INTRODUCTION — In vitro fertilization (IVF) refers to a procedure designed to overcome infertility and produce a live birth as a direct result of the intervention. It is one type of assisted reproductive technology and is now used for indications beyond infertility. In general, IVF involves stimulating the ovaries with a combination of fertility medications, retrieving oocyte(s) from ovarian follicles, and fertilizing these oocytes in the laboratory ("in vitro"). The resultant embryo(s) are transferred into the uterine cavity. These steps typically occur over approximately a two-week interval of time, which is called an IVF cycle.
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.
TERMINOLOGY — The European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) have released terminology guidelines in attempt to standardize language for patients, clinicians, and researchers [1,2]. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'Terminology'.)
INITIAL EVALUATION AND TREATMENT
Infertility evaluation — Prior to IVF, patients undergo a complete evaluation to identify potential contributors to infertility or issues that may limit IVF success (eg, for patients using IVF for family building unrelated to infertility).
●(See "Female infertility: Evaluation".)
●(See "Approach to the male with infertility".)
Assessment of ovarian reserve — A variety of tests are available for measurement of ovarian reserve; no single test has demonstrated superiority over the others [3]. We perform cycle day 3 serum follicle-stimulating hormone (FSH) and estradiol levels because they are simple to obtain and cost effective [4]. (See "Female infertility: Evaluation", section on 'Assessment of ovarian reserve'.)
●Our approach – FSH is checked and used to prognosticate response to stimulation but not exclude patients from undergoing IVF. We measure serum FSH and estradiol on cycle day 3 (third day of menstrual bleeding) as the values can help predict patient response to ovarian stimulation. While we do not start IVF cycles in those with serum FSH concentrations >20 milli-international units/mL or serum estradiol concentrations >100 pg/mL (367 pmol/L) because these levels are associated with a poor prognosis, other practices may differ [5-8]. Since FSH concentrations fluctuate from cycle to cycle, individuals with mild to moderate elevations undergo repeat testing [9]. Very high levels (two or more times the upper range of normal for a given assay) have high-negative predictive value for pregnancy and other forms of therapy, including oocyte donation, should be discussed. For individuals with decreased ovarian reserve, there appears to be no age-related decline in fertility when donor oocytes are used [10]. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?'.)
●AMH – AMH alone is a good predictor of poor or excessive ovarian response but not of live birth [11-14].
●Ultrasound – For the ultrasound-based tests, a systematic review concluded that an abnormally low antral follicle count (AFC) was a better predictor of poor IVF response than ovarian volume, but neither ultrasound-based test was highly predictive of a low chance of pregnancy [15]. Several studies comparing AMH and ultrasound assessment of AFC reported that AMH more strongly correlated with oocyte yield after controlled ovarian stimulation than AFC [14,16-18].
●Additional tests – Other centers may use the following tests to identify individuals likely to have a poor response to IVF: clomiphene challenge test (CCCT), ultrasound assessment of antral follicle count (AFC) or ovarian volume, exogenous FSH ovarian reserve test (EFORT), or measurement of inhibin B levels [4,15,19-27]. While virtually all ART programs perform some type of ovarian reserve testing, the value of performing any of these tests has been questioned given their limitations [3,28].
Semen analysis — A semen analysis is a key component of evaluating male patients prior to fertility therapy, including IVF. (See "Approach to the male with infertility".)
Consider alternate therapies if appropriate — Most individuals pursue less invasive treatment options prior to IVF. Exceptions include individuals whose source of infertility is only resolved with IVF (eg, blocked fallopian tubes, severe male factor) and females over 40 years of age. The evaluation and management of older female patients is presented separately. (See "Evaluation and management of infertility in females of advancing age".)
Therapies may include:
●Targeted treatment for likely cause of infertility – Initial treatments are aimed at specific causes identified during the infertility evaluation, including ovulatory disorders and uterine factors (eg, intrauterine adhesions). (See "Female infertility: Treatments".)
●Observation with unprotected intercourse – For younger individuals with no identified block to conception, we typically advise one year of unprotected intercourse as approximately 85 percent will conceive during that time [29]. A shorter time period (six months of unprotected intercourse) is generally used for individuals aged 35 years or older. (See "Evaluation and management of infertility in females of advancing age".)
The rationale for a period of correctly timed intercourse is that individuals with open fallopian tubes and without severe male factor infertility have substantial treatment-independent pregnancy rates even if some indications for IVF are present (eg, pelvic disease, endometriosis, and/or unexplained fertility). (See "In vitro fertilization: Overview of clinical issues and questions", section on 'What are the pregnancy and live birth rates?'.)
●Ovulation induction with IUI – After an appropriate period of attempted conception with correctly timed intercourse, individuals who have not conceived may be offered three to six cycles of medication-induced ovulation (ie, superovulation) and intrauterine insemination (IUI) before proceeding with IVF.
•(See "Overview of ovulation induction".)
•(See "Procedure for intrauterine insemination (IUI) using processed sperm".)
IVF CYCLE — The general components of an IVF cycle are pharmacologic ovarian stimulation (ie, ovulation induction or superovulation) and oocyte aspiration. Depending on the goals of the patient, the oocytes may then be fertilized or cryopreserved.
Preparation — Prior to an IVF cycle, patients participate in the informed consent process to understand the procedure risks and alternatives. Most patients do not require prophylactic antibiotics, thromboprophylaxis, or steroid therapy but individual care plans may vary based on medical history and risk factors.
●Informed consent – The usual surgical risks of bleeding and infection are also included. A general discussion of the informed consent process is presented elsewhere. (See "Informed procedural consent".)
Specific risks of controlled hyperstimulation and IVF are discussed with all patients and include the following:
•Surgical risks <1 percent (bleeding, infection, damage to nearby structures) [30]
•Other (ovarian torsion <1 percent [31], ovarian hyperstimulation syndrome [OHSS] 1 to 5 percent of cycles [32-34] )
-(See "Ovarian and fallopian tube torsion".)
-(See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome".)
•Risks associated with pregnancy after IVF, including a higher risk of preeclampsia, preterm birth, low birth weight, and congenital anomalies, which are magnified in the setting of multiple gestation
-(See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
-(See "Assisted reproductive technology: Infant and child outcomes".)
●For select patients – Most patients undergoing IVF do not require thromboprophylaxis or glucocorticoids.
•Antibiotic prophylaxis – While routine use of antibiotics prior to embryo retrieval is not advised, antibiotic prophylaxis is planned for patients with higher risk of infection, including those with endometriosis, a history of multiple pelvic surgeries, ruptured appendicitis, and pelvic inflammatory disease [35,36].
