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Year : 2015  |  Volume : 2  |  Issue : 1  |  Page : 30-36

A prospective trial comparing sequential day 3/day 5 transfer with cleavage stage transfer and blastocyst stage transfer

Department of IVF, Lilavati Hospital and Research Centre, Bandra West, Mumbai, Maharashtra, India

Date of Web Publication15-Jun-2015

Correspondence Address:
Dr. Rutvij Dalal
20, Shreerang society, Near Old Pilot Dairy, Kankaria, Ahmedabad - 380 022
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2348-2907.151972

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The purpose of this study was to critically evaluate the effect of sequential embryo transfer in randomized patients undergoing assisted in vitro conception. A randomized prospective study was conducted and the outcomes of 505 patients were analyzed, of which 107 women underwent sequential embryo transfer on day 3 and day 5 (D3/D5 group), 283 women underwent day-3 embryo transfer only (D3 control group) and 115 women underwent day-5 embryo transfer only (D5 control group) in the assisted reproduction center of Lilavati Hospital, Mumbai from March 2012 to March 2013. The results showed that the clinical pregnancy rate of the D3/D5 group was significantly higher than that of the D3 group (48.5% versus 29.3%), whereas the clinical pregnancy rates of the D3/D5 and D5 groups were not significantly different (48.5% vs. 53.0%). Day-3/day-5 sequential embryo transfer yields satisfactory clinical pregnancy rates in a subset of patients with repeated implantation failures (35.2%), while avoiding cycle cancellation that happened with about 11% patients that were meant for blastocyst only transfer.

Keywords: Blastocyst transfer, consecutive transfer, sequential transfer

How to cite this article:
Dalal R, Mishra A, Pai HD, Palshetkar N. A prospective trial comparing sequential day 3/day 5 transfer with cleavage stage transfer and blastocyst stage transfer. IVF Lite 2015;2:30-6

How to cite this URL:
Dalal R, Mishra A, Pai HD, Palshetkar N. A prospective trial comparing sequential day 3/day 5 transfer with cleavage stage transfer and blastocyst stage transfer. IVF Lite [serial online] 2015 [cited 2022 Jan 18];2:30-6. Available from: http://www.ivflite.org/text.asp?2015/2/1/30/151972

  Introduction Top

Traditionally, embryos generated after fertilization, either by in vivo fertilization (IVF) or ICSI, have been replaced back into the uterine cavity either or the 2 nd or 3 rd day of oocyte fertilization. Since IVF involves the blastocyst implanting in the uterine wall at around day 5 or day 6, in vitro blastocyst transfer has been proposed, mimicking the natural cycle. Blastocyst transfer has inherent advantages compared to cleavage stage transfer such as better synchrony with the endometrium, lesser uterine contractility, better embryo euploidy status and higher implantation potential per embryo. Accordingly many units started adopting the policy of "pure" blastocyst transfer. The major disadvantage of relying on "pure" blastocyst(s) transfer is the possible situation in which the transfer might have to be cancelled due to embryonic block in which there is a failure of embryos to proceed to the blastocyst stage. This has financial, legal, emotional and psychological burdens on both the patient and the treating doctor. To avoid this disastrous consequence, a "sequential" transfer, in which both, cleavage stage embryo(s) and blastocyst(s) are sequentially transferred in the same cycle has been proposed. This policy can have the potential advantages of blastocyst transfer along with the insurance against potential cancellation by having a cleavage stage transfer as well.

  Materials and Methods Top

This investigation is a prospective randomized trial that had received Institutional Review Board approval. Participation in this study was offered to all patients undergoing IVF-ET with their own oocytes during a 12-month period who met our inclusion criteria. These criteria included age of the female partner < 37 years, a day 3 follicle stimulating hormone (FSH) level < 10 IU/L, E 2 < 80 pg/ml, hysteroscopically normal endometrial cavity and at least 10 follicles > 14 mm in diameter on the day of receiving human chorionic gonadotropin administration. A total of 505 patients were enrolled after informed consent was taken.

