INTRODUCTION — In vitro fertilization (IVF) refers to a complex 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 (ART). In general, IVF involves stimulating ovaries with a combination of fertility medications and retrieving oocyte(s) from ovarian follicles. The retrieved oocytes may be cryopreserved for future use or fertilized in the laboratory (ie, in vitro) to create embryos. 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-expansive individuals.
TERMINOLOGY — The European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Endocrinology (ASRM) have released terminology guidelines in attempt to standardize language for patients, clinicians, and researchers [1,2]. Some relevant terms include:
●Assisted reproductive technology (ART) – ART includes "all interventions that include the in vitro handling of both human oocytes and sperm or of embryos for the purpose of reproduction. This includes, but is not limited to, in vitro fertilization (IVF) and embryo transfer (ET), intracytoplasmic sperm injection (ICSI), embryo biopsy, preimplantation genetic testing (PGT), assisted hatching, gamete intrafallopian transfer, zygote intrafallopian transfer, gamete and embryo cryopreservation, semen, oocyte and embryo donation, and gestational carrier cycles. Thus, ART does not, and ART-only registries do not, include assisted insemination using sperm from either a woman's partner or a sperm donor" [1].
●Infertility – Infertility can affect both females and males. One common definition, from the American Society for Reproductive Medicine, defines "infertility as "a disease, condition, or status characterized by any of the following" [3]:
•"The inability to achieve a successful pregnancy based on a patient’s medical, sexual, and reproductive history, age, physical findings, diagnostic testing, or any combination of those factors."
•"The need for medical intervention, including, but not limited to, the use of donor gametes or donor embryos in order to achieve a successful pregnancy either as an individual or with a partner."
•"In patients having regular, unprotected intercourse and without any known etiology for either partner suggestive of impaired reproductive ability, evaluation should be initiated at 12 months when the female partner is under 35 years of age and at 6 months when the female partner is 35 years of age or older."
●In vitro fertilization (IVF) – IVF is "a sequence of procedures that involves extracorporeal fertilization of gametes. It includes conventional in vitro insemination and ICSI" [1]. IVF involves ovarian stimulation of the female to create oocytes, oocyte retrieval, in vitro insemination, and transfer of the resultant embryos to a uterus.
●Intracytoplasmic sperm injection (ICSI) – ICSI is "a procedure in which a single spermatozoon is injected into the oocyte cytoplasm" [1]. This procedure is typically used for severe male factor infertility.
●Intrauterine insemination (IUI) – IUI describes "a procedure in which laboratory processed sperm are placed in the uterus to attempt a pregnancy" [1].
●Medically assisted reproduction – MAR incorporates "reproduction brought about through various interventions, procedures, surgeries, and technologies to treat different forms of fertility impairment and infertility. These include ovulation induction, ovarian stimulation, ovulation triggering, all ART procedures, uterine transplantation and intra-uterine, intracervical and intravaginal insemination with semen of husband/partner or donor" [1]. This is a broader phrase compared with ART.
BACKGROUND AND IMPACT — The first pregnancy after the fertilization of a human egg in vitro and the first birth from an in vitro-fertilized embryo were reported in 1976 and 1978 [4,5]. Since then, an estimated eight million pregnancies have been achieved worldwide by IVF and its modifications (table 1), known generically as assisted reproductive technologies (ARTs) [6]. As experience has accumulated, success rates have increased, and the indications for these procedures have expanded, ART now accounts for 1 to 3 percent of live births in the United States and Europe, and is upwards of 4.3 percent in higher-consuming countries like Israel [7]. In 2018, 2 percent of all infants born in the United States were conceived with ART (range: 0.4 percent in Puerto Rico to 5.1 percent in Massachusetts) [8]. Access to insurance coverage for treatment has been associated with increased utilization of IVF technology [9].
WHY IS IVF USED? — While IVF was first used to overcome tubal disease as a cause of infertility [4,5], the technique is now used to treat multiple types of diagnoses.
Main fertility issues — Multiple causes of infertility can be treated with IVF, including:
●Tubal factor – IVF is the primary therapy for individuals whose fallopian tubes are completely blocked or nonfunctional due to prior damage from surgery or infection.
