Unexplained infertility- could be due to embryo failing to implant

Pregnancy is impossible without successful implantation.

Fertilisation takes place in the fallopian tubes and the embryo enters the uterus 3-4 days after fertilisation. Implantation takes place 1-3 days after the embryo enters the uterine cavity.

Many embryos produced are abnormal and will never implant. Approximately 46% of all pregnancies end before the pregnancy is clinically detected.

However, without a normal receptive endometrium (uterine lining), even the best embryo would not be able to implant.

How endometrium prepares for implantation:

Following ovulation the corpus luteum produces progesterone, which is fundamental in preparing the endometrium for implantation.

The endometrium is receptive to embryo only during a small window 16-22 days of a 28-day cycle (5-10 days after the LH surge). A large number of biochemical and molecular changes is needed in the endometrium to achieve normal implantation.

In addition, the endometrium needs to undergo a series of ultrastructure changes, without which implantation would not be possible.

The endometrium (uterine lining) needs to undergo various ultrastructure and biochemical changes, without which even the best embryo will fail to implant

Process of implantation:

Implantation happens in three stages:

Apposition – The embryo changes to blastocyst before implantation. Implantation begins with the hatching of the zona pellucida (outer wall of the embryo), 1-3 days after it enters the uterine cavity. It then attaches itself to the wall of the uterus.

Adhesion: Both endometrium and early embryo expresses specific molecules that helps in binding the embryo to the wall of the uterus.

Invasion: Implantation continues with the migration of the outer cells of the blastocysts (trophoblasts) into the endometrium. Uterine blood vessels near the site of implantation change their structure that allows high flow of blood and interchange between mother and developing foetus.

What causes embryo fail to implant?

• The most common cause for the embryo failing to implant is wrong number of chromosomes (aneuploidy), which increases as the woman grows older.

• Defective endometrium: Alterations in the various biochemical factors necessary to prepare the endometrium for implantation like cytokines, LIF (leukemia inhibitory factors), IL-1 (interleukin -1), chemokines, can also cause defective endometrium and failure of implantation.

• Intrauterine adhesions (scarring) - Previous uterine surgery like surgical treatment for miscarriage, retained placenta, caesarean section, myomectomy (surgery for fibroids, both open and hysteroscopic), Uterine artery embolization, infections like tuberculosis, can cause adhesions (scarring) in the uterine lining (endometrium). The adhesions can be subtle to severe. While subtle adhesions might not cause any symptoms, severe adhesions can lead to lighter period following surgery or infection. It can be present in 2.8 – 45.5% of patients with subfertility.

Most of the embryos fail to implant as they have wrong number of chromosomes. However, in some cases the problem is in the endometrium.

What investigations can be done?

Following investigations can be done to detect intrauterine adhesions:

· Saline sonography (instilling water into the uterus during transvaginal ultrasound scan) +3D scan is highly effective way to assess adhesions (uterine lining)

· Hysteroscopy – camera test inside the uterus provides assessment and treatment of adhesions at the same setting.

There are no standard tests for other causes of implantation failure.

While ultrasound and hysteroscopy can detect intrauterine adhesions (scarring), many subtle factors causing defective endometrium remains undetectable.

What are the treatments for intrauterine adhesions?

Treatment of intrauterine adhesions is mainly surgical, done hysteroscopically. Severe adhesions can be challenging and might need surgery in multiple sessions.

Stem cell treatment for intrauterine adhesions is still in experimental stage.

Intrauterine adhesions can be treated surgically. Improving implantation in absence of intrauterine adhesions, remains a challenge, even in sophisticated treatments like IVF.

written by: Dr Anupa Nandi