IVF

Patient's question:

No

Doctor's answer:

In vitro fertilization combined with embryo transfer technology (IVF): Also known as test-tube baby, it refers to the process of collecting eggs and sperm separately, placing them in a test tube to allow fertilization, and then transplanting the embryo precursor—zygote—back into the mother's uterus for development into a fetus. Test-tube baby is a baby born through artificial methods that allow eggs and sperm to fertilize in vitro and undergo early embryonic development before being transplanted into the mother's uterus for gestation.
The term "test-tube baby" emerged alongside the development of in vitro fertilization technology and was successfully achieved through collaborative research by British obstetrician Patrick Steptoe and physiologist Robert Edwards. The birth of the test-tube baby immediately caused a sensation in the world scientific community, even being hailed as a major breakthrough in human reproductive technology and opening new avenues for treating infertility. The test-tube baby involves the combination of sperm and eggs in a test tube to form a zygote, which is then transplanted back into the woman's uterus (embryo transfer) to develop in the uterine cavity, similar to normal pregnancy, and the baby is delivered at full term. This technology has brought hope to couples who can produce normal sperm and eggs but are unable to conceive due to certain factors or underlying conditions. Currently, this technology has been implemented in some parts of China. In 1944, Americans Rock and Menkin first attempted this approach. The world's first test-tube baby, Louise Brown, was born on July 25, 1978, at 23:47 in Oldham Hospital, England. Since then, this research has developed rapidly, expanding to more than 10 countries by 1981. Today, the total number of test-tube babies worldwide has reached thousands. Several medical schools in China have begun this research, with the first successful case reported by Peking Medical College in 1985.
[Principle]
The test-tube baby is not an infant that truly grows in a test tube but rather involves retrieving several eggs from the ovaries, allowing them to combine with the male's sperm in a laboratory to form an embryo, and then transferring the embryo to the uterus, where it implants and gestates in the mother's uterus. Normal conception requires sperm and eggs to meet in the fallopian tubes, combine to form a zygote, and then the zygote returns to the uterine cavity to continue gestation. Therefore, the test-tube baby can be simply understood as a laboratory test tube replacing the function of the fallopian tubes and hence called a test-tube baby. Although in vitro fertilization was originally used to treat infertility caused by blocked fallopian tubes, it has since been found to be helpful for infertility caused by endometriosis, abnormal sperm (abnormal number or morphology), and even unexplained infertility. Studies show that the pregnancy rate after one cycle of treatment is about 40%, with a slightly lower birth rate.
[Third-Generation Test-Tube Baby]
Advances in reproductive medicine research have pushed human reproductive self-control to a new limit—first-generation test-tube baby technology addresses infertility caused by female factors; second-generation test-tube baby technology addresses infertility caused by male factors; while the breakthrough achieved by third-generation test-tube baby technology is revolutionary, as it helps humans choose to give birth to the healthiest offspring from a biological genetics perspective, providing future parents with healthy children despite genetic diseases.
Currently, China's third-generation test-tube baby technology is fully mature, with Professor Zhuang Guanglun leading the reproductive medicine center as the only research unit in China conducting clinical applications of third-generation test-tube babies.
The principle behind the ability of third-generation test-tube baby technology to achieve eugenics is as follows: The reproductive medicine center cultivates several embryos for each couple choosing to have children through test-tube baby technology before implanting them into the mother's body. According to genetic principles, these embryos undergo diagnosis (abbreviated as PGD) to select the one that best meets eugenic conditions for implantation.
This eugenically suitable embryo is screened out as follows: Certain genetic diseases in humans, such as X-linked diseases, affect different genders of offspring selectively. For example, a male with hemophilia generally has normal sons, while his daughters have a 50% chance of being normal and a 50% chance of carrying the hemophilia gene (carriers of the hemophilia gene generally do not develop the disease). If the hemophiliac is female, her sons will be affected, while her daughters have a 50% chance of being normal and a 50% chance of carrying the hemophilia gene. The eugenic principle for genetic diseases such as malnutrition and color blindness is the same as that for hemophilia. As long as one understands these genetic characteristics, the cells of the embryos cultured in vitro can be genetically tested to select embryos without pathogenic genes for implantation, thereby avoiding the birth of children with genetic diseases.
Many hereditary diseases in humans can use this PGD method to prevent them from being inherited by offspring, such as thalassemia and Down syndrome, etc.
Two couples weigh the pros and cons and make two different decisions: One couple agrees to use third-generation test-tube baby technology to choose to have a girl, while the other couple, hoping to take their chances, does not want to use this technology and still tries to have a boy, but it is certain that the boy born will be like the previous one and will also be a hemophiliac.