●Severe male factor infertility – IVF, including intracytoplasmic sperm injection (ICSI), is selected for individuals for severe male factor infertility.
●Diminished ovarian reserve – Individuals with diminished ovarian reserve may benefit from IVF, particularly if they desire more than one child with fertility treatment as they may be able to cryopreserve excess embryos for future use.
●Primary ovarian insufficiency – Individuals diagnosed with primary ovarian insufficiency may conceive with IVF using donor eggs.
●All other causes of infertility that have not responded to less invasive therapies – Individuals with ovulatory dysfunction, endometriosis, unexplained infertility, among other diagnoses, generally begin treatment with less invasive, and less costly, fertility therapies. However, if they are unable to achieve live birth, then IVF becomes an option.
●Gestational carrier pregnancy – IVF has been used to achieve pregnancy in gestational carriers for individuals with severe uterine factor infertility (eg, Asherman syndrome, Müllerian agenesis) or medical contraindications to pregnancy. (See "Gestational carrier pregnancy".)
Other uses — IVF can be useful in the following clinical settings:
●Preimplantation genetic testing (PGT) – PGT can be performed to detect aneuploidy, monogenic (single-gene) disorders, or structural rearrangements. Studies are ongoing regarding its use in screening for polygenic risk (PGT-P) [10,11]. (See "Preimplantation genetic testing".)
●Genetic parenthood for individuals or same-sex couples – Assisted reproductive techniques, including intrauterine insemination (IUI) and IVF, can be employed by individuals or same-sex couples who desire genetic parenthood. Same-sex male couples may donate semen from either one or both partners to fertilize a donated oocyte and create an embryo with a genetic connection. The embryo is then transferred to a gestational carrier. Same-sex female couples may use IVF to harvest an oocyte from one woman (genetic parent), fertilize the oocyte in vitro, and then transfer the resultant embryo in the other woman (gestational parent). This approach is sometimes referred to as "reciprocal IVF."
●Sex selection and/or balanced family planning – Sex selection can be performed to avoid sex-linked genetic disease or diseases with unequal sex incidence as well as for personal preferences or balanced family planning. (See "Sex selection".)
●Prevention of mitochondrial disorders – Two IVF techniques, maternal spindle transfer (ST) and pronuclear transfer, have been developed for females with inherited mutations in mitochondrial DNA (mtDNA), which are an important cause of genetic diseases for which there is no effective treatment (figure 1) [12-14]. This technology is available in limited settings. Data supporting use of these techniques for other causes of infertility are lacking [15]. These procedures have been referred to as three-person IVF or three-parent IVF, but this overstates the role of the donor of the enucleated oocyte.
•Maternal spindle transfer (ST) – In maternal spindle-chromosomal transfer, the nucleus is removed from a donor egg and replaced with the nucleus from the intended mother's egg. A potential application of this technology is the ability to decrease the risk of passing on inherited mitochondrial disorders, which are inherited through mitochondria that is passed on from the cytoplasm of the oocyte. One study of research embryos created from donated eggs and sperm reported similar aneuploid rates and gene expression patterns in embryos created with and without ST [16]. The major difference was a slow DNA demethylation process in ST-created embryos, for which the clinical implications are to be determined. Further studies are needed to understand the safety and efficacy of this procedure.
•Pronuclear transfer – For pronuclear transfer, both eggs are fertilized, and the nuclear DNA from the mother's fertilized egg is transferred to the fertilized donor egg, from which the donor nuclear DNA has been removed.
In 2015, the United Kingdom House of Commons approved regulations to allow transplant of a nucleus from the genetic parent into a donor egg, which is equivalent to mitochondrial donation [17]. The procedure is estimated to potentially benefit 150 women in the United Kingdom per year [12]. As of 2016, the US Food and Drug Administration was unable to approve the technique for use in humans according to federal law, although an advisory panel recommended approving the procedure for use in male embryos (males do not pass their mitochondria on to the next generation of offspring) [18]. (See "Mitochondrial myopathies: Clinical features and diagnosis".)
