The merits of blastocyst versus cleavage stage embryo transfer: a Cochrane review

This paper is based on a Cochrane review published in The Cochrane Library, issue 2, 2002 (see www.CochraneLibrary.net for information) with permission from The Cochrane Collaboration and John Wiley and Sons. Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms, and The Cochrane Library should be consulted for the most recent version of the review. BACKGROUND: The aim of this study was to determine the relative merits of blastocyst versus cleavage stage embryo transfer, concerning the chance of pregnancy, live birth, multiple pregnancy and the factors contributing to these primary outcomes, from the best available evidence. METHODS: A systematic review employing the principles of the Cochrane Menstrual Disorders and Subfertility Group was undertaken. Fourteen randomized controlled trials, all comparing day 2/3 with day 5/6 embryo transfer, were included in a meta-analysis. RESULTS: For day 2/3 versus day 5/6 transfer, there was no significant difference in the odds of pregnancy [odds ratio (OR) = 0.91, 95% confidence interval (CI) 0.71-1.17] nor of live birth (OR = 0.83, 95% CI 0.48-1.42) per treated couple. These results were similar whether all trials, only trials with transfer of equal numbers of day 2/3 versus day 5/6, or only trials with transfer of fewer day 5/6 than day 2/3 embryos, were pooled. There was no significant difference in the odds of multiple pregnancy for day 2/3 versus day 5/6 transfer overall (OR 0.77, 95% CI 0.52-1.13) nor when fewer day 5/6 than day 2/3 embryos were transferred (day 2/3 versus day 5/6 OR 0.69, 95% CI 0.42-1.12). CONCLUSION: The current evidence fails to support a widespread change of practice from cleavage stage to blastocyst stage embryo transfer in couples undergoing IVF.     

The merits of blastocyst versus cleavage stage embryo transfer: a Cochrane review

Hum. Reprod., 19, 795–807, 2004 The authors wish to point out the following about their paperpublished in Human Reproduction 19/4: We have been contacted by a trial author concerning the abovereview. The randomised controlled trial (RCT) published     

Pregnancy outcome after blastocyst transfer as compared to early cleavage stage embryo transfer

BACKGROUND: Retrospective cohort study to evaluate differences in outcome when embryo transfer was performed either on day 2-3 (cleavage stage, CS-group) or on day 4-5 (blastocyst stage, BS-group). METHODS: A total of 1259 consecutive cycles yielding 500 live born babies performed at a single centre in Bregenz, Austria, were included. Main outcome measures were implantation and (multiple) pregnancy rates and neonatal outcome including birth defects. RESULTS: Total Pregnancy rate was 44% vs 28% (P < 0.001) and the total 'take home baby rate' was 37% vs 22% in the BS-group and the CS-group, respectively. Rate of multiple gestations (34% vs 17%, P = 0.001) was significantly higher among the BS-group, resulting in a higher rate of preterm deliveries < 36 weeks (26% vs 17%, P = 0.045). Female factor causing infertility (40% vs 21%, P < 0.001) was significantly higher among the BS-group. For the CS-group, rate of singleton pregnancies (83% vs 66%, P = 0.001) and idiopathic cause of infertility (34% vs 22%, P = 0.012) were significantly higher. No statistically significant differences were found in sex, Caesarean section rate, Apgar score and umbilical artery pH-values, total mean birth weight, admission rate to intensive care unit, days of hospitalization and number of minor and major birth defects. CONCLUSIONS: Our data suggest that blastocyst transfer may lead to a higher pregnancy rate with an overall better take-home baby rate (THBR) at the cost of higher rates of multiples and preterm deliveries.     

Three blastocyst stage embryo transfer resulting in a quintuplet pregnancy

High-order pregnancies are associated with high morbidity and mortality and the incidence is increased as a drastic complication of assisted reproductive technology. This case presents a high-order pregnancy achieved by transfer of three blastocyst stage embryos resulting in a quintuplet pregnancy including a monochorionic triplet. Following the selective termination of the monochorionic triplet, two healthy children were born. The mechanism of monochorionic development and its association with assisted reproductive technology are discussed.     

