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IVF Treatmets

In Vitro Fertilization (IVF) treatment is one of the most significant advances in reproductive technologies and is a primary treatment option for couples experiencing infertility today. Modern IVF centers manage a complex series of biological and technological processes, including not only the fertilization of eggs and sperm in the laboratory but also genetic diagnosis, embryo preservation, and microsurgical techniques for male factor infertility. This comprehensive report meticulously examines all procedures carried out in IVF centers, their objectives, technical details, and the legal framework in Turkey.

STAGES AND MECHANISMS OF CLASSIC IN VITRO FERTILIZATION (IVF) TREATMENT

A classic IVF cycle consists of five main phases, meticulously planned and monitored, starting from the woman’s hormonal stimulation up to the embryo transfer to the uterus.

1. Controlled Ovarian Hyperstimulation (COH)

Objective: To aim for the retrieval of ideally 8 to 15 healthy eggs (oocytes) to increase the success of IVF, compared to the single dominant egg that develops in a normal menstrual cycle.

Protocols and Mechanisms:

  • Antagonist Protocol: The most commonly used protocol today. Egg development is achieved with gonadotropin (FSH/LH) injections starting on the 2nd or 3rd day of the menstrual cycle. To prevent premature ovulation (spiking), a GnRH Antagonist (Cetrotide, Orgalutran) is added when the follicles reach a certain size (usually 12-14 mm). This approach is shorter and requires less medication.
  • Agonist Protocol (Long Protocol): Popular in previous years. GnRH Agonists (Lucrin, Decapeptyl) are started in the middle of the previous cycle to suppress the pituitary gland. This suppression prevents the natural LH surge and allows the ovaries to respond more controllably to the externally administered hormones.
  • Minimal Stimulation Protocols: Used for patients with low ovarian reserve or a high risk of OHSS, aiming to develop eggs with lower doses of medication, sometimes using oral agents (Clomiphene Citrate, Letrozole).

Triggering: When the eggs reach an appropriate size (usually 17-20 mm), an “ovulation trigger shot” containing hCG (Human Chorionic Gonadotropin) or a GnRH Agonist (Decapeptyl) is administered to ensure final maturation and time the OPU (Oocyte Pick-Up) procedure. This must be done exactly 34-36 hours before the OPU procedure.

2. Oocyte Pick-Up (OPU)

Procedure Details: OPU is a surgical procedure performed 34-36 hours after the trigger shot, typically under sedation (light anesthesia).

  • Technique: Guided by transvaginal ultrasonography, a thin, single-use needle (aspiration needle) is advanced through the vaginal wall towards the ovaries.
  • Procedure: The fluid inside each follicle, along with the egg, is aspirated using negative pressure and immediately transferred to the adjacent embryology laboratory. The embryologist examines this fluid under a microscope to find, clean, and transfer the eggs to a culture medium.
  • Risks: The procedure is generally safe, but rarely carries the risk of bleeding, infection, or injury to adjacent organs (bowel or bladder).

3. Fertilization Procedure: IVF and ICSI

The eggs collected on the day of OPU are combined with sperm collected from the male on the same day or previously frozen.

  • Classic IVF: If there is a sufficient number and quality of sperm (generally more than 100,000 motile sperm per milliliter), a certain concentration of sperm is placed around the eggs in a petri dish, and the fertilization process is expected to occur naturally.
  • Intracytoplasmic Sperm Injection (ICSI): A method frequently preferred today, and mandatory in cases of male infertility.
    • Technical Detail: The egg is held stable using a micro-manipulation device (needles with very precise movements). A single, morphologically best-selected sperm is drawn into a special micro-pipette and directly injected into the cytoplasm of the egg.
    • Indications: Severe male factor infertility (azoospermia, severe oligozoospermia, asthenozoospermia, teratozoospermia), fertilization failure in previous IVF attempts, or patients with a low number of eggs.

4. Embryo Development and Culture

Culture Medium: Fertilized eggs (zygotes) are kept in special culture fluids that mimic the in-vivo environment (in terms of pH, temperature, and gas balance), inside devices called incubators.

Developmental Stages:

  • Day 1 (Zygote): Fertilization check is performed (2 Pronuclei appearance).
  • Day 2: The embryo is at the 2 to 4 cell stage.
  • Day 3 (Cleavage Stage): The embryo reaches 6 to 10 cells. At this stage, embryo quality (Grade) is determined by evaluating cell number, symmetry, and amount of fragmentation.
  • Day 5 or 6 (Blastocyst Stage): The embryo reaches a stage consisting of approximately 100-150 cells, with distinct inner cell mass (the part that will form the fetus) and trophectoderm (the part that will form the placenta) structures. Blastocyst transfer significantly increases success rates because it improves synchronization with the uterus and only the most viable embryos reach this stage.

