In-Vitro Fertilization (IVF)

In-Vitro Fertilization

Fertilization is described as the union of spermatozoa with the oocyte, also known as the egg, in order to reestablish the diploid state, generate a zygote through the process of egg activation, and initiate a series of mitotic divisions that culminate in cell differentiation and embryo development.

In vitro fertilization (IVF) is the most prevalent type of assisted reproductive technology and is used to treat people who are having problems conceiving. Because oocytes mature in the ovary and embryos grow into pregnancy in the uterus, the phrase "in vitro" refers to outside of a living creature, although the oocytes are fertilized in a petri dish.

In-Vitro Fertilization (IVF) definition

In-Vitro Fertilization (IVF) definition

In vitro fertilization (IVF) is a method of fertilization in which an egg is joined with sperm in a laboratory ("in glass"). The procedure entails monitoring and promoting a woman's ovulatory process, taking an ovum or ova from their ovaries, and allowing sperm to fertilize them in a laboratory culture medium. After the fertilized egg (zygote) has been cultured for 2–6 days, it is placed in a uterus in order to generate a viable pregnancy.

Since this key discovery in infertility therapy, the discipline of reproductive endocrinology/infertility has advanced swiftly, with IVF currently accounting for 1.6 percent and 4.5 percent of all live births in the United States and Europe, respectively. IVF was originally created to treat irreversible tubal illness, but it is now commonly used to treat infertility due to a number of factors, including endometriosis, male factor, and unexplained infertility.

Women who are unable to use their own oocytes owing to primary ovarian insufficiency (POI) or age-related oocyte decrease can now become pregnant with donor oocyte IVF.

Anatomy and Physiology

Grasp and conducting IVF requires a thorough understanding of female pelvic anatomy. Certain forms of anatomy tend to be connected with success rates of oocyte retrieval and embryo transfer in order to get the best results in IVF. The uterus is a Mullerian structure of the female pelvis that offers a space for a developing fetus. The uterus is made up of three layers: serosa, myometrium, and endometrium.

The endometrium, also known as the uterine lining, is a glandular tissue structure that changes predictably over the menstrual cycle in response to hormone levels in the blood.

Approximately 10% to 15% of couples will have difficulty getting pregnant. Infertility is defined as the inability to conceive after 12 months of unprotected sexual intercourse in women under the age of 35, or six months in women 35 and older.

An early assessment is recommended if the female spouse has oligomenorrhea or amenorrhea, endometriosis, tubal illness, or there is a known male problem. The workup for infertile couples involves an evaluation of ovulatory function, ovarian reserve, uterine cavity, tubal patency, and a semen analysis. A diagnostic laparoscopy should be considered if there is evidence of endometriosis, tubal occlusions, or adnexal adhesions.

Indications

In-Vitro Fertilization Indications

Tuboperitoneal illness is present in 25% to 35% of infertile women, with pelvic inflammatory disease (PID) being the most prevalent cause of tubal damage. PID is often caused by Chlamydia trachomatis infections. Bacterial infections can cause tubal blockage or peritubular adhesions, making in vivo fertilization impossible. By putting embryos directly into the uterus, IVF avoids tubal damage.

Endometriosis, a chronic inflammatory illness characterized by the presence of endometrial tissue outside of the uterine cavity, is substantially more common in women who are infertile than in those who are not. The processes by which endometriosis causes infertility are not entirely known, however research has indicated that women with endometriosis have pelvic adhesions, chronic intraperitoneal inflammation, altered folliculogenesis, and reduced embryo implantation.

Laparoscopic surgery has been shown to raise the rate of spontaneous conception from 4.7 percent to 30.7 percent, demonstrating the necessity of restoring normal pelvic architecture for a spontaneous pregnancy. Unfortunately, as compared to other causes of infertility, women with endometriosis have a considerably lower success rate with IVF, with more advanced illness being associated with poorer outcomes.

Poor sperm quality is the single cause of infertility in 20% of couples and contributes to fertility problems in another 20%. In roughly 50% of men, decreased sperm count, motility, or morphology (form of the sperm) can be effectively treated medically or surgically. In couples when the male partner has a low amount of motile sperm, intrauterine insemination can also boost conception rates.