●Posthumous reproduction – In rare cases, IVF can be used to assist posthumous reproduction. This information is reviewed in detail elsewhere. (See "Posthumous assisted reproduction".)
●Potential correction of germline mutations – An investigated therapy, gene editing of an embryo prior to transfer has the potential to correct heritable mutations that cause significant disease. In a landmark study of human embryos heterozygous for a MYBPC3 mutation that would result in hypertrophic cardiomyopathy, CRISPR-Cas9-based targeting technology was used to "induce double-strand breaks (DSBs) at the mutant paternal allele (that) were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template" (figure 2) [19]. The cell cycle was modulated to control the timing of the DSBs in order to avoid mosaicism; of the CRISPR-injected embryos, 67 percent were uniformly homologous for the wild-type allele, compared with 47 percent of the control embryos. Thus, with the use of such gene-editing technology, heritable mutations could be reversed and more embryos would be available for transfer in an IVF cycle, compared with the current standard of transferring unaffected embryos as identified by PGT. Note that this type of therapy is considered experimental at this time, and has not been approved for human use anywhere in the world.
•(See "Overview of gene therapy, gene editing, and gene silencing", section on 'Methods and development'.)
•(See "Preimplantation genetic testing".)
WHO IS A CANDIDATE?
●Candidates – Anyone who cannot conceive without IVF is considered a candidate for this treatment. In heterosexual couples, this would typically be a couple that is diagnosed with infertility. The female partner provides the oocytes and carries the pregnancy and the male partner provides the sperm. If the couple requires embryo selection for genetic reasons, IVF with preimplantation genetic testing (PGT) may be used. If the female partner has inadequate ovarian function, donor eggs may be used. If the female partner doesn't have a uterus or cannot carry the pregnancy due to a medical condition, use of a gestational carrier surrogacy is appropriate. Uterus transplantation is an experimental technology. Sperm donation is generally treated with donor sperm insemination, but IVF may be needed. In same-sex couples or single individuals, family building often involves IVF to allow for gamete donation or gestational surrogacy.
●Relative contraindications – Patients with significant comorbidities, such as cardiac or pulmonary disease, may not be healthy enough to undergo ovarian stimulation and oocyte retrieval, although the procedure is relatively simple and only minimally invasive [20]. Severely obese individuals (eg, body mass index [BMI] >45) may experience increased risk of anesthesia and thus may not be able to tolerate oocyte retrieval.
WHAT FACTORS IMPACT IVF SUCCESS? — Several preprocedure factors can affect the success of IVF (eg, female age, type of infertility diagnosis, and past reproductive-obstetric history) [21].
Age of the individual donating oocytes — The major determinant of the success of IVF is the biologic age of the individual who is providing the oocytes. Although IVF may largely overcome infertility in younger females, it does not reverse the age-dependent decline in fertility in older females, particularly those over 40 years [21,22]. This decrease in success parallels that seen with other forms of fertility treatment in females of advancing age [23]. Specific to IVF, the diminished success is due both to decreased ovarian responsiveness to gonadotropin stimulation, which results in a decreased number of oocytes available for IVF, and a decreased implantation rate per embryo transferred due to poor egg quality [24,25]. In addition, the risk of pregnancy loss (ie, miscarriage or spontaneous abortion) and chromosomal abnormality rises with increasing female age [26]. These issues are discussed in detail in related content.
●(See "Effects of advanced maternal age on pregnancy", section on 'Early pregnancy issues'.)
The upper limit for performing IVF with autologous eggs (ie, not using donor eggs) is controversial and varies by site, but typically ranges from 41 to 45 years of age (depending on ovarian function) [27]. In one series in which IVF with autologous eggs was attempted in females aged 45 to 49 years, cycles were cancelled before retrieval in 30 percent (70 of 231) and the overall pregnancy rate per retrieval was 21 percent (34 of 161). However, only 5 of the 34 pregnancies resulted in live-born delivery and all of these were in patients 45 years of age [28]. The live birth rate per cycle initiated was 2.1 percent (5 of 231). (See "Effects of advanced maternal age on pregnancy".)
Negative effect
●Poor ovarian reserve – