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Why can in vitro fertilization treatments fail

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For many couples who go through infertility treatments, in vitro fertilization (IVF) represents the last hope for a child. Many have already gone through less complex treatments without success, such as ovary stimulation, intrauterine insemination – IUI and artificial insemination; therefore, it is very frustrating for those who place all their expectations in this treatment to see all efforts go in vain. Time lost, disciplined schedules, injections, ultrasounds, money spent, expectation, anxiety – life on hold during this time – and it didn’t work!!! One common question after a negative pregnancy test is: why the transferred embryo or embryos didn’t implant? In general, the response is not simple. Nevertheless some hypotheses should be considered to help clarify the problems that have not been looked into yet, but when diagnosed they can increase the chances in future treatments.

The causes of failure can be due to problems with the embryos, uterus-endometrium, endometriosis, and immunological problems.

Embryos

A common problem is the possible chromosomal abnormalities of the embryo that hinders implantation, mainly in women over 40 years old, even when they have a near to perfection aspect on the day of the transfer. This does not mean that it will be a repetitive problem in every treatment. However, this possibility should be considered in order to understand that it could have been due to natural selection of the maternal organism that hindered the implantation of an unhealthy embryo. When there is suspicion, the couple can be subjected to a karyotype test that identifies the abnormal chromosomes that are “dormant” in each of them, i.e. recessive characteristics that do not appear in the individual. However, when they are transmitted to the embryo, they become evident and cause an illness which makes it impossible for the baby to develop. The karyotype is a simple blood test and, in these cases, must be done by both the woman and the man. It is important to clarify that men who have low sperm count have greater chances of chromosomal abnormalities.

An alternative exam in such cases is PGD (Pre-implantation Genetic Diagnosis). It screens the embryo for chromosomal abnormalities. This exam is done on day 3 afterfertilization in the laboratory, when the embryos are at the 6 to 8-cell stage. One of the cells is removed and sent to the genetic laboratory, where the results about the baby’s health are issued within a few hours. The healthy embryos are transferred to the uterus. This screening process can increase the chances of a treatment to be successful.

Another exam called HLA-G (Human Leukocyte Antigen-G) which screens the quality of the embryo by analyzing the culture medium in which it developed in the laboratory.It has been demonstrated to be useful in the selection of the embryo, among all others, having the greatest chance of implantation. However, further studies are required for more definitive conclusions on this matter.

Another problem is the increased thickness of the zona pellucida, the membrane that surrounds the embryo, which in these conditions, interferes with implantation. To alter the zona pellucida, assisted hatching is used. It is a laser procedure that makes small openings on the layer to help with the implantation. This technique can also be used on fragmented embryos, removing the fragments and improving its potential for implantation.

The male factor can also be responsible for poor embryo quality. Besides the repetition of a spermogram, other exams can be done and repeated. Recently, a sperm DNA fragmentation exam (SCSA – Sperm Chromatin Structure Assay) has been recommended. Abnormal results indicate reduced reproductive capacity of men. Still there is no proof that these abnormalities have any influence on the pregnancy rates, but there is a possibility that this relation exists. It is believed that when the fragmentation index is equal to or greater than 30, the rate of success is compromised. The most common cause for this alteration is oxidative stress caused by bad habits (cigarettes, alcohol, etc.) and obesity, among others. Vitamin C and E, along with orienting patients to a healthy lifestyle, could be the solution to the problem. Therefore, it is always good to recommend a daily routine based on healthy habits before starting any infertility treatment.

When a man has spermatozoa with serious alterations of motility, morphology, high rates of DNA fragmentation, and the presence of vacuoles – the combination of these alterations is given the acronym MSOME (Motile Sperm Organelle Morphology Examination) – after repeated miscarriages, he can be recommended IMSI (Intracytoplasmic Morphologically Selected Sperm Injection), “Super ICSI”, “ICSI of high magnification”, or “ICSI magnified”, considered one of the most recent advancements in assisted fertilization techniques. It is a new version of the well-known ICSI (Intracytoplasmic Sperm Injection).

IMSI utilizes a new optical system called “interferential phase contrast”. The higher optical power electronic magnification lenses present better images, allow the observation of more spermatozoa details, detect its defects, and select the best ones, for they are magnified up to 12,000 times. The conventional ICSI magnifies only 400 times. There is a prospect of a powerful microscope that will be able to extract the healthy spermatozoa from the compromised ones, so that only those are introduced into the egg. However, this is still a distant reality.

The ovulation induction protocols and the drugs used can have a direct influence on the number and quality of the eggs and embryos. For this reason, changes in this aspect may be helpful. There is no single medical protocol that is ideal for all women. A lot of high quality medications exist that are ideal for some patients, but not for others. It is not always possible to get it right in the first attempt. Therefore, after a thorough analysis of the previous cycle, a new possibility can be recommended.