Effect of developmental stage of embryo at freezing on pregnancy outcome of frozen-thawed embryo transfer

BACKGROUND: The study aim was to investigate the impact of the developmental stage of embryos on pregnancy outcome of frozen embryo transfer (FET). METHODS: The survival rates of embryos after thawing and pregnancy outcome following FET were compared retrospectively between three cryopreservation strategies utilizing either zygote, day 2 or day 3 embryo freezing. RESULTS: A total of 4006 embryos was analysed in 1657 thaw cycles. The highest (P < 0.0001) survival rate (all cells survived) was observed for zygotes (86.5%), followed by day 2 (61.7%) and day 3 (43.1%) embryos. FET was performed in 1586 (95.7%) of all thaw cycles, resulting in overall clinical pregnancy and implantation rates of 20.7 and 14.2% respectively. The delivery rate per transfer was 16.5%, and live birth rate per transferred embryo 11%. There were no significant differences in clinical pregnancy, implantation, delivery and birth rates between frozen zygote, day 2 and 3 embryo transfers. However, an elevated miscarriage rate was observed in the day 3 group (45%) compared with zygotes (21.3%; P = 0.049) and day 2 embryos (18.3%; P = 0.004). The overall efficacy of FET (birth rate per thawed embryo) was 7.3%. The efficacy was lower in day 3 group (4.2%) than in the zygote (7.1%; P = 0.082) and day 2 (7.6%; P = 0.027) groups. CONCLUSIONS: The developmental stage of embryos at freezing has a profound effect on their post-thaw survival, but seems to have little effect on rates of clinical pregnancy, implantation, delivery and birth after FET. The elevated miscarriage rate for day 3 frozen embryo transfers may be caused by damage during freeze-thaw procedures. The low survival rate and elevated miscarriage rate were both responsible for a reduced overall efficacy for day 3 FET when compared with zygotes and day 2 embryos.     

Reply: Pregnancy outcome after blastocyst transfer as compared to early cleavage stage embryo transfer

Sir, We appreciate the interest of van der Ven and Montag in ourstudy and their useful comments. The primary aim of our retrospective cohort study was neonataloutcome. Hence, the purpose     

Comparison of concurrent pregnancy rates for in-vitro fertilization-embryo transfer, pronuclear stage embryo transfer and gamete intra-Fallopian transfer

Concurrent pregnancy and implantation (sacs/embryos transferred)rates were compared for 84, 77 and 49 cases of in-vitro fertilization–embryotransfer (TVF–ET), pronuclear stage embryo transfer (PROST)and gamete intra-Fallopian transfer (GIFT), respectively. Allcases reported occurred during an 18-month interval since theinitiation of PROST by our programme. Leuprolide acetate wasused with follicle stimulating hormone and human menopausalgonadotrophin for follicular stimulation of all but donor oocytecases (n = 9). Clinical pregnancy (per transfer) and implantationrates were significantly higher (P < 0.03) for PROST (52.4%,20.2%) in comparison with IVF–ET (26.9%, 11.4%). Ratesfor GIFT (48.9%, 18.4%) were not significantly higher (P = 0.10,0.14) than for IVF—ET. This was probably due to the lowernumber of GIFT than PROST procedures performed. The total pregnancyrate for GIFT (biochemical, ectopk and clinical combined) wassignificantly greater (P < 0.05) than for IVF—ET. Pregnancyand implantation rates for PROST and GIFT were similar. Theseresults support the use of PROST rather than IVF—ET forall cases in which the woman has one functional Fallopian tube.Furthermore, to maintain equivalent rates of pregnancy withPROST and GIFT, it is suggested that GIFT should not be usedfor cases of male-factor infertility without first documentingnormal rates of in-vitro fertilization with PROST.     

Single embryo transfer is an option in frozen embryo transfer

BACKGROUND: A good strategy to decrease multiple pregnancy rate in assisted reproduction technology (ART) is the use of single embryo transfer (SET). METHODS: This retrospective study analysed 1647 frozen embryo transfers carried out during 1998-2003 in Helsinki University Central Hospital; of these, 872 were double embryo transfers (DETs) and 775 SETs. The SET group included 140 (18.1%) elective SETs (eSETs). RESULTS: The yearly rate of SETs in frozen cycles increased from 28 to 66%. Overall, the clinical pregnancy rate per frozen embryo transfer was 30.7% and the delivery rate 22.6%. The delivery rate was significantly higher in DET cryocycles than in SET cryocycles (25.7 versus 19.2%, respectively; P < 0.01). In DET cryocycles, the multiple delivery rate was 21.9%, 10 times higher than that observed in cryocycles with SET (2.0%) (P < 0.0001). When eSET was applied, no difference in delivery rate was observed when compared with cryocycles with DET (28.6 and 25.7%, respectively). CONCLUSIONS: SET can be used in frozen cycles to reduce multiple delivery rates.     

