You have been wanting to have children for a long time, but until now you have not been able to achieve your wish naturally. You will apply to a specialist, but you do not know what awaits you at the first meeting.
Here’s what will happen in the first meeting, which is considered the first step in IVF treatment.
The couple’s first meeting with the doctor aims to decide which treatment method they are suitable for. During the interview, the history of the couple is taken, the previous tests are evaluated, and the men and women are examined.
Semen (sperm, semen) Analysis forms the basis of the evaluation of the man. This analysis should be done in the laboratory of our IVF unit. After the gynecological examination and ultrasound examination of the woman, samples are taken for the Pap Smear (test for detecting cervical cancer and pre-cancerous conditions) test and various bacteriological examinations.
With the hormone tests performed on the third day of menstruation, it is tried to be understood in advance how the ovaries will respond to the drugs. If it has not been taken before or if the quality is insufficient even though it has been taken, a womb-tube film may be requested to view the uterus and tubes.
AIDS, Jaundice Test for both spouses, Rubella Test and blood count for women only.
Second interview: The purpose of this is to evaluate the examinations requested in the first interview, to draw up a treatment plan and to discuss it with the couples. After a plan is made and it is decided which drugs will be applied according to which protocol, treatment is started.
Suppression of Hormones
After starting IVF treatment, the woman’s hormones are suppressed first.
The most important reason for this is to prevent the eggs from cracking and spilling into the abdomen at an undesirable time as a result of suppression, and to obtain more embryos. This means that more embryos can be created and the chance of pregnancy can increase.
The purpose of stimulating the ovaries (Controlled ovarian hyperstimulation – KOH), which is applied to suppress hormones in IVF treatment, is to increase the number of dominant follicles, which is normally 1, and to obtain more mature egg cells.
The first successful IVF pregnancy was achieved in a natural menstrual period without any warning. However, transferring more than one embryo increases the probability of success. The only way to obtain more embryos is to obtain more egg cells. Today, KOH (Controlled ovarian hyperstimulation) is applied in almost all reproductive health centers in the world.
Controlled Ovarian hyperstimulation can be applied with different drugs and different methods. Some hormones are used to stimulate the ovaries. Although clomiphene citrate (CC) is the most commonly used drug all over the world, it is not the drug of choice in IVF / microinjection applications. The reason for this is that the number of stimulated follicles is generally insufficient and the uncontrolled cracking rate of the follicles reaches up to 30%. CC is a drug that is generally used in vaccination treatments.
Hormones preferred in IVF / Microinjection applications are Human Menopausal Gonadotrophin (hMG is a substance obtained from the urine of menopausal women and contains equal amounts of FSH and LH hormones) and Follicle stimulating hormone, namely FSH. FSH is secreted by the brain in the body. FSH alone is produced either by separating these urines or artificially by recombinant technology, which is a new technology.
When hMG or FSH is given alone, the follicles may crack uncontrollably and untimely due to the hormones secreted from the person’s own body. In this case, the treatment is left halfway. This is called premature luteinization. In the first years of IVF applications, approximately 17% of the treatments were canceled for this reason. In order to minimize this risk, it is necessary to suppress the woman’s own hormones before stimulating the ovaries. For this purpose, some drugs called GnRH analogues (GnRHa) are used.
GnRHa first causes an excessive stimulation in the ovaries. However, it then creates a strong suppression. The arousal that occurs at first is called the flare-up effect. In this way, the event is completely under control. The suppression of the ovaries can also be done with new types of drugs called GnRh antagonists. These drugs directly and quickly prevent ovulation without causing the initial warning.
Printing can be done according to different protocols.
Short Protocol: GnRHa application is started on the first day of menstrual bleeding and continued until the end of the treatment (the day of the cracking injection). Starting from the 3rd day of menstrual bleeding, hMG or FSH is added to the treatment.
Ultrashort protocol: GnRHa is started on the first day of menstrual bleeding and stopped after 3 days of administration. Treatment is continued with either hMG or FSH. The aim is just to take advantage of the flare-up effect.
Microdose short protocol: The difference from other short protocols is that the GnRh dose used is kept very low. For this purpose, the medicine taken from the pharmacy is diluted in the IVF laboratory and the dose is reduced. This protocol is applied to women who have recently had weak ovaries.
Long protocol: It is the most preferred KOH protocol all over the world. GnRHa application is started on the 21st day of the previous menstrual period. On the 3rd day of the following menstrual bleeding, whether there is suppression or not is determined by the blood test. If the blood estrogen level is decreased, it means that suppression is achieved. In this case, stimulation therapy with hMG or FSH is started. However, the GnRHa application is not terminated. GnRH and hMG or FSH are used together until the cracking needle is made.
GnRh Antagonists: In this treatment, hMG, FSH or recombinant drugs are started directly on the 2nd or 3rd day of menstruation. The GnRh antagonist is started daily at the start of high-dose therapy or when the eggs reach a size of 14 – 15 mm. The amount of medication to be used varies greatly depending on the age of the patient and the response of the ovaries. While 3 ampoules a day are usually sufficient in young patients, 6 or 8 ampoules a day may be necessary in advanced elderly or patients whose ovaries are not in good condition.
