures were the live-birth (LBR), ongoing pregnancy (OPR), and clinical pregnancy rates (CPR). Assessments of the endometrial cavity length (ECL) and the distance from the fundus to the tip of the catheter (DTC) were utilized. Six studies were identified, of which three were excluded. Meta-analysis was conducted with the Mantel-Haenszel method, utilizing the fixed-effects model. The LBR and OPR showed an increasing trend when transfers were performed to the lower half of the uterine cavity. For the DTC, all rates were significantly higher for the approximately 20 mm versus approximately 10 mm distance from the uterine fundus, supporting the results of the ECL analysis. The results of this systematic review show that there is limited evidence of the superiority of lower cavity transfers (e.g. approximately 20 mm) compared with the traditional high cavity (e.g. approximately 10 mm) transfers. More well-designed and powered randomized trials are needed to confirm this conclusion.

HMG versus rFSH for ovulation induction in developing countries: a cost–effectiveness analysis based on the results of a recent meta-analysis

Both cost and effectiveness should be considered conjointly to aid judgments about drug choice. Therefore, based on the results of a recent published meta-analysis, a Markov model was developed to conduct a cost-effectiveness analysis for estimation of the cost of an ongoing pregnancy in IVF/intracytoplasmic sperm injection (ICSI) cycles. In addition, Monte Carlo micro-simulation was used to examine the potential impact of assumptions and other uncertainties represented in the model. The results of the study reveal that the estimated average cost of an ongoing pregnancy is 13,946 Egyptian pounds (EGP), and 18,721 EGP for a human menopausal gonadotrophin (HMG) and rFSH cycle respectively. On performing a sensitivity analysis on cycle costs, it was demonstrated that the rFSH price should be 0.61 EGP/IU to be as cost-effective as HMG at the price of 0.64 EGP/IU (i.e. around 60% reduction in its current price). The difference in cost between HMG and rFSH in over 100,000 cycles would result in an additional 4565 ongoing pregnancies if HMG was used. Therefore, HMG was clearly more cost-effective than rFSH. The decision to adopt a more expensive, cost-ineffective treatment could result in a lower number of cycles of IVF/ICSI treatment undertaken, especially in the case of most developing countries.

Effect of passive uterine straightening during embryo transfer: a systematic review and meta‐analysis

Background. Part of the success of ultrasound‐guided embryo transfer has been associated with the beneficial effect of uterine straightening by passive bladder distention. Even so, this has not been properly analysed in the literature. Methods. This is a systematic review and meta‐analysis of prospective, randomised, controlled trials, comparing embryo transfer with a full versus empty bladder. Electronic (e.g. PubMed, EMBASE, Cochrane Library) and hand searches were performed to locate trials. Primary outcomes were live‐birth, ongoing and clinical pregnancy rates. Secondary outcomes were rates of implantation, miscarriage, multiple and ectopic pregnancies, and retained embryos. Also, the ease of transfer, need for instrumental assistance, and presence of blood on the catheter tip were evaluated. Four studies were identified, of which 1 study was excluded. Meta‐analysis was conducted with the Mantel–Haenszel method, utilising the fixed‐effect model. Results. For the primary outcome measures, no data was available for the LBR rate. There was a significantly higher chance of an ongoing pregnancy [OR = 1.44 (95% CI = 1.04–2.04)] and clinical pregnancy [OR = 1.55 (95% CI = 1.16–2.08)] with a full bladder. For the secondary outcomes, there was a significantly greater incidence of difficulty, or need for instrumental assistance, with an empty bladder. Other outcome measures were not significantly different. Conclusion. There is evidence in the literature advising to fill the bladder prior to embryo transfer.