Similar situations have been encountered by Zhuang Guanglun many times. He says, "Although modern technology can now use genetic techniques to avoid some hereditary diseases, some people still hold traditional notions about the gender of their children."
[Role of Test-Tube Baby—Assisted Reproductive Technology]
Infertility is caused by various factors or underlying conditions that block the fallopian tubes, preventing sperm and eggs from meeting, leading to infertility. The solution is to artificially allow sperm and eggs to meet and fertilize in vitro, which is commonly known as test-tube baby. The specific procedure involves first using medication to stimulate the growth of more eggs in both ovaries, then retrieving the eggs once they mature, placing them in a culture medium that simulates the human body's internal environment, adding processed semen, and culturing for a period of time. Afterward, the sperm and eggs can fuse to form a zygote and divide into 4-8 cells. Then, 2-3 of the best-developing embryos are selected and placed back into the uterine cavity to continue growth and development. The medical term for in vitro fertilization-embryo transfer is used for couples with blocked fallopian tubes who have no other options. It can also be used to treat other forms of infertility that do not respond to other treatments. Test-tube baby and the embryo transfer developed on this basis can address certain infertility issues in women while providing an effective means for genetic engineering in humans, domestic animals, and crops, as well as for preserving endangered species facing extinction. Additionally, in line with China's population control policy of limiting population size and improving population quality, conducting research in this field can open up a new path for the eugenics of the Chinese nation. Test-tube baby is a major achievement of modern science, marking a new era in embryonic research and reproductive control.
[Steps in Conducting Test-Tube Baby]
1. Controlled hyperstimulation of ovulation
2. Monitoring follicles
3. Egg retrieval
4. Sperm retrieval
5. In vitro fertilization
6. In vitro embryo culture
7. Embryo transfer
8. Post-transfer progesterone supplementation
9. Determining pregnancy 14 days after transfer through morning urine test
10. 14 days after pregnancy, ultrasound examination to determine the number of fetuses and the site of embryo implantation
Controlled Hyperstimulation of Ovulation:
Due to the variability of natural menstrual cycles from person to person and even within the same individual across different cycles, it is difficult to schedule egg retrieval, and natural cycles typically only develop a single dominant follicle, resulting in only one embryo after fertilization. Transferring a single embryo has a very low pregnancy rate. Therefore, controlled hyperstimulation of ovulation is used to enhance and improve ovarian function, allowing multiple healthy eggs to be obtained without being limited by natural cycles, providing multiple embryos for transfer, and ensuring synchronization between luteal development and endometrial function. Controlled hyperstimulation typically involves first using a GnRH agonist to suppress endogenous FSH and LH, followed by administration of HMG or FSH ovulation drugs to stimulate follicular growth in the ovaries. The dosage of medication is adjusted based on the patient's response to the drug, and the number of eggs obtained varies depending on the patient's age and the dosage of medication used.
Monitoring Follicles:
To evaluate the effectiveness of ovarian stimulation and determine the timing of egg retrieval, vaginal ultrasound is used to monitor follicular size, accompanied by blood tests to check E2 levels (estrogen) to adjust medication dosage. When two to three follicles are greater than 1.8 cm in diameter, and the number of follicles greater than 1.4 cm is comparable to the E2 level, human chorionic gonadotropin (hCG) is injected to promote follicular maturation. Eggs are retrieved 34–36 hours after hCG injection.
Egg Retrieval:
The most common method for egg retrieval is under local anesthesia, with the guidance of vaginal ultrasound, a needle is inserted through the vaginal to reach the ovaries to aspirate the eggs, which are immediately moved to a culture dish containing embryo culture medium and placed in a 37°C incubator for culture.
Sperm Retrieval:
Sperm retrieval is performed on the same day as egg retrieval. Beforehand, the hands are washed, and semen is collected through masturbation. The cup provided is sterile, and care should be taken not to touch the rim or the inside of the cup. The collected semen is processed using the upstream method or Percoll density gradient centrifugation.
In Vitro Fertilization:
Four to five hours after egg retrieval, the processed sperm and eggs are placed in the same culture dish and co-cultured for 18 hours. Under a microscope, fertilization can be observed. If the sperm quality is too poor to fertilize naturally, intracytoplasmic sperm injection (ICSI) must be used to force fertilization (see intracytoplasmic sperm injection).
