Patient education: In vitro fertilization (IVF) (Beyond the Basics)

IN VITRO FERTILIZATION OVERVIEW — In vitro fertilization (IVF) is a treatment for infertility. Doctors generally use the term "infertility" when a couple is unable to become pregnant after one year of unprotected sex.

For IVF, a person's eggs are fertilized by sperm in a laboratory. The fertilized eggs develop into embryos. One or more of the embryos are then transferred into the uterus, where it is hoped that one will implant and produce a pregnancy.

This topic will discuss the reasons IVF might be recommended, the medications used to prepare for IVF, and the outcomes of treatment. Other topics that discuss infertility are available separately:

●Diagnosis and evaluation of infertility (see "Patient education: Evaluation of infertility in couples (Beyond the Basics)")

●Treatment of infertility (see "Patient education: Treatment of male infertility (Beyond the Basics)" and "Patient education: Ovulation induction with clomiphene or letrozole (Beyond the Basics)" and "Patient education: Infertility treatment with gonadotropins (Beyond the Basics)")

WHO SHOULD CONSIDER IN VITRO FERTILIZATION? — Examples of people who might choose IVF include those who:

●Have infertility due to absent or blocked fallopian tubes or severe "male factor infertility" (when sperm counts or sperm motility is low, or sperm needs to be extracted surgically from the testicles)

●Have infertility due to other causes (eg, endometriosis, ovulation disorders, unexplained infertility), if other treatments have not worked

●Have infertility and are age 40 years or older, and want to maximize chances of pregnancy as soon as possible

●Have an inherited genetic disease that they wish to avoid passing on to their child – In this case, IVF is combined with "preimplantation genetic testing." This means that the embryos (or in some cases, just the eggs) are tested for the disease, and only those without the disease are transferred to the uterus.

●Have ovarian insufficiency (when the ovaries stop producing eggs earlier than normal) and plan to use "donor" eggs from another person

●Wish to get pregnant with donor sperm or a donor embryo (eg, single females, female couples)

●Plan to use a gestational carrier or "surrogate" to carry a pregnancy for them (eg, people with a health condition that makes it impossible or unsafe to get pregnant, single males, male couples)

Although IVF has a high rate of success in helping people get pregnant and allows for the freezing and storing of embryos for future use, it has some disadvantages. These include high costs, potential side effects of injectable fertility medications and invasive procedures used, and a potentially increased risk of multiple gestation (ie, twins or triplets) if multiple embryos are transferred, which also increases the risk of ovarian hyperstimulation syndrome (see 'Side effects of treatment' below). There may also be an increased risk of some pregnancy complications, such as hypertensive disorders in pregnancy and preterm birth. Ectopic pregnancies can occur after IVF, although the risk is much lower than with other fertility therapies.

If you are considering IVF, it's important to discuss the risks, benefits, and alternatives with your health care provider before beginning treatment. In most cases, several cycles of a less expensive and less invasive infertility treatment are recommended before moving on to IVF.

IN VITRO FERTILIZATION PROCEDURE — The IVF procedure consists of several steps that take place over a period of weeks:

●Education of the person undergoing IVF (and their partner, if applicable) about the complex steps involved, the risks and benefits of IVF, and techniques for giving injections at home

●Stimulation of the ovaries to produce several ovarian follicles, each of which contains an egg ("oocyte")

●Retrieval of the eggs from the ovaries and obtaining a semen sample

●Fertilization of the eggs with sperm and growth of the embryos in the laboratory

●Transfer of one or more embryos into the uterus

IVF can also be done using donor eggs and/or sperm from another person.

More than one cycle of IVF treatment may be necessary before pregnancy occurs. Unfortunately, some people will not become pregnant despite multiple IVF attempts.

Ovarian stimulation — The first step of the IVF procedure generally involves the use of fertility medications to increase the number of eggs (follicles) that develop in the ovaries and control the time of ovulation. The medication regimen depends on the reason the person is doing IVF (ie, whether there are specific causes for infertility) as well as the IVF center's protocols.