5. Embryo Transfer (ET)

Procedure: The embryo is placed into the uterus of the woman, whose uterine preparation is completed, usually on Day 3 or Day 5.

  • Technique: The procedure is painless and does not require anesthesia. Under abdominal ultrasound guidance, a thin and flexible catheter (guide tube) is passed through the cervix and advanced into the uterine cavity (to the upper 1/3 of the endometrium). The embryos are released into the uterus via this catheter.
  • Number of Embryos to be Transferred: Legal regulations in Turkey restrict the number of embryos to be transferred to reduce the risk of multiple pregnancies. Single embryo transfer is mandatory in the first two attempts. In the third attempt and thereafter, single embryo transfer is still required for women under 35 years of age; a maximum of two embryos can be transferred for women over 35 and/or those with previous failed attempts.

ADVANCED LABORATORY AND PRESERVATION TECHNIQUES

These are modern techniques that increase the competence of IVF centers and offer patient-specific treatment options.

1. Preimplantation Genetic Diagnosis/Screening (PGT/PGS)

Definition: The process of examining the genetic and chromosomal structure of the embryo before it is transferred to the uterus.

A. PGT-A (Aneuploidy Screening)

  • Objective: To check whether the embryo contains an abnormal number of chromosomes (aneuploidy). (E.g.: Extra 21st chromosome – Down Syndrome).
  • Indications: Advanced maternal age, recurrent failed IVF attempts, recurrent pregnancy loss. By transferring only healthy (euploid) embryos with PGT-A, pregnancy rates are increased and the risk of miscarriage is reduced.
  • Biopsy Technique: For PGT, a small biopsy is usually taken from the trophectoderm cells (which will form the placenta) at the Day 5 blastocyst stage. The inner cell mass (the part that will form the baby) is not harmed.

B. PGT-M (Monogenic Disease Diagnosis)

  • Objective: To detect the presence of a known single-gene disorder in the family (Cystic Fibrosis, Spinal Muscular Atrophy, Thalassemia, etc.) in the embryo.
  • Mechanism: Embryos that do not carry these diseases are transferred, thereby eliminating the risk of having an affected child.

C. PGT-SR (Structural Rearrangement Diagnosis)

  • Objective: If one of the partners has structural chromosomal abnormalities such as translocation or inversion, to determine if these unbalanced structures have been passed on to the embryo.

2. Embryo Freezing and Storage (Cryopreservation – Vitrification)

Procedure: Healthy embryos that are of good quality and not transferred are stored in liquid nitrogen (-196 °C).

  • Technique (Vitrification): The ultra-rapid freezing technique used today minimizes cell damage by preventing the formation of ice crystals in intracellular water. With this method, the embryo survival rate after thawing is over 95%.
  • Advantages of Frozen Embryo Transfer (FET):
    • Offers the possibility of transferring the embryo to the mother’s uterus under the most physiologically suitable conditions, free from the hormonal effects of stimulation drugs (“Freeze-All” strategy).
    • Allows for another attempt after a failed fresh transfer without the need for a new OPU cycle.
    • Allows for the cancellation of a fresh transfer and freezing of all embryos in patients at risk of OHSS.

3. Oocyte and Sperm Freezing

  • Oocyte Freezing (Egg Freezing): Performed to preserve fertility for women. Used for medical indications (cancer treatment, risk of premature menopause) or Social Indications (delaying marriage, career planning).
  • Sperm Freezing: Performed for men before treatments that may affect sperm quality (such as chemotherapy, surgery) or for men at risk of being unable to provide sperm on the day of OPU.

4. Assisted Hatching (AH)

  • Objective: To increase the chance of implantation by thinning or microscopically opening a small hole in the protective layer (Zona Pellucida) around the embryo.
  • Indications: Advanced maternal age, thick zona pellucida structure, previous failed IVF attempts, and frozen-thawed embryos. This procedure is performed precisely using laser technology.

SPECIAL TREATMENT AREAS AND TECHNICAL SUPPORT

1. Male Infertility and Surgical Sperm Retrieval Methods

Surgical techniques applied in cases of severe male factor infertility and azoospermia (absence of sperm in the semen).

  • Micro-TESE (Microdissection Testicular Sperm Extraction): The most precise method performed under a surgical microscope to find sperm-producing areas in the testicular tissue of azoospermic men. The success rate is higher than other TESE methods, and it causes less damage to the testicular tissue.
  • TESE (Testicular Sperm Extraction): Searching for sperm by taking random biopsy samples from the testicles.
  • MESA (Micro Epididymal Sperm Aspiration): Sperm retrieval by aspirating fluid from the epididymal ducts with microsurgery in azoospermia due to obstruction.

