Repeated implantation failure (RIF) is determined when embryos of good quality fail to
implant following several in vitro fertilization (IVF) treatment cycles. Implantation failure
is related to either maternal factors or embryonic causes. Maternal factors include
uterine anatomic abnormalities, thrombophilia, non-receptive endometrium, and
immunological factors. Failure of implantation due to embryonic causes is associated
with either genetic abnormalities or other factors intrinsic to the embryo that impair its
ability to develop in utero, to hatch, and to implant. New methods of time-lapse imaging
of embryos and assessment of their metabolic functions may improve selection of
embryos for transfer, and subsequent outcomes for IVF patients, as well as for those
diagnosed with RIF. This review discusses the various causes associated with RIF and
addresses appropriate treatments.
Introduction
Repeated implantation failure is determined when transferred embryos fail to implant
following several in vitro fertilization treatment cycles. However, there are no formal
criteria defining the number of failed cycles or the total number of embryos transferred
in these IVF attempts. Accordingly, different fertility centers practicing IVF may use
different definitions for RIF. Considering the current success rate of IVF treatments and
the mean number of embryos transferred in each cycle, it is recommended to define RIF
as failure of implantation in at least three consecutive IVF attempts, in which one to two
embryos of high grade quality are transferred in each cycle.
The process of implantation involves two main components: a healthy embryo that
should have the potential to implant and a receptive endometrium that should enable
implantation. The “cross-talk” between the embryo and the endometrium that finally
leads to apposition, attachment, and invasion of embryos is mandatory for successful
implantation and subsequent normal placentation. These processes are under thorough
investigation and seem to involve many mediators originating in the embryo, as well as
in the endometrium; they seem to involve the maternal immunologic system as well.
Any abnormality attributed to the embryo, the endometrium, or the immune system will
result in implantation failure. Therefore, in assessing RIF, the embryo should be
evaluated, with reference to the uterus and its functional endometrium. Accordingly,
treatment of RIF should be targeted to the abnormality detected, and the correction of
any potential malfunction that might contribute to the failure of implantation.
Why Does In Vitro Fertilization Sometimes Fail?
Failed IVF is a frustrating situation for couples and their fertility doctors.
There is an equation that we can use to illustrate the implantation process: Embryo
quality + receptivity of uterine lining = chance for implantation and pregnancy.
We know that many human embryos will arrest (die) before day five. Unfortunately,
embryonic arrest also occurs after day five. Some of the embryos that we transfer that
“look good” will die after we put them in the uterus. This is the explanation for IVF failure
in the large majority of cases. The problem is rarely the sperm, and uncommonly the
uterus. It is usually a weakness in the embryo that leads to failed implantation.
On average, only about 25 percent of transferred embryos continue to develop and
become children. This percentage of implanting embryos is greatly dependent
on female age: we see about 45 percent implant under age 35 and 1 percent implant at
age 40-42.
Patients Who Fail IVF Will Often Ask:
- “Why didn’t the embryos stick, did you put them in the right spot?”
- “What’s wrong with my uterus? It’s not accepting the embryos.”
- Sometimes, after repeated failure to implant any embryos with IVF, women will
say, “Obviously, I need a surrogate to carry the embryos because my uterus
can’t do the job.”
Although this could be logical, it does not fit with the science. When IVF does not work
after numerous attempts, switching the uterus is not likely to result in success. However,
the egg donation experience teaches us that switching to eggs from a young egg donor
would be very likely to be successful. This tells us that the problem is not the uterus but
is the egg quality.
Some animal species have much higher implantation rates per embryo transferred than
humans do. Human IVF is not as efficient due to the relative weakness of the human
egg as compared to those animal species.
This is not to say that the sperm and the uterus are not sometimes contributing factors
in the IVF success equation. However, the sperm and the uterus are relatively minor
factors as compared to the major factor of egg quality.
Genetic and Chromosomal Issues Causing Failure of Implantation in IVF
We know that one of the major factors contributing to in vitro fertilization failure is the
high rate of chromosomal abnormalities in human embryos.
As women age, the incidence of chromosomal abnormalities in mature eggs increases
significantly. Studies have shown that starting in the early 30s, the rate of chromosomal
abnormalities in human eggs (and therefore in human embryos) starts to increase
significantly.
The rate continues to increase with advancing female age so that by the mid-40s, a very
high percentage of human embryos are chromosomally abnormal (over 75 percent). It is
believed that this is mainly due to problems with the spindle apparatus in the egg
nucleus. The spindle is involved with properly lining up and segregating the
chromosomes as the egg matures at the time of ovulation. Older eggs have an
inefficient spindle apparatus that does not line up the chromosome pairs properly and
“mistakes” are made when splitting pairs of chromosomes. This leads to eggs that do
not have the proper balance of 23 chromosomes, and it will result in a chromosomally
abnormal embryo if fertilized. It has been shown that about one to two percent of human
sperm are chromosomally abnormal on the average, as compared to about 20 to 90
percent of human eggs (depending on female age).
PGS (preimplantation genetic screening) can be done on embryos prior to transfer to
evaluate chromosomal competence.
Other “Genetic Causes” of Implantation Failure
- Implantation failure is probably sometimes caused by other genetic mutations,
with a perfectly normal “karyotype” or chromosome complement. - There are tens of thousands of genes in the human genome, which means that
there are many places where something can go wrong. - With time, there will be genes discovered that are crucial for efficient embryo
implantation, both on the embryo side and on the uterine side, and perhaps
involving the immune system as well.