Embryo Transfer:
Zygotes can develop to the 8–16 cell stage embryo in vitro within 48–72 hours. At this stage, the number of embryos to be transferred is determined based on the patient's age, previous pregnancy history, and embryo quality. Excess embryos can be cryopreserved. Embryo transfer generally does not require anesthesia. Currently, embryos are often transferred 2–3 days after fertilization, while our center adopts embryo transfer 3–5 days after fertilization. Delaying embryo transfer time requires higher conditions for in vitro culture, but delaying transfer time is more physiologically appropriate and can also naturally select and eliminate inferior embryos, thereby increasing pregnancy rates and reducing multiple pregnancies.
Hormone Supplementation After Embryo Transfer:
Currently, we primarily use injections to provide progesterone support for the corpus luteum. If pregnancy is confirmed, hCG is used to continue supplementation until the 10th week of pregnancy. Fourteen days after embryo transfer, pregnancy can be determined through a morning urine test or blood draw.
[Suitable Populations for Test-Tube Baby]
1. Severe fallopian tube diseases, such as pelvic inflammatory disease leading to blocked ored fallopian tubes; or tubal endometritis with normal endometrium; or tubal pregnancy surgery resulting in blocked fallopian tubes
2. Endometriosis
3. Immunological infertility, where anti-sperm antibodies are present in the male's semen or the female's cervical mucus
4. Male factors, such as oligospermia, asthenospermia, or teratospermia
5. Unexplained infertility
6. Infertility due to other factors or underlying conditions that have not responded to treatment
7. Couples with genetic diseases requiring pre-implantation diagnosis
8. Other: such as luteinized unruptured follicle syndrome
[Preparations Before Patient Consultation]
First, it is necessary to identify the cause of infertility and determine if the patient is suitable for test-tube baby treatment. It is best to bring past medical records and proof of treatment to the consultation to avoid redundant tests. The following documents should be provided:
1. Reports on fallopian tube patency: X-ray films of hysterosalpingography, reports of fallopian tube hydrotubation under ultrasound, or hospital certificates of laparoscopy or laparotomy
2. Tests for ovulation: Endometrial pathology reports within the past year and three months of basal body temperature records
3. Recent six months of husband's semen analysis reports
4. Hepatitis B surface antigen antibody, e antigen antibody, and core antibody; hepatitis C antibody; liver function and blood type test reports; female blood sedimentation rate and tuberculin test; serum HIV antibody
After all the above documents are complete, the patient can visit the infertility treatment center and formally enter the cycle 10 days before the expected menstrual period for a second gynecological examination and a trial transfer to probe the depth of the uterine cavity and the direction of the catheter for embryo transfer.
[Success Rate of Test-Tube Baby]
The success rate of test-tube baby is a key concern for those preparing to receive treatment with this technology. Since the birth of the first test-tube baby over 20 years ago, significant advancements have been made in assisted reproductive technology. Especially in recent years, due to the maturity of various technologies, including the improvement of cell culture media and the experience of medical staff, the success rate of test-tube babies has gradually increased worldwide, from about 20%–25% to 60% or even higher levels.
The success rate of test-tube baby depends on many factors, including endocrine and laboratory conditions, the technical level of the personnel, the patient's age, the condition of the uterus and ovaries, and the presence of other diseases, all of which are factors that affect the success rate. For example, the patient's age is the most significant factor. For women aged 25 to 35, the success rate of test-tube baby is higher than the average of 30%–40%, with some reaching 50% or even higher, but after the age of 35, the success rate gradually decreases, reaching about 20% at the age of 40. This is due to the decline in both the quality and quantity of eggs as the age increases.
[How Long Does a Test-Tube Baby Stay in the Test Tube?]
After the eggs are retrieved, they are incubated with sperm in the test tube, with each egg requiring about 100,000 sperm. After fertilization, the zygote divides to form an early-stage embryo, consisting of 2–8 blastomeres, at which point embryo transfer (ET) can be performed. This is approximately 48 hours after egg retrieval, though this time may be slightly adjusted, such as by delaying by one day, which may be more beneficial for selecting the best embryo. If it is too early, the uterine environment may not be conducive to accepting the embryo. Generally, a trial transfer is performed in the outpatient clinic before the stimulation cycle to understand the uterine position, the angle between the cervix and the uterine body, and the length of the uterine cavity, with slight dilation of the cervix. After disinfecting the external genitalia, the speculum exposes the cervix, which is cleaned and then wiped with culture medium to clean the cervix and fornix as well as the cervical canal, removing as much cervical mucus as possible. Movements should be as gentle as possible to minimize stimulation of the uterine muscles. A special transfer catheter is used to inject the embryo. It is inserted into the uterine cavity and the embryo is injected 0.5 cm from the fundus. After waiting for one minute, the head is rotated 90° to shake off the last drop of liquid, and the catheter is slowly withdrawn. After the catheter is removed, it is examined under a microscope to ensure no embryo is left behind. After transfer, the patient can lie down with the hips elevated, or adopt a prone position if the uterus is highly anteverted, to keep the injected embryo in the upper part of the uterine cavity. Rest for about 3–6 hours, during which the patient can urinate to avoid urine retention. On the day of transfer, HCG 5000 international units and progesterone 30 mg are injected, followed by routine daily injections of progesterone. If the urine HCG test is negative after 14 days, the injection is stopped. If pregnant, continue until a fetal heartbeat is visible on ultrasound, then gradually reduce the dose. HCG should not be used for patients at risk of ovarian hyperstimulation syndrome.