Ovarian stimulation and IVFD

The standard gonadotrophin-releasing hormone agonist long protocol (mid-luteal phase) was utilized. 0.5 ml or 1 mg Leuprolide (Leuprolide acetate; Sun Pharma, India) was administered for down-regulation from day 21 of preceding cycle, and 100-300 IU recombinant FSH (Puregon; Organon, Oss, The Netherlands; or Gonal-F; Serono, Switzerland) was administered daily for ovarian stimulation. Follicle growth monitoring included serum estradiol, progesterone and LH measurements and vaginal ultrasound investigation. When one follicle reached a diameter of ≥18 mm or two follicles reached ≥17 mm, and at least 10 follicles were more than 14 mm, 250 μg of Ovitrelle (recombinant human chorionic gonadotrophin (Merck Serono, Switzerland) was administered, and oocytes were retrieved 36 h later. Routine IVF or intracytoplasmic sperm injection was performed 4 h after oocyte retrieval, and the oocytes were checked for fertilization 16-18 h later. Normal fertilization was indicated by the appearance of two pronuclei.

Embryo culture and grading

Embryos were cultured in commercial sequential IVF medium (Quinn's Advantage Cleavage Medium; SAGE, Pasadena, CA, USA) in triple gas bench-top incubators with gas concentrations of 6% CO 2 , 5% O 2 and 89% N2. Embryo transfer was performed in 20 μl of media using a continuous column in a Wallace catheter (Edwards-Wallace catheter, Marlow Technologies, Inc. Willoughby, OH) under ultrasound guidance.

Embryos were observed at 48 h (day 2) and 72 h (day 3) after oocyte retrieval. The grading criteria for the embryos were as follows: Grade 1, the size of the blastomeres was uniform, with no fragmentation; grade 2, the blastomere size was slightly uneven and/or had <20% fragmentation; grade 3, the blastomere size was heterogeneous, or with 20-50% fragmentation; and grade 4, >50% fragmentation. The number and grade of the embryonic blastomeres were recorded. Good-quality embryos were defined as embryos containing ≥4 cells on day 2 (48 h after oocyte retrieval) and ≥6 cells on day 3 (72 h after oocyte retrieval) with a grade of 1-2.

Blastocyst grading was done according to the Gardener and Schoolcraft grading system. [2] Grading is according to size:

  • Early blastocyst, the blastocoel is less than half the volume of the embryo
  • Blastocyst, the blastocoel is greater than or equal to half the volume of the embryo
  • Full blastocyst, the blastocoel completely fills the embryo
  • Expanded blastocyst, blastocoel volume is larger than that of the early embryo and zona is thinning
  • Hatching blastocyst, the trophectoderm has started to herniate through the zona
  • Hatched blastocyst, the blastocyst has completely escaped from the zona.

For blastocysts graded as 3-6 that is, full blastocysts onward, the development of the inner cell mass (ICM) and trophectoderm was assessed as follows:

Inner cell mass grading:

  • Tightly packed, many cells
  • Loosely grouped, several cells
  • Very few cells.

Trophectoderm grading:

  • Many cells are forming a tightly knit epithelium
  • Few cells
  • Very few cells are forming a loose epithelium.

No embryos underwent assisted hatching before transfer.

Embryo cryopreservation

Embryos were frozen only at the blastocyst stage on day 5 or 6 after sequential media culturing. So, for example, in the day 3 transfer control group, after transferring two embryos on day 3 the embryos were allowed to progress until day 5 and observed. In the day 5 transfer control group if there are more than 2 high grade (3BB and above) available two are selected for transfer on day 5 and the rest frozen the same day. Cryopreservation of supernumerary embryos on day 5 or 6 was performed by Vitrification using Kitazato Vitrification medium (Kitazato ® , Tokyo, Japan). Only blastocysts scoring 3BB or higher by 6 were frozen, the rest were discarded.

Luteal support and pregnancy testing

All patients in the three groups received 2 embryos - either two day 3 embryos (day 3 control group), one day 3 and one day 5 embryo (the day 3/5 study group) or two day 5 blastocysts on day 5 (the day 5 control group). Luteal supported consisted of 50 mg of progesterone in oil initiated on the day of oocyte retrieval and continued until the day of pregnancy testing. Estrogen supplementation was given in the form of oral estradiol valerate 2 mg tablets twice a day.

