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- Diagnosis and treatment of female infertility
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- Analyses to be made prior to the IVF
Louise Brown was born in 1978 after in-vitro fertilization (IVF) which made the enormous breakthrough in infertility treatment.
The in-vitro fertilization technology drastically changed the possibilities for treating sterile couples and resulted in emergence of diverse assisted reproductive technologies (ART). Just on the lapse of 20 years the extracorporal fertilization became the keystone of the reproductive medicine. Today, in our clinic, IVF technologies are used daily though just one generation before it seemed as something belonging to the science fiction. Due to extracorporal fertilization many sterile married couples gave birth to healthy children after unsuccessful application of other methods.
By now more than two million of children were born in the world with the aid of IVF method.
The stages of treating infertility using the IVF method:
- Examination of the married couple prior to the IVF procedure is accomplished in compliance with the effective standards and Order of the Ministry of Health of Ukraine of 12.2008 No.771.
- Stimulation of superovulation of ovaries (stimulation of maturation of several ova in the follicle with ovum). To achieve it, beginning from the 2nd-3rd day of the menstrual (treatment) cycle a woman gets injections of special medical preparations containing gonadotropic hormone (“Menopur”, “Puregon”. “Gonal-F”). Under the effect of the injected gonadotropic hormones not just one ovum matures in the ovary, as in a natural menstrual cycle, but several at once which considerably improves the frequency of pregnancy in the IVF program. In the course of stimulation of superovulation of ovaries a hormonal and ultrasonic monitoring is performed. In 10-11 days after commencement of the ovaries follicle stimulation, the ova mature. This process is optimized by introducing a trigger dose of the human chorionic gonadotropic hormone (CGH).
- Retrieval of ova from the ovary follicle is accomplished in 34-36 hours after injecting chorionic gonadotropic hormone by paracentesis of the ovaries via the vagina using a special thin needle under the ultrasonic control. As a rule, during the paracentesis a short-term intravenous anesthesia is applied. In those instances when it is impossible to obtain the own good quality ova, the extracorporal fertilization procedure with the use of donors’ ova is performed.
- Simultaneously the husband’s sperm is sampled which undergoes special treatment. In a number of cases (e.g., in case of an absolute male sterility) patients can make use of the donor sperm bank.
- Embryologic stage. Ova fertilization with the husband’s / donor’s sperm and culture of the obtained embryos are made in the laboratory within 3-5 days. In 16-18 hours after fertilization a zygote – fertilized ovum with male and female pronuclei is being formed in the course of the IVF program. On the lapse of 20-22 hours the first cell fission of the fertilized ovum takes place. If the fission is correct, on the second day after fertilization the embryo consists already of 4 cells (blastomeres). On the forth day a morula (cell mass) is being formed by the confluent blastomeres. On the fifth day after fertilization the morula is transformed into a blastocyst – accumulation of trophoblasta and embryoblasta cells thereby forming a small cavity filled with fluid.
- Transfer of embryos into the uterine cavity is accomplished on the 3rd-5th day after the paracentesis of the ovaries. As a rule, not more than 2-3 embryos are transferred into the uterine cavity. This procedure is made in the medical office in the gynecological chair without extension of the uterine cervix and with the use of a special catheter. The procedure does not require anesthesia.
- Post-transfer period. To keep up pregnancy after the embryos have been transferred in the IVF cycle, the doctor prescribes the medicines containing chorionic gonadotropic hormone, progesterone or its analogues. On the 10th-14th day after the transfer of the embryos a pregnancy test is made: a level of the chorionic gonadotropic hormone (CGH) in the blood serum is determined. US-diagnosis of pregnancy is made on the 21st day after the embryos have been transferred in the IVF cycle.
Book an appointment to the gynecologist-reproductive specialist of “Gameta” Reproductive Health Medical Centre by phone: 738-68-69.