Other new techniques have been proposed in order to improve the quality of the embryos such as the transfer of cytoplasm. In this technique, the cytoplasm of the egg from the donor is injected into the egg of the recipient before fertilization. Although this technique can improve the embryonic quality, it contradicts ethical principles due to the integration of various chromosomal patterns.

Uterus-Endometrium

Normally, the evaluation of the uterine cavity is done before the in vitro fertilization programs. However, in case it has not yet been done, this examination can help to eliminate alterations such as polyps, myomas, or adhesions which can impede the implantation of the embryos. The best exam for this investigation is the video hysteroscopy (visualization of the uterine cavity by endoscopy), besides diagnosing these alterations, it can identify inflammatory aspects (endometritis) not noticed in other common exams. A biopsy of the endometrium can conclude this hypothesis and a treatment with antibiotics will resolve the problem.

Another problem is the absence of some proteins in the endometrium that facilitates the implantation of the embryos. Already more than 50 have been detected, but the most studied are the Claudin-4 and LIF (leukemia inhibitory factor or essential implantation factor). When they are missing or the ratio is unbalanced, the chance of embryonic implantation will be lower, but not impossible. This diagnosis is rare and should only be investigated in special situations. At one time, there were controversies in the interpretation of the results.

Patients who had thin endometrium during ovulation induction, in previous attempts, could benefit from the use of estrogênio, aspirin, and other vasodilator drugs. Other evaluations of the endometrium can be done in the near future. Hydrosalpinx, which is a result from an inflammatory problem that dilates the fallopian tubes and causes the accumulation of a liquid content in its interior, damages the uterine environment, obstructs the implantation of the embryos, and increases the incidence of miscarriages.

The removal of the affected fallopian tubes significantly increases the rate of pregnancy because the content that existed in them and that probably was flowing into the interior of the uterus inhibiting pregnancy ceases to exist. The diagnosis of hydrosalpinx can be done by ultrasound, hysterosalpingogram, and video laparoscopy.

Problems during embryo transfer may cause trauma in the endometrium and hinder the implantation of the embryo, particularly when accompanied by pain. Video hysteroscopy with the dilation of the cervix or simply the dilation of the uterus benefits the next attempt which, preferably, should be done under sedation. The transfer of the embryo assisted by ultrasound is even more beneficial, for it allows the doctor to observe the path of the catheter in the direction towards the uterine cavity, as well as to show the couple the exact location of the placement of the embryos.

Immunological System

Immunological problems have been responsible for some failures in in vitro fertilization cases and repeated miscarriages. Some researchers believe that many cases of failure are, indeed, very premature miscarriages. After a short period of embryonic implantation, which cannot be detected by the pregnancy tests, the embryos do not develop and are expelled. There are controversies regarding this topic; however, the positive results after a therapy of vaccines have encouraged us to pursue this treatment and to be recommended in special situations.

Cross Match: For one to understand this exam, it is necessary to comprehend that all human beings possess the capability of rejecting foreign bodies, and the embryo can be considered as such. It carries the paternal DNA that is foreign to the maternal body. Nevertheless, under normal conditions, the organism of the mother should produce an “antibody protector” – called HLA-G – that protects the embryo against this “immunological attack” and inhibits the rejection. When this “antibody protector” is not formed, the mechanism of immunological aggression follows its natural course hindering pregnancy or much later causing a miscarriage. This alteration of the organism – that curiously appears when there is an immunological resemblance between the father and the mother, and not when they are considerably different – is detected by the Cross Match test. For this examination, a blood sample needs to be withdrawn from both the man and the woman. In the laboratory, a cross test between the two takes place, in order to identify the presence of the antibodies. If they are not present, a treatment with vaccines will be necessary. This immunization process requires the paternal blood, from where the white blood cells (lymphocytes) are separated. Then the vaccines are prepared and injected intradermally into the mother. Two or three doses are administered, each dose being separated by a three week period. After the completion of the series, the Cross Match test is repeated to confirm that the result has changed from the previous one and is now positive. Then another attempt for in vitro fertilization can be initiated. In case no change is detected, another series of two applications are administered.

Thrombophilias: Other exams are available to diagnose immunological factors. Thrombophilias are within this group of exams. These disorders are infrequent and cause abnormal coagulation of the blood. These abnormalities are not detected in common blood exams, and when they exist, it increases the chance to form blood clots and to cause minimal thromboses capable of impeding implantation of the embryo or causing miscarriages. Exams to identify this disorder are done by withdrawing blood that is sent to a specialized laboratory and it must be prescribed by a doctor. They are the following:

  • Antiphospholipid antibodies
  • Antiphosphatidylserine antibody (IgG, IgM, and IgA)
  • Antithyroid antibodies
  • Antinuclear antibodies
  • IgA
  • NK (Natural Killer) cells
  • Antisperm antibodies
  • Factor V Leiden
  • Antithrombin III
  • MTHFR
  • Prothrombin mutation
  • Homocysteine
  • Protein S
  • Protein C

The presence of these abnormalities in the blood of women suggests immunological causes or thrombophilias.

The treatments vary from one simple baby aspirin to more sophisticated medications such as heparin, corticosteroid, and intravenous immunoglobulin.

It is important to emphasize that this technology does not guarantee that pregnancy will be achieved but it is an alternative for those who at this moment have not been successful with previous treatments.

Endometriosis

The association of endometriosis with fertility has been subjected to discussion for many years. The debates, around the importance of how this condition affects the capacity of a woman to have children, have many times caused turn abouts in the medical conducts and treatments. All types and degrees of endometriosis can affect fertility; however, frequently the diagnosis is not so clear and remains as the last option in the investigation, among other causes of infertility.

In some cases, this delay can be caused by nonexistent symptoms, the absence of clinical complaints, and the lack of laboratory proof from the blood exams and the endovaginal ultrasound. Many times only after passing a certain period, in which treatments were unsuccessful, video laparoscopy is recommended, that corroborates the diagnosis. The wait for this explanation delays the conception and prolongs the suffering of the couple. Endometriosis can interfere with the pregnancy result even under in vitro fertilization programs. For this reason after the failure of these treatments, the possibility of such a diagnosis should be evaluated, even in the absence of symptoms. We have observed a greater rate of pregnancy in patients with unknown symptomatology who went through video laparoscopy, compared with others who did not and, therefore, we strongly believe in the importance of this diagnosis.

Endometriosis causes infertility for the following reasons:

  • Affects the hormones during the ovulation process and the implantation of the embryo.
  • Alters also the prolactin hormone and the prostaglandins which negatively act against fertility.
  • Causes immunological disorders – cellular abnormalities responsible for the immunology of the organism (NK cells, interleukin, macrophages, etc.).
  • Interferes with endometrial receptivity. The endometrium, the inner membrane of the uterine cavity where the embryo implants, suffers from the activity of the substances produced by endometriosis (ILH and LIF – leukemia inhibitory factor) which interferes with the implantation of the embryo.
  • Can interfere with the embryonic development and increase the rate of a miscarriage.

Summary Chart

FAILURE CAUSES FOR IN VITRO FERTILIZATION
Embryo
  • Age
  • Zona pellucida (Assisted Hatching)
  • DNA fragmentation of the spermatozoon
  • Chromosomal abnormalities
  • Ovarian stimulation protocols
  • IMSI (Intracytoplasmic Morphologically Selected Sperm Injection)
Uterus / Endometrium
  • myomas
  • adhesions
  • polyps
  • endometrite
  • endometritis
  • thin endometrium
  • hydrosalpinx
  • transfer of the embryos
  • problems with the endometrium
Immunological System
  • Cross Match
  • Thrombophilias
Endometriosis
  • Peritoneal
  • Ovarian
  • Deep
  • Infiltrative
Future Prospects Annexin V, Anti-annexin V, Th1 and Th2 Cytokines, Glycodelin-A and IGFBB-L, Vitamin D, HLA-G (human leukocyte antigen-G), it’s already a reality but further studies are necessary), CGH (comparative genomic hybridization – similar to PGD, identifies the embryos with chormosomal problems), INVOcell (the fertilization occurs inside a capsule that is placed inside the vagina), ORG36286 (a new injectable medication to be applied once a week rather than daily), and SEED (Sub Endometrial Embryo Delivery)

Summary Chart

Conclusion and new prospects

The evaluation of failed in vitro fertilization treatments is very complex and should be individualized for each couple. Many patients when given a new diagnosis that may justify the failure of their treatments ask themselves and their doctors why this initiative was not taken before the successive failures occurred. It is important to emphasize that several of these exams are subject to controversies and discussions around the world. There are others such as Annexin V, Anti-annexin V, Th1 and Th2 Cytokines, Glycodelin-A and IGFBB-L, HLA-G (human leukocyte angtigen-G which helps in selecting the best embryo), CGH (comparative genomic hybridization – somewhat similar to PGD that identifies the embryos with chromosomal problems, but in a less aggressive way), INVOcell (the fertilization occurs inside a capsule that is placed inside the vagina), ORG36286 (a new injectable medication to be applied once a week rather than daily), and SEED (Sub Endometrial Embryo Delivery – a mini camera is inserted inside the uterus at the moment of the transfer in order to locate the best site for implantation), that have limited evidence, but perhaps in the near future, can be utilized.

Many people question the true value of some of these diagnoses and techniques, and if they really justify the reason for not becoming pregnant.

Therefore, not all professionals concur in requesting these exams, and when they do, it is the last likely option. Each doctor has his or her own professional experience and complies strictly with the concept of “medicine based on evidence” and hence does not think highly of these treatments. However, many of them that “still do not have evidence” but could have in the future, have given positive pregnancy results in the present.

We are watchful for all new updates that help couples build their family.
“Our mission is to do what is best for those who desire to have children and are unable to do so naturally.”

Dr. Arnaldo Schizzi Cambiaghi

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