It is also possible to perform IVF without ovarian stimulation. This is known as "natural cycle IVF," "unstimulated IVF," or "modified natural cycle IVF"; usually only one egg is retrieved. However, the vast majority of IVF cycles worldwide are performed with some type of ovarian stimulation because natural cycle IVF is associated with very low pregnancy rates.

The ovarian stimulation regimen described below is an example and may differ from that recommended by your doctor.

●Many clinicians will prescribe a birth control pill to take for one or more weeks before beginning IVF. The pill helps to prevent your body from releasing hormones that could stimulate natural ovulation.

●Most programs ask that you call on the first or second day of your period to schedule an appointment for blood tests and an ultrasound. The first day of menstrual bleeding is considered day one of the cycle.

●On day two or three, you may be asked to have a pelvic (vaginal) ultrasound to evaluate your ovaries and blood testing to measure hormone levels. If everything looks as expected, you will be given a date to start giving yourself injections with follicle-stimulating hormone (FSH). This hormone stimulates the growth of egg follicles.

In most cases, you will give yourself injections of FSH once per day, generally in the evening. The injection can usually be given under the skin, rather than deep into the muscle.

●After a few days of injections, you will be asked to have a pelvic ultrasound to measure follicle growth and a blood test to measure hormone levels. Depending upon the results of these tests, the dose of FSH may be increased or decreased. Blood testing and pelvic ultrasound may be repeated several times during a cycle.

●In some cases, a class of medication called a GnRH antagonist such as cetrorelix (brand name: Cetrotide) or ganirelix (brand name: Antagon) will be recommended instead of the GnRH agonist. In this case, stimulation with FSH is started immediately after stopping the birth control pill and the antagonist is added once the follicles have reached a certain size (often around 14 mm). This medication helps to prevent premature ovulation.

●The goal of stimulation is to have at least two follicles that are approximately 15 to 18 mm in size. The number of follicles that develops depends on your ovaries and hormone levels. In most cases, more than 2 follicles develop; in some cases, more than 20 may develop. When blood testing and ultrasound measurements show that the follicles are "ready," you will be instructed to give an injection of hCG to trigger ovulation. hCG stands for "human chorionic gonadotropin." It is usually injected under the skin at a specific time in the evening. This allows the follicles to be ready for egg retrieval during a window of time, approximately 36 hours later. In some cases, a GnRH agonist like leuprolide (brand name: Lupron) may be used to trigger ovulation.

Side effects of treatment — FSH injections do not cause side effects directly. However, the ovaries become enlarged during treatment, which can cause abdominal swelling and discomfort, and in more severe cases, nausea or even vomiting.

Ovarian hyperstimulation syndrome (OHSS) is a condition in which the side effects of ovarian enlargement and abdominal swelling become extreme. This can cause severe abdominal pain, vomiting, and if untreated, blood clots in the legs or lungs and fluid imbalances in the blood. Mild forms of OHSS occur in 2 to 6 percent of people undergoing ovulation induction for IVF. Severe cases of OHSS occur in approximately 1 percent of cases, typically in association with the retrieval of more than 20 eggs.

The risk of OHSS can be reduced by utilizing a GnRH agonist medication such as depot leuprolide, avoiding fresh embryo transfer (ie, transferring embryo(s) immediately after the retrieval), or by canceling the IVF cycle when blood estrogen levels become too high or there are too many follicles seen on ultrasound (these are uncommon). Using a GnRH agonist instead of hCG to trigger ovulation may decrease the risk of OHSS and may be recommended in some cases. If the decision to defer embryo transfer is made after eggs are retrieved, they are often fertilized and cryopreserved for use in a subsequent cycle. (See 'Storing unused embryos' below.)