Outcome measures

The primary outcome measures were the clinical pregnancy rate and implantation rate in the fresh cycle only. The secondary outcome measure was the miscarriage rate. Pregnancy testing was performed 14 days after embryo transfer. Ultrasound examination was performed at week 7 (about 5 weeks after transfer) to assess the fetal sac number and the fetal heartbeat. Clinical pregnancy was defined as the presence of a fetal heartbeat on ultrasound examination at 7 weeks of pregnancy. The implantation rate was defined as the number of gestational sacs seen on the ultrasound divided by the total number of embryos/blastocysts transferred. Implantation rate was calculated for all patients having ET and not just those who became pregnant. Spontaneous miscarriage was defined as a clinical pregnancy loss before 28 weeks of gestation age. Multiple pregnancies were defined as two or more gestational sacs observed on ultrasound. Frozen cycles were not taken into consideration and therefore cumulative pregnancy rates are not considered in this study.

Statistical analyses

A total of 107 women underwent sequential embryo transfer on day 3 and day 5 (D3/D5 study group), 283 women underwent day-3 embryo transfer only (D3 control group) and 115 women underwent day-5 embryo transfer only (D5 control group) at the IVF department of Lilavati Hospital and Research Centre, Mumbai over a period of 12 months.

The Statistical Package for Social Sciences (SPSS, Chicago, IL, USA) was applied for data analysis. Data were expressed as mean ± standard deviation unless stated otherwise. Qualitative data was analyzed with Chi-Square test with continuity correction. quantitative data analyzed with unpaired t-test. Fisher's exact test was used whenever appropriate. P <0.05 was considered as statistically significant.

  Results Top

The indication for IVF, average age and duration of infertility in the sequential transfer and both control groups were not significantly different [Table 1]. No statistically significant differences existed between the groups with respect to the number of previous failed cycles, number of oocytes retrieved, fertilization rate, cleavage rate and percentage of good-quality embryos.
Table 1: Comparison of infertility diagnosis in the sequential transfer and once-only transfer groups

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Out of the 283 patients that consented and were chosen for day 3 transfer group 2 had no embryos available on day 3 due to fertilization failure making the total fertilization failure rate of 0.7%. Clinical pregnancy rate in this group was 29.3%. For the Day 3/Day 5 sequential study group, one grade 1 or grade 2 embryo was transferred on day 3 and all other embryos were left for blastocyst culture. All 107 women who participated in this study had one embryo transferred on day 3, that is, none had total fertilization failure. Eight women out of 107 had no blastocysts available at day 5. Out of these eight only one patient conceived with a single day 3 transferred embryo. For the remaining 99 patients, day 5 blastocyst morphology assessment was done, and one good quality blastocyst (grade 3 BB and above) was selected for transfer. The study group had a clinical pregnancy rate of 48.5%. 115 patients consented to be in the blastocyst-only transfer control group. In this group, all embryos were kept for extended culture. The embryos were then assessed on day 5 and if two good quality embryos were available for transferring they were transferred. Out of 115 patients 13 patients were cancelled due to unavailability of two good blastocysts on day 5. In spite of this, the clinical pregnancy rate in this group was the highest 56.3%.

The clinical pregnancy and implantation rates in the D3/D5 group were significantly higher than the D3 group [48.5% vs. 29.3%, P = 0.0006 and 29.1% vs. 16%, P = 0.00007, respectively; [Table 2]. The multiple pregnancy rate was not significantly different between the two groups.
Table 2: Comparison of outcomes for day 3/day 5 sequential transfer and day-3 only transfer

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No statistically significant differences existed between the D3/D5 group and the D5 group with respect to pregnancy rates; however, the cancellation rate was higher in the Day 5 group [Table 3]. Implantation rate, as well as twinning (multiple pregnancy) rate, was higher in the D5 group.
Table 3: Comparison of outcomes for day-3/day 5 sequential and day-5 only transfer

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We defined recurrent implantation failure as one having four or more cycles of embryo transfer cycles (fresh or frozen) failed in the past for a woman under 40 years of age. A total of 66 patients were suffering from recurrent implantation failure in this prospective study. Their distribution among the groups and outcome was as follows in [Table 4].
Table 4: Outcomes of recurrent implantation failure patients in each group

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  Discussion Top

The advantages of blastocyst transfer

There are several advantages of blastocyst(s) transfer in an ART program. A more efficient synchronization between the developing endometrium and embryo is the foremost. [2] Second, since there is activation of the embryonic genome roughly around day 3 (8 celled stage) of fertilization, a blastocyst transfer ensures that only those embryos are selected for transfer who have undergone the genomic shift. It, therefore, allows a clinician to naturally select competent embryos that have the potential of continued development under embryonic genomic control. [3]

Various factors like the number of oocytes retrieved maternal age and male fertility influence embryonic progression and block. There are several papers showing that the male infertility significantly reduces blastulation rate. This is understandable, considering that paternal genes in the embryo are not expressed until day 3 of culture. [4] Accordingly, blastocyst transfer is recommended in clinical cases where severe male infertility is involved. Additionally, blastocyst culture and growth assists in the natural selection process of chromosomally competent embryos with a higher implantation potential. It has also been shown that most embryos with multiple aneuploidies fail to develop in extended culture unto the blastocyst stage. [5]

It is now firmly established that the implantation potential of a blastocyst is superior to that of a cleavage stage embryo. In nine prospective randomized trials using sequential culture media, [2],[5],[6],[7],[8],[9],[10],[11],[12] five reported a significant increase in implantation rates when embryos were transferred at the blastocyst stage on day 5 rather than at cleavage stage. Three trials reported no difference, whereas one trial reported a lower implantation rate when day 5 transfer was used. In the latest Cochrane meta-analysis of 25 studies addressing this issue, [13] there was a small significant increase in live birth rates with blastocyst transfer compared with cleavage transfer. However, cumulative pregnancy rates were higher with a cleavage transfer. Blastocyst transfer yields a better clinical pregnancy as well as live birth rate, if one considers pregnancy rate per transfer attempt.

Implantation rate is the determining factor in evaluating success in human IVF. Historically, cleavage transfer yields implantation rates between 10% and 30%. As a direct result of these low implantation rates, it became an accepted procedure to transfer more than one embryo to the patient to achieve acceptable ongoing pregnancy rates.

The transfer of more than one embryo results in the possibility of multiple gestation. Multiple gestation has well-known adverse gestational outcomes such as preterm delivery, low birth weight, fetal and infant death, long-term disabilities, medical complications, etc., Furthermore, there are heavy economic costs to society associated with the delivery of multiples and long term care. [14] Since the implantation rate per embryo is significantly better with blastocyst transfer, one can afford to transfer only one embryo or two embryos and attain satisfactory clinical pregnancy and live birth rates, at the same time avoiding complications of multiple gestation. [15]

Another major advantage of blastocyst transfer is its role in patients with previous multiple failed attempts at IVF. Two large RCTs have shown that blastocyst transfer after recurrent implantation failure following day 2 or 3 transfer carried higher liver birth rate per cycle (27.9% vs. 19.7%) and implantation rates per cycle (25.4% vs. 12.4%). [16],[17] Blastocyst transfer could be the only option in patients with Műllerian anomalies in whom multiple pregnancies have to be avoided. Again, patients who require pre-implantation genetic diagnosis can require and benefit from a blastocyst transfer so that the results of genetic analysis are available at the time of transfer and better embryo selection can be done. [18]

Disadvantages of blastocyst transfer

Culture and IVF laboratory parameters have a strong influence on successful blastocyst progression rates. Substandard laboratory environment, fluctuations in temperature or pH of culture conditions can severely affect blastulation. Again, proper maintenance of humidity, osmolality of culture media and optimal O 2 concentrations are all imperative to prevent embryonic block. One should not attempt routine blastocyst transfer policy unless all these parameters are well-optimized along with the presence of an efficient sequential media.

Blastocyst transfer policy is associated with increased cost, increased incidence (3-5%) of monozygotic twinning [19] and reduced number of frozen embryos available for future transfers. The last disadvantage could be the reason why Cochrane meta-analysis found lower cumulative pregnancy rates with blastocyst transfer compared with cleavage stage transfer. Proponents of cleavage stage transfer believe that the human womb is the best incubator and culturing the embryos for prolonged periods of 5-6 days could affect their viability in vivo. Relying on "pure" blastocyst transfer could arise a situation in which no embryos are available for transfer due to embryonic block at cleavage stage. For example, it has been shown that having even 8 zygotes on day 1 has about 11-13% chance of no blastocyst growth at day 5. [5],[20] The consequent cancellation of the cycle has disastrous consequences on patient's psychological and financial wellbeing. Ironically, if this happens, one is not sure that the embryos that failed to develop from the cleavage to the blastocyst stage in vitro would not have done so in vivo either. This is a frustrating situation for the clinician as well.

Why do two-step or sequential transfer?

To avoid a frustrating situation of no transfer at all in cases planned for blastocyst transfer, a strategy of sequential or two-step transfer has been suggested. [20] The proposed logic was to get "the best of both worlds" or rather find a useful middle ground to have high pregnancy rates of blastocyst transfer along with avoiding its potential hazard, that is, cleavage transfer preceding it to avoid a cancellation. There have been criticisms of this technique, namely increased cost, patient inconvenience, increase in multiple pregnancy rates and the possible chance of harming the transferred embryos during the second transfer.

Literature review

The consecutive embryo transfer approach was studied by Ashkenazi et al. in a case-controlled study during 1997-98. [20] In their observation sequential, transfer had no advantage over day 2/3 transfer. They concluded that transferring two good day 3 embryos, followed by a blastocyst transfer did not improve the pregnancy rate when compared to the transfer of three good day 3 embryos (36.8% and 37.4% clinical pregnancy rate, respectively). However, it was discovered that in the former group (of sequential transfer) the incidences of multiple pregnancy were high (45.7%). To prevent this, it was decided that the total number of embryos to be transferred will be decided beforehand. Less number of cleavage embryos were transferred, followed by a blastocyst, and any additional blastocysts were cryopreserved. This approach simultaneously eliminated the risk of transfer failure as well as multiple pregnancy.

Goto et al. [21] in their retrospective study in 2003 concluded that the ongoing pregnancy rate with 2-step ET (51.6%) was significantly higher than with the conventional ET (26.7%) (P < 0.01). The policy was to do sequential transfer only if the patients had more than three embryos on day 2. The same authors published another case-control study in 2005 [22] in which they found pregnancy and implantation rates in the two-step group (n = 92), 33.3% and 17.2%, respectively, were significantly higher than those in the day 2 transfer (n = 90) group, 18.9% and 9.4% respectively. This later study had policy of sequential transfer in patients with only 2 embryos (at least one high-grade embryo) on day two. Interestingly, whereas the pregnancy rate was 30% in the two-step group, it was only 10% among patients in the two-step group in whom no blastocyst or morula were available for transfer in the second step.

Phillips et al. [23] found consecutive transfers of day 3 followed by day 5 transfer increases overall pregnancy rates. Notably in this study, 22.5% of patients who were designated for extended culture failed to reach the blastocyst stage, still a 37.5% pregnancy rate was achieved in this group. Some researchers have reported that two-thirds of IVF-embryo transfer failures are due to a lack of endometrial receptivity and one-third due to poor embryo quality. [24] Therefore, at a state-of-the-art reproductive center, assuming that the embryo culture environment is good, the key to improving the pregnancy rate is to improve endometrial receptivity. This study's findings suggest that day-2 and day-3 sequential transfer or day-3 and day-5 sequential transfer can improve the clinical pregnancy and implantation rates in patients with repeated IVF-embryo transfer failures. In the case of day-2 and day-3 sequential transfer, one embryo was transferred on day 2, which may induce an increase in endometrial receptivity, thereby creating a better endometrial environment for the second transfer on day 3.