Stimulation of the Ovaries
After the suppression of the hormones, the ovaries are stimulated in the IVF treatment. Stimulating the ovaries to produce more eggs.
The purpose of stimulating the ovaries is to obtain as many follicles with a diameter of 16 – 20 mm as possible. During the follow-ups, the drug dose can be adjusted by controlling the blood estrogen levels. The target is to reach 200 pg/mL estrogen level per follicle larger than 14 mm. When the follicles reach a sufficient size, 5,000 – 10,000 units of human chorionic gonadotropin (hCG) are injected to ensure final maturation. Although the duration of the treatment is variable, it is 11 days on average in our clinic. Egg collection is done 32 – 36 hours after the cracking needle.
In all protocols (in vitro fertilization procedures), basic ultrasound examination and blood estrogen determination (test) are performed on the 2nd or 3rd day of menstrual bleeding. Thus, the drug dose to be used is decided. After the warning treatment starts, the patient is called for control at regular intervals. In these controls, the number and size of the developing follicles are checked by performing vaginal ultrasonography. From time to time, depending on the condition of the ovaries, a blood estrogen analysis may be required.
Another factor evaluated during ultrasound follow-ups is the structure and thickness of the layer that covers the inside of the uterus, called the endometrium. Since the embryo will settle in the endometrium when pregnancy occurs, its structure is extremely important. When the endometrium is 6 mm or thinner on the day of administration of the hCG hormone, the chance of pregnancy decreases. In our practice, the clinical pregnancy rate in such patients is 11.8%. Endometrial thickness of more than 14 mm also has a negative effect, and even if pregnancy is achieved, the probability of miscarriage increases.
The most serious complication of ovulation induction (stimulation of the ovaries) is Ovarian Hyperstimulation Syndrome (OHSS, ovarian overstimulation syndrome), which can sometimes reach life-threatening dimensions. Due to the effect of the hormones secreted here and the excessive response of the ovaries, fluid is collected in areas such as the abdominal cavity, the chest cavity, and the subcutaneous tissue. Serious cases require hospitalization. When the fluid collected in the abdomen is too much, it is drained with a needle and the taken fluid is given back to the patient through the vein after undergoing some procedures. The duration of treatment is variable. Embryo transfer may be delayed or canceled in women at high risk of OHSS. One of the most controversial issues on ovulation induction (stimulation of the ovaries) is whether it causes cancer as a long-term side effect. Unfortunately, the answer to this question is not yet fully known. However, research to date shows that there is no such risk.
After the stimulation of the ovaries (ovulation induction), follicles of a certain size are obtained. It’s time to collect these eggs to be fertilized outside (Ovum pick-up, OPU).
Before the collection process, the hCG hormone, popularly known as the cracking injection, is administered. The collection process is performed approximately 32 – 36 hours after this injection. In order to obtain sufficient and good quality eggs, it is extremely important to have the injection done at the specified time and to be at the clinic for egg collection at the specified time. In the first years of IVF applications, collection was done by laparoscopy. This was a very laborious process for both the patient and the physician.
How is the procedure done?
Today, the egg retrieval procedure (OPU) is performed quite easily and comfortably with vaginal ultrasonography. The patient lies in the gynecological examination position and is covered with sterile covers. After the vagina is cleaned, local anesthesia is applied to the vagina. Then, vaginal ultrasonography is started. The ovaries are reached with a needle passed through the guide on the vaginal ultrasonography. It is entered into each follicle and its contents are emptied with the help of a special aspirator. The fluid taken is immediately sent to the laboratory, where it is examined under a microscope whether it contains eggs. If there is an egg cell, it separates. If an egg cannot be obtained from the follicle, a special liquid is given through the same needle and the follicle cavity is washed. An attempt is made to remove any eggs that may have remained inside. In this way, the process is continued until all follicles are aspirated (suction with the help of vacuum). It takes about 15 – 30 minutes to aspirate both ovaries.
Are complications possible?
After the procedure, the patient is taken to the rest room and allowed to rest for a while. General anesthesia may be preferred in cases that cannot tolerate local anesthesia or in cases where the procedure is thought to be technically difficult due to the special condition of the ovaries and/or follicles. Sometimes, although the number of follicles is high, egg cells do not come out of them. One of the most important reasons for this condition called empty follicle syndrome is that the patient had the hCG injection done at the wrong time. In such cases, after the follicles on one side are aspirated, hCG is administered again. After 24 hours, the egg retrieval (OPU) process is repeated in the other ovary.
The complication rate of the egg (oocyte) retrieval procedure is quite low. The most common complication is bleeding from the bottom of the vagina where the OPU needle passes. These bleedings can be easily stopped with packing. Very rarely, injuries to adjacent organs such as intestines, bladder, and veins can be seen. Another rare complication is pelvic (lower abdomen) abscess. The presence of endometrioma (chocolate cyst) is an important risk factor for pelvic abscess, since the blood it contains is a suitable nutrient site. Abscess involving the tube and ovary developed in 3 patients in our series of 5,400 cases in our clinic. Since there was no response to the antibiotic treatment, that ovary had to be surgically removed.