Egg retrieval — Approximately 35 to 36 hours after injecting hCG, a procedure is performed to retrieve the eggs. The doctor inserts an ultrasound probe into the vagina and then uses a needle to withdraw the egg from each follicle. The procedure takes approximately 15 to 30 minutes, depending upon how many follicles are present, and is performed under conscious sedation (ie, light anesthesia).

Serious complications of egg retrieval are uncommon, but side effects such as pelvic cramping, light bleeding, and vaginal discharge often occur. If these problems are persistent or become severe, it is important to call your health care provider as soon as possible. Abdominal swelling and discomfort may also be signs of early ovarian hyperstimulation syndrome (OHSS), so close contact with the health care provider(s) is a good idea.

After the retrieval, you will be monitored in a recovery area for a few hours and then allowed to go home. Due to the effects of the anesthesia, you should not drive or return to work for approximately 24 hours.

Fertilization — After the retrieval procedure, the eggs are combined with sperm in a laboratory dish so they will fertilize. The sperm can be from your partner or from a donor bank. In general, approximately 65 percent of eggs are successfully fertilized. The fertilized egg is called an "embryo."

In cases of severe male factor infertility, fertilization is done with a procedure called "intracytoplasmic sperm injection" (ICSI), which involves injecting one sperm into an egg using a micro-needle and a microscope. ICSI is an option for all males with severe male factor infertility, regardless of their sperm count. Fertilization rates with ICSI range from 50 to 70 percent

Embryo transfer — Embryos can be transferred a few days after oocyte retrieval (known as a "fresh cycle") or after having been previously frozen and thawed ("frozen cycle"). Frozen embryo transfer is more common as it provides time to obtain results from preimplantation genetic testing.

●Fresh embryo transfer – Fresh embryo transfer is generally performed on day 3 or day 5 after egg retrieval. One or more embryos are placed in the uterus using a thin, flexible tube (catheter) inserted through the cervix.

●Frozen embryo transfer – A frozen embryo transfer cycle can be done in the cycle after an IVF cycle. Hormones such as estrogen (in the form of pills, patches, or an injection) are given to build the lining of the uterus, and progesterone injections and/or vaginal suppositories are given in timing with the embryo transfer later in the cycle. Natural or modified natural cycle embryo transfers can also be performed, in which the timing of the embryo transfer is related to the date of ovulation, typically three to five days after ovulation occurs (depending on the stage of the embryo).

●Procedure and aftercare – A speculum is placed in the vagina and a soft plastic catheter is inserted through the cervix as gently as possible to minimize uterine cramping. Traumatic transfer procedures are associated with lower success rates. Anesthesia is not usually needed for this procedure.

Following the transfer procedure, you will most likely be encouraged to rest at home for several hours. Although studies do not show that rest increases the chance of pregnancy, many people prefer not to resume their normal activities immediately.

Most clinicians will prescribe a progesterone medication to improve the chances that the embryo will implant inside the uterus. This medication is started either on the day of retrieval or the day of transfer. There are several ways to administer progesterone, with the most common being a vaginal gel or suppository, or an injection given into a muscle.

How many embryos to transfer? — The number of embryos transferred depends upon your preferences, history of pregnancy and/or pregnancy loss (miscarriage), age, and the quality of the embryos. Younger people (under age 35) in their first cycle of IVF are often encouraged to have only one embryo transferred. If you do not get pregnant after multiple IVF cycles, your doctor may recommend transferring more than one or two embryos to increase the chances of pregnancy. However, this may also increase the risk of multiple gestation (such as twins or triplets).

The rate of successful implantation is lower in people over age 40 years; as a result, more embryos (eg, up to five) are often transferred in these cases. However, older people who are using eggs from younger donors (eg, donor eggs) have a rate of implantation similar to that of younger people, and are generally advised to transfer no more than one or two embryos.

Storing unused embryos — Embryos that are not transferred may be stored by freezing them (called "cryopreservation"). The chances of a successful pregnancy are similar for frozen and fresh embryos.