2. Embryo Monitoring Systems (Time-lapse)

  • Procedure: Advanced incubator systems (e.g., EmbryoScope, Primo Vision) that take continuous (24/7) photo and video recordings without removing the embryos from the incubator.
  • Advantage:
    • Reduces embryo stress by providing a continuous culture environment.
    • Facilitates the selection of the healthiest embryo for transfer by allowing embryologists to identify critical time points (cell division rate and abnormalities) in embryo development.
    • Ensures objectivity in transfer selection by detecting abnormal divisions that might be missed in classic observation.

3. Endometrial Preparation and Uterine Support

  • Endometrial Synchronization: Preparing the uterine lining (endometrium) to have the appropriate thickness and structure for embryo implantation. This is achieved using estrogen and progesterone hormones. It is critically important, especially in frozen embryo transfers (FET).
  • ERA Test (Endometrial Receptivity Analysis): A genetic test performed on patients with recurrent implantation failure to determine the “Implantation Window”—the time when the uterine lining is most ready to accept the embryo—in hours.

LEGAL AND ETHICAL BOUNDARIES IN TURKEY

The operation of IVF centers is strictly regulated by the Regulation on Assisted Reproductive Treatment Practices issued by the Ministry of Health of the Republic of Turkey.

1. Prohibition of Sex Selection

  • Legal Status: Sex selection in embryos for social or familial preference is strictly prohibited in the Republic of Turkey.
  • Medical Necessity Exception: Sex selection can only be performed in conjunction with the PGT-M procedure and with the permission of the Ministry of Health, if there is a medical necessity to prevent a sex-linked hereditary disease (e.g., hemophilia, Duchenne Muscular Dystrophy) known in the family that occurs only in one sex, through the selection of a healthy embryo.

2. Prohibition of Donation

  • Legal Status: Oocyte donation, sperm donation, and embryo donation (gift) procedures are prohibited in Turkey.
  • IVF treatment can only be performed using the reproductive cells (eggs and sperm) belonging to the couple themselves (obtained from their own bodies).

3. Storage Periods for Reproductive Cells

  • Egg and Sperm Storage: Eggs and sperm frozen for medical reasons such as cancer treatment can be stored for many years with the individual’s consent and within the framework of medical necessities.
  • Embryo Storage: The initial storage period for embryos is 5 years. At the end of this period, the duration can be extended for further 5-year periods upon the couple’s application and if there are medical justifications (e.g., still wishing for a second child or ongoing attempt at pregnancy with frozen embryos).

RISKS, COMPLICATIONS, AND SUCCESS FACTORS

1. Possible Complications and Risks

  • Ovarian Hyperstimulation Syndrome (OHSS): A condition that can lead to abdominal swelling, fluid accumulation, and rarely, serious organ dysfunction as a result of the ovaries over-responding during stimulation. The use of Antagonist protocols and GnRH Agonist triggering has significantly reduced the risk of OHSS.
  • Risk of Multiple Pregnancy: The risk of multiple pregnancies such as twins or triplets increases with the number of embryos transferred. This situation is risky for both the mother and the baby (premature birth, low birth weight). For this reason, legal restrictions are enforced.
  • Ectopic Pregnancy: The risk of the embryo implanting outside the uterus (usually in the fallopian tubes). The risk is slightly higher in IVF than in natural pregnancy.
  • Egg Retrieval Risks: Although rare, there are risks of infection and bleeding.

2. Key Factors Affecting IVF Success

The success of IVF treatment depends on a complex interaction of many variables:

  • Female Age: The most critical factor. Success rates begin to decline after age 35 and seriously decrease after age 40. As age advances, both the number (reserve) and quality (rate of genetically healthy eggs) of eggs decrease.
  • Embryo Quality: Morphologically well-graded embryos that reach the Day 5 blastocyst stage have a high chance of success. PGT-based euploid embryo selection increases this success.
  • Endometrial Receptivity: The suitability of the uterine lining (endometrium) to accept the embryo. Thickness, structure, and accurate timing of the implantation window are important.
  • Cause of Infertility: Success is higher in some causes, such as unexplained infertility or tubal factor, while success rates may be lower in conditions like severe endometriosis or severe male factor.
  • Quality of the Center and Laboratory: The experience of the embryologists, the culture media used, incubator technologies, and the general quality standards of the center directly affect success.
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