Furthermore, mechanical stimulation of the endometrium has been reported to increase the pregnancy rate in patients with repeated IVF-embryo transfer failures. [25],[26] During the first transfer on day 2, insertion of the catheter may be some kind of mechanical stimulation of the endometrium, inducing an increase in endometrial receptivity. Finally, increasing the likelihood of transferring embryos at the receptivity window of the endometrium by sequential transfer has been cited by some authors as another explanation for improved success rates in patients with repeated IVF/embryo transfer failures. [27],[28]

Ashkenazi et al. [20] suggested that the second transfer procedure might have a deleterious influence, possibly related to infection or trauma, on the implantation of embryos transferred earlier. However, Tur-Kaspa et al. [29] reported no significant differences in pregnancy rates with and without immediately repeated transfers. The current study concurs with Tur-Kaspa et al. and shows that the second transfer had no adverse effect on the implantation process. Concern remains regarding the risk of multiple pregnancy associated with sequential embryo transfer due to the high number of embryos transferred. However, in this study, a total of only two (1 on day 3 and 1 on day 5) were transferred with a multiple pregnancy occurring for 8 patients out of a total of 107 patients and 52 pregnancies. All 8 of these were twin gestations. Thus, day 3/day 5 transfer group attained a high clinical pregnancy rate of 48.5% at an acceptable twin pregnancy rate.

  Conclusion Top

A policy of sequential or consecutive transfer on day 3 and day 5 in patients with adequate number of retrieved oocytes yields the advantages of a good embryo implantation rate, satisfactory pregnancy rate and an acceptable multiple pregnancy rate at the same time avoiding complications of blastocyst transfer like cancellation of the transfer cycle and higher multiple order births. Sequential transfer can be a useful middle ground for an ART program and deserves more attention in clinical practice.

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Conflict of interest

There are no conflict of interest.