•Thromboprophylaxis – Given the relatively young ages and good health of individuals undergoing IVF, most do not require pharmacologic or mechanical thromboprophylaxis prior to an IVF cycle [37,38]. Individuals who may benefit from pharmacologic prophylaxis include those with known thrombophilia or history of venous thromboembolism. Treatment decisions for these patients are made on an individual basis.
Calculation of the Caprini score (table 1) to assess individual risk of thromboembolism and selection of prophylaxis is reviewed in detail separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
•Use of glucocorticoids – Glucocorticoids are often used prior to IVF but use is not routine nor standardized across IVF programs and the benefit remains unclear. A meta-analysis of two trials comparing the impact of glucocorticoid supplementation or placebo reported similar live birth rates between the groups (odds ratio 1.37, 95% CI 0.69-2.21) [39]. More data is needed to determine whether glucocorticoid supplementation increases the live birth rate.
Ovarian stimulation — Ovarian stimulation refers to "pharmacologic treatment with the intent of inducing development of multiple ovarian follicles" [40]. Previously used terminology included "superovulation," "ovarian hyperstimulation," and "controlled ovarian stimulation." Ovarian stimulation differs from ovulation induction that is used for anovulatory individuals.
Rationale, candidates, and impact on pregnancy rate
●Rationale – Ovarian stimulation involves giving the patient drugs to increase the number of mature oocytes available for fertilization with the ultimate goal of increasing live birth rate [41,42]. Use of these protocols also increased the rate of multiple gestations.
●Candidates – Ovarian stimulation is for individuals planning an IVF cycle using fresh (ie, not frozen-thawed) embryos. Patients who are using donor eggs or frozen-thawed embryos do not need this step and proceed to preparation for embryo transfer.
●Impact on pregnancy rate and endometrial receptivity – Although controlled ovarian stimulation increases the number of oocytes obtained, it also appears to inhibit endometrial receptivity to some degree [43]. The resultant pregnancy rates are at least 10 percent lower compared with cycles without controlled ovarian hyperstimulation [44-47]. The most likely reason for diminished endometrial receptivity is the premature increase in progesterone that occurs with all forms of ovarian stimulation [48] and leads to an earlier appearance of the window of implantation and a relative degree of embryo-endometrial dyssynchrony [49]. The magnitude of the effect on endometrial receptivity is not clear, and embryo quality also likely plays a role. Controlled ovarian stimulation not only diminishes endometrial receptivity, but also may interfere with placental development and, in turn, pregnancy outcome [50-53]. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
Anticipated ovarian response — Approximately 10 percent of cycles are discontinued before egg retrieval [54]; the rate increases with increasing age. A cycle may be cancelled if there is poor or excessive ovarian response. Approximately 84 percent of discontinued cycles are due to no or inadequate egg production and 4 percent are due to hyperresponsiveness.
●Poor response – A poor response describes individuals whose ovaries require large doses of medication for stimulation but produce less than an optimal number of oocytes and/or achieve relatively low estradiol levels. The diagnosis has been applied to (1) individuals who have had a poor ovarian response after going through an IVF cycle, as well as (2) individuals who are likely to have a poor response based on their older age and a pre-cycle abnormal test of ovarian reserve (also called "expected poor responder" [55]). However, there is wide variation in the specific criteria used clinically and in research studies to define poor response [55,56]. In systematic reviews of randomized trials, no interventions have been highly effective for improving poor ovarian response in such patients [57-60]. The important consideration in these patients is whether or not to proceed with IVF using a modified approach, such as a mild stimulation protocol [61,62].
●High or excessive response – Individuals with a high response to ovarian stimulation produce large numbers of mature oocytes and/or high estradiol levels. Modification of the stimulation protocol is important to avoid ovarian hyperstimulation syndrome (OHSS). (See "In vitro fertilization: Overview of clinical issues and questions", section on 'What are the risks of the IVF procedure?'.)
●Protocol selection based on anticipated ovarian response – The selection of a long or short protocol and the specific agents are influenced by the anticipated ovarian response as determined by risk factors or the outcome of a prior IVF cycle. Long protocols are started in the cycle prior to the planned IVF cycle; short cycles are not. The following text is a brief overview:
•Good response – When a good ovarian response is anticipated, then a long protocol with either gonadotropin-releasing hormone (GnRH) agonist or GnRH antagonist is typically selected. Agonist protocols are generally preferred over antagonists because of lower cost. GnRH agonist protocols start with Lupron acetate given alone (started in the luteal phase of the prior cycle) or in combination with an oral contraceptive pill (OCP). For an OCP protocol, OCPs are started on day 2 to 3 of the cycle and gonadotropins are started typically on the fourth day after discontinuing OCPs.
•Poor response – Short protocols are typically used when a poor ovarian response is anticipated. Stimulation is achieved with human menopausal gonadotropins (hMG) or follicle-stimulating hormone (FSH) and spontaneous ovulation is blocked with either a GnRH agonist (by using the initial stimulation of leuprolide followed by the down regulation) or with a GnRH antagonist. GnRH antagonists are preferred over GnRH agonists for the short protocol.
Ovarian stimulation protocols — The following is an overview of commonly used protocols for controlled ovarian hyperstimulation.
●Role of FSH injection – Whereas multiple regimens of ovarian stimulation may be used, including those that use selective estrogen receptor modulators, such as clomiphene or tamoxifen, most programs utilize regimens that include daily injections of exogenous FSH. This is because these regimens result in higher oocyte yields as well as higher live birth rates per IVF cycle. While a 2015 meta-analysis reported that weekly use of long-acting FSH at doses of 150 to 180 mcg resulted in similar live birth rates compared with daily FSH injections [63], these medications are available for clinical use outside of the United States. Both standard and long-acting FSH preparations cause a reliable increase in serum FSH levels, which then stimulate multifollicular development in the ovaries. Choice of medication is determined by availability and cost.
●GnRH agonist (long) protocol – Long protocols have two parts: pituitary suppression followed by ovarian stimulation (figure 1). Pituitary suppression is begun the cycle prior to the planned ovarian stimulation to prevent luteinizing hormone (LH) surge before the cohort of stimulated ovarian follicles is mature. The long GnRH agonist protocol is typically chosen for those with good ovarian reserve to achieve synchronous follicle growth. It is not as commonly used as a GnRH antagonist protocol because a GnRH agonist trigger is not part of the protocol (use of a GnRH agonist trigger can decrease risk of OHSS).