If these therapies are unsuccessful, IVF with or without intracytoplasmic sperm injection (ICSI) can be used. In situations of obstructive azoospermia or testicular hypofunction, sperm collected from the testicle or epididymis may only be utilized in an IVF cycle with ICSI since the sperm have not accomplished the final in vivo maturation step, allowing it to fertilize an egg.

Women who are unable to generate their own oocytes owing to POI or low ovarian reserve can conceive using donation oocytes or donor embryos. Because IVF cannot overcome the effect of age on oocyte function and fertilizability, many women in their late thirties and older will use donor oocytes. These oocytes have been extracted from a younger woman (typically under 30 years old) and are either saved for future use or utilized in a new IVF cycle.

IVF is also used in women who want to keep their fertility. Women suffering from cancer or other diseases may be required to endure gonadotoxic therapies that endanger ovarian function. Prior to chemotherapy or radiation, these women can cryopreserve oocytes or embryos, which can subsequently be transplanted at a later date.

Oocyte cryopreservation is also an option for women who want to postpone childbirth. It is commonly known that women's fertility declines considerably in their forties. This decline in fecundity is caused by a decrease in both oocyte number and quality. Women who do not want to become pregnant in the near future might cryopreserve their oocytes for later usage.

Contraindications

In-Vitro Fertilization Contraindications

The IVF treatment has no definite contraindications. It should not, however, be conducted in women who are at high risk of morbidity and death from pregnancy if IVF is successful. These high-risk conditions include, but are not limited to, Marfan syndrome, NYHA class 3 or 4 heart failure, Eisenmenger syndrome, severe valvular stenosis, pulmonary hypertension, and aortic coarctation. Women with these serious medical conditions who want to have a biological child can have IVF with oocyte aspiration and fertilization with their partner's sperm, but the embryos will be transferred to a gestational carrier.

Technique

Equipment

In-Vitro Fertilization Equipment

For the embryology lab:

Triple gas control incubators
MultiBlok heaters
Precision water bath
Stage warmers
Hoods with a stereomicroscope and heated stage
Inverted microscopes with micromanipulation technology (ICSI)
Anti-vibration tables
Laser for embryo biopsy for preimplantation genetic diagnosis (PGT)
Tabletop incubators for embryo culture
Air-filtration systems
Alarm system
Wireless monitoring systems for liquid nitrogen tanks
Liquid nitrogen tanks for sperm, oocyte and embryo cryopreservation

Preparation

Individuals considering IVF are subjected to a series of tests prior to the commencement of the treatment cycle. Cycle day three follicle-stimulating hormone (FSH) and estradiol (E2), anti-Mullerian hormone (AMH), or antral follicle count are used to assess a woman's ovarian reserve. If the woman's ovarian reserve is assessed to be low based on any of these numbers, she can still attempt IVF but may need to consider using donor oocytes.

Based on sperm morphology, count, and motility, the male partner undergoes a sperm study to determine whether ICSI is necessary. Uterine cavity imaging detects any structural abnormalities that may impede with embryo implantation, such as endometrial polyps or fibroids, adhesions, or septa. Both partners should be screened for infectious diseases such as HIV, hepatitis B and C, and syphilis.

The procedure

Controlled Ovarian Stimulation

Controlled Ovarian Stimulation

The IVF cycle begins with ovarian stimulation. Multiple regimens have been used, ranging from no stimulation to varying amounts of ovarian stimulation with clomiphene citrate, letrozole, and exogenous gonadotropins (FSH and LH). Gonadotropin-releasing hormone (GnRH) analogs are used in IVF cycles to suppress the woman's LH surge, allowing doctors to timing egg retrieval. Transvaginal ultrasonography is used to monitor follicular development, and blood levels of E2 assist identify any necessary adjustments in the stimulation strategy.

The egg is harvested before the mid-cycle LH surge occurs in natural cycle IVF, or a GnRH antagonist (GnRHant) is administered to block LH release. When the lead follicle matures, hCG is administered in place of the LH surge. The pregnancy rate is roughly 8% every cycle, with a cumulative rate of 21% after three cycles, and rates as high as 44% in couples with male factor infertility. Because of the decreased clinical pregnancy rate, natural cycle IVF is not routinely used.