Ultrasound-guided embryo transfer and the accuracy of trial embryo transfer

BACKGROUND: Studies have suggested that ultrasound-guided embryo transfer (UG-ET) may improve the outcome in IVF; however, several factors may account for the improvement in pregnancy rate. This study examines the use of ultrasound to determine the accuracy of trial transfer (TT) in preparation for ET. METHODS: Sixty-seven consecutive patients prospectively underwent UG-ET over a 2 month period. Total cavity length by US was compared with the length noted by TT. A difference of > or = 1 cm was considered significant. All embryos were placed within 1-2 cm of the fundus by US. RESULTS: Twenty patients (29.9%) had a difference of > or = 1 cm and 13 patients (19.4%) had a difference of < or = 1.5 cm. Patients with a difference of > or = 1 or > or = 1.5 cm had a significantly greater depth at transfer (P < 0.001) and uterine cavity length (P < 0.001) when compared with patients without a difference. Clinical pregnancy, implantation, delivery and overall miscarriage rates did not differ between patients with a difference of > or = 1 or > or = 1.5 cm versus no difference. There were no ectopic pregnancies. CONCLUSIONS: Nineteen percent of patients had a discrepancy of > or = 1.5 cm and approximately 30% had a difference of > or = 1 cm from TT at UG-ET, suggesting a benefit to UG-ET. A large prospective randomized trial comparing UG-ET with blind transfer is required to assess further if UG-ET should be used in all cases of ET.     

Uterine position at real embryo transfer compared with mock embryo transfer

BACKGROUND: The purpose of this study was to determine the consistency in the uterine position between mock and real embryo transfer. METHODS: We reviewed 996 consecutive embryo transfer cycles (585 patients); 74% of patients had an anteverted (AV) uterus and 26% had a retroverted (RV) uterus at mock embryo transfer. All mock and real embryo transfers were performed under abdominal ultrasound guidance. RESULTS: Of 623 fresh embryo transfers in patients with an AV uterus at mock embryo transfer, only 2% became RV, while 55% of 213 embryo transfers in patients with an RV uterus on mock embryo transfer converted to AV at real embryo transfer (P < 0.0001). For frozen-thawed embryo transfer, 12% of AV uteri at mock embryo transfer became RV, while 33% of RV uteri became AV (P = 0.01). CONCLUSIONS: Our data suggest that an RV uterus at mock embryo transfer will often change position at real embryo transfer. Misdirecting the embryo transfer catheter can be avoided by accurate knowledge of the uterine position at the time of embryo transfer, which can be more accurately assessed by routine ultrasound guidance. Additionally, patients with an RV uterus at mock embryo transfer should still present with a full bladder for embryo transfer, since a significant number will convert to an AV position.     

Zygote transfer on day 1 versus cleavage stage embryo transfer on day 3: a prospective randomized trial

BACKGROUND: It has been reported that pronuclear morphology is related to embryo quality and viability, and that zygote stage embryos might establish pregnancies after being transferred to the uterus. The objective of this study was to investigate whether transferring zygotes on day 1 would result in similar pregnancy rates compared to transferring cleavage stage embryos on day 3 in a prospective randomized trial. METHODS: Patients undergoing IVF/ICSI treatments were randomized to either day 1 or day 3 transfers by envelope withdrawal technique. Zygotes were classified as 'pattern 0' and 'non-pattern 0' according to the size and alignment of pronuclei, the number and distribution of nucleoli. The two best zygotes or embryos were transferred on day 1 or day 3 respectively. The primary outcome measure was pregnancy rate. RESULTS: Pregnancy rates were higher in day 3 group (55/131, 42%) when compared to day 1 (34/123, 28%, P = 0.024). Similarly, implantation rates were higher in day 3 group (P = 0.03). There were more cycles with cryopreservation in the day 1 group (P < 0.001). Embryo quality on day 3 was similar between pattern 0 and non-pattern 0 zygotes. CONCLUSIONS: Day 3 embryo transfers result in better pregnancy and implantation rates compared to day 1 zygote transfers. The present pronuclei scoring cannot reliably select zygotes for transfer on day 1.     

Preliminary results on transvaginal tubal embryo stage transfer (TV-TEST) without ultrasound guidance

IVF procedures have been increasingly used in male subfertility for both therapeutic and diagnostic purposes. As we assume a positive influence of the tubal milieu on the early embryonal development, any therapy should aim at intratubal embryo transfer. In this respect, only invasive techniques such as laparoscopy or laparotomy have been available hitherto (Asch et al., 1986; Balmaceda et al., 1988; Diedrich et al., 1989). Transvaginal intra-tubal embryo stage transfer (TV-TEST) was performed in 15 patients. After stimulation with clomiphene/HMG, HMG or GnRHA/HMG, patients with a follicle size of 18 mm were given 10000 IU HCG. Thirty six hours later, the transvaginal oocyte retrieval was performed without anaesthesia. Altogether, 109 oocytes were recovered. A fertilization rate of 30.3% yielded 33 embryos. Forty-eight hours after oocyte retrieval, the TV-TEST was performed without anaesthesia, in the course of which a maximum of three embryos in the 2- to 8-cell stage were transferred into one tube. Six of these patients are now pregnant.     

Hydrosalpinx reduces in-vitro fertilization/embryo transfer pregnancy rates

A retrospective study was designed to examine whether the presenceof a hydrosalpinx influenced pregnancy outcome following in-vitrofertilization (IVF) treatment In stimulated cycles. A totalof 254 women with tubal lesions were included. Patients withone or two hydrosalpinges were compared with patients havingother tubal lesions and pregnancy outcome was analysed. Bothpregnancy and delivery rates were significantly higher in thepatient group without a hydrosalplnx. The results after frozenembryo transfer showed the same tendency. These findings stronglyindicate that a permanent hydrosalpinx has a negative influenceon implantation, as well as on pregnancy, and suggest that amore active approach against large hydrosalpinges should beundertaken before I.VF treatment, in order to improve the pregnancyrates.     

Impact of patients' choice for single embryo transfer of a top quality embryo versus double embryo transfer in the first IVF/ICSI cycle

BACKGROUND: The aim of this study was to evaluate the impact of transferring a single top quality embryo in the first IVF/ICSI cycle of patients <38 years old who chose to have one or two embryos transferred. METHODS: A total of 262 patients participated in the study, and 243 transfers were performed: 156 (64%) patients chose the transfer of a single top quality embryo, if available, and two non-top quality embryos if not available; 87 (36%) patients chose to have a double embryo transfer regardless of embryo quality. RESULTS: In the first group an ongoing pregnancy rate of 40% (63/156) with a twin pregnancy rate of 2% (1/63) was achieved. In the second group the ongoing pregnancy rate was 44% (38/87) with 26% (10/38) twin pregnancies. In the patient group with only one embryo transferred, irrespective of the patient's choice, the ongoing pregnancy rate was 43% (54/127) with no twin pregnancies. For the study population as a whole, the ongoing pregnancy rate was 42% (101/243) with 11% (11/101) twins. CONCLUSION: We conclude that the introduction of single embryo transfer in the first IVF/ICSI cycle is highly acceptable in women <38 years old.     

Non-surgical tubal embryo transfer

Selective cannulation of the Fallopian tubes via the utero-tubal junction, without analgesia, anaesthesia or surgery, has been carried out to replace three embryos in a patient. Cannulating the Fallopian tubes did not appear materially to affect the transport of embryos or the receptivity of the endometrium for implantation.     

The relative myth of elective single embryo transfer

The option of single embryo transfer (SET) has recently dominated the pages of this and other medical journals. Opinions, in regards to the utility of such an approach, appear to differ between Europe and the US. While US guidelines promote a more individualized approach, European opinions, at times, even advocate mandated practice patterns. The European approach, however, fails to recognize the rather significant differences in supportive arguments between the historical switch from multiple embryo transfers to 2-embryo transfers and the current discussion, favouring a switch from 2-embryo transfer to elective (e)-SET. In the former, a significant risk of (at times, high-order) multiple pregnancies was reduced without loss of pregnancy potential. In the latter, a comparably relatively low twinning risk is reduced at the expense of declining pregnancy rates, a need for more treatment cycles, a potential delay in treatment success and, potentially, higher treatment costs. These consequences of e-SET, together with the preference of some infertility patients to actually conceive twins, raise serious questions about the wide utilization of e-SET, as has been propagated by many authorities. According to US guidelines, e-SET, therefore, appears to represent an appropriate transfer option for only a small minority of IVF patients. Argument in favour of indiscriminate SET appears unrealistic and should be reconsidered.     

A randomized clinical trial comparing recombinant hyaluronan/recombinant albumin versus human tubal fluid for cleavage stage embryo transfer in patients with multiple IVF-embryo transfer failure

BACKGROUND: We aimed to examine the efficacy of using an embryo transfer medium enriched with hyaluronan (HA) to improve implantation in a selected group of patients aged <43 years with repeated (>4) implantation failures after IVF-embryo transfer. METHODS: About 101 patients, meeting our selection criteria, were randomly allocated to undergo embryo transfer either using our routine embryo transfer medium without HA (control group) or a HA enriched commercial embryo transfer medium (study group). The primary outcome was clinical pregnancy rate. RESULTS: After a similar treatment protocol, the ovarian hormonal response, the mean number of ova retrieved and injected per patient, fertilization and cleavage rates and mean embryo quality were comparable between the study and control groups. Although a similar number of embryos was transferred in both groups (3.1 +/- 0.7 versus 2.9 +/- 0.6, mean +/- SD), a significantly higher implantation rate (16.3% versus 4.8%, P = 0.002) and clinical pregnancy rate (35.2% versus 10.0%, P = 0.004) and delivered or ongoing pregnancy rate (31.3% versus 4.0%, P = 0.0005) were observed in the study group. When mean implantation rate per patient was calculated, the difference between the study (0.148 +/- 0.23) and control (0.04 +/- 0.13) group was significant (P = 0.003). CONCLUSIONS: In this selected group of patients after multiple IVF-embryo transfer failures, the use of HA enriched embryo transfer medium is beneficial.