“My doctor said that my embryos looked picture-perfect,
yet they failed to implant – why did this happen? “
This is the question in the minds of women who
undergo IVF failure and this becomes a particularly nagging doubt when they face
multiple IVF failures. Many women naturally think that their uterus is
defective or their body is not good enough to accept the embryo and hence the
transferred embryo is getting rejected by their uterus , or it is being killed
by their own body. After all, fertilization happened in the lab , the embryo
grew well in vitro , and they even saw their embryo (remember, you must always see
your embryos and ask for photos before
embryo transfer !) The embryologist assured them that they looked perfect, , and
they’ve read lots of IVF success stories of women who got pregnant with such good
embryos. As a result, they naturally come to the conclusion that good
embryos are meant to implant – and if they
didn’t, this clearly means there’s a problem with their uterus or their body. Because
they have low self-esteem because of their infertility, it’s easy for them to
jump to this conclusion and beat up on themselves. A bad situation is often
made worse by relatives telling them that their embryo must have “fallen out”
because they did not rest sufficiently; or that the cycle failed because they
are too stressed out or have too much “body heat”. This is why many women who
undergo repeated implantation failure opt for surrogacy. This article has been written
to help you understand what causes repeated implantation failure (is the cause
really known ? and which is the culprit – the seed (embryo) or the soil
(uterus) ?
What is implantation
failure?
When an egg and sperm unite together an embryo
is formed (this event takes place in the fallopian tube in your body and in the
IVF lab it takes place in a “ test tube” ( actually a petri dish ) which
contains nourishing culture medium). The embryo thus formed divides rapidly and
reaches the uterus in the blastocyst stage (or is transferred to the uterus on
day 3 or day 5 during an IVF cycle). When in the uterus, the blastocyst starts
to communicate (initiates a molecular conversation) with the endometrium ( the
uterine lining) by secreting protein molecules which results in implantation,
if the embryo is competent enough and if the endometrium is receptive. Implantation
is the attachment of the blastocyst stage embryo to the endometrial lining of
the uterus , so that it further develops into a baby (imagine planting a seed
in the soil).
When a woman undergoes three or more failed IVF
attempts (with good quality embryos) or if implantation doesn’t happen even
after transferring more than 10 ‘good-looking’ embryos over many cycle, then
the woman is said to have “ implantation failure” . When an embryo fails to
implant , there can only be two logical reasons: the embryo is not good enough
(genetically abnormal), the endometrium is not “receptive” (doesn’t allow the
embryo to implant) enough. So, what
really causes implantation failure? Please keep reading!
Which is the culprit –
the seed or the soil?
Imagine a farmer who owns a piece of land and
wants to cultivate rice. He ploughs and tills the land , making it ready for
sowing, finds the right season (a season which provides good water, air and
temperature so that the environment is conducive enough for the sprouting and growth
of saplings) and he carefully selects the seeds. This is analogous to how an
IVF doctor prepares a woman for undergoing an IVF cycle. He gives hormone
injections so that the eggs are collected and fertilized with her partner’s
sperms to form embryos (seeds), hormones (estrogen and progesterone) are also used
make the uterus ready for accepting the embryo (just like ploughing the land,
adding fertilizers and so on) . The woman needs to be in good health (analogous
to waiting for the right season to sow the seeds).
When a farmer takes care of all these things
and sows the seeds, he expects the seeds to germinate and grow. But what
happens when the seeds fail to sprout? There are three plausible reasons for
this happening:
- Poor
seed quality (embryo)
- Soil
which is not fertile (uterus)
- The
environment is not conducive enough (physical health of the mother-to-be)
There are also other minor factors which can
prevent seed germination like, improper seeding (improper embryo transfer), the
seed getting eaten by insects and so on!
In the same way, there can be three logical reasons
for implantation failure:
·
Poor
quality embryo (genetically abnormal embryos)
·
Non-receptive
endometrium (due to defects in the uterus)
·
The
body is unhealthy
Other minor factors which play a role in failed
implantation are: difficult or traumatic embryo transfers, infections present
in the uterus and so on!
How does embryo
quality impact successful implantation?
It is a
well-known fact that young women fall pregnant quickly when compared to their
older counterparts. This is because eggs from older women are more prone to
genetic defects , such as aneuploidies (presence of the wrong number of
chromosomes ), and contain incorrect or insufficient genetic information
necessary to build a healthy baby).When such eggs are fertilized by a sperm , it
leads to the generation of embryos which are genetically incompetent (either
such embryos do not implant and even if they do , the pregnancy ends in early
miscarriage . In rare instances , they can also lead to a full-term birth , where
the new born has genetic defects). With the advent of comprehensive chromosome
screening, it is now possible to screen all “24-chromosomes” (22 autosomes and
2 sex chromosomes) for the presence of aneuploidy (even though the
effectiveness of such a technique to increase live birth via ART in clinical
practise is still not provem ). One such study using CGH showed that 96% of
aneuploid embryos failed to implant (http://www.ncbi.nlm.nih.gov/pubmed/?term=22305103). This clearly shows that embryo competency
plays a major role in implantation. This is why older women find it difficult
to find success with IVF , or require more attempts than their younger
counterparts. When an older woman uses
donor eggs her chance of achieving IVF success goes up dramatically! This is
irrefutable proof that it is embryo quality which plays a major role in
implantation and IVF success.