Extracorporal fertilization process is the latest achievement of the contemporary medical science
Causes of unsuccessful IVF
The IVF cycle consists of several stages, each of them should be successfully overcome before a transition to the next stage:
- at least one follicle should begin to grow and develop;
- the follicles should get matured;
- no premature ovulation should occur before the follicular puncture;
- ova should be successfully taken out of the follicles during the puncture;
- sperm should fertilize at least one ovum;
- the fertilized ovum should start fission and development;
- the embryo should implant in the uterine.
In that series of events the implantation still remains a mystery for scientists – why not every embryo becomes a child?
With the use of modern technologies we managed to successfully obtain embryos in the laboratory but we still may not control the implantation process. We do not know which embryo becomes a child, and this situation brings much disappointment both to doctors and patients.
Extracorporal fertilization in Odessa
Implantation is a very complicated process. First of all the embryo should continue its development until to blastocyst stage and then come out of its shell (pellucid area). The hatched out blastocyst should then implant in the uterine endometrium during a short period called “implantation window”.
Three main phases of implantation are knows as opposition, adhesion and invasion.
The opposition or orientation of the embryo in the uterine cavity commences at the moment when the uterine cavity reduces maximally because the fluid contained therein is sucked by pinopodes (small knobby formations appearing on the outside membrane of cells inlaying the uterine).
Blastocyst adhesion means a chain of biochemical reactions leading to the blastocyst attachment to the endometrium. Many molecules such as cytokines, growth factors and integrins play an important role in this complicated process when the blastocyst and the mother’s endometrium commence their fine “dialogue”.
Invasion means a self-controlled process that allows the embryonal trophoblast (blastocyst cells which will become the placenta cells later) to deeply penetrate in the decidual mother tissue (endometrium cells which will form the mother part of the placenta later) and implant I the endometrium blood circulation. It happens due to production of special chemical substances called proteinase.
For the blastocysts to implant successfully, a great importance is attached to immune mechanisms that ensure the dialogue between the mother tissue and the embryo tissue which differ both genetically and immunologically. Activated cells of the decidual tissue and trophoblast cells produce a lot of immunologically active substances that cause the necessary immune reactions.
Assisted reproductive technologies in Odessa
It remains unknown how implantation is regulated and occurs, however, it should be mentioned that the implantation process in humans is, surprisingly, of low efficiency. It turns out tat nature is not always competent! An absolutely healthy married couple has the 20-25% probability to conceive a child in each menstrual cycle only. It is the embryo and the disorder in the embryo-endometrium dialogue which is responsible for such low efficiency.
Nowadays we know that genetic pathologies of the embryo are one of the main reasons of unsuccessful implantation. Fundamental studies of implantation are of great interest as it is, probably, the implantation which is the main factor limiting efficiency of the ART. Still, we need to make extensive researches before we shall be able to really control this process.
Analysis of the unsuccessful IVF cycle
If You do not become pregnant after the first IVF attempt, it is certain that You will be very frustrated and disappointed. However, You should remember that this is not the end of the road – it is just the beginning. After the unsuccessful IVF cycle You will meet the doctor and jointly analyse possible conclusions.
When analyzing the unsuccessful IVF the doctor pays special attention to quality of embryos and endometrium as well as to other important facts:
- Was the organism optimally ready for pregnancy? Surely, presence of various general and gynecological diseases does not always influence the beginning of pregnancy but, on the other side, we may not exclude reduction of the conception ability because of many diseases. Therefore, it is necessary to prepare the organism for conception and perform IVF in the period when there is no acute exacerbation of any chronic diseases.
- Did the ovaries respond to stimulation sufficiently well?
- Did the fertilization take place?
- Were the obtained embryos of good quality? Did they develop normally under laboratory conditions?
- Was the endometrium thickness and structure optimal by the moment of the transfer?
- Have any deviations in the endometrium development been detected in the course of IVF program?
- Did implantation occurred which was detected by the blood analysis for human chorionic gonadotropin in two weeks after the embryos had been transferred?
- Why pregnancy did not take place (though there is no answer to just this question!).
- Is it necessary to make any additional examination before the next IVF attempt?
- Is it necessary to apply any treatment before the next IVF attempt?
- Is it possible to repeat the same treatment scheme or is it necessary to make changes in it before starting the new attempt?
- When can we begin the refresher IVF cycle?
Should You not become pregnant, even the fact that You have passed the IVF program means that You will live knowing that You made everything you can using the most advanced technologies offered by the contemporary medicine.
Refresher IVF course
The majority of doctors advise to wait for at least a month before starting the new treatment cycle. Though from the medical viewpoint the refresher IVF course is possible even next month, the majority of patients need a break to pull themselves up and restore emotional equilibrium before starting all over again.
Depending on the previous cycle results the doctor may change the treatment scheme. For instance, if the ovaries response to stimulation was insufficient, the doctor may increase the dose of the preparation for stimulation superovulation or change the stimulation protocol. If no fertilization took place, You may need intracytoplasmic sperm injection (ICSI).
If the ova quality was bad, the doctor may recommend using the donor’s ova. However, if the results of the previous cycle were satisfactory, the doctor may advise to repeat the same treatment scheme: all required by many patients to reach success in the IVF cycle is time and one more attempt.
It is interesting to note that the couples who get the refresher IVF cycle are, as a rule, more clam and handle the situation better. Possible, it is so because they already know all necessary medical procedures and are better prepared for coping with them; also, they have already established a personal touch with the doctor and personnel of the Centre.
The medical risk of the IVF depends on the treatment stage. Stimulation of superovulation entails a risk of the ovarian hyperstimulation syndrome development (OHS). The OHS develops due to the development of a great number of follicles (more than 15) and, consequently, due to high ovarian activity that leads to high content of estrogens (female sex hormone) in blood.
High estrogen level facilitates disturbance of vascular permeability. As a result, the fluid from vessels comes out first in the cavity of the lesser pelvis and, then, in the abdominal cavity. Because of fluid accumulation in the abdominal and pleural space the patient can feel fullness, nausea, vomit and lack of appetite.
About 30% of the ovarian stimulation patients have the light form of OHS. To overcome it, it is sufficient to limit physical activity and take pain relievers.
In case of the medium severity hyperstimulation syndrome fluid is accumulated in the abdominal cavity and a pain is felt in the area of the gastrointestinal tract. Such women should be permanently monitored though it is sufficient, as a rule, to apply out-patient treatment. Gradually the condition of such patients is improving without additional interference but if pregnancy takes place, the improvement may take up to several weeks.
About 1–2 % of patients suffer the severe OHS characterized by accumulation of fluid in the abdominal and pleural cavities, disturbance of the electrolytic balance, high blood coagulation and, sometimes, formation of blood clots. In case of laboured respiration it might be necessary to pump out the fluid from the abdominal cavity. The patients suffering from severe ovarian hyperstimulation should be hospitalized until their condition improves, which can take up to several weeks.
As a rule, after stimulation of superovulation the ovaries remain, for some time, enlarged by 1.5-2 times. It happens so because “yellow bodies” that support pregnancy up to 10-12 weeks are being formed in the places of aspirated follicles. Enlarged ovaries become very mobile and can, in rare instances, torsion on their ligaments.
Ovarian torsion leads to disturbed circulation in the ovary, then to necrosis and loss of the ovary. Torsion is manifested by acute pain which intensity is permanently increasing. Under such circumstances it is recommended to make laparoscopy and “untwist” the ovary. If the ovary has irreversible changes, it is required to eviscerate a part or the entire ovary.
Hemorrhage from the enlarged ovary cysts is another rare complication which necessitates laparoscopic operation. Hemorrhage is manifested by development of fatigue, drowsiness, rapid heartbeat and, sometimes, by bellyache.