The frozen embryos can be stored for an unlimited period of time. However, most couples are encouraged to eventually choose one of the following options:

●Transfer the embryos at a later date

●Donate them for research or for use by another couple

●Dispose of the embryos

Preimplantation genetic testing (PGT) of embryos — Preimplantation genetic testing (PGT) can be done to determine the number of chromosomes (PGT-A), test for presence of a specific disease or gene abnormality (PGT-M), or test for abnormal chromosome structure (PGT-SR). Your health care provider can talk to you about your options and whether PGT is appropriate for your situation.

●PGT-A – Embryos can be tested to see if they are chromosomally normal ("euploid") or abnormal ("aneuploid"). This is called "preimplantation genetic testing for aneuploidy" (PGT-A). If you choose to do this, your embryo(s) will be grown to the blastocyst stage (which can happen between days 5 to 7), then tested and frozen for potential future use.

●PGT-M – Some people learn that they (or their partner) are carriers of a disease-specific gene or a known genetic mutation that could be passed on to their children. For example, if both parents have a gene for cystic fibrosis or sickle cell anemia, each of their children will have a one in four chance of inheriting both genes and having the disease. People with a mutation in their BRCA gene, which increases the risk of breast and ovarian cancer, may want to avoid passing this gene on to a child. In these situations, a person or couple may choose to have their embryos tested prior to transfer to find out which of the embryos have the disease or genetic mutation, and then transfer only those which do not. This is called "preimplantation genetic testing for monogenic disease" (PGT-M).

●PGT–SR – Rarely, some couples with recurrent pregnancy loss (multiple miscarriages) will have one partner diagnosed with a "translocation," in which pieces of DNA between two chromosomes exchange material. This can result in a higher number of eggs or sperm with unbalanced chromosomes. People in this situation may do IVF to test embryos for these translocations; this is called "preimplantation genetic testing for structural rearrangements" (PGT-SR).

In other instances, the chromosomes of the embryo may be tested in an effort to decrease the risk of chromosomal anomalies (such as Down syndrome). Chromosomal testing can also be done for sex selection, for example, if there is a risk for a particular disease that is much more prevalent in boys or girls, or for balanced family planning.

It is important to be aware that, while helpful in certain situations, pre-implantation testing is not perfect, and people who get pregnant after such testing still need to have standard prenatal testing. Furthermore, the process is still inefficient, meaning there can potentially be embryos that are lost as a result of the testing. Therefore, routine testing of all embryos prior to embryo transfer is not recommended, but rather decided on an individualized basis.

TESTING FOR PREGNANCY AFTER IN VITRO FERTILIZATION

Blood testing — Approximately two weeks after the embryo transfer, your provider will schedule a blood or urine test for human chorionic gonadotropin (hCG), the hormone that signifies pregnancy. Home urine pregnancy testing is not recommended, as it is less sensitive than blood testing for detecting an early pregnancy.

●If your first blood hCG level is <5 international units/L, this means you are not pregnant.

●If your first hCG level is >10 international units/L, the test is usually repeated 48 hours later to confirm that the levels are increasing. If you are pregnant, your hCG level should approximately double every 48 hours during the first 21 days after embryo transfer.

●If your second hCG level does not double or if it decreases, the blood test may be repeated again 48 hours later. Depending upon the situation, there is a possibility that the pregnancy is not viable or that it is growing outside of the uterus, such as in a fallopian tube (ie, ectopic pregnancy). hCG levels do not increase or begin to decline when the pregnancy is not progressing normally. (See 'When in vitro fertilization is not successful' below.)

Ultrasound — If your hCG levels increase as expected, a pelvic ultrasound may be done three to four weeks after the transfer. At this time, it is usually possible to see a gestational sac inside the uterus. The gestational sac is a fluid-filled sac containing the embryo (image 1).

At five to six weeks of pregnancy (three to four weeks after the transfer), the yolk sac is usually visible. The yolk sac provides nourishment to the embryo early in development. Fetal cardiac (heart) activity is usually visible by 6 to 6.5 weeks of pregnancy (4 to 4.5 weeks after the transfer).

Pregnancy care — In most cases, prenatal care begins at 6 to 10 weeks of pregnancy. At this time, you will begin to see your obstetrician, nurse, or midwife on a regular basis. These visits allow your provider to monitor you and your fetus and to answer any questions.

PREDICTING THE OUTCOME OF IN VITRO FERTILIZATION — A prediction model has been developed to predict the probability of IVF success over the course of the first three fresh autologous (non-donor) cycles and the first fresh donor cycle, and the effect of transferring one versus two embryos on the live birth rate and the multiple birth rate [1]. The model is available free of charge on the Society for Assisted Reproductive Technology (SART) website. People considering IVF can input their data on the website to generate their expected outcomes.

WHEN IN VITRO FERTILIZATION IS NOT SUCCESSFUL — IVF has a reasonable rate of success in most cases. Overall, approximately 30 percent of IVF cycles will end in a live birth, and the cumulative chances of success are higher when more than one cycle of IVF is done.

However, an individual's chance of success depends on several factors, including age, cause of infertility, and treatment approach. For example, in the United States in 2021, the live birth rate for each IVF cycle started was approximately 45 percent for people under age 35 years; 32 percent for people ages 35 to 37; 21 percent for people ages 38 to 40; 10 percent for people ages 41 to 42; and 3 percent for people over age 42. The success rates of individual infertility clinics in the United States are published on the internet at the Society for Assisted Reproductive Technology (www.sart.org/).

It can be difficult to deal with the emotional highs and lows of infertility treatment. This is especially true if you have been trying to conceive for a long time, if treatment is not covered by insurance, or if you are dealing with any underlying stressors (such as medical conditions, relationship problems with your partner or family, or job or financial stress).

Support groups and counseling services are available at many infertility treatment centers, as well as on the internet (see 'Where to get more information' below). To find a reputable group, talk to your health care provider.

COSTS OF IN VITRO FERTILIZATION TREATMENT — The costs of IVF treatments can be high, depending upon which tests are required, the type and dose of medication(s) used, and the number of cycles required to become pregnant. The average cost of an IVF cycle in the United States is more than USD $15,000. Insurance policies cover the costs of infertility treatment in some states, although this varies by location and individual insurance policy. Less than one-half of the states within the United States have laws requiring insurers to cover infertility treatment.

More information about a state's laws can be obtained by calling your state Insurance Commissioner's office.

WHERE TO GET MORE INFORMATION — Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Female infertility (The Basics)
Patient education: Male infertility (The Basics)
Patient education: Infertility in couples (The Basics)
Patient education: Endometriosis (The Basics)
Patient education: Ectopic pregnancy (The Basics)
Patient education: Turner syndrome (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient education: Evaluation of infertility in couples (Beyond the Basics)
Patient education: Treatment of male infertility (Beyond the Basics)
Patient education: Ovulation induction with clomiphene or letrozole (Beyond the Basics)
Patient education: Infertility treatment with gonadotropins (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Effects of advanced maternal age on pregnancy
Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history
Approach to the male with infertility
Gestational carrier pregnancy
In vitro fertilization: Overview of clinical issues and questions
Intracytoplasmic sperm injection
Female infertility: Treatments
Endometriosis: Treatment of infertility in females
Assisted reproductive technology: Pregnancy and maternal outcomes
Preimplantation genetic testing
Psychological stress and infertility
Strategies to control the rate of high order multiple gestation
Sex selection
Treatments for male infertility
Use of assisted reproduction in HIV- and hepatitis-infected couples

The following organizations also provide reliable health information.

●National Library of Medicine

     (www.nlm.nih.gov/medlineplus/healthtopics.html)

●American Society for Reproductive Medicine

     (www.asrm.org)

●Resolve: The National Infertility Association

     (www.resolve.org)

●The International Council on Infertility Information Dissemination

     (www.inciid.org/)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Paulson, MD, MS, who contributed to earlier versions of this topic review.