[Development of Test-Tube Baby Technology in China]
The research on test-tube babies has a long history. As early as the 1940s, scientists began experiments on animals. In 1947, the British journal Nature reported experiments involving the retrieval of rabbit eggs and their transfer to other rabbits for gestation. In 1959, the Chinese-American biologist Zhang Mingju combined sperm and eggs retrieved after rabbit mating in vitro and transplanted the fertilized eggs into the uteri of other rabbits, successfully giving birth to normal rabbits. The successful completion of the rabbit in vitro fertilization experiment made Zhang Mingju a pioneer in the field of in vitro fertilization. His animal experimental results laid a solid foundation for later human in vitro fertilization and test-tube baby research.
On July 25, 1978, the world's first test-tube baby, Louise Brown, was born in Oldham Hospital, England. The earliest stage of IVF had a pregnancy success rate of only 2.94%. In June 1980, Australia's first test-tube baby achieved pregnancy success. By November 1981, a total of 15 cases had been born in the UK and Australia. In December 1981, the first test-tube baby was born in the US. Today, more than 10,000 test-tube babies have been born worldwide, with pregnancy success rates rapidly improving to 20-30%. Hope for treating infertility caused by fallopian tube factors has shifted from tubal microsurgery in the 1960s and 1970s to IVF-ET technology. Of course, the choice between these two treatments still depends on the patient's specific circumstances. China's work in this field started relatively late. In 1985, the first test-tube baby was born in Taiwan Province, and in 1986, one was born in Hong Kong. The first test-tube baby in mainland China was born on March 10, 1988, and is now over ten years old, healthy and intelligent. Her mother was a 38-year-old woman with 20 years of primary infertility and blocked bilateral fallopian tubes. Reproductive medicine research centers at Hunan Medical University and the First Affiliated Hospital of Zhongshan Medical University have also succeeded in this field. So far, more than 100 medical institutions in China have conducted IVF-ET, but the number of cases is not yet large, with clinical pregnancy success rates reaching around 20%. In terms of new technologies, Shandong Provincial Hospital reported the first successful pregnancy in China through gamete intrauterine transfer in 1992, with delivery in May 1992. Zhongshan Medical University conducted the first test-tube baby using micromanipulation intracytoplasmic sperm injection (ICSI) in April 1996, marking the advancement of in vitro fertilization and embryo transfer in mainland China.
[World Test-Tube Baby Birth Records]
1978.7.25 British female, the world's first test-tube baby
1978.10.3 Indian female, the first in India
1979.1.14 British male, the first male baby
1979.6.23 Australian female, the first in Australia
1980.6.6 Australian, first set of test-tube baby twins
1981.10.19 British female, the first mixed-race test-tube baby
1981.12.28 American female, the first in the US
1982.1.20 Greek female, the first in Greece
1982.2.24 French female, the first in France
1982.6.25 British female, the first test-tube baby mother gives birth to another test-tube baby
1982.9.22 Israeli female, the first in Israel
1982.9.27 Swedish female, the first in Sweden
1983.5.20 Singapore male, the first test-tube baby in Southeast Asia
1983.6.8 Australian, first set of triplets
1984.1.16 Australian, first set of quadruplets
1985.4.16 Taiwanese male, first test-tube baby in Taiwan
1988.3.10 Chinese female, the first test-tube baby in mainland China
[Defects]
Currently, scientists cannot accurately explain why test-tube babies may face greater health risks. Some assisted reproductive technology (IVF) experts point out that the high incidence of disease-related issues associated with test-tube fertilization can be traced back to the defects of the eggs used to create the embryos.
Three new studies show that an average of 42% of eggs prepared for test-tube fertilization carry genetic variations, making it difficult for the resulting fetus to be delivered vaginally. Some experts suggest this is attributed to the drugs used to stimulate ovulation. To make it easier to obtain eggs, doctors give women undergoing test-tube fertilization surgery medication in advance.
According to a BBC report, the eggs used in the laboratory to create embryos often carry genetic defects, leading more IVF experts to call for all eggs used to be screened. Currently, UK IVF policy requires eggs from women over 35 to be scanned for abnormal chromosome numbers.
This finding has predictably increased the demand for pre-implantation genetic diagnosis (PGD) before embryo transfer to the uterus, which is a program to check for abnormal genes in a single cell of an early embryo. This program may sometimes directly cause the death of the embryo, but more importantly, as a "search-and-destroy" method, it effectively reduces the number of children believed to have poor genetic quality.
Now, the first generation of test-tube babies has grown up. The birth of their offspring has made the health-related issues caused by test-tube babies even more complex.
Severe Consequences of Abuse
The International Committee for Monitoring Assisted Reproductive Technology released a report on June 21, 2006, stating that since the birth of the world's first test-tube baby in 1978, more than 3 million infants have been born worldwide through test-tube fertilization. Committee expert Jacques Cohen said that about 1 million test-tube fertilization procedures are performed annually, with approximately 200,000 babies born each year.
Although it has developed rapidly for over 20 years, test-tube fertilization technology has spawned an industry with annual revenues exceeding 100 million US dollars, but recent safety issues have led to increasing criticism of it.
In fact, before it was discovered that test-tube babies may face greater health risks, the application of test-tube fertilization technology had already caused many problems. Many women believe that with test-tube fertilization technology, they can postpone childbirth indefinitely and pay to have a child when they are ready. However, most people do not know that the average pregnancy rate of test-tube fertilization is only 25.1%, with a birth rate of 18.5%; nor do they know that the process is painful and often dangerous.
Professor He Fangfang from the Department of Assisted Reproduction and Prenatal Diagnosis at Peking Union Medical College said that the number of infertile people in China is increasing year by year. "Apart from congenital diseases, many people have themselves," she said. "Many women, due to high work pressure, always think they can put off having children for later, making those who are naturally fertile suffer from infertility, while test-tube fertilization technology is only suitable for 1%～2% of infertile women."
In China, one in every 10 couples of childbearing age is infertile. The huge market demand has led many medical institutions to carry out test-tube fertilization technology. Geneticist Lu Guang believes that if the abuse of this technology is not curbed, it will affect China's population security. She said, "This is far more serious than farmers buying fake seeds causing a grain shortage, and if the application and management of test-tube babies is out of control, problems such as defective children, gender imbalance, and inbreeding will arise one after another, severely affecting China's population security."
[Explanation of Test-Tube Baby Technology]
Immature Ovum Culture (IVM)
While the traditional test-tube baby technology has helped many patients realize their dream of having children, some patients, such as those with polycystic ovary syndrome and ovarian hyperstimulation syndrome, require immature ovum culture technology in clinical practice. The characteristic of this technology is that eggs are retrieved from the body when they are very young and cultured in specific conditions outside the body to mature into mature eggs, thus avoiding the problem of immature eggs in polycystic ovary syndrome patients and the difficulty of ovulation induction in ovarian hyperstimulation syndrome patients.
The success rate of IVM is lower than that of the first and second-generation test-tube babies, ranging between 15-30%, and only a few reproductive medicine centers in China currently possess this technology.
Natural Cycle Test-Tube Baby
Natural cycle test-tube baby is a new treatment method that has recently attracted attention. Its theoretical basis is that some patients have good ovarian reserves and can completely adopt immature ovum culture technology to cultivate their own mature follicles, and then proceed with test-tube baby. This does not require ovulation-inducing drugs, avoiding repeated stimulation of the ovaries by drugs, reducing ovarian hyperstimulation, and also reducing treatment costs, as drug costs account for 50% of the total cost of conventional test-tube baby treatment. If the conventional test-tube baby treatment fails, it is usually necessary to rest the ovaries for 2－3 months before starting treatment in the next cycle. However, due to the lack of stimulation of the ovaries by drugs in the natural cycle, it is possible to enter the next cycle of treatment immediately after failure. This continuity of time is also more convenient for professional women and women of advanced age to shorten the treatment cycle.
Natural cycle has not yet been widely adopted, and there is currently no clear literature report on its success rate, but it is generally believed that the success rate of the natural cycle is lower than that of the ovulation-stimulated cycle, with excellent centers achieving success rates above 30%.