After the embryos have been transferred, the patients should carefully monitor their condition. In order to preclude development of such serious complications, the patients are recommended to restrict physical activity and exclude sexual intercourse during the first two months of pregnancy after the IVF. Though some early publications supposed that the use of stimulating preparations may increase the risk of the ovary cancer, numerous recent studies did not reveal any links between the preparations for superovulation stimulation and cancer of ovaries or other organs.
Certain risk is associated with the ovary puncture procedure. The puncture may be accompanied by the same complications as any other surgery that requires application of anesthesia.
Besides, the puncture brings a small risk of hemorrhage, infection and damage to urinary bladder or a blood vessel. However, a surgery aimed at elimination of complications after the puncture of ovaries is required for less than one patient out of a thousand. In rare instances inflammation process may develop already after the embryos transfer.
In the course of pregnancy and labours various pathologies of fetus development, exfetation, spontaneous miscarriage, stillbirth, multifetation and birth of a child with congenital defects may occur. If You undergo the IVF treatment You should know that the mere fact of infertility, age and multifetation may increase the risk of premature birth or stillbirth.
Multifetal pregnancy increases the risks of premature birth and neurological disease development such as infantile cerebral palsy. In case of multifetal pregnancy (twins or triplet babies) You should be attended by the experienced obstetrician-gynecologist who can refer You to a medical institution that has the appropriate neonatal service.
Risk of multifetal pregnancy exists in all alternative assisted reproductive technologies connected with a transfer of more than one embryo. Still, many patients consider twins to be a very good treatment outcome; multifetation involves many problems in pregnancy and these problems occur more frequently and become more serious in triplet pregnancy and each following fetus.
The women with triplet pregnancy may have to spend weeks and, even, months in bed or at hospital so as to try to avoid premature delivery. Risk of premature delivery in multifetal pregnancy is very high and children may be born too early to survive. Premature newborns require long-time intensive care and quite often have various health problems throughout entire life.
Assisted reproductive technologies in Odessa
Some couples can consider reduction of multifetal pregnancy in order to reduce risks associated with multifetation but such decision will be very hard. Selective reduction provides for stopping development of one or several feta (usually by injecting a toxic chemical such as potassium chloride in the fetus heart under ultrasonic control).
In many cases this fetus wanes while the other feta continue to develop. Certainly, there exists a risk of losing all feta by miscarriage (as a consequence of accidental trauma during reduction) – such risk is about 10% even with experienced doctors.
Blood-tinged discharges during the first trimester of pregnancy may indicate the beginning of miscarriage or exfetation. If blood-tinged discharges have started, it is necessary to urgently examine the patient so as to find a cause of such bleeding. According to some data the early blood-tinged discharges are often met with women after the IVF but they are not necessarily associated with the risk of pregnancy termination, as it happens with women conceived in a natural way. Therefore, it is not allowed to independently terminate taking medications prescribed by a doctor after the embryo transfer because early blood-tinged discharges do not always mean beginning of menstruation.
Risk of exfetation after the IVF equals 2-3%. Exfetation occurs not because of the IVF procedure proper but because many women undergoing treatment by the IVF methods have damaged fallopian tubes which increases their predisposition to exfetation.
Risk of congenital pathologies in case of IVF does not exceed the risk of congenital pathologies at natural conception. Certain risk of genetic pathologies exists irrespective of whether a child was conceived with the aid of IVF or naturally. When performing ICSI because of severe male sterility, the genetic defects causing male sterility may be inherited from father to son.
Assisted reproductive technologies require that the couple bear considerable physical, financial and emotional contributions. Psychological stress is possible and many couples tell that they suffer from real psychological shock. The required treatment is rather expensive. As a rule, the patients hope for the favourable outcome but the treatment cycle may end in a failure as well. A patient can feel disappointment, anger, indignation and loneliness.
