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Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 58-60

Delayed implantation may be a cause of recurrent implantation failure

Center of Reproduction and Gynecologic Endoscopic Surgery, Sanno Hospital, Tokyo, Japan

Date of Web Publication14-Oct-2016

Correspondence Address:
Maki Kusumi
Center of Reproduction and Gynecologic Endoscopic Surgery, Sanno Hospital, 8-10-16, Akasaka, Minato-ku, Tokyo 107-0052
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2348-2907.192289

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We report a rare case of delayed implantation of frozen-thawed embryo transfer in a hormone-controlled cycle due to delayed window of implantation (WOI). Synchronizing embryo growth with the endometrial hormonal environment is important for successful implantation. Initially, our patient underwent multiple unsuccessful endometrium-matched blastocyst transfers after five days of progesterone treatment. We found that day 3 embryo and two-day delayed blastocyst transfers were more successful than the normal blastocyst transfer. Finally she underwent two successful single embryo implants that resulted in pregnancies. We suggest that a delay in the WOI may have been the cause for the recurrent implantation failure.

Keywords: Blastocyst transfer, frozen-thawed embryo transfer, recurrent implantation failure, window of implantation

How to cite this article:
Kusumi M, Kurosawa T, Fujiwara T, Tsutsumi O. Delayed implantation may be a cause of recurrent implantation failure. IVF Lite 2016;3:58-60

How to cite this URL:
Kusumi M, Kurosawa T, Fujiwara T, Tsutsumi O. Delayed implantation may be a cause of recurrent implantation failure. IVF Lite [serial online] 2016 [cited 2022 Jan 18];3:58-60. Available from: http://www.ivflite.org/text.asp?2016/3/2/58/192289

  Introduction Top

In vitro fertilization (IVF) is becoming more prevalent worldwide. Because frozen-thawed embryo transfer is continuously increasing, recurrent implantation failure (RIF) is a concerning issue.

More than three unsuccessful transfers of at least four high-quality embryos are considered as RIF. [1] The period when the endometrium has acquired the receptivity for embryonic implantation is called the window of implantation (WOI), which starts on day 6 after ovulation and continues for 4-5 days. [2] Synchronizing embryonic stage with hormonal stage of endometrium is important for successful implantation. [3]

We report a case of an unsuccessful embryo implantation caused by a suspected delay in the WOI.

  Case report Top

A 31-year-old, gravida 1, para 0, woman visited our hospital to undergo IVF because of tubal factors. She underwent laparoscopic bilateral tubal resection owing to a right tubal pregnancy and had a damaged left tube caused by chlamydial infection at the age of 30 years.

After retrieving twenty mature eggs by the gonadotropin-releasing hormone (GnRH) antagonist method, ten good blastocysts and two good day (D) 3 embryos were cryopreserved.

Embryo transfer therapy in the first pregnancy

Elective single embryo transfer (eSET) was performed four times. However, all attempts were unsuccessful. All embryos were blastocysts and 4AB based on Gardner's scoring grade. Embryo transfer was scheduled thrice on luteal phase (L) 5 five days after progesterone replacement therapy in a hormone-controlled cycle (HCC) and scheduled once on L5 five days after ovulation in a natural ovulation cycle. After four unsuccessful embryo transfers, double D3-embryo transfer in the HCC on L3 became successful. The human chorionic gonadotropin value after embryo transfer was 38.3 mIU/mL or considerably low on L14 [Figure 1]. The gestational sac was first detected by ultrasound at 5 weeks and 3 days of gestation, and a fetal heartbeat was detected at 7 weeks and 0 days of gestation [Table 1]. Initially, fetal growth was slightly delayed compared with the average fetal growth; however, the patient finally delivered a healthy male infant (weight, 2365 g) at 35 weeks and 6 days of gestation due to preterm rupture of membranes.
Figure 1: Double-embryo transfer of the day-3 embryo performed on luteal phase 3. The human chorionic gonadotropin level increased gradually during early days of pregnancy

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Table 1: Early ultrasound findings during both pregnancies

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Embryo transfer therapy in the second pregnancy

Two years later, the patient visited our hospital for another conception. The first embryo transfer with a single blastocyst (4BA) on L5 in the HCC was unsuccessful, similar to the previous therapy. The next sequential two blastocyst embryo transfers (4AC and 4BA, respectively) were performed on L5 and L7, respectively, because of the suspected delayed implantation. The patient eventually became pregnant, and a single pregnancy was confirmed at 10 weeks of gestation. Her pregnancy course was quite similar to the previous pregnancy course [Table 1].

  Discussion Top

The eSET and blastocyst transfer have recently become prevalent in Japan and are practiced to minimize the occurrence of multiple pregnancies. The implantation rate for a blastocyst whose grade is more than 4BB was more than 50% in women younger than 35 years in our hospital (unpublished data).

