Who is a candidate for in vitro fertilization?

Couples who have not been able to conceive naturally may be advised to try IVF to increase their chances of having a baby. Many of these couples try other fertility treatments first, such as intrauterine insemination (IUI) or timed intercourse with the aid of ovulation predictor kits and/or ovulation medication. Same-sex couples or single people may also use in vitro fertilization to have a baby.

Female factor infertility is a common reason that people consider IVF,ⁱ with fallopian tube damage, endometriosis, inability to ovulate, advanced age, and/or diminished ovarian reserve being common examples of female factors. For couples with male factor infertility, IVF (often with the use of intracytoplasmic sperm injection (ICSI)) is an option when there is a decreased sperm count, poor motility of sperm, and abnormal shape or size of sperm. IVF may also be a good choice for anyone with unexplained fertility problems, which affect about one third of people who seek fertility treatment.

Another instance when IVF may be helpful is when one or both parents have a genetic disorder or are carriers of the same condition — even if they could conceive without intervention. Preimplantation genetic testing (PGT) can help parents prevent passing on these conditions.

There are two types of genetic testing used prior to IVF:

• Preimplantation genetic testing for monogenic disorders (PGT-M), which tests for inherited conditions caused by a single gene
• Preimplantation genetic testing for structural rearrangements (PGT-SR), which can identify structural chromosomal abnormalities

A third type of PGT called preimplantation genetic testing for aneuploidies (PGT-A) may be used by anyone undergoing IVF to help identify embryos that have a normal number of chromosomes (“euploid”).

The chances of success with IVF depend on a number of factors, including age, overall health, and the cause and duration of the fertility issues. According to the Centers for Disease Control and Prevention (CDC), 1.9 percent of babies born in the U.S. in 2018 were conceived using assisted reproductive technology (ART) such as IVF.ⁱⁱ

What is the IVF process?

In vitro fertilization can be a long process involving numerous steps, many of them tied to hormonal cycles.ⁱⁱⁱ These steps are listed below.

Preparation and priming

In preparation for IVF, doctors will order a series of tests and examinations.

To assess ovarian reserve, which helps estimate the quantity of eggs remaining in the ovaries, doctors will measure the level of anti-Müllerian hormone (AMH). AMH plays an important role in regulating the ovarian follicle production process. There is an established relationship between AMH levels and follicle count, pregnancy rate, and live birth rate.^iv

To further understand a patient’s ovarian reserve, doctors may perform an antral follicle count (AFC). Follicles, which are the fluid-filled sacs within the ovaries that contain eggs, can be seen and counted during a transvaginal ultrasound. AMH and AFC ovarian reserve testing are often used together to predict ovarian reserve.^v

Blood tests may also be used or required by insurance to assess follicle-stimulating hormone (FSH), which may help in predicting response to ovarian stimulation drugs during IVF. In addition, physicians may sometimes test other hormone levels that could impact the IVF process, including luteinizing hormone (LH), thyroid-stimulating hormone, prolactin, and progesterone.

A complete workup will include an evaluation of the female's uterus and its endometrial lining. These tests may include a saline infusion sonohysterogram (SIS), which is a type of ultrasound, and a hysterosalpingogram (HSG), which is an X-ray of the uterus.

Around this time in the process, a sperm sample will be taken from the male partner for testing.

To prepare for IVF, doctors may prescribe hormones such as birth control pills,^vi growth hormone, estrogen, testosterone (such as AndroGel), or a gonadotropin-releasing hormone (GnRH) agonist (such as Lupron) up to a few menstrual cycles before IVF. Some people may also be told to take natural supplements during the cycles before IVF.

Ovarian stimulation ("stimming")

During a typical menstrual cycle, a female’s body produces a single egg. However, during the IVF process, medications are used to stimulate the production of multiple eggs to increase the chances of creating a viable embryo. Ovarian stimulation is the process of using fertility drugs to stimulate the ovaries to produce multiple eggs in a single cycle.