In the great majority of IVF cycles, ovarian stimulation is used in order to extract 10 to 20 oocytes. The two primary procedures are a lengthy luteal GnRH agonist (GnRHa) cycle and a GnRHant cycle.

The extended luteal GnRHa regimen begins with 0.1 mg GnRHa administered daily beginning on cycle-day 21 of the prior month. This inhibits pituitary LH (and FSH) release during ovarian stimulation, whereas GnRHa is maintained until the hCG injection. Starting on cycle day 2, gonadotropins are injected at dosages ranging from 75 to 450 IU daily, with dose changes according to on follicular development and estradiol levels. When at least three follicles reach 18 mm in size, the hCG injection is given.

The GnRHant regimen comprises daily gonadotropin injection (75 to 450 IU) beginning on cycle day 2 or 3. When the lead follicular diameter reaches 14 mm or on the sixth day of ovarian stimulation, the GnRHant is begun to block the natural LH surge. When at least three follicles are reached, 18 mm hCG is given.

Clomiphene citrate, a selective estrogen receptor modulator (SERM), or letrozole, an aromatase inhibitor, with or without gonadotropins, is used in the minimum stimulation regimen. The expense to the couple is lowered when gonadotropin stimulation is minimized or eliminated. The minimum stimulation regimen is gaining popularity as studies show that, while the live birth rate is slightly lower , there are much reduced occurrences of ovarian hyperstimulation syndrome and multiple pregnancies.

Oocyte Retrieval

Mature oocytes are recovered 34 to 36 hours after hCG treatment, regardless of the stimulation strategy. Ultrasound-guided transvaginal aspiration and intravenous sedation are used to retrieve the oocytes. A vaginal ultrasonography probe is used to see the ovaries, and an attached needle guide assists the physician in directing the needle into each follicle and aspirating the oocyte and follicular fluid.

Embryo Fertilization

To fertilize the oocytes, insemination or ICSI is employed. The sperm sample is prepared by density centrifugation and washing it in high protein concentration solution to enhance capacitation, a procedure required for sperm to become fertilizable. For 12-18 hours, 50,000 to 100,000 sperm are incubated with an oocyte. Male factor infertility may need ICSI, in which one immobilized sperm is delivered directly into the oocyte. This eliminates the requirement for sperm to travel through the zona pellucida, the glycoprotein matrix that surrounds the egg.

Embryo Transfer

Fertilized embryos are transplanted at the blastocyst stage (3 days after fertilization) or the cleavage stage (5 days after fertilization). The blastocyst stage transfer results in more live births each cycle while using fewer embryos and thereby lowering multiple gestation rates. The disadvantage of blastocyst stage transfer is that fewer embryos may be available for transfer as a result of the loss of embryos that did not survive in culture until day 5.

Embryos are delivered into the uterus through a catheter that passes through the cervix under transabdominal ultrasound monitoring. The embryo(s) are inserted one to two centimeters from the uterine fundus. Following the transfer, the catheter is examined under a microscope to confirm that no embryos have been retained in the catheter and that all embryos have been successfully implanted in the uterus. The number of embryos transplanted will be determined by the embryo's stage, quality, mother's age, and patient desire. The American Society for Reproductive Medicine recommends transferring no more than two blastocysts in women 37 years of age or younger, and no more than three blastocysts in women 38 to 40 years of age and 41 to 42 years of age.

Due to the lower likelihood of successful implantation, a greater number of cleavage stage embryos can be transferred; no more than two embryos in women 35 years of age, no more than three embryos in women 35 to 37 years of age, no more than four embryos in women 38 to 40, and five or fewer embryos in women 41 to 42 years of age.

Progesterone supplementation is started on the day of oocyte retrieval or embryo transfer to maximize embryo implantation and pregnancy continuation. Excessive high-quality embryos are cryopreserved for later use.