•Pituitary suppression – One commonly used regimen to suppress pituitary LH release begins with a GnRH agonist that is administered daily for approximately two weeks or until down-regulation is complete (hence, "long protocol"). This protocol is used in a good-responder population, including those with favorable ovarian reserve markers. The long GnRH agonist protocol is less commonly used than antagonist protocols due to an inability to use the GnRH agonist trigger (which is used to prevent OHSS). It is still a protocol option for expected good responders in whom OHSS is less likely.
In the United States, either OCPs or norethindrone acetate are given orally for five to seven days prior to initiating the leuprolide acetate, after which there is an overlap of leuprolide and OCPs/norethindrone acetate for roughly one week. A daily dose of leuprolide acetate 0.5 to 1 mg is given subcutaneously during this time and for the remainder of the stimulation. Typically the leuprolide acetate is given for a minimum of 10 days before stimulation starts, and subsequently throughout the stimulation until the day of the trigger shot (another 10 days on average).
European clinicians more commonly use a single depot injection containing higher doses of the drug (typically the daily dosing is performed in the United States) [64]. Alternatively, leuprolide acetate can be initiated in the luteal phase of the proceeding cycle to avoid stimulating a release of endogenous FSH and LH since those hormones are relatively low in the luteal phase. Down-regulation is verified by serum estradiol measurement less than 30 pg/mL, prior to starting stimulation medications. Serum estradiol is measured on the day of stimulation start (if starting on day 2/3 of menses) or prior to stimulation start while on OCPs before they are discontinued approximately four days before stimulation start.
•Ovarian stimulation – For ovarian stimulation, hMG, FSH, or both [65] is administered in a dose of 150 to 450 (maximum dose) international units/day subcutaneously to stimulate follicular growth [65,66]. Individuals with good ovarian response require lower doses of medication.
While one meta-analysis of seven trials reported increased live birth rates with use of hMG versus recombinant FSH, the issue of hMG versus FSH alone remains controversial and a definitive advantage of one type of stimulation over the other has not yet been established. The GnRH agonist is continued at a lower dose to prevent a premature surge in LH secretion. The dose of hMG, FSH, or both is subsequently adjusted according to follicular growth (as determined by transvaginal ultrasonography) and serum estradiol concentrations (an indicator of granulosa cell proliferation).
-In a "step-down" protocol, the starting dose of gonadotropin is high, and this is followed by gradual reductions in dose during the cycle depending on the response.
-In a "step-up" protocol, the starting dose of gonadotropin is low and is then gradually increased during the cycle depending on the response.
●GnRH agonist flare (short) protocol – There are several variations of short GnRH agonist protocols (figure 1). The general approach is described here.
•Background – In patients who are poor responders to ovarian stimulation, the GnRH agonist may be administered in conjunction with ovarian stimulation, so that the initial (agonistic) response of the pituitary can be used for ovarian stimulation. These so-called "flare" protocols are initiated at the time of spontaneous menstruation or after several days or weeks of OCPs.
•Regimen – While several regimens exist, a common one uses a low-dose of leuprolide, 40 mcg twice daily, started on day 2 of bleeding or three to five days after the last OCP. This regimen is called a "microdose Lupron flare" and is most often combined with 450 international units of FSH or hMG. If a pure FSH protocol is used, then low-dose hCG can be added when the lead follicle is 14 mm to provide LH activity for follicular maturation. Initially, the release of FSH and LH from endogenous stores caused by leuprolide provides additional stimulation to the growing follicles, and subsequently prevents premature LH surges, as down-regulation is complete by day 5 of stimulation [67].
●GnRH antagonist protocol
•Background – GnRH antagonists result in more rapid pituitary desensitization than GnRH agonists. The GnRH antagonist protocol can be utilized in conjunction with oral ovulation induction agents such as clomiphene citrate or letrozole in patients with a predicted poor response.
-In good-responder protocols, a lower dose of gonadotropins is used. Providers trigger ovulation with a GnRH agonist, which minimizes the risk of OHSS.
-In poor-responder protocols, typically the maximum dose of gonadotropins is used in combination with an oral agent like clomiphene citrate, which harnesses endogenous stores of FSH and LH that help stimulate follicle growth in addition to the exogenous gonadotropins.
•Regimens – A GnRH antagonist-based protocol allows for ovarian stimulation to begin either at the onset of menses or in the luteal phase of the menstrual cycle (luteal start) to speed the IVF process for medically indicated indications.
An antagonist is administered mid-stimulation in a flexible or fixed protocol.
-In a flexible protocol, the GnRH antagonist is initiated when the lead follicle is typically around 14 mm in greatest diameter as this is when LH receptors are typically found on follicles, which places the oocyte at risk of premature ovulation.
-In a fixed protocol, the GnRH antagonist is administered first, starting on a particular cycle day, usually day 6.This approach has been associated with reduced risk of ovarian hyperstimulation syndrome [68].
In both protocols GnRH antagonists, once started, are continued until the night of ovulatory trigger to prevent breakthrough ovulation.
Triggers for ovulation — When the ovarian follicles are judged to be mature (commonly two or more follicles with a mean diameter of 16 to 18 mm, depending on the protocol utilized, and, in some centers, a serum estradiol level of 200 pg/mL [734 pmol/L] per codominant follicle), a trigger is administered to initiate the ovulatory cascade.
●Commonly used drugs – Available agents to trigger ovulation include hCG (recombinant or urinary) and/or GnRH agonists. Selection is based on patient characteristics, risk for OHSS, intent to transfer fresh embryos among others.
•hCG only – hCG binds the LH receptor to induce the ovulatory cascade and can be used for triggering ovulation in any protocol.
-hCG recommended – hCG is the only option for triggering ovulation in GnRH agonist protocols. It is recommended over GnRH agonist triggers in patients with hypothalamic amenorrhea (who will not respond to a GnRH agonist), in those at low risk for OHSS, and those considering fresh embryo transfer.
-hCG preferred – hCG trigger is preferred over GnRH agonist in patients for whom fresh embryo transfer is considered as there is no regression of the corpus luteum (unlike with the GnRh agonist trigger).
-Urinary versus recombinant hCG – Urinary and recombinant hCG preparations result in similar clinical outcomes when used for induction of final follicular maturation [69]. A dose of 250 mcg of recombinant hCG appears to be equivalent to the standard doses of urinary hCG (5000 to 10,000 units) [68]. However, one concern with hCG is its long half-life and association with increasing risk of OHSS. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'What are the risks of the IVF procedure?'.)