Role of endometrium in embryo implantation
The old scripture, Manu Smriti says “Subeejam
Sukshetre Jayate Sampadyathe” i.e., Good seed in good soil yields abundantly.
The importance of soil quality in agriculture is well-known. Does endometrium play such a crucial role in
embryo implantation? What happens when a fertile seed (genetically competent
embryo) is seeded on defective soil (non-receptive endometrium)?
The period during which the uterus is able to
receive the embryo (blastocyst) is called the “window of implantation.” Human
uterus is receptive only during a short period of time and this period is also
called as the period of “uterine receptivity”. In humans, the receptivity
period is between day 20 to day 24 of regular menstrual cycle i.e, 7-11 days
after the LH surge that triggers ovulation. During IVF, embryos are transferred
to the uterus either day 3 (embryo transfer) or day 5 (blastocyst transfer)
after egg collection (the day of ovulation) which coincides with the “window of
implantation” of natural menstrual cycle. During FET transfer, the day of
starting progesterone is taken as the first day of ovulation and embryo transfer
is done accordingly.
Human embryo implantation is an enigmatic
biological phenomenon – after all, in-vivo experiments are impractical and
unethical to conduct; and studies with animal models do not translate well to
humans. But it is well-known fact that embryo and endometrium exhibit
cross-talk with each other (talk to each other) using molecular signals and
such cross-talk is necessary for successful implantation. However, no reliable molecular
markers for endometrial receptivity have been identified. This makes it
difficult to find out whether an endometrium is receptive or not during an IVF
cycle.
During IVF, endometrial receptivity is assessed
crudely with the help of ultrasound images. Endometrial thickness is measured
using ultrasound images and an endometrium of greater than 8mm which is
trilaminar is said to be optimum for embryo transfer.
It is a well-known fact that the endometrium
becomes receptive only after progesterone exposure. Progesterone brings about necessary
changes in endometrium (converts the endometrium from proliferative to
secretory phase) so that it becomes ready to accept the embryo. Recently,
frozen embryo transfers are becoming much more successful than fresh embryo
transfers in the field of IVF. It is hypothesized that high estrogen
concentration in the body during the fresh IVF cycle compromises endometrial
receptivity.
What are the possible reasons
for “non-receptive” uterus during an IVF cycle?
- If
the uterus contain adhesions, polyps or fibroids in the cavity, then its
receptivity will be impaired
- If
there is premature increase in progesterone levels (that is, rise in
progesterone levels before egg collection due to premature luteinisation
of follicles) during an IVF cycle, then the receptivity of the uterus
doesn’t synchronize well with the time of embryo transfer and this can
lead to failed implantation. This problem can be solved by careful
monitoring of the IVF cycle.
- It
is believed that thin endometrial lining (a lining which is less than 8mm)
is not receptive enough.
- An infection
of the uterus has also been hypothesized to prevent implantation, by making
the uterine environment less optimal.
There are also so many unproved reasons cited
for lack of uterine receptivity, which include: immunological theories like the
presence of high number of uterine NK cells, excessive HLA matching between
partners ; and blood clotting issues.
What factors other
than the embryo and uterus might contribute to implantation failure?
The ease with which the uterus can be negotiated
for the embryo transfer also plays a pivotal role in achieving successful
implantation. If the uterus is hard to access via the cervix ( for example, in
patients with cervical stenosis) , then other embryo transfer methods like ZIFT
should be used in order to enhance implantation.
Can implantation
failure be successfully treated? What kinds of evidence based therapies are
available?
Yes, it can be treated , but only if the reason
is known. The one and only well-known, scientifically proven reason for implantation
failure is genetically incompetent embryos. If you are a women of advanced
maternal age or if you have premature ovarian aging, even if you get some
embryos to transfer during an IVF cycle, many a time they can be genetically
abnormal and will not implant successfully. The irony is many women do not want
to accept this fact ( after all, it is very difficult to accept the fact that
they can’t have their genetic baby) and try to blame their uterus for the failed
implantation. As a result they believe that surrogacy can help them conceive,
which is not true! Doctors make use of their ignorance and “treat” them with
many different therapies which are not evidence based. I have seen so many
women of advanced maternal age subjecting themselves to many useless therapies
and ultimately finding success when they finally use donor eggs. So if advanced
maternal age or poor ovarian reserve is the cause of failed implantation, the
only reasonable solution is to use donor eggs.
If your uterine cavity contains adhesions,
fibroids or polyps which interfere with implantation, removing them will help
in achieving embryo implantation.
The role of endometrial thickness in successful
implantation is still a question. Many women with thin endometrium do have
successful implantation, but the scientific literature shows that an
endometrium thickness of more than 8mm is optimum for achieving implantation.
What kinds of
“non-evidence” based therapies are available to treat implantation failure?
The following therapies do not have solid proof
for their efficacy and are very speculative:
- Use
of blood thinners like aspirin and heparin.