Vaginal egg retrieval (OPU) under local anesthesia is a procedure that is generally easy to tolerate, relatively less invasive, and has a low probability of complications.
After the egg collection process, this time the egg taken from the woman and the sperm taken from the man are fertilized in the laboratory environment. This is the last step before the embryo transfer is performed.
During the egg retrieval (OPU) process, the sucked-out follicle content is immediately sent to the laboratory. This liquid, which is examined with a special microscope, is placed in the egg culture liquid and lifted into a device called an incubator. The incubator keeps the temperature constant at 37 oC and the carbon dioxide rate at the level of 5-6%. Mature egg cells become ready for fertilization after 4 – 6 hours. After stimulation, mature eggs suitable for fertilization can be obtained from approximately 80% of follicles with a diameter between 18 and 22 mm.
During the collection of eggs (oocyte) from the woman, the man also gives sperm. The most ideal method for obtaining sperm is masturbation. In people who cannot find live sperm in their semen, sperm is searched surgically. The semen obtained is taken into a special container and it is expected to liquefy. The liquefied semen is examined in terms of sperm count, motility and shape.
The most important criterion in patients who are planned for IVF is the number of motile sperm. The examined sperm are prepared for fertilization. Sperm preparation is important for two reasons. The first of these is to clear the foreign proteins in the semen, and the second is to trigger some reactions to make the sperm hyperactive.
After the egg culture and sperm preparation are completed, the fertilization process begins. Sperm and eggs are left here. 20,000 sperm are used for each egg cell. This number can be increased in cases where sperm parameters are defective. Microinjection (ICSI) should be preferred in the presence of male factor or in cases of unexplained infertility. It is checked whether there is fertilization 16-18 hours after the procedure. The number of single cells in the fertilized egg increased to two.
Fertilized eggs are put back into the culture medium and they are expected to reach advanced stages. When the appropriate stage is reached, a certain number of high-quality embryos are taken and transferred into the uterus of the woman.
The resulting fertilized eggs are called embryos. Embryos can be transferred at any stage from the bicellular stage to the multicellular blastocyst stage.
The most preferred transfer time is the 4 – 8 cell stage. Embryos usually reach this stage on the 2nd or 3rd day. Embryo transfer can be done between the 2nd and 6th days.
There is a direct relationship between the number of embryos transferred in assisted reproductive techniques and clinical pregnancy rates. The best clinical results are obtained by transferring 2 – 4 embryos. Multiple pregnancy rates increase considerably when more than two embryos are transferred. However, this risk decreases with increasing female age. Due to the high complication rates of multiple pregnancies and the increase in costs due to reasons such as premature birth, the number of embryos transferred has been limited in many countries. More than two embryos are made only in patients older than 37 years of age and in whom previous IVF/ICSI attempts have failed. In fact, some researchers recommend that only 1 blastocyst be transferred for each patient younger than 35 years of age.
How to transfer?
During embryo transfer, the patient is placed in the gynecological examination position. A speculum is inserted into the vagina. Then, cleaning is done with sterile saline. Then the cervix is cleaned with special culture fluids. The embryologist brings the embryos to be transferred from the laboratory in a catheter. The physician who will perform the procedure leaves the embryos in the uterus under ultrasound guidance from the abdomen. Embryo transfer process is not a painful procedure and does not require anesthesia.
After the procedure, the patient is given hormone drugs in the form of injections, suppositories or creams to support the endometrium (the tissue that covers the inside of the uterus). This treatment, called luteal phase support, continues until the 10th week if pregnancy occurs. In cases where pregnancy does not occur and there is menstrual bleeding, treatment is discontinued with the onset of bleeding. On the 12th day after embryo transfer, the patient is called for a pregnancy test.
12 days after embryo transfer, the patient is called back to the clinic for pregnancy test.
Here, a pregnancy test (beta-hCG) is performed first in the urine and then in the blood. According to the results of the blood test, it is decided whether or not there is a pregnancy. Those whose test is positive are called again for a blood pregnancy test 2 days later. The relationship between the results of the two tests is evaluated and it is decided whether the pregnancy is healthy or not. Two days later in a healthy pregnancy, the blood beta-hCG value should increase approximately 2 times.
In some cases, after a while, the blood beta-hCG value drops to zero. This condition is called a biochemical pregnancy. Increases in beta-hCG more than expected are one of the findings suggesting an ectopic pregnancy (ectopic pregnancy).
Cases whose beta-hCG values increase as desired on the 12th and 14th days are considered clinical pregnancy and are called for the first pregnancy ultrasound 2 weeks later. In this first ultrasound, it is investigated whether there is a gestational sac in the uterus and if there is, how many sacs there are. Twins, triplets or more fetuses can be seen in this first ultrasound.
From time to time, the number of fetuses decreases in multiple pregnancies. For example, a pregnancy that started as triplets may later fall into two or even one baby. This condition is called spontaneous fetal reduction. Surgical reduction of the excess number of babies is called fetal reduction. Especially in cases where triplets, quadruplets or more babies develop, fetal reduction is recommended as it increases the life chances of other babies.