•Recombinant human LH – Recombinant human LH (15,000 to 30,000 international units), which has a shorter half-life and is available outside of the United States, has been compared with hCG (5,000 international units) as the ovulatory trigger in 259 women undergoing IVF [70]. An LH dose between 15 and 30,000 international units was as effective as hCG for number of oocytes retrieved, embryo number, and clinical pregnancy, and recombinant LH was associated with a significantly lower risk of OHSS than hCG.
•GnRH agonists only – GnRH agonist trigger is generally reserved for individuals on GnRH antagonist-based stimulation protocols who are at increased risk of OHSS as it is associated with reduced rates of OHSS; however, it may be associated with lower pregnancy and live birth rates when used with fresh embryo transfer without luteal support [71]. Formulations include injection and nasal spray.
Patients that have hypothalamic amenorrhea or dysfunction (ie, those that have been on long-standing OCPs) are at high risk of not responding to the trigger. To determine whether or not someone is an appropriate candidate for GnRH agonist trigger, we assess menstrual history and prior combined oral contraceptive (COC) use and duration. Post-trigger labs, including an LH and progesterone the morning after trigger is obtained, and an LH above 15 international units and/or progesterone above 3 are used as cutoffs for assessing adequate response [72,73]. A detectable LH (ideally above 5 international units) and day of trigger LH >0.5 international units are also helpful predictors in assessing appropriate candidates for GnRH agonist trigger. In our practice, we give leuprolide acetate 4 mg intramuscularly (IM) 35 hours prior to retrieval followed by a second dose 12 hours later.
●Other options – A clomiphene/gonadotropin regimen has also been used for ovulation induction, but a systematic review found insufficient evidence to recommend its use in routine IVF practice [74]. Nevertheless, protocols utilizing clomiphene and gonadotropins may be useful in minimal stimulation regimens or in poor responders [75,76]. (See "Ovulation induction with clomiphene citrate".)
●Poor and high response to ovarian stimulation – Approximately 10 percent of cycles are discontinued before egg retrieval [54]; the rate increases with increasing age. A cycle may be cancelled if there is poor or excessive ovarian response. Approximately 84 percent of discontinued cycles are due to no or inadequate egg production and 4 percent are due to hyperresponsiveness.
Oocyte retrieval — Oocyte retrieval is typically performed by transvaginal ultrasound-guided follicle aspiration done 34 to 36 hours after giving the ovulatory trigger. In patients with:
●Analgesia – Patients are commonly given intravenous sedation and narcotics for analgesia (United States approach), although conscious sedation or regional anesthesia may also be used [77].
●Procedure – Under ultrasound guidance, a needle is introduced through the vaginal side wall and into the ovary (transvaginal aspiration) or through the abdominal wall (if the ovaries are not easily accessible through the vagina). Each follicle is sequentially aspirated until all visible follicles are collapsed (figure 2). This procedure can take 5 to 30 minutes depending on the number of follicles to be retrieved. Follicular flushing has been found to be helpful [78].
●Risks – There are few complications of transvaginal follicle aspiration. There is a low risk of intraperitoneal bleeding from the ovary or a pelvic blood vessel as well as a small risk of needle injury to the urinary or gastrointestinal tracts. Since the adoption of prophylactic antibiotics, postprocedure infection rates approach 0 percent [79-82].
Fertilization in vitro — To achieve fertilization, recovered oocytes are mixed with spermatozoa in a small volume of culture medium. The optimum number of hours for incubation of sperm and oocytes has not been determined [83].
●Fertilization – Typical fertilization rates with IVF are around 70 to 80 percent. Among couples with mild male factor infertility, the probability of fertilization may be increased by the use of high concentrations of sperm or preincubation of sperm in special buffer solutions [84]. For patients who use donor sperm, there does not appear to be a difference in live birth rates for donor versus nondonor sperm, per transfer [85].
●Fertilization failure – The incidence of total fertilization failure after IVF with normal sperm ranges from 4 to 16 percent; for these individuals, the likelihood of recurrent failure in subsequent IVF cycles is approximately 30 percent [86,87]. Patients with past fertilization problems or with severe male factor infertility are offered micromanipulation and intracytoplasmic sperm injection (ICSI) [88]. The resultant fertilization rates are comparable to those in couples without male factor infertility [89]. Fertilization can be performed with freshly ejaculated sperm or sperm obtained from the epididymis or testis [90,91].
Embryo management — Initial embryo management includes confirmation of fertilization and embryo hatching. Embryos are selected for transfer either by morphologic grading or the results of preimplantation genetic testing (PGT; if performed). A detailed discussion of culture media and embryo growth in vitro is beyond the scope of this review, and can be found elsewhere [92,93].
Initial embryo management — Briefly, initial embryo management consists of the following:
●Confirm fertilization – Fertilization of the oocyte is confirmed by observing two pronuclei within the zygote approximately 18 hours after insemination or ICSI. After fertilization, the individual cells of each embryo ("blastomeres") divide every 12 to 14 hours, so that the embryo reaches approximately eight cells by 72 hours after egg retrieval. Embryos between days 2 and 4 are called "cleavage stage embryos." The blastocyst stage is reached by approximately day 5 after retrieval, and implantation is expected by day 7 after egg retrieval, so transfer should take place prior to this time.
●Embryo hatching – "Hatching" is a natural process in which an embryo expands and eventually breaks through the zona pellucida in order to implant on the surface of the endometrium (the lining of the uterus). "Assisted hatching" refers to a laboratory procedure whereby the zona pellucida around the day 3 embryo is mechanically or chemically opened to assist the embryo in hatching from the zona approximately three days later (or at the blastocyst stage, for which the embryo will hatch one day later). The procedure may improve the percentage of embryos that implant in selected cases with poor prognosis (eg, ≥2 failed IVF cycles and poor embryo quality and older women [94,95]), but its value remains controversial [95,96].
Role of preimplantation genetic testing for aneuploidy (PGT-A) — PGT-A is commonly used to evaluate embryos for chromosomal aneuploidy, prioritize which embryos to transfer, and increase utilization of single embryo transfer to reduce rates of multiple gestation [97,98]. If PGT-A is planned, embryonic DNA is obtained from the embryo by removing cells from the trophectoderm at the blastocyst stage, when the embryonic cells have differentiated into the inner cell mass and the trophectoderm.
●Universal PGT-A – While the use of PGT-A has been increasing with the goals of improving live birth rate and reducing the rate of pregnancy loss, universal PGT-A to increase live birth rates has not been established and universal PGT-A may actually reduce live birth rate [99-101].
●PGT-A for advanced reproductive age – Patients of advanced reproductive age may benefit from PGT-A as this group has a higher proportion of aneuploid embryos. The ongoing pregnancy and live birth rates from a euploid transfer are higher than those from an untested blastocyst and the miscarriage rate is reduced when transferring a euploid embryo [102]. However, counseling regarding the attrition through the IVF process is important as more than one cycle may be required to achieve a euploid embryo.
Detailed discussions of PGT and advanced maternal age can be found separately.
●(See "Preimplantation genetic testing".)
●(See "Evaluation and management of infertility in females of advancing age".)
Embryo selection — Embryo(s) with high-implantation potential are selected from an available cohort based on morphological criteria or based on genetic test results (if PGT-A was performed).
Additional modalities for embryo selection that have been investigated but are of unclear value include:
●Time lapse monitoring – Time lapse monitoring is a novel technology for performing semiquantitative evaluation of embryo morphology and developmental kinetics over time without removing the embryo from the incubator; however, systematic reviews have not determined whether it adds value to conventional morphology [103-105].
●Embryo metabolome evaluation – Embryo metabolome evaluation is of unclear value in selecting embryos. A meta-analysis of four trials that evaluated the embryonic metabolome (by assessing the culture medium) as a predictor of pregnancy outcomes reported no improvement in live birth or pregnancy rates (OR 1.11, 95% CI 0.83-1.48; I² = 0 percent; four randomized controlled trials [RCTs]; n = 802), or miscarriage (OR 0.96, 95% CI 0.52-1.78; I² = 0 percent; two RCTs; n = 434) [106].
●Evaluation of embryo culture media – PGT performed on spent embryo culture media has been explored as a potential alternative to trophectoderm biopsy for the selection of euploid embryos. However, studies have yet to demonstrate consistent accuracy and it is not routinely used in clinical settings [107-109].
Embryo transfer — After fertilization, embryos are maintained in culture for a variable time period prior to transfer. Guidelines are available regarding IVF laboratories and embryo transfer technique [110-112].
Endometrial preparation for frozen-thawed embryo transfer
●Hormonal priming – Patients undergoing embryo transfer with frozen embryos can either undergo priming with exogenous estrogen and progesterone or use a modified or natural cycle regimen. Natural cycle regimens, including home monitoring of ovulation, may be an option for patients with regular ovulatory menstrual cycles [113]. Anovulatory patients have the option of a modified natural FET cycle that includes use of an ovulation induction drug. The regimens used with hormonal priming cycles are identical to those used during egg donation.
•(See 'Natural cycle IVF' below.)
A meta-analysis concluded that no specific protocol for endometrial preparation was superior to any other; all led to similar results in terms of endometrial receptivity and implantation rate [114]. However, the timing of progesterone administration influenced the outcome: when progesterone was initiated prior to egg retrieval in oocyte donation, the pregnancy rate was lower than when progesterone started on the day of egg retrieval or the day after.
●Techniques not advised
•Endometrial injury – Endometrial injury (ie, scratch) is not recommended in individuals undergoing their first IVF cycle but considered for patients with a prior failed IVF cycle. The technique has been proposed to increase the implantation rate, and ultimately, increase the live birth rate, although supporting data are limited. If performed, this procedure is typically done with an endometrial biopsy-type pipelle in the luteal phase prior to the IVF cycle or transfer.
-Similar outcomes with and without endometrial scratch – A 2019 meta-analysis evaluated data from 14 trials, including over 2500 participants, on the impact of endometrial scratch on pregnancy rates with IVF. Due to the significant heterogeneity in the trials, they were only able to evaluate the outcome in couples with one failed full IVF/ICSI cycle. Both groups had similar outcomes for live birth rate (relative risk [RR] 1.01, 95% CI 0.68-1.51), clinical pregnancy rate (RR 1.04, 95% CI 0.74-1.45), pregnancy loss (RR 0.82, 95% CI 0.57-1.17), and multiple pregnancy rate (RR 1.06, 95% CI 0.84-1.35) [115].
-Possibly increased live birth rate with endometrial scratch – A subsequent randomly assigned trial (SCRATCH trial) that included 933 participants reported a possible improvement in live birth rates with use of endometrial scratch prior to IVF (4.6 percent more live births in the scratch versus control group in women with one prior failed IVF/ICSI [RR 1.24, 95% CI 0.96-1.59]) [116].
•Testing of endometrial receptivity – Analysis of endometrial gene expression to identify the receptive phase, and therefore optimal timing for embryo transfer, has been proposed as a technique to increase the live birth rate, particularly for patients with prior unsuccessful transfers or implantations [117-119]. However, a multicenter trial comparing outcomes of euploid blastocyst transfers based on endometrial receptivity testing or using standard timing practices reported similar live birth rates between the groups (live birth rates 58.5 versus 61.9 percent, respectively, rate ratio 0.95, 95% CI 0.79-1.13) [120]. The trial findings add to the body of evidence that routine use of genomic endometrial receptivity testing to time embryo transfer does not improve outcomes [121].
Embryo stage
●Cleavage stage – Cleavage-stage embryos (two to four days after retrieval) are transferred to the uterus approximately 72 hours after egg retrieval (four to eight cell, cleavage stage) [54]. While a meta-analysis of 12 trials did not find a difference in live birth, miscarriage, or ectopic pregnancy rates between day 2 and day 3 embryo transfers, the additional 24 hours in culture from day 2 to day 3 allowed identification of embryos that stopped dividing and thus were not viable [122].
●Blastocyst stage – Blastocyst-stage embryos (five to seven days after retrieval) are transferred on day 5 (figure 3). Delaying transfer until the blastocyst stage allows selection of higher quality embryos and enables transfer at the time a naturally fertilized in vivo embryo would have reached the uterine cavity. However, the live birth rate per oocyte retrieval may not improve because fewer embryos are available for transfer due to loss of embryos that did not survive in vitro to day 5.
•Advantages – Major advantages of blastocyst stage transfer are the ability to perform PGT and the resultant reduction in multiple gestation achieved with single blastocyst transfer [123]. (See "Preimplantation genetic testing".)
-Disadvantages – Compared with cleavage stage transfer, blastocyst transfer does not appear to increase the risk of congenital anomalies compared with cleavage-stage transfer or spontaneous conception but may be associated adverse pregnancy outcomes such as preterm birth [124,125]. (See "Spontaneous preterm birth: Pathogenesis".)
•Impact on sex ratio and multiple gestation – With blastocyst culture, there is a higher male-to-female sex ratio, and there is an association with male sex and preterm birth, which may be the driver of the increased preterm birth rate with this approach [126].