During the stimulation phase, doctors will prescribe fertility medications called gonadotropins. Gonadotropins are a class of hormones, including FSH and LH, that are naturally found in the body to stimulate follicle growth and ovulation. They are generally taken by self-administered injection.

There are different protocols used for ovarian stimulation, and doctors select one based on a patient’s individual factors.^vii Typical stimulation drugs include Gonal-F (FSH), Menopur (FSH/LH), Lupron (GnRH agonist), and Cetrotide (GnRH antagonist). Multiple combinations of these drugs can be used for varying durations and at different times, depending on the protocol type. The two main types of protocols are agonist and antagonist:

• ‍The agonist protocol: It uses Lupron to slowly suppress the pituitary, after which ovarian stimulation proceeds.
• ‍The antagonist protocol: It involves much quicker pituitary suppression, making it a shorter process overall and reducing the chance of ovarian hyperstimulation syndrome (OHSS), a rare but dangerous condition where the ovaries swell as an exaggerated response to the fertility medication.^viii

While there is no difference in live birth rate between protocols, patients may respond better to one over the other and have fewer side effects based on which regimen they follow.

In addition to the two most frequently used protocols, there are several other protocols that may be indicated depending on a female’s individual circumstances:

• ‍Duo stim protocol: It involves stimulating egg production twice in a single cycle, during both the follicular and luteal phases.
• ‍Mini IVF: It involves lower doses of medications.
• ‍Flare protocol: It may be tried when a patient doesn't respond well to other protocols. It uses lower doses of a GnRH agonist.

During stims, patients’ cycles are monitored frequently using bloodwork to measure estrogen, LH, and serum progesterone (P4). Ultrasounds are also used to check follicle count and endometrial lining. It is crucial to check all these factors to ensure patients respond to medications and to determine when to proceed to the next step in the protocol. LH and P4 levels are sometimes tracked to ensure that patients are not ovulating early. For individuals planning a fresh embryo transfer, the endometrial lining is measured to ensure adequate thickness and to check for a trilaminar structure, which is ideal for embryo implantation.

Triggering

Triggering is when doctors induce maturation of the oocytes. Mature eggs are needed before retrieval, as only mature eggs can be fertilized.

Once the follicles reach an adequate size, usually 14 to 22 millimeters, patients will inject a trigger medication to prompt the eggs to undergo maturation, which is the final step before ovulation. The egg retrieval will be scheduled for about 34 to 36 hours later, prior to actual ovulation.

The trigger medication is typically a human chorionic gonadotropin (hCG) medication such as Pregnyl or Ovidrel. Alternatively, a GnRH agonist (such as Lupron) may be used to trigger, particularly when there is a high risk of OHSS. Many females take both triggers, known as dual trigger, to prompt maturation.

Egg retrieval

Egg retrieval, also known as follicular aspiration or oocyte pick up, is a surgical procedure where a needle is inserted into the ovary (typically through the vagina) to suction out eggs for fertilization. This roughly half-hour procedure is performed under general anesthetic, or narcotic conscious sedation, depending on the clinic.

There is some debate about the optimal goal, or a desirable number of eggs to obtain during retrieval. A 2018 study of nearly 14,500 females under 40 found that the mean number of eggs retrieved during an IVF cycle was 12.3 for individuals who eventually had a live birth, and 8.9 for those who did not end up giving birth.^ix

Another study out of Sweden in 2018 looked at 39,387 patients undergoing numerous cycles of IVF and found that retrieving 18 eggs offered the optimal balance between live births and minimal adverse outcomes. The study also reported a 30.3 percent live birth rate for a patient of 34 years old when using 11 eggs or more.^x

After egg retrieval, some patients may freeze their eggs in a process known as egg cryopreservation.

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Fertilization

Once the eggs have been retrieved, they are combined with sperm — typically a freshly collected or previously frozen sperm sample from a male partner or donor.

A process called intracytoplasmic sperm injection (ICSI) injects the sperm directly into the egg and is often used in cases of male factor infertility, or when fertilization rates are lower than expected.^xi Some clinics use ICSI for all patients. While the ICSI process may increase fertilization rates, it does not guarantee it.

Embryo culture

Embryo culture is the process of monitoring the inseminated eggs as they develop into embryos. Doctors examine the eggs for evidence of fertilization and evaluate their appearance and growth as they mature.

Once the sperm and the egg have combined into a fertilized egg, the newly formed cell is called a zygote. The zygote then begins to divide, first into two cells, and then four, eight, and so on. A blastocyst is formed five to six days after fertilization; it contains around 100 to 150 cells.^xii The inner cell mass will later become the embryo, and an outer layer of cells — called the trophoblast — later becomes the placenta.

Embryo transfer

Embryo transfer involves placing the embryos into the uterus of the parent or gestational carrier.

The process entails inserting a tube into the female’s uterus through the vagina and passing the embryo or embryos through the tube. A female becomes pregnant when one or more blastocysts implant into the lining of the uterus. Pregnancy is determined with a blood test (beta-hCG), typically administered nine to 12 days after the procedure.

The decision of how many embryos to transfer is made by the doctor and patient in advance. If a patient has surplus healthy, potentially viable unused embryos, they can be frozen for future transfers. That patient will not need to undergo the stimming process or retrieval again. They can simply use their existing embryos to potentially achieve a pregnancy.

Some clinics recommend a “freeze-all” strategy, in which all embryos are frozen, and the transfer occurs after the next menstrual cycle instead of immediately. There are several reasons for this recommendation:

• Ovarian stimulation can impact the lining of the uterus and lead to lower pregnancy rates
• Ovarian simulation may cause the endometrial receptivity to be out of sync with embryo development (in cases of premature luteinization)
• Some patients prefer to have a “break” after going through stimulation and retrieval
• The embryos will be undergoing genetic testing^xiii  

When frozen embryos are used, the transfer is called a frozen embryo transfer (FET).

A 2020 review found that a freeze-all strategy led to a higher cumulative live birth rate among females who had produced over 10 eggs.^xiv However, for females who do not produce as many eggs, fresh transfers led to a higher live birth rate when compared to individuals receiving frozen embryos, according to a 2018 report.^xv

How to choose an IVF clinic?

Anyone who is considering in vitro fertilization should spend time researching fertility clinics and physicians. It may be beneficial to schedule consultations with a few different clinics before selecting one.

The cost of IVF and the availability of publicly funded care and private insurance coverage vary greatly. The clinic should give potential clients a breakdown of all different costs for every stage of IVF. Some clinics will offer payment plans.

Fertility clinic staff should also be able to answer these important questions:

1. Are there particular protocols that the clinic (or doctor) prefers?
2. Does the clinic provide a one-doctor-per-patient model or a rotational-doctors-per-patient model? Will you see doctors or nurse practitioners for consultations? Who will perform the ultrasound monitoring, retrieval(s), and transfer(s)?
3. Does the clinic have cut-offs or exclusions regarding age or other factors?
4. Can more than one embryo be transferred (for advanced age or poor prognosis)?
5. Is the doctor for or against PGT? If the embryos are PGT-A tested, what occurs to the mosaics or abnormal embryos? Is the clinic willing to transfer them?
6. What are the clinic’s processes for the embryos after treatments cease? Will they destroy or donate to other families (with permission)?
7. Are there certain days of the week where retrievals and transfers are not performed? Does the clinic “batch” patients?
8. What is the fertilization rate of the IVF laboratory?
9. What is the rate of blastocyst formation for the IVF laboratory?

What are the risks of IVF?

In vitro fertilization is a medical procedure and, as such, has risks associated with the process.

Multiple pregnancy

The risk of multiple pregnancy has traditionally been the biggest health risk of fertility treatment.^xvi Originally, it was estimated that roughly 30 percent of IVF pregnancies result in multiple births.^xvii More recently, this figure has been reduced to around 10 percent in some clinics,^xviii largely due to single embryo transfer (SET) becoming the preferred practice. In cases where IVF treatments result in a multiple pregnancy, selective reduction may also be used to reduce the number of embryos, particularly if there is concern regarding the health of the developing fetuses or the person carrying the pregnancy.

