Embryo implantation dysfunction – an MD’s deep-dive 101

Sadly, IVF can fail for many reasons. And it’s not all about embryo quality, or incompetency. Did you know that in about 20% of cases, a failed round is due to implantation dysfunction? 

The Sher Fertility Solutions (SFS) team have pioneered this area of assisted reproduction study for over three decades. And with Dr. Sher himself leading the very first study on endometrial thickness and its impact on implantation in 1989, there’s really no one better to give us the deep-dive on embryo implantation dysfunction. 

Read about our partnership with Sher Fertility Solutions and book a consultation with the team, or continue reading for all things implantation in part one of our embryo implantation dysfunction mini-series. 

Over to Dr. Sher – 

Why is embryo implantation dysfunction important?

Doctors agree that embryo incompetency is by far the number one cause of IVF failure. In over 60% of cases, failure is due to numerical chromosomal irregularities (aneuploidy) of the embryo. And in turn, this is usually due to egg (rather than sperm) abnormalities. 

But in about 20% of cases, the cause is due to implantation dysfunction, rather than egg/embryo incompetence. So, to optimize IVF outcomes, clinicians need to consider all of the ‘known variables’, which could impact egg/embryo competency (e.g. maternal age, ovarian reserve, stimulation protocols, etc.) as well as implantation. 

For implantation dysfunction we mainly focus on:

• Anatomical factors
• Immunologic factors

We’ll jump into both of these, but let’s start with the impact of embryo implantation dysfunction.

The connection with IVF failure

Cases of ‘unexplained’ IVF failure and/or recurrent pregnancy loss (RPL) often point to embryo implantation dysfunction. It’s also connected to cases where a woman has a personal or family history of autoimmune disease and/or endometriosis (regardless of its severity).

By focusing on embryo implantation dysfunction, we can go a long way towards enhancing development of the placenta and maximizing the chance of a healthy pregnancy.

Does it impact success rates?

IVF success rates have been improving over the last decade. The average live birth rate per embryo transfer in the USA for women under age 40, using their own eggs, is better than 1:3. 

However, there’s still a wide variation from program to program with live birth rates, ranging from 20% to nearly 50%. Based on these statistics, the majority of people undergoing IVF in the United States will need two or more attempts to have a baby. Practitioners usually attribute this to variability in expertise between embryology labs.

In my opinion, this is far from accurate. Other factors, such as anatomical and immunologic implantation dysfunction, are often just as significant and, in some cases, can be even more important. 

What causes embryo implantation dysfunction?

We typically see three main causes of implantation dysfunction: 

• Anatomical abnormalities in the uterine cavity
• Thinner endometrial linings 
• Immunologic Implantation Dysfunction (IID)

Let’s focus now on these key causes, and their impact on implantation.

1. Anatomical abnormalities 

Uterine conditions such as polyps, scarring and/or internal fibroids which encroach upon the uterine cavity are often missed, and can be crucial.

In approximately 20% of cases, a dye x-ray (Hysterosalpingogram, or HSG) procedure – involving injection of radio-opaque dyes which x-rays can’t pass through – will obscure small endouterine surface lesions. And even very small lesions can affect implantation. 

Many IVF doctors now prefer to use hysteroscopy and/or saline ultrasound (syn., hysterosonogram (HSN)/sonohysterogram) to assess the uterine cavity. A hysteroscopy allows for direct endoscopic visualization of the uterine cavity, while the saline ultrasound involves distention of the uterine cavity with an aqueous solution that allows the passage of sound waves, facilitating clear ultrasound imaging of the inner uterine wall. 

An HSN/sonohysterogram is minimally invasive, and less expensive than a hysteroscopy or HSG. 

2. Endometrial thickness

Way back in 1989, I published a study looking at the correlation between the thickness of the uterine lining (the endometrium), and the chances of embryo implantation in IVF patients. The study revealed that the ideal endometrial thickness at ovulation or egg retrieval is over 8 mm, and that thinner linings are connected to decreased embryo implantation rates.

Thinner uterine linings are mainly caused by:  

• Damage to the basal endometrium (Sher Fertility Solutions examine the potential causes of this in our thin uterine lining deep-dive)
• Over-use of anti-estrogenic drugs, such as clomiphene citrate, without an adequate break between cycles
• Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone) 
• Reduced blood flow to the basal endometrium, often involving multiple uterine fibroids, and/or uterine adenomyosis 
• Prolonged estrogen deprivation of the uterus, which might occur with premature ovarian failure (POF) or menopause, or result from the indiscriminate and prolonged administration of gonadotropin releasing hormone agonists (GnRHa), such as Lupron, Buserelin, Superfact, Decapeptyl

Viagra suppository, IVF and uterine blood flow

Decades ago, we announced the world’s first Viagra Baby, after reporting on the benefits of using vaginal Sildenafil (Viagra) with women experiencing implantation dysfunction due to thin endometrial lining. 

Compounded Viagra administered vaginally (not orally) can improve uterine blood flow. This increases the amount of estrogen delivered to the endometrium, helping it to thicken. 

The treatment comes with very few side effects, because the vaginally administered Viagra is so rapidly absorbed into the bloodstream. However, it’s not effective in all cases – a third of women who receive treatment don’t see any improvement, unfortunately. This is usually due to previous and permanent damage to the endometrium, leaving it unresponsive to estrogen. 

3. Immunologic Implantation Dysfunction (IID)

Right now, practitioners generally connect unexplained and/or repeated IVF failure to poor embryo quality. And with this, the popular course of action is to change the protocol for ovarian stimulation, and/or gamete and embryo preparation. 

But this is over-simplifying a highly complex area. 

The implantation process starts six or seven days after fertilization. And at this time, specialized embryonic cells, which later form the placenta, engage in a “cross-talk” with the uterine lining and its immune cells, via hormone-like substances called cytokines. And it’s through this immunologic interplay, that the uterus can support an embryo’s successful growth. It’s the foundation for nutritional, hormonal and respiratory interchange between mother and baby, and central to healthy early pregnancy. 

There’s an ever-growing realization, recognition and acceptance of the fact that uterine immunologic dysfunction can lead to immunologic implantation dysfunction (IID). And through this, its connection to “unexplained” infertility, IVF failure and recurrent pregnancy loss (RPL). 

Join us next time with Dr Sher, for his expert take on immunologic problems, risk factors, diagnosis, and the connection to implantation failure.