-Additionally, with blastocyst transfers there is a small increased risk of monozygotic twinning (blastocyst stage 2.8 versus cleavage stage 2.09 percent) [127]. However, these risks are offset by the increased utilization of single embryo transfer with blastocysts (particularly euploid blastocysts after PGT for aneuploidies [PGT-A]), which results in a higher rate of singleton birth and a decrease in multifetal gestation as opposed to transfers with multiple cleavage stage embryos. (See "Strategies to control the rate of high order multiple gestation".)
Transfer
●Procedure – Embryos are inserted into the uterus using a catheter via the cervix [128]. Embryo transfer is performed in a procedure room where anesthesia is offered. The transcervical route is the easiest and the least traumatic to the patient. All embryos that are to be transferred are loaded into the transfer catheter at one time in a volume of approximately 20 microliters. Under ultrasound guidance, they are placed 1 to 2 cm from the top of the uterine cavity.
●Number of embryos transferred – The number of embryos transferred is influenced by maternal age, the number of oocytes retrieved, and availability of embryos for cryopreservation as well as by regional laws and guidelines (table 2 and table 3) [129]. In general, one to two embryos are transferred [129]. Cycles that result in a high number of oocytes and yield a large number of embryos for cryopreservation are associated with higher pregnancy rates [130,131]. Transferring more than one embryo increases the chance for a pregnancy, but also increases the chance of multiple gestation (table 2) [129,132]. (See "Strategies to control the rate of high order multiple gestation".)
●Impact of technique variations – Touching the catheter to the top of the cavity or otherwise inducing uterine cramping by a traumatic transfer technique is thought to decrease the success of the procedure. Despite initial conflicting opinions and data, endometrial scratching prior to embryo transfer does not significantly increase the live birth rate [133-135]. However, the type of catheter (soft versus hard) and other aspects of the transfer technique, such as use of ultrasound guidance, can affect the success of transfer [136-140]. Operator experience remains a major factor in the success of the procedure, and details of the technique must be adapted to each patient on an individual basis.
●Post-transfer – After transfer, the catheter is checked to ensure there are no retained embryos. Although there is a theoretic possibility of losing embryos out of the cervix or into the fallopian tubes after embryo transfer, available evidence does not support use of a fibrin sealant or other types of "embryo glue" post-embryo transfer improve clinical pregnancy rates [141].
Luteal phase support — To optimize endometrial receptivity, a progesterone supplement is commonly initiated on the day of or one day after oocyte retrieval or at the time of embryo transfer (ie, the luteal phase) [43,114,142-145]. The optimum route and duration of supplementation has not been established; treatment duration has ranged from obtaining a positive or negative pregnancy test to the end of the first trimester [146-150].
In the absence of data indicating superiority of one treatment, we do the following:
●Fresh embryo transfer – Continue progesterone support until 10 weeks gestation with micronized progesterone 200 mg in the vagina twice daily. Other experts may use intravaginal progestin inserts (100 mg twice daily) or gel (90 mg once or twice daily).
●Frozen embryo transfer – Continue estrogen and progesterone support until the end of the first trimester. We use IM progesterone 50 mg daily in combination with vaginal progesterone 200 mg BID for frozen embryo transfers. One trial evaluating vitrified embryo transfer cycles reported that luteal phase support with IM progesterone led to higher live birth rates as compared with vaginal progesterone used alone [151].
While intramuscular progesterone (progesterone in oil) and vaginal progesterone preparations (suppositories, tablets, gel, or ring) are similarly effective [152-155], oral progesterone appears to be less effective [156]. Although intramuscular progesterone is more painful for the patient, it is commonly used because it is associated with less luteal phase bleeding than vaginal progesterone. Regardless of route of administration, these progesterone preparations and doses are not associated with congenital anomalies or virilization [143].
While hCG can be used with progesterone or alone for luteal phase support, it is not more effective than progesterone alone and increases the risk of OHSS [157]. Meta-analyses show that estrogen supplementation does not enhance pregnancy rates [158,159]. However, estradiol is commonly administered along with vaginal progesterone to prevent late luteal vaginal bleeding.
Cryopreservation — Excess embryos (ie, beyond those that can be safely transferred) can be cryopreserved for future use. Having excess embryos available for cryopreservation is a surrogate marker of embryo quality [160]. (See "Fertility preservation: Cryopreservation options", section on 'Embryo'.)
Outcomes of frozen-thawed embryos
●Embryo survival – While both slow freezing and vitrification (ultrarapid freezing) are safe and effective methods of cryopreservation, vitrification is preferred because of survival rates above 90 percent [161,162]. In the past, approximately 20 percent of embryos did not survive the freezing/thawing process, which is thought to be due to subtle damage suffered by the embryo during the cooling and/or warming transition.
●Perinatal outcomes – Systematic reviews of observational studies have reported that children born after transfer of cryopreserved embryos have different perinatal outcomes than those born after transfer of fresh embryos [46,161,163-165]:
•Lower rates of preterm birth, low birth weight, growth restriction, perinatal mortality
•Comparable rates of congenital malformation
•Increased rates of preeclampsia and placenta accreta spectrum
The reason for some better perinatal outcomes of children born after cryopreservation as compared with children born after fresh transfer in most studies is not known but may be related to differences in endometrial receptivity between women undergoing fresh versus cryopreserved embryo transfer (eg, adverse effects of ovarian stimulation in fresh cycles, asynchrony). The lower serum E2 levels associated with frozen-thawed embryo and donor egg transfer cycles may result in better placentation. It is also possible that embryos that survive freezing and thawing are of better quality than fresh embryos. (See "Assisted reproductive technology: Infant and child outcomes".)
●Pediatric outcomes – Outcome data on growth, childhood morbidity, and mental development are limited, but few differences have been reported between children born from cryopreserved embryos compared with fresh embryos.
Freeze-all cycles — Based on improved obstetric outcomes with frozen-thawed embryos, some experts have proposed freeze-all cycles, in which all embryos are frozen for future use in a cycle that is not linked to ovarian hyperstimulation. The live birth rates from cycles using frozen-thawed embryos appear to be similar to cycles using fresh embryo cycles [166-170], and systematic reviews suggest improved obstetric outcomes [46,161,163,164]. Other potential benefits of freeze-all cycles include lower rates of OHSS for patients with polycystic ovarian syndrome undergoing IVF and lower incidence of ectopic pregnancy [167,171-174]. However, factors that may negatively impact live birth rates following a freeze-all strategy include embryo stage at transfer (cleavage stage embryos compared with blastocysts) and increasing duration of storage (up to two years) [175-177].