Ectopic pregnancy

An ectopic pregnancy occurs when the implanted embryo attaches to somewhere other than the uterine lining, most often in the fallopian tubes. An ectopic pregnancy can cause maternal death if it is not detected, then treated and/or removed.

Previously, IVF was associated with a significantly higher rate of ectopic pregnancy compared to natural conception.^xix But advances in assisted reproductive technology have reduced this rate significantly such that it is now comparable to natural conception, especially when only one embryo is transferred. The risk of ectopic pregnancy increases with each embryo transferred.

Ovarian hyperstimulation syndrome (OHSS)

Ovarian hyperstimulation syndrome is a reaction to the ovary-stimulating hormones used during IVF. While most cases of OHSS are mild, the condition can become serious and life-threatening.^xx

It is estimated that moderate OHSS occurs in 3 to 6 percent of assisted reproductive technology (ART) cycles and severe OHSS in 0.1 to 2 percent of cycles.^xxi,xxii Overall, the risk of mild OHSS complications in ART cycles may occur in over 20 percent of cycles.^xxiii,xxiv

However, it is worth nothing that incidence rates for OHSS are variable between studies and populations. In addition, as alternatives to hCG triggers (or lower doses) become more common in at-risk patients, and more freeze-all cycles are conducted, the incidence of OHSS continues to decline.^xxv

What are the success rates of IVF?

There are numerous factors that impact a female’s chances of success with in vitro fertilization. These include the length of time of fertility problems, maternal age, and the presence of reproductive-related health conditions such as endometriosis.^xxvi

Here are the live birth per embryo transfer rates according to the National Health Service in the U.K.:.^xxvii

• 29 percent for females under 35
• 23 percent for females aged 35 to 37
• 15 percent for females aged 38 to 39
• 9 percent for females aged 40 to 42
• 3 percent for females aged 43 to 44
• 2 percent for females over 44

Alternatively, a 2019 retrospective study of 201 couples undergoing IVF with an average age of 34 reported that the pregnancy rate was 21.9 percent and live birth rate was 13.2 percent for the first cycle.^xxviii The study reported that longer duration of fertility problems and more advanced maternal age predicted lower success rates.

Some statistics are derived from looking at live birth rates after six or more IVF cycles. A study published in 2015 in the Journal of the American Medical Association looked at the cumulative live birth rates of IVF patients after analyzing 257,398 IVF cycles.^xxix This rate continued to increase up to the ninth cycle of IVF, with 65.3 percent of patients achieving a live birth by the sixth cycle. Live birth rates were also stratified by age:

• ‍Females under 40: Cumulative live birth rate of 68.4 percent after six IVF cycles
• ‍Females 40 to 42: Cumulative live birth rate of 31.5 percent after six cycles
• ‍Females over 42: Cumulative live birth rate of less than 4 percent for any number of cycles

Reproductive health and IVF success rates

Certain factors or health conditions may impact the success of in vitro fertilization.

In females, the most significant factor for IVF success is age. Increasing age is associated with reduced chance of clinical pregnancy and live birth outcomes.^xxx Severe endometriosis can also have repercussions and is associated with reduced implantation and clinical pregnancy rates in patients undergoing IVF, according to a 2013 meta-analysis.^xxxi The thickness of the endometrial lining is another factor. A 2018 retrospective cohort study found that pregnancy and live birth rates improved with increased endometrial thickness.^xxxii

In males, many factors contribute to IVF’s possible success. A 2019 study published in Human Reproduction that looked at 2,425 IVF cycles in heterosexual couples with unexplained fertility challenges found that pregnancy and live birth rates worsened with every year of male age, with a significant difference for males over 50 compared to those 40 or younger.^xxxiii

Conclusion

In vitro fertilization is a complex and expensive procedure that can be emotionally and physically taxing. However, it may be a way to achieve a successful pregnancy where other options have failed.