Embryo transfer & Window of receptivity

The embryo transfer is the final stage of the IVF process in which an embryo is placed into the endometrial lining. There are a few key decisions to be made during this stage:

1. Frozen or fresh embryo transfer?
2. How many embryos should I transfer?
3. How thick should the endometrial lining be at transfer?
4. How thick should the endometrial lining be at transfer?

1. Frozen or fresh embryo transfer?

There are two types of embryo transfers:

• Fresh embryo transfer: when the best embryo (or embryos) are transferred into your uterus 3-5 days after the retrieval. Any remaining embryos are frozen for transfer during a later cycle.
• Frozen embryo transfer: when a frozen embryo from a previous IVF cycle is thawed and transferred back into your uterus. It may be that you choose to freeze all the embryos from the start - even the best ones - so that they can be thawed and transferred at a later date. 

The course of action depends on various factors and often it will be apparent even before the cycle starts which option is best for you. For example, if you have PCOS, which can mean a higher risk of OHSS, or if you want to do a PGT-A test to check the embryos for chromosomal abnormalities, then your only option is to do a frozen embryo transfer.  

The question you’re guaranteed to find yourself asking at this stage is: is one of these options more likely to lead to a viable pregnancy? The answer is, there is no clear-cut difference in success rates in general - the specific circumstances have to be considered. 

Some groups should not transfer straight after IVF

Certain groups benefit from not transferring an embryo immediately after an IVF, i.e. it’s better for them to transfer a frozen embryo in a later cycle. These groups are outlined below.

PCOS and other OHSS vulnerable groups

If doctors suspect you may be at risk of OHSS - for example, if your AMH blood test displayed elevated results, your Antral Follicle Count (AFC) was high on ultrasound, or if you previously produced a high number of eggs in an earlier cycle - a fresh transfer may increase the risk further as a pregnancy at this point can trigger OHSS. For this reason, the transfer is typically postponed at any sign of OHSS.

Endometriosis

Endometriosis is a painful condition where endometrial-like tissue behaves as endometrial tissue would and grows in a location outside of the uterus. Ovarian stimulation triggers a rise in estrogen, which can be problematic for women who suffer from endometriosis as it is an estrogen-dependent condition. In other words, the higher the amount of estrogen, the worse the symptoms of endometriosis. A handful of studies suggest that women with endometriosis may be better suited to frozen transfers than fresh transfers since fresh transfers happen shortly after stimulation when estrogen levels are raised.

Thin endometrial lining

It’s essential that the endometrial lining is receptive at the time of the transfer. This is normally judged by looking at the structure and thickness of the lining via ultrasound. The lining should have three layers and be at least 6mm on the day of the transfer, although different clinics have different standards. If the lining doesn’t look as it should, it is usually recommended to freeze all embryos and wait to do the transfer during a later cycle when it can be optimized. 

Read more about the endometrial lining below.

High progesterone levels at egg retrieval

If you have high progesterone levels at the time of the trigger shot, your window of receptivity is more likely to shift and therefore a fresh transfer has lower chances of success (see section about the implantation window below for further explanation). As a consequence, a frozen transfer may be preferable. This might come as a disappointment as the decision will be made just days before you were due to have the fresh transfer, but remember it’s done to optimize the chances by giving your precious embryo the best possible circumstances to develop.

Transfer of genetically tested embryos

If you choose to do genetic testing (PGT-A) on your embryos, the logistics involved most often require that you freeze all embryos. This allows time for the testing (which is often not performed at the clinic but a separate facility) and test results to arrive before transfer.

The pros of fresh transfers

1. Faster results: you’re understandably anxious to get this show on the road but do remember that waiting just a couple of months can be worth it if you have better chances of conceiving and a lower risk of OHSS.
2. Less risk of damaged embryos: there's always a risk that the embryos may be damaged during the freeze-thaw process. Although most embryos survive the process, some may not. It differs between clinics but between 90-99% of frozen embryos remain intact after thawing.
3. For women with fewer embryos: if you have created just one good embryo, a 1-in-10 chance of that embryo being damaged may feel out of the question. Unless there is a convincing reason for why you should freeze the embryo for later transferral (if you show signs of OHSS, for example) then it’s likely your doctor will recommend a fresh embryo transfer.

2. How many embryos should I transfer?

It’s somewhat of a misconception that IVF in itself increases the likelihood of having twins. This is only true if two embryos are transferred at once, which was often the case in the past as it was thought this would better your chances.

However, what we know now (thanks, data!) is that transferring two embryos does not improve the likelihood for a live birth resulting from that transfer - it may feel illogical, but it’s true. 

The combination of this and the risks associated with multiple pregnancies do that it’s usually recommended to transfer only one embryo at a time. The ‘risk of having twins’ that doctors warn you about might not sound like such a bad thing; when struggling to have one baby, two might sound like a reward for all the hard work. Except this ‘risk’ doctors are warning you about is not the risk of ending up with two healthy babies, rather the medical risks associated with multiple pregnancies (miscarriage, for example) - it’s important to remember that success is not just pregnancy, it’s being able to carry that pregnancy full term. 

Having said this, there may be circumstances when doctors advise transferring more than one embryo at once. Just make sure to find out whether the reason is justified and remember not to get carried away by the idea that more is better.

3. How thick should the endometrial lining be at transfer?

While a great start, good eggs and a healthy embryo are not the only requisites for a viable pregnancy. For successful implantation following embryo transfer, you also need a receptive endometrial lining (also known as the uterine lining).

So then, how do doctors determine whether the endometrial lining is receptive? Looking at the structure of the lining with ultrasound and measuring its thickness is the most straightforward way.

An endometrial thickness of 7mm and above is considered optimal and traditionally, it was the thicker the better (up to around 12mm). However, more recent studies suggest that thickness is not the most important factor - many women conceive without thick linings - and rather it’s structure that plays a more significant role. For example, three layers of endometrial lining are paramount for successful implantation. Nowadays, most clinics will continue with the transfer provided the lining is 6mm or more.

What causes a thin endometrial lining?

There’s more than one reason for a thin endometrium:

• Insufficient estrogen 

In a natural cycle, it’s estrogen produced by the growing follicles that makes the lining thicken, and progesterone that is produced by the collapsed follicle after ovulation that then continues to grow the lining. So if you, for some reason, don’t produce enough estrogen, it will affect the thickness of the endometrium. 

In a stimulated cycle you normally get estrogen pills or patches (and later, progesterone) to help the lining grow and, for some women, finding the correct dosage can take more than one cycle. Some women for example do better with patched than pills.

• Intrauterine adhesions

Past injury or infection of the endometrium may cause intrauterine adhesions. This refers to a build-up of scar tissue between the inner walls of the uterus, causing the walls to bind together. These should be ruled out with a hysterosonogram, hysterosalpingogram, or hysteroscopy before starting an IVF cycle.

• Decreased blood flow to the uterus

Some studies have indicated that decreased blood flow to the uterus could prevent it from thickening as it should. If an ultrasound detects decreased blood flow to the uterus, high doses of Vitamin E and an amino acid called L-arginine may be used to increase endometrial thickness. Decreased blood flow to the uterus is not a common cause of thin endometrial lining and, in cases where it is, treatment only works in about half of the patients.

4. Window of implantation: Should I do the ERA test?

In the past, embryo transfers were performed at the same time for all IVF patients as it was assumed that all women followed the same pattern of receptivity. But we know now that what works for one woman won’t necessarily work for the next. Each woman has her own individual window of receptivity during which the conditions are right for an embryo to implant in her uterus. Today it is generally thought that up to 30% of patients may have a window that is considered ‘out of the norm’.

There is a limited optimal time for implantation and so it’s important to identify this ‘window’ when the uterus is most receptive. For the uterus to accept the embryo and implantation to be achieved, the embryo itself must have reached a certain stage in development. This period is known as the “window of implantation”.

Traditionally it was assumed that implantation took place 8-10 days after ovulation. As such, the timing of the embryo transfer was designed to mirror the natural cycle and consequently was the same for all IVF patients. Knowing what we know now, the focus is instead on determining the receptivity of an individual woman’s uterus. If this window shifts for any reason, the embryo, and the uterus won’t be in sync which may prevent implantation.

Measuring the window of receptivity

The window of receptivity is measured using a genetic test called Endometrial Receptivity Analysis (ERA). More than 200 genes are responsible for preparing the endometrium for implantation. The ERA analyses these genes to give doctors a better understanding of when the endometrium will be most receptive and therefore predict the best time for the embryo transfer to take place.

A biopsy of the endometrium is taken on the day you would otherwise have had the embryo transfer. This is done at the doctor’s office; a tiny plastic tube called a pipelle is inserted through the cervix and into the uterus to take a small sample of endometrial tissue. The tissue then undergoes molecular analysis (to deem the endometrium either ‘receptive’ or ‘non-receptive' on the day the embryo transfer would have taken place) to more accurately predict your window of receptivity.

If the endometrium is found to be receptive, the time of the embryo transfer will be adjusted to match the found window of implantation.

Who should take the ERA test?

ERA testing can be beneficial to any woman undergoing fertility treatment, but as always the investment of cost and time needs to be weighed up against the potential benefits. After all, the majority of women do not have a deviating window of receptivity. 

ERA tests are normally recommended after multiple failed cycles despite good-quality embryos. Likewise, women who have experienced multiple miscarriages or very early pregnancy loss (occurring when an egg is fertilized but never manages to fully implant, also known as a ‘chemical pregnancy’) may be good candidates. Keep in mind: Various factors including Body Mass Index (BMI) and age may affect the window of receptivity so ERA tests may have to be retaken if you have not had one done for some time.