When IVF Fails: Exploring Reasons for Implantation Failure - Part 1
While in-vitro fertilization remains the most powerful treatment available to help infertile couples achieve pregnancy, the fact remains that it often fails. This communication is one of a series exploring various causes for repeat implantation failure. In fact, depending upon a woman’s age, growing embryos placed in the uterus fail to result in an ongoing pregnancy in 40-80% of treated cycles. When treatment fails repeatedly, it is important to consider all potential explanations. Repeated implantation failure may occur due to abnormalities of the uterus, fallopian tubes, or the ovary. Repeated IVF failure may also be related to lifestyle choices, parental or embryonic genetic abnormalities, unmet physiological needs of the embryo, male factors, or caused by difficult or poorly executed embryo transfer. In this review, we will briefly describe uterine explanations for repeated implantation failure (RIF) with explanations of how these causes for failure may be identified and addressed. In future blogs we will address other causes for repeated implantation failure.
UTERINE CAUSES OF REPEAT IMPLANTATION FAILURE
The uterus is often neglected as a potential source of implantation failure. Among uterine causes for implantation failure are the following:
1- Uterine fibroids that distort the uterine cavity - While it is generally accepted that most uterine fibroids do not contribute to infertility or repeat implantation failure, when fibroids lie within the uterine cavity or distort the uterine cavity, they adversely affect outcomes and should be removed. In addition, there is some data to suggest that women who have multiple uterine fibroids within the walls of the uterus (intra-mural) may have lower IVF pregnancy rates, although this concept is not universally accepted.
2- Uterine scar tissue from prior surgical procedures may be detected by telescopic, x-ray (hysterosalpingogram), or ultrasound (saline sonohysterogram) evaluation of the uterus. Scar tissue in the uterine cavity is uncommon. When it does occur, it is usually the result of a previously performed surgical procedure (D&E) to remove products of conception. Treatment involves telescopic resection of the scar tissue followed by hormonal restoration of the uterine lining.
3- Undiagnosed congenital uterine malformations such as a septate uterus may lead to poor outcomes with IVF. Studies have shown that whether the septum is large or small, it is associated with a very high miscarriage rate (80% in one study). When septae were removed surgically in the same study, miscarriage rates dropped to 30%. These congenital malformations may be discovered by hysteroscopy, hysterosalpingogram, or saline infusion sonogram. Another congenital abnormality of the uterus, the bicornuate uterus has not been shown to reduce IVF success rates or interfere with implantation.
4- Significant uterine polyps measuring 1.5cm in diameter or larger have been associated with decreased IVF success rates and should be removed prior to treatment. The case for removing smaller polyps in the uterine cavity (less than 1.5cm in diameter) is much weaker and removal of these smaller polyps may not be necessary.
5- Excessively thin uterine lining may be a cause for repeated implantation failure and has been addressed in many ways with limited success including aspirin, vaginal sildenafil (Viagra), and high dose vaginal estrogens. Antifibrotic treatment with pentoxyfyline and high dose vitamin E has been shown to increase pregnancy rates in patients with a thin endometrium. If embryo quality is good, there is no fluid in the endometrial canal, and uterine scar tissue has been ruled out, a thin endometrium may not be problematic
6- Lack of synchronization of the uterine lining to the development of the embryo has received a lot of attention lately. It has long been recognized that IVF stimulation protocols accelerate the development of the uterine lining. When the embryo is returned to the uterus the uterine lining may have advanced past the ideal window of time for the embryo to implant. A blood progesterone level on the day of HCG trigger shot administration is currently being recommended as an indicator of accelerated endometrial development. When the progesterone is elevated above a specific threshold, the best choice may be to freeze all of the embryos and delay the transfer to a future cycle when endometrial development may be synchronized to embryonic development (so called “freeze all”)
7- Uterine wall abnormalities caused by the presence of glandular tissue deep within the uterine muscular walls (adenomyosis) may be a cause for repeat implantation failure. Diagnosis of this condition is difficult and although it may be diagnosed with ultrasonography, usually requires MRI of the pelvis. If adenomyosis is diagnosed, pretreatment with Lupron (GnRH agonist) or Letrozole may be helpful. In cases of diffuse adenomyosis, the use of a gestational carrier may be the best option.
8- Abnormal gene expression at the uterine lining (endometrium) may be a cause for repeated implantation failure. Several studies have focused on the genetic regulation of the uterine lining in preparation for embryo implantation. The genes involved with regulating the uterine lining have to do with cell adhesion mechanisms, developmental processes, and immunologic factors. Investigators have concluded that elevations in progesterone on the day that the HCG trigger shot is given in an IVF cycle results in significant alterations in the gene expression profile of the uterine lining. If alteration of gene expression is suspected or proven, a reasonable strategy may be to freeze embryos and transfer them in a natural cycle or similar cycle with strict hormonal control.
*** It is worth noting that very often the uterine cavity has been evaluated prior to the IVF treatment cycle and has been deemed to be normal. However, studies have shown that direct telescopic evaluation of the inside of the uterus (hysteroscopy) often identifies abnormalities that may be missed on the more standard uterine cavity evaluations (saline sonohysterogram or hysterosalpingogram). When patients experience repeated implantation failure with no other explanation, hysteroscopy should be considered.