My embryos fail to implant repeatedly – Recurrent Implantation Failure in IVF !

“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.