- Causing
local injury to endometrium before embryo transfer, to improve local
uterine blood flow
- Therapies
like use of steroids, IVIG, intralipids etc which claim to reduce NK cell
levels in the uterus.
- Paternal
lymphocyte immunotherapy to “ treat “ HLA matching between partners.
- Use
of G-CSF (Granulocyte-Colony Stimulating Factor) which is commercially
known as neupogen.
- Use
of embryo glue (a substance which is claimed to enhance the attachment of
embryo to the uterus).
- Routinely
making a hole in the zona pellucida of the embryo (outer coat of the
embryo) with the aim of helping the embryo to hatch out of the shell
successfully. This is known as laser assisted embryo hatching.
- Co-culturing
embryos with endometrial epithelial cells.
- Intrauterine
administration of PBMCs ( Peripheral Blood Mononuclear Cell)
Doctors must actually resist offering such
treatments that are not evidence based or at least they must share information honestly
with their patients. They must make sure that the patient understands that the
above mentioned therapies are not a panacea for their problem.
What can I do if I have
repeated implantation failure?
- Test
your AMH ; day 3 FSH and E2 value ; and your antral follicle count – are
they normal? Do you have good ovarian reserve? If you have poor ovarian
reserve or are older than 40 years of age and have suffered repeated
implantation failure, you should consider using donor eggs.
- If
you are young and have good ovarian reserve, ask the embryologist how your
embryos look – are they of good quality? If they are of good quality (dividing
well according to their age) , then the chances are that the embryos which
were transferred may have been genetically normal ( sadly, we still do not
have the technology to test for all possible genetic defects before the
transfer)
- Do
you have PCOD? Did they retrieve lots of eggs (more than 25 eggs) from your
ovaries? PCOD could be a reason for the lack of embryo implantation. Taking
insulin sensitizers like metformin and myoinositol might solve your problem.
- If
your doctor has used the same ovarian stimulation protocol for retrieving
eggs from your ovaries, you can try other ovarian stimulation protocols
too. Mild ovarian stimulation protocols are found to be superior in
producing better quality eggs and embryos in a selected subset of IVF
patients (mostly patients with poor ovarian reserve).
- If
you have failed IVF several times by using a day 3 embryo transfer, try
having a day 5 embryo transfer. The fact that embryos are developing to
blastocyst stage is a good indication (not an ultimate proof though) that
your embryos are good enough.
- You
can try doing a frozen embryo transfer instead of a fresh transfer. High
levels of estrogen in the body during a fresh cycle can damage uterine
receptivity.
- If
you have cervical stenosis and embryo transfer through cervical route
becomes difficult you can try other modes of embryo transfer (like ZIFT )
- You
can try changing the clinic – sometimes this works!
- Another
option available is to use donor embryos!
- If
your uterine cavity contains adhesions, polyps or fibroids, you need to
remove these. If there are lots of adhesions or if you suffer from a thin
endometrial lining because of Asherman’s syndrome (and if it is
untreatable!) you can opt for surrogacy.
So following are the
options in front of you:
- Change
the ovarian stimulation protocol
- Use
frozen embryo transfer instead of fresh transfer
- Change
the mode of embryo transfer ( do a ZIFT ) if cervical embryo transfer is
difficult
- Change
the clinic
- Change
the egg
- Change
the sperm
- Use
donor embryos
- Consider
surrogacy
What is the take home
message?
When an embryo enters the uterus in the
blastocyst stage, it initiates a molecular cross-talk with the endometrium.
Perhaps it says, “Hey I am here and I want to establish connection with you,
attach and grow, are you ready to accept me ? ” The endometrium senses the
signal sent by the embryo and responds accordingly. All this cross-talk happens
by releasing appropriate protein molecules. It is believed that if there is
some problem with this cross-talk, embryo implantation fails.
It is hypothesized that the endometrium acts as
a biosensor of embryo quality. This means, if a genetically abnormal blastocyst
enters the uterine cavity, the endometrium senses this by the signals sent by
the embryo and prevents the implantation of the embryo. So if this biosensor
mechanism is defective in some women, they paradoxically become “ superfertile”
. That is, such women fall pregnant very easily because even genetically
abnormal embryos are allowed to attach to the endometrium and establish a
pregnancy. On the other hand, they suffer from recurrent biochemical
pregnancies or miscarriages because even if the genetically abnormal embryo
implants , it can’t develop into a healthy baby and gets aborted eventually.
There are also studies which show that even if
the endometrium is not optimally receptive, a genetically competent embryo can modify the
endometrial environment to make it favourable, so that successful implantation is achieved.
When you talk to a well-experienced IVF
specialist, he will say from his practical experience that when women suffer
from recurrent implantation failure, most of the time changing the egg can
bring about successful implantation and pregnancy!
The endometrium seems to act as a passive
recipient. After all a seed , can sprout even in the absence of soil ( for
example, in women who have ectopic pregnancies, where the embryo implants in
the fallopian tube, where there is no endometrium at all ! ) If you are
suffering from recurrent implantation failure, please do not blame your uterus ,
if it doesn’t have any obvious defects.