The rates of ovarian hyperstimulation are lower for frozen cycles [168]. (See "Prevention of ovarian hyperstimulation syndrome".)
Storage duration and future use — There is no scientific basis for a maximum duration of storage [178]. Options for cryopreserved embryos include transfer at a future date, donation to other subfertile couples or for research, or disposal [179-181].
IVF variations
Natural cycle IVF — Natural cycle (unstimulated) IVF refers to IVF without the use of exogenous gonadotropins to induce growth of multiple follicles. The natural cycle is commonly augmented with a mid-cycle dose of hCG to stimulate ovulation [182,183]. In a few centers, however, timing of oocyte retrieval is based on the occurrence of a spontaneous LH surge [184]. Natural cycle IVF accounts for <1 percent of IVF cycles in the United States, but is more popular elsewhere [185]. Candidates are generally females ≤35 years of age or those >36 years with normal ovarian response [186].
●Potential benefits – Compared with conventional IVF, unstimulated IVF or cycles that utilize "gentle" stimulation protocols are associated with decreased risk of OHSS and multiple gestation, lower cost, and potentially less stress. Cost is lower because fewer drugs are used and there is no need for embryo storage. Additionally, natural cycle IVF has been associated with lower rates of preterm birth and low birth weight, although the absolute difference in risk is likely small [187]. At least one study has reported that the experience of unstimulated IVF was less stressful for patients than IVF with gonadotropin stimulation [188].
●Lower live birth rate – Compared with conventional IVF, natural cycle IVF has a higher implantation rate per oocyte collected but lower success rates, in part because fewer oocytes are obtained per cycle [189]. In a meta-analysis of six trials comparing natural cycle or modified natural cycle IVF versus standard IVF, the authors concluded a female with a 53 percent chance of live birth using standard IVF would have a 34 to 53 percent chance of success with natural cycle IVF [190]. The findings were imprecise for these and other outcomes (eg, multiple gestation rate).
In vitro maturation — In vitro maturation of immature oocytes from unstimulated cycles is an emerging technology. Major advantages are the avoidance of large doses of gonadotropins and their associated high costs, risk of OHSS, and potential adverse effects on hormone-sensitive tissues (eg, breast cancer) [191]. Development of the technique and assessment of its role in fertility treatment, as well as assessment of children conceived with this technology, is ongoing.
A variation of the above technique involves in vitro maturation of immature oocytes that are retrieved during a typical stimulated IVF cycle (approximately 20 percent of retrieved oocytes are immature) [192]. Fertilization and clinical pregnancy rates may be lower than with oocytes matured in vivo, but data are limited [192-195].
POST-CYCLE CARE
Expected course — Post-transfer, the patient can resume regular daily activities.
●Activity and diet – Neither physical activity nor diet has been shown to have an impact upon the success of embryo implantation or conception. Trials have not reported improved implantation rates with post-transfer bedrest [141]. We typically counsel patients to refrain from intercourse or vigorous activity until the first beta-human chorionic gonadotropin (hCG) is drawn.
●Common symptoms – Mild cramping and bloating are normal. Since the cervix is swabbed prior to embryo transfer, some women may pass a small amount of clear or bloody fluid from the vagina shortly after the procedure; this is normal and not a sign that the embryos are being expelled. Breast tenderness and engorgement, bloating, and constipation are not uncommon; they are due to the elevated hormone levels associated with ovarian stimulation, and, to a lesser extent, due to the supplemental hormones used for luteal phase support. Cramping during embryo transfer may be caused by touching the inside of the uterus with the transfer catheter. Cramping after the procedure is likely due to varying degrees of ovarian enlargement and the ovarian hyperstimulation syndrome (OHSS).
●Symptoms requiring additional evaluation – Patients with moderate or severe pain or heavy vaginal bleeding require evaluation. Potential IVF-specific causes include infection, ovarian torsion, ectopic pregnancy, heterotopic pregnancy, and more severe forms of OHSS, which is the most common cause of such pain. Other causes of abdominal and pelvic pain, such as appendicitis or urinary tract infection, should also be excluded.
•(See "Ovarian and fallopian tube torsion".)
•(See "Ectopic pregnancy: Clinical manifestations and diagnosis".)
•(See "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Heterotopic pregnancy' and "Cesarean scar pregnancy" and "Hysterectomy: Abdominal (open) route".)
•(See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome".)
Pelvic pain occurring many weeks after an IVF cycle should be evaluated as in any woman, pregnant or not, with acute pain. (See "Acute pelvic pain in nonpregnant adult females: Evaluation" and "Approach to acute abdominal/pelvic pain in pregnant and postpartum patients".)
Monitoring for pregnancy — Pregnancy is diagnosed by identification of rising serum hCG levels after transfer.
●Timing of serum hCG test – Initial serum hCG is usually obtained no earlier than 12 days after egg retrieval, although some programs start testing later. The rationale is that implantation is thought to occur no earlier than seven days after retrieval; hCG levels may be detected one or two days later. However, late implantations do occur. Once a positive hCG is obtained, serial hCG measurements are performed to monitor whether the rise is normal and consistent with a developing intrauterine pregnancy.
•In frozen embryo transfers, the first beta hCG is drawn nine days after blastocyst transfer or 11 days after cleavage stage transfer (when the patient would be four weeks gestational age).
•In either fresh or frozen transfers, if the first beta is positive, we repeat the beta hCG 48 hours later, followed by another beta hCG at five weeks gestational age. We repeat the beta hCG level sooner if an abnormal rise is detected and there is suspicion for an abnormal pregnancy (biochemical pregnancy, abnormal intrauterine pregnancy, or ectopic pregnancy).
●Impact of exogenous hCG – Exogenous hCG administration prior to oocyte retrieval results in serum hCG levels between 60 and 300 milli-international units/mL. This hCG is generally cleared by two weeks after administration. As initial serum hCG testing is begun no sooner than 12 days after retrieval, it should not interfere with pregnancy testing.
●Initiation of ultrasound – If the hCG test is positive, ultrasound evaluation of the pregnancy generally begins at six weeks of gestational age (four weeks after retrieval), which is when the fetal heartbeat may first be detected. Both embryo viability and intrauterine location are confirmed.
●Referral for obstetric care – Patients are typically referred for obstetric care once both viability and intrauterine location of the pregnancy have been confirmed. Continued contact is worthwhile for the rare case of heterotopic pregnancy that may occur after IVF, and which may not become apparent until later in the first trimester. The major symptom is pelvic pain. (See "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Heterotopic pregnancy'.)