Sometimes a feeling of disappointment leads to depression and low self-esteem, particularly at once after the unsuccessful IVF attempt. At this time it is essential to have support of friends and relatives. As an additional means of support and stress coping it is possible to get advice of a psychologist who will assist in coping stress, fear and agony caused by infertility and its treatment.
ICSI is the intracytoplasmic sperm injection in the ovum, it is a relatively new but already well developed laboratory procedure first accomplished in 1992. ICSI was developed with a view of remedying male infertility. ICSI provides for injecting a single sperm cell in the ovum cytoplasm with the aid of a thin glass needle.
The first child was born with the aid of ICSI in 1992. ICSI replaced two earlier applied laboratory methods – PZD (pellucida area drilling) and SUZI (spermatozoid under pellucid-area injection) as it allows of getting much higher fertilization percentage.
In this section You will find complete information about ICSI procedure:
- Who is advised to perform ICSI
- Description of ICSI
- IMSI – the improved ICSI procedure
- ICSI effectiveness
- Risks associated with ICSI
Who is advised to perform ICSI:
- Married couples who failed to fertilize ova in the standard IVF cycle or their percentage of artificial fertilization was very low.
- Men having pathological changes in sperm (e.g., low number of sperm cells, poor mobility of sperm cells, high percentage of sperm cells with pathological morphology and high level of antispermatozoal antibodies in sperm) that reduce a chance of successful treatment with the aid of a standard extracorporal fertilization (IVF).
- Men with azoospermia (complete absence of speramatozoids in the ejaculate) whose spermatozoids were obtained by testicle biopsy. Such patology may be due to congenital absence or an obstruction of spermaducts as well as unobstructive azoospermia.
- If cryopreserved sperm with low number and low quality spermatozoids was used.
- Married couples with whom a low fertilization percentage can be expected at standard IVF, e.g., with patients suffering from severe endometriosis or infertility of uncertain origin.
Description of ICSI procedure
ICSI procedure under a microscope
The first ICSI stages look like the standard IVF cycle. A woman is prescribed injections of hormonal preparations which stimulate maturation of several follicles in the ovaries. Ova are taken out in the course of an outpatient procedure under ultrasonic control and are placed in a special medium for culture.
After the ova have been obtained, they are examined under a microscope and their quality is assessed. Then the ova are placed in an incubator for 2-6 hours, taken out of the incubator and remove the cells surrounding the ovum so as to assess a degree of maturity of the ovum because the ICSI can be performed with mature ova only. Oocytes can be left in the medium for culture and make the ICSI next day in case the ova become fully mature.
Spermatozoids obtained from the ejaculate by biopsy of a testicle or epididumis (testicular sperm aspiration (TESA), testicular sperm extraction (TESE), percutaneous sperm aspiration (PESA) are processed in special media. Spermatozoids can also be obtained from the frozen sperm sample.
Having assessed maturity level of the ova, spermatozoids are placed in a special medium, those spermatozoids which have normal morphology are selected, then the selected spermatozoids are immobilized, sucked in the tip of a very thin glass needle and injected, afterwards, directly into the ovum. At that, the ovum is held in place by means of a slight sucking from the opposite side with a holding pipette. This is a very sophisticated procedure that is to be performed by a micromanipulator.
The described procedure is repeated for each obtained ovum. The ovum membrane is rather elastic and the microscopic hole made by the needle closes up very quickly, however, about 1% of the ova can be damaged in the course of the ICSI.
Next morning the ova are studied to check for fertilization.
The developing embryos are cultured during next 2-5 days while cleavage and further development of the embryos take place. Cleavage occurs not in all fertilized ova, some embryos can terminate their development at the earliest stages.
Usually, 2 embryos are transferred to the uterine cavity (3 embryos in exceptional cases). The remaining embryos of good quality are frozen for further transfer to the uterine cavity.
