When Good Embryos Don't Implant -- Options to Consider

Ronald F. Feinberg MD, PhD
IVF Medical Director, Reproductive Associates of Delaware
Newark, Wilmington, and Dover, Delaware
www.ivf-de.org
rfeinberg@ivf-de.org

"We were told we produce good embryos" is a common concern and source of frustration for patients who haven't achieved success with IVF treatments.  This situation often leaves patients in a quandary as to how they should next proceed.  The purpose of this article is to describe diagnostic and treatment options that could provide more information, detect and treat underlying disease, and improve the chances for a successful outcome.

What defines a 'good embryo'?  For years, IVF success has depended on the fertilization of eggs and subsequent development 24 to 48 hours later of early, 2 to 8-cell stage embryos.  The “best” embryos are then selected for transfer to the uterus.  Not surprisingly, we now know that a minority of these early cleavage embryos can actually grow and divide into blastocysts.  As multi-cell ‘seeds’ that are actively developing, blastocysts have a much higher ability to attach and implant within the uterus.

IVF facilities that routinely work with blastocysts have learned that ‘good embryos’ at the 2 to 8 cell stage often don’t develop into blastocysts, and that ‘not-so-good embryos’ can become high quality blastocysts and lead to successful pregnancies.  Thus, the development of quality blastocysts adds predictability and information to the IVF cycle.

In 2008, over 80% of our facility’s cycles have involved blastocyst culture, and approximately half of these cycles have utilized single embryo transfer.  Pregnancy rates since 2006 have been eye-popping, with implantation and ongoing pregnancy rates of over 50% per transfer for all ages.1  When blastocysts are frozen by vitrification and later thawed, ongoing/delivered published pregnancy rates were 53% per transfer in 2006 in women under age 35, with 1.8 average number of embryos transferred.2  This indicates that healthy blastocysts are quite amenable to successful cryopreservation and storage, and that frozen/thawed blastocysts yield pregnancy rates similar to those seen with fresh transfers.

Are all blastocysts normal?  Probably not.  In many situations, genetically abnormal embryos are still capable of forming healthy-appearing blastocysts, especially in older patients.  Pre-implantation genetic testing of cleavage-stage embryos, or possibly unfertilized eggs, is a controversial, newer technology that is not yet considered a standard for all patients.3  Genetic testing of blastocysts themselves by removing several outer layer cells (called trophectoderm biopsy) may hold some future promise in helping decide which blastocysts should be transferred to the uterus.

Approximately 1 to 2% of all IVF patients – women and men – have subtle genetic abnormalities in their chromosomes, and should consider being tested with a blood sample.  Abnormal chromosomes in prospective parents may be more common in a setting of repeated implantation failures and/or early pregnancy loss.  The incidence of chromosomal abnormalities is highest in men with severe male factor infertility.4

Good seeds need good soil -- uterine implantation and beyond.  A great deal of attention has been paid in recent years to subtle or not-so-subtle abnormalities within the uterine lining, also called the endometrium.  It is generally believed that the endometrium needs to produce a perfectly orchestrated sequence of small molecules, which promote initial attachment for the embryo, as well as the deeper burrowing of the embryo into endometrial tissue and blood vessels.  The following reproductive diseases have been largely recognized to undermine successful implantation, and treatment for these problems has often reversed infertility and IVF failure:

1) Endometriosis.  A female-specific disease that may cause mild to severe pelvic pain symptoms, or be a silent cause of infertility.  In patients with endometriosis, diverse molecules are produced in an abnormal fashion within the endometrium, a finding correlated with low rates of implantation.  Minimally invasive laparoscopy and/or hysteroscopy can effectively treat endometriosis.  Treatment of endometriosis has been clearly demonstrated to enhance fertility, potentially making IVF unnecessary in some instances, or allowing IVF to be more effective by improving implantation potential.5,6

2) Endometrial polyps.  Abnormal, benign thickening and overgrowth of the endometrial ‘soil’ impedes implantation.  Treatment by hysteroscopic removal can be quite effective.  Endometrial polyps are commonly seen in women with endometriosis, as well as those with chronic lack of ovulation, as in polycystic ovary syndrome (PCOS).

3) Uterine fibroids.  Benign muscle growths within the uterine wall can often impinge on the endometrium, causing a hostile environment for implantation.  Fibroids are also linked to miscarriage and preterm delivery.  In our facility, fibroids up to 8 to 9 cm in diameter can usually be removed laparoscopically.  Smaller fibroids within the uterine cavity should be removed hysteroscopically.7

4) Uterine septum.  A congenital fibrous tissue band within the uterus has been linked to early miscarriage and possibly implantation failure.  A septum can be excised via hysteroscopy, and often reverses miscarriage risk.

5) Fallopian tube disease.  Fluid-filled fallopian tubes (hydrosalpinx) from previous infection and/or severe endometriosis impede production of pro-implantation molecules within the endometrium.  Diseased tubes can be removed via laparoscopy prior to embryo transfer, with evidence strongly supporting the removal of a hydrosalpinx prior to starting an IVF cycle.8

In summary, many patients in the U.S. and around the world pursue IVF treatments without having a clearcut diagnosis or explanation for their fertility challenges.  Given the high prevalence of infertility, even couples pursuing IVF for male factor should consider underlying problems in the female partner.  This is especially true when ‘good embryos’, i.e. those at the blastocyst stage of development, fail to implant.

Recommendations to overcome this challenge require careful assessment of embryo development and well being, in the context of blastocyst culture.  In addition, effective diagnosis and treatment of underlying disease, which includes several common causes of infertility, will often yield a successful treatment outcome.

References

Portmann MP, Morrison LS, Carney SM, Boylan C, Kovalevsky G, Feinberg RF, “On The Road to Single Embryo Transfer”, Abstract P-667, Fertil Steril 88 (Supplement 1): S328-9 (2007).

Society for Assisted Reproductive Technologies (SART) Clinic Summary Report, https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=2442 (2006)

Preimplantation genetic testing: A Practice Committee Opinion, Fertil Steril 88 (6): 1497-504 (2007).

Riccaboni A, Lalatta F, Caliari I, Bonetti S, Somigliana E, Ragni G. “Genetic screening in 2,710 infertile candidate couples for assisted reproductive techniques: results of application of Italian guidelines for the appropriate use of genetic tests,” Fertil Steril 89 (4): 800-8 (2008).

Littman E, Giudice L, Lathi R, Berker B, Milki A, Nezhat C. “Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles,” Fertil Steril 84 (6): 1574-8 (2005).

Marcoux S, Maheux R, Berube S. “Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group,” N Engl J Med 337 (4): 217-22 (1997).

Agdi M, Tulandi T. “Endoscopic management of uterine fibroids,” Best Pract Res Clin Obstet Gynaecol 22(4): 707-16 (2008).

Bontis JN, Theodoridis TD. “Laparoscopic management of hydrosalpinx,” Ann NY Acad Sci 1092:199-210 (2006).