  References Top

Gardener DK, Schoolcraft WB. In-vitro culture of human blastocysts. In: Jansen R, Mortimer D, editors. Towards Reproductive Certainty: Fertility and Genetics Beyond 1999. Carnforth: Parthenon Press; 1999. p. 378-88.  Back to cited text no. 1
Gardner DK, Schoolcraft WB, Wagley L, Schlenker T, Stevens J, Hesla J. A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Hum Reprod 1998;13:3434-40.  Back to cited text no. 2
Braude P, Bolton V, Moore S. Human gene expression first occurs between the four-and eight-cell stages of preimplantation development. Nature 1988;332:459-61.  Back to cited text no. 3
Shoukir Y, Chardonnens D, Campana A, Sakkas D. Blastocyst development from supernumerary embryos after intracytoplasmic sperm injection: A paternal influence? Hum Reprod 1998;13:1632-7.  Back to cited text no. 4
Karaki RZ, Samarraie SS, Younis NA, Lahloub TM, Ibrahim MH. Blastocyst culture and transfer: A step toward improved in vitro fertilization outcome. Fertil Steril 2002;77:114-8.  Back to cited text no. 5
Coskun S, Hollanders J, Al-Hassan S, Al-Sufyan H, Al-Mayman H, Jaroudi K. Day 5 versus day 3 embryo transfer: A controlled randomized trial. Hum Reprod 2000;15:1947-52.  Back to cited text no. 6
Levron J, Shulman A, Bider D, Seidman D, Levin T, Dor J. A prospective randomized study comparing day 3 with blastocyst-stage embryo transfer. Fertil Steril 2002;77:1300-1.  Back to cited text no. 7
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Rienzi L, Ubaldi F, Iacobelli M, Ferrero S, Minasi MG, Martinez F, et al. Day 3 embryo transfer with combined evaluation at the pronuclear and cleavage stages compares favourably with day 5 blastocyst transfer. Hum Reprod 2002;17:1852-5.  Back to cited text no. 9
Van der Auwera I, Debrock S, Spiessens C, Afschrift H, Bakelants E, Meuleman C, et al. A prospective randomized study: Day 2 versus day 5 embryo transfer. Hum Reprod 2002;17:1507-12.  Back to cited text no. 10
Frattarelli JL, Leondires MP, McKeeby JL, Miller BT, Segars JH. Blastocyst transfer decreases multiple pregnancy rates in in vitro fertilization cycles: A randomized controlled trial. Fertil Steril 2003;79:228-30.  Back to cited text no. 11
Margreiter M, Weghofer A, Kogosowski A, Mahmoud KZ, Feichtinger W. A prospective randomized multicenter study to evaluate the best day for embryo transfer: Does the outcome justify prolonged embryo culture? J Assist Reprod Genet 2003;20:91-4.  Back to cited text no. 12
Glujovsky D, Blake D, Farquhar C, Bardach A. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev 2012;7:CD002118.  Back to cited text no. 13
Collins J. Cost-effectiveness of in vitro fertilization. Semin Reprod Med 2001;19:279-89.  Back to cited text no. 14
Schoolcraft WB, Gardner DK, Lane M, Schlenker T, Hamilton F, Meldrum DR. Blastocyst culture and transfer: Analysis of results and parameters affecting outcome in two in vitro fertilization programs. Fertil Steril 1999;72:604-9.  Back to cited text no. 15
Guerif F, Bidault R, Gasnier O, Couet ML, Gervereau O, Lansac J, et al. Efficacy of blastocyst transfer after implantation failure. Reprod Biomed Online 2004;9:630-6.  Back to cited text no. 16
Blake DA, Farquhar CM, Johnson N, Proctor M. Cleavage stage versus blastocyst stage embryo transfer in assisted conception. Cochrane Database Syst Rev 2007:CD002118.  Back to cited text no. 17
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Ashkenazi J, Yoeli R, Orvieto R, Shalev J, Ben-Rafael Z, Bar-Hava I. Double (consecutive) transfer of early embryos and blastocysts: Aims and results. Fertil Steril 2000;74:936-40.  Back to cited text no. 20
Goto S, Takebayashi K, Shiotani M, Fujiwara M, Hirose M, Noda Y. Effectiveness of 2-step (consecutive) embryo transfer. Comparison with cleavage-stage transfer. J Reprod Med 2003;48:370-4.  Back to cited text no. 21
Goto S, Shiotani M, Kitagawa M, Kadowaki T, Noda Y. Effectiveness of two-step (consecutive) embryo transfer in patients who have two embryos on day 2: Comparison with cleavage-stage embryo transfer. Fertil Steril 2005;83:721-3.  Back to cited text no. 22
Phillips SJ, Dean NL, Buckett WM, Tan SL. Consecutive transfer of day 3 embryos and of day 5-6 blastocysts increases overall pregnancy rates associated with blastocyst culture. J Assist Reprod Genet 2003;20:461-4.  Back to cited text no. 23
Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update 2006;12:731-46.  Back to cited text no. 24
Barash A, Dekel N, Fieldust S, Segal I, Schechtman E, Granot I. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fertil Steril 2003;79:1317-22.  Back to cited text no. 25
Zhou L, Li R, Wang R, Huang HX, Zhong K. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertil Steril 2008;89:1166-76.  Back to cited text no. 26
Almog B, Levin I, Wagman I, Kapustiansky R, Schwartz T, Mey-Raz N, et al. Interval double transfer improves treatment success in patients with repeated IVF/ET failures. J Assist Reprod Genet 2008;25:353-7.  Back to cited text no. 27
Loutradis D, Drakakis P, Dallianidis K, Bletsa SR, Milingos S, Doumplis N, et al. A double embryo transfer on days 2 and 4 or 5 improves pregnancy outcome in patients with good embryos but repeated failures in IVF or ICSI. Clin Exp Obstet Gynecol 2004;31:63-6.  Back to cited text no. 28
Tur-Kaspa I, Yuval Y, Bider D, Levron J, Shulman A, Dor J. Difficult or repeated sequential embryo transfers do not adversely affect in-vitro fertilization pregnancy rates or outcome. Hum Reprod 1998;13:2452-5.  Back to cited text no. 29

  Authors Top

Dr Rutvij Dalal while attaining his diploma and masters in Obstetrics and Gynaecology developed a fascination for Reproductive Medicine which made him pursue its National Board 2 year fellowship at Lilavati Hospital, Mumbai. Awarded with several accolades and honours, Dr Dalal now provides his expertise to several budding and established ART centres in India and abroad. He has recently been awarded the 'best young scientist award' by the largest gynaecology professional body of India. With several publications and textbook chapters written by him, he also is a peer reviewer of several journals of repute.


  [Table 1], [Table 2], [Table 3], [Table 4]

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