When in vitro fertilization ends unsuccessfully… What are the causes? (Part two)

Patients do not like the answer that doctors do not know all the reasons behind a negative result. This naturally makes them doubt the competence of the doctor: If he doesn’t know everything… it means he is not as good as he should be. Should we go somewhere else for a more accurate opinion? This thought is reinforced even more when the doctor does not respond or is not available to explain the reasons for the negative result.

Even worse is when coughing or stress or other pseudoscientific reasons like TORCH or NK cells are referred to as the reasons for failure. This leads to a series of other unnecessary tests or analyses with additional financial costs. Only a doctor with the appropriate experience will answer that "unfortunately, the reason cannot be identified. We can only hypothesize some of the possibilities, but by no means individualize one definitively".

Of course, there will be immature patients who will be disappointed by such an answer. This is inevitable! It is precisely these patients who are very easily convinced by doctors who find the reason for failure as soon as they shake hands with the patient or promise them the moon within 30 seconds. After all, the patient deserves the doctor they choose…

What happens when an In Vitro Fertilization cycle fails?

Even if the patient tries to understand that there is no definitive answer for the reason of a negative result of an IVF cycle, often she is not able to accept this fact. Here the saying "the heart has reasons that reason does not understand" is also valuable. Thus, many patients try to find a failure factor in order to correct it before starting another IVF procedure.

What should a patient who receives a negative result in IVF do?

Try again! If the indication for in vitro fertilization is correct, then a serious doctor will recommend another cycle of In Vitro Fertilization. Of course, there will be a reevaluation of the case, there will be changes based on your response during the first stimulation and these should be explained to you. Before another attempt at in vitro fertilization, the doctor may request the performance of some analyses or diagnostic procedures which are thought to be related to the lack of implantation. However, additional examinations are usually requested after 2-3 unsuccessful in vitro fertilization cycles. This is because in most infertile couples, pregnancy will be achieved within 3 IVF cycles.

Repeated failures of in vitro fertilization

A portion of patients will have more than 2 consecutive negative results in In Vitro Fertilization (> 2 cycles). In these cases, we are dealing with recurrent IVF failures or consecutive IVF failures. This group will include all those patients with 2-3 consecutive negative IVF results who had good embryos, technically easy embryo transfers, and no apparent problems with the uterus (womb).

What are the causes of repeated IVF failures?

The causes may be related to the embryo, the uterus, and other extragenital causes but with an impact in the reproduction field.

Embryonic causes (Poor quality of embryos)

Genetic defects that embryos may contain are the first reason why they do not implant in the uterus (womb). These defects are not possible to be identified in standard in vitro fertilization procedures. Even pre-implantation genetic diagnosis (PGD) cannot identify all these defects. For the embryologist, it is often very difficult to distinguish which of the embryos is of normal quality and which contains genetic defects, as in many cases they look alike.

Sometimes embryos have anomalies of the zona pellucida (the capsule that surrounds embryos and that must "hatch" in order for the embryos to have the opportunity to implant). In cases with repeated IVF failures, PGD and assisted hatching are recommended.

We must bear in mind that in most cases, the egg cell is responsible for the quality of the embryos. With the increase in the patient's age, the reduction in ovarian reserve also leads to a reduction in the quality of the remaining eggs and an increase in the possibility of anomalies during conception (union with the sperm and turning into an embryo). Sometimes the egg cell is of reduced quality even at younger ages. This is why a woman undergoing IVF at the age of 40 has more abnormal embryos than a woman undergoing IVF at the age of 25.

In some cases, one of the partners (or both) may be carriers of genetic/chromosomal anomalies (such as translocations) making the eggs or sperm contain anomalies which are inherited by the embryos. These embryos with anomalies do not implant or when they do implant, they result in an early miscarriage. That's why in cases with more than 2 unsuccessful IVF cycles, genetic analyses are recommended for the couple.

Can we change the quality of the embryos? No! This is impossible. In in vitro fertilization, nothing is invented or changed! The quality of the embryos will depend on the quality of the eggs and the sperm.

Non-receptive uterus (womb) – is the second reason why embryos do not implant in the womb. This is also very frustrating especially when we have very good embryos but they do not result in pregnancy.

Different infections:

• of the inner layer that lines the uterine cavity (endometrium) can cause failure of embryo implantation regardless of their quality. Usually, these infections are asymptomatic (without signs) and cannot be detected by the patient or the doctor. In cases with repeated IVF failures, antibiotic treatment is recommended before the next IVF cycle.
• of the tubes – hydrosalpinx (HSX). In cases with hydrosalpinx, tubal fluid may pass into the endometrium before, during, or after embryo transfer causing a failure in embryo implantation or even early miscarriages. Therefore, in repeated IVF failures, HSG is recommended and if hydrosalpinx (HSX) is evident, it should be removed through laparoscopy before the next IVF procedure.

Endometrium anomalies can cause failure of embryo implantation. Here we mention:

• acquired anomalies (endometrial polyps, endometrial hyperplasia, submucosal fibroids, synechiae)
• congenital anomalies (septa, hypoplastic uterus, etc.).

Identifying them is only possible through hysteroscopy. Therefore, before a 3rd IVF procedure, hysteroscopy is always recommended if it has not been performed yet or if there are doubts about the quality of the endometrium (the layer in which the embryos are placed).

Defects of the implantation window. This window is the period during which, thanks to progesterone, the embryo is allowed to implant in the endometrium. This period in which the endometrium is receptive is believed to last 2-6 days. Since the organic and functional characteristics of different patients are different, not all can benefit equally from the standard progesterone support protocols that doctors give after oocyte aspiration and after embryo transfer. For this reason, in cases with repeated IVF failures, high doses of progesterone are recommended.

Other causes (extragenital):

• Thrombophilia – It has been seen that thrombophilia is much more common in women with repeated implantation failures (IVF with negative results and miscarriage diseases) without any apparent reason. Performing the appropriate analyses in this direction and correct therapy (aspirin/heparin) increases the chances for a positive result in the next IVF procedure.
• Thyroid problems
• Glucose intolerance
• Autoimmune problems – their impact on IVF implantation failures is controversial. As we know, in pregnancy, there is an immunotolerance towards the embryo (Which as we know consists of 50% of the father's genetic material, so it is something foreign to the mother's immune system). Thanks to this immunotolerance, the embryo implants and the pregnancy is allowed to go to term.
  
  However, it has been seen that in some patients the phenomenon of immunotolerance does not occur and consequently the embryo is considered as something foreign to the mother's immune system and for this reason, it is fought by the antibodies of this system resulting in a failure of implantation by IVF and consequently in a negative result. For this reason, in cases with IVF failures, immunosuppressive therapy is recommended.