Medication therapy intended to support the luteal phase is prescribed according to the same scheme as after the standard IVF cycle.
IMSI means the improved ICSI procedure
Selection of spermatozoids for introducing them in the ovum is the most important ICSI stage. As far as the natural selection does not take place here, the embryologist should thoroughly select the best spermatozoids and exclude those with pathological morphology that are also present in the ejaculate of each man.
Under influence of active forms of oxygen apoptotic bubbles are being formed in the spermatozoids leading to damage / fragmentation of the DNA of the spermatozoids, which drastically reduces pregnancy probability after the embryos obtained as a result of artificial fertilization by such spermatozoids have been transferred.
Said defects may not always be found out under a standard microscope. To detect such apoptotic defects, use is made of a special expensive super-high resolution high-contract videomicroscopy which was specially produced at the optical factory in accordance with the developed technical assignment.
Such method to select spermatozoids takes up much more time than the conventional ICSI procedure, however it allows of considerably increasing IVF efficiency in severe male sterility cases. Such selection method is also used in a number of leading world clinics where it is called IMSI (intracytoplasmic morphologically normal sperm injection).
By today ICSI has been applied for more than 15 years; several hundred thousand of children have been born by now all over the world thanks to these procedures. Percentage of fertilized ova after making ICSI is about70%, and approximately 80% of the fertilized ova commence normal cleavage.
The risk of non-fertilization of none ovum after ICSI is less than 5%. ICSI results are comparable with the results of the conventional IVF, however, it can differ considerably in various clinics because it directly depends on the experience and professionalism of the embryologists. The other factors that impact frequency of pregnancy after ICSI include the age of a woman, duration of the infertility period and the number of transferred embryos.
Risks associated with ICSI
Apart of the known risk connected with the standard extracorporal fertilization procedure the specialists supposed earlier that ICSI procedure may have additional risks.
These concerns were connected mainly with a possibility of injecting a defective spermatozoid in the ovum because ICSI bypasses the stage of the natural selection of spermatozoids for fertilization which might lead to birth of child patients. Besides there were concerns that a defective ovum can be fertilized in the course of ICSI (with the natural fertilization and in the conventional IVF there is the natural selection and a probability of successful fertilization of the defective ovum is small).
However, the results of health examination of children born after ICSI were, on the whole, rather encouraging though we still do not possess enough information about long-term aspects of this procedure.
Some data is available concerning somewhat higher probability of genetic pathologies emergence with children after ICSI, in particular, Shereshevsky-Turner syndrome and Klinefelter syndrome (1.2% as compared with 0.5% in the general population). Still, there are no reasons to suggest that such situation is due to ICSI procedure proper. As far as ICSI is performed in the cases of severe male infertility, the genetic pathologies that, allegedly, caused spermatogenesis problems with the father can be inherited by the child.
It is confirmed by the researches which revealed a connection between the male infertility and the following pathologies:
- defects of Y-chromosome called “micro-deletion” occurred with 5% of the examined infertile men;
- disorders of the number or structure of chromosomes, e.g., Klinefelter syndrome (occurred 10 times frequently than in the general population), and translocation;
- cystic fibrosis;
- defects in the androgen receptor gene. As far as this gene is in X-chromosome, the daughters of such men who became fathers with the aid of ICSI will be carriers of this defect and the sons of such women will be ill at 50% probability.
Before commencing ICSI treatment the couple should pass a medical and genetic consultation and examination for the above described pathologies. If a genetic pathology will be identified, it will be necessary to consult a genetic specialist and obtain full information about the risk of transferring this pathology to offspring.
Book an appointment to the gynecologist-fertility specialist of “Gameta” Reproductive Health Medical Centre by phone 738-68-69.
The “Gameta” Medical Centre team numbers more than 20 doctors, including the leading specialists of Ukraine and other countries.
They are honoured doctors, professors, doctors in medicine and specialists with many years’ experience.
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