Complications

The consequence of ovarian stimulation known as ovarian hyperstimulation syndrome (OHSS) is potentially fatal. Women report stomach distension, nausea, and vomiting in moderate instances. Ascites develops in more severe instances with significant stomach discomfort and possibly pleural effusion, which can lead to impaired pulmonary function and hypoxia.

Hypovolemia, oliguria, raised creatinine, increased liver transaminases, leukocytosis, and electrolyte abnormalities may occur in patients. The risk of thromboembolism is increased by hemoconcentration. Acute renal failure with disseminated intravascular coagulation may result in mortality in severe situations. The World Health Organization (WHO) estimates that severe OHSS occurs in 0.2 to 1% of all stimulation cycles.

From 1980 to 2015, the prevalence of twins increased, and it is believed that IVF is responsible for 19% of all twins and 25% of all triplets. The number of triplets has been decreasing as a result of the new ASRM recommendations for reducing the number of transplanted embryos. Multiple gestations can raise the risk of hypertensive diseases of pregnancy and premature delivery. Surprisingly, the risk of hypertensive problems in IVF twin pregnancies does not differ from that of spontaneously produced twins.

Similarly, there does not appear to be a significant difference in the likelihood of premature delivery between IVF twin vs. spontaneously conceived twin pregnancies, which is most likely owing to the increased risk of both hypertension and preterm birth in twin pregnancies in general.

When comparing singleton pregnancies, one systematic review and meta-analysis discovered significant differences. Pregnancies with a solitary IVF are connected with a higher risk of hypertensive disorders of pregnancy, premature delivery, gestational diabetes, antepartum hemorrhage, congenital abnormalities, cesarean sections, low birth weight, small for gestational age, and perinatal death.

Ectopic pregnancy occurs when a fertilized egg grows outside the uterus, typically in the fallopian tubes, necessitating the prompt death of the baby. When the confounder of infertility is removed, IVF does not appear to be related with an increased risk of cervical cancer, ovarian cancer, or endometrial cancer. It also does not appear to enhance the risk of breast cancer.

IVF therapy is typically stressful for patients, regardless of pregnancy outcome. Neuroticism and the adoption of escapist coping methods are linked to increased levels of discomfort, but the presence of social support has a calming impact. A negative pregnancy test following IVF is linked to an increased risk of depression in women, but not to an increased risk of anxiety disorders. Pregnancy test results do not appear to be a risk factor for male sadness or anxiety.

Clinical Significance

Clinical Significance

Infertility affects about 1 in every 8 couples in the United States. IVF has been used to conceive approximately 5 million children globally since 1978. According to the 2018 Society for Assisted Reproductive Technology, the following age groups had the highest live birth rates per targeted egg retrieval:

Women <35 years:

Live births - 47.6%
Singleton (%of live births) - 89.4%
Twins (%of live births) - 10.4%
Triplets (%of live births) - 0.2%

35-37 years:

Live births - 30.7%
Singleton (%of live births) - 90.3%
Twins (%of live births) - 9.5%
Triplets (%of live births) - 0.2%

38-40 years:

Live births - 21.7%
Singleton (%of live births) - 90.9%
Twins (%of live births) - 8.9%
Triplets (%of live births) - 0.1%

41-42 years:

Live births - 10.4%
Singleton (%of live births) - 93.6%
Twins (%of live births) - 6.3%
Triplets (%of live births) - 0.2%

>42 years:

Live births - 3.1%
Singleton (%of live births) - 94.9%
Twins (%of live births) - 5.1%
Triplets (%of live births) - 0%

Conclusion

The study of reproductive endocrinology and infertility is very multidisciplinary. To give successful therapy to patients, a team of physicians, nurses, embryologists, and other staff is required. Good communication between staff and patients is crucial in assisting patients in navigating the complexity of IVF therapy. Furthermore, it is crucial to recognize the heightened psychological stress that many patients experience when undergoing IVF.

Patients frequently do not receive appropriate emotional support from their close social contacts, and research reveals that this lack of support leads to decreased conception rates and is one of the primary causes for IVF treatment attrition. As a result, it is vital that all members of the treatment team take the time to communicate with the patients and offer patient-centered care.