●Negative hCG test – A negative hCG level 14 days after egg retrieval is a strong indication of a failed IVF cycle. The patient is instructed to stop luteal phase supplementation, and menstruation commonly occurs after one to three days. Lack of menses or unusual irregular bleeding should be evaluated with hormonal measurements, since ectopic pregnancies may rarely present with very delayed appearance of hCG in the circulation.
Occasionally, a very early positive hCG test becomes negative on follow-up testing and before there is evidence of an intrauterine or extrauterine pregnancy on ultrasound. Menses often occur at the expected time. These very early pregnancy losses are termed "chemical pregnancies."
Obstetric care — Individuals who conceive using IVF procedures are not considered to have high-risk pregnancies based on the fertility treatment. Decisions regarding level of obstetric care and provider are made based on the usual obstetric indications such as underlying medical conditions or advancing age. (See "Prenatal care: Initial assessment", section on 'Care provider'.)
REPEAT IVF CYCLES — The optimal timing of repeat embryo transfer following either live birth or pregnancy loss is a common clinical question. While short-interval embryo transfer may be desired by the patient, observational data suggest that intervals of at least six months are associated with improved outcomes [196,197]. Definitive conclusions are limited by the retrospective nature of the available studies and inclusion of embryos that were untested for aneuploidy.
●Interval following live birth – Following live birth, interpregnancy intervals (IPIs) <12 months are associated with increased risks of preterm birth following both fresh and frozen embryo transfers [197,198]. However, the observational nature of the data and small sample sizes across different preterm birth cut-offs limit definitive conclusions regarding the absolute effect. Risk of preterm birth appears to be attenuated for IPIs of 6 to <12 months compared with IPIs of <6 months [197].
●Interval following pregnancy loss – An observational study of 2433 patients who underwent a frozen blastocyst transfer after a clinical pregnancy loss reported that, compared with IPIs 6 to 12 months, IPIs of <3 months and 3 to <6 months were associated with lower live birth rates and higher overall pregnancy loss rates. For each group, singleton live births were: IPI <3 months, 37.6 percent; IPI 3 to <6 months, 40.6 percent; IPI 6 to 12 months, 46.3 percent [196]. The impact on both live birth and pregnancy loss rates were greater for IPIs of <3 months compared with IPIs of 3 to <6 months. Study limitations include use of untested embryos,
RESOURCES FOR PATIENTS AND CLINICIANS — In the United States, over 450 fertility clinics provide verified data on the outcomes of all ART cycles started in their clinic. Annual summary reports with detailed descriptions of patient characteristics, procedures, and outcomes are available online from registries in the United States and Europe:
●United States Data: Society for Assisted Reproductive Technology (SART)
●European Data: The European Society of Human Reproduction and Embryology (ESHRE) Resources
●US Centers for Disease Control and Prevention (CDC) IVF Success Estimator
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Female infertility" and "Society guideline links: Male infertility or hypogonadism".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they 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. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: In vitro fertilization (IVF) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Evaluation – Prior to IVF, both female and male partners undergo a complete infertility evaluation to identify all potential contributors to infertility. Key components include assessment of ovarian reserve and tubal patency for females and semen analysis for males. (See 'Initial evaluation and treatment' above.)
●IVF cycle – The general components of an IVF cycle are pharmacologic ovarian stimulation (ie, ovulation induction or superovulation), oocyte aspiration and fertilization, and embryo transfer. (See 'IVF cycle' above.)
•Preprocedure preparation – Prior to initiating an IVF cycle, patients participate in the formed consent process to understand the procedure risks and alternatives. Most patients do not require prophylactic antibiotics, thromboprophylaxis, or steroid therapy, but individual care plans may vary based on medical history and risk factors. (See 'Preparation' above.)
•Ovarian stimulation – Ovarian stimulation involves giving the patient drugs to increase the number of mature oocytes available for fertilization with the goal of increasing live birth rate. Use of these protocols also increased the rate of multiple gestations. Individuals who are not using fresh embryos (ie, frozen embryo or donor egg cycle) do not need ovarian stimulation and go directly to endometrial preparation instead. (See 'Ovarian stimulation' above.)
•Trigger for ovulation – When the ovarian follicles are judged to be mature (two or more follicles with a mean diameter of 18 mm or more and a serum estradiol level of 200 pg/mL [734 pmol/L] per codominant follicle), a trigger is administered to initiate the ovulatory cascade. Commonly used drugs include human chorionic gonadotropin (hCG; recombinant or urinary), recombinant human luteinizing hormone (LH), or gonadotropin-releasing hormone (GnRH) agonists. Selection is mainly based on patient characteristics and influenced by drug availability. (See 'Triggers for ovulation' above.)
•Oocyte retrieval – Oocyte retrieval is typically performed by transvaginal ultrasound-guided follicle aspiration done 34 to 36 hours after hCG administration. Using transvaginal ultrasound guidance, a needle is introduced sequentially into each follicle and the follicular contents are aspirated (figure 2). (See 'Oocyte retrieval' above.)
•Fertilization – To achieve fertilization, recovered oocytes are mixed with spermatozoa in a small volume of culture medium. The optimum number of hours for incubation of sperm and oocytes has not been determined. Typical fertilization rates with IVF are approximately 70 to 80 percent. (See 'Fertilization in vitro' above.)
•Embryo management – Initial embryo management includes confirmation of fertilization and embryo hatching. Embryos are selected for transfer either by morphologic grading or the results of preimplantation genetic testing (PGT; if performed). (See 'Embryo management' above.)
•Embryo transfer – After fertilization, embryos are maintained in culture for a variable time period prior to cryopreservation or transfer. Guidelines are available regarding IVF laboratories and embryo transfer technique. (See 'Embryo transfer' above.)
•Embryo cryopreservation – Excess embryos (ie, beyond those that can be safely transferred) can be cryopreserved for future use. Having excess embryos available for cryopreservation is a surrogate marker of embryo quality. (See 'Cryopreservation' above.)
●IVF cycle variations – Variations to conventional IVF include natural cycle IVF and in vitro maturation. Natural cycle (unstimulated) IVF refers to IVF without the use of exogenous gonadotropins to induce growth of multiple follicles; the natural cycle is commonly augmented with a mid-cycle dose of hCG to stimulate ovulation. In vitro maturation of immature oocytes from an unstimulated cycle is an emerging technology. (See 'IVF variations' above.)
●Post-cycle care – Post-transfer, the patient can resume regular daily activities. Pregnancy monitoring is performed to confirm both viability and intrauterine location of an established pregnancy. (See 'Post-cycle care' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Paulson, MD, MS, who contributed to earlier versions of this topic review.
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