Our patient was a 31-year-old woman and had experienced five unsuccessful eSETs of high-quality blastocysts, which is quite rare. In addition, the cause of her infertility was tubal factor, which has a favorable pregnancy rate by IVF. This method can be performed with either HCC or natural ovulation cycle with similar pregnancy rates. [4] We used a modified HCC with estrogen and progesterone and without a GnRH analog. However, we attempted the natural ovulation cycle, anticipating for an unknown effect. All transferred embryos were followed by assisted hatching. All test results possibly associated with RIF were negative, including coagulation disorders and chromosomal analysis of both she and her partner by blood tests and hysteroscope. [1] To improve implantation, we attempted stimulation of endometrium embryo transfer, where a culture medium is transferred three days before blastocyst embryo transfer, [5] and also adopted the empirical use of low-dose aspirin. [1]

The patient's first pregnancy suggested that the patient's WOI was delayed by several days. Based on human embryo culture, blastocyst development generally occurs from D5 to D6. [6] The implantation and live birth rates are the same when frozen-thawed blastocyst derived from 5- or 6-day culture was transferred on L5. [3],[6] Synchronization between the embryo and endometrium is important; therefore, delayed development of the embryo normally correlates with a delayed WOI in the uterus. The success rate of blastocyst transfers would correlate more closely with the WOI than with D3 embryo transfers.

For the second pregnancy, we considered that blastocyst transfer shifted further to L7. Some factors can affect endometrial receptivity, or some patients' WOI is not within the normal range. SimÓn developed the endometrial receptivity array (ERA, IGENOMIX, Valencia, Spain) to investigate WOI by gene expression profiles of the endometrial biopsy. This group has reported that approximately 25% of RIF is caused by unsuitable WOI. [7],[8] They also reported that a two day delay of WOI is seen most frequently under the HCC for RIF. [8] Because ERA could not be assessed in this case, we proposed to perform sequential blastocyst transfer to cover a possible more than two day implantation delay. Owing to this sequential embryo transfer, knowing which of the embryos were transferred, either on L5 or on L7, or implanted is impossible. However, because of the unsuccessful repeated blastocyst transfer on L5, it is conceivable that the blastocyst transferred on L7 would have implanted. We began ERA for RIF through this case since March 2016.

Double-embryo cryotransfer was performed in both successful instances. However, we did not consider this to be the key for the successful implantation. Some reports have already shown that double-embryo transfer does not improve pregnancy rates in women aged <35 years. [9],[10]

  Conclusion Top

This is a suggestive report regarding a delayed WOI in two pregnancy courses of the same mother. We believe that in some cases, the WOI does not match the time of embryo transfer. Trying to change the time of embryo transfer or, if possible, testing the WOI is important. The findings of this case report will be useful for patients with RIF.


The authors wish to thank the hospital staff who assisted with this case, especially Dr. Momo Noma's meaningful discussion.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Coughlan C, Ledger W, Wang Q, Liu F, Demirol A, Gurgan T, et al. Recurrent implantation failure: Definition and management. Reprod Biomed Online 2014;28:14-38.  Back to cited text no. 1
Bergh PA, Navot D. The impact of embryonic development and endometrial maturity on the timing of implantation. Fertil Steril 1992;58:537-42.  Back to cited text no. 2
Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Ross R. Contrasting patterns in in vitro fertilization pregnancy rates among fresh autologous, fresh oocyte donor, and cryopreserved cycles with the use of day 5 or day 6 blastocysts may reflect differences in embryo-endometrium synchrony. Fertil Steril 2008;89:20-6.  Back to cited text no. 3
Groenewoud ER, Macklon NS, Cohlen BJ; ANTARCTICA Trial Study Group. Cryo-thawed embryo transfer: Natural versus artificial cycle. A non-inferiority trial. (ANTARCTICA trial). BMC Womens Health 2012;12:27.  Back to cited text no. 4
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. 5
Sunkara SK, Siozos A, Bolton VN, Khalaf Y, Braude PR, El-Toukhy T. The influence of delayed blastocyst formation on the outcome of frozen-thawed blastocyst transfer: A systematic review and meta-analysis. Hum Reprod 2010;25:1906-15.  Back to cited text no. 6
Ruiz-Alonso M, Blesa D, Díaz-Gimeno P, Gómez E, Fernández-Sánchez M, Carranza F, et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril 2013;100:818-24.  Back to cited text no. 7
Ruiz-Alonso M, Galindo N, Pellicer A, Simón C. What a difference two days make: "Personalized" embryo transfer (pET) paradigm: A case report and pilot study. Hum Reprod 2014;29:1244-7.  Back to cited text no. 8
Lopez-Regalado ML, Clavero A, Gonzalvo MC, Serrano M, Martínez L, Mozas J, et al. Randomised clinical trial comparing elective single-embryo transfer followed by single-embryo cryotransfer versus double embryo transfer. Eur J Obstet Gynecol Reprod Biol 2014;178:192-8.  Back to cited text no. 9
Yanaihara A, Yorimitsu T, Motoyama H, Ohara M, Kawamura T. Clinical outcome of frozen blastocyst transfer; single vs. double transfer. J Assist Reprod Genet 2008;25:531-4.  Back to cited text no. 10

  Authors Top

Dr. Maki Kusumi is a graduate of Faculty of Medicine, the University of Tokyo and obtained her PhD degree in Obstetrics and Gynecology from the University of Tokyo. She has been working in the Center for Human Reproducion and Gynecologic Endoscopy, Sanno Hospital since 2012. She is also engaged as an assistant proffessor in Graduate School of Internaional University of Health and Welfare. Her current research interests include assisted reproduction technology, recurrent implantation failure, recurrent pregnancy loss, epigenetics, genetic counseling and Gynecological Endoscopic Surgery.


  [Figure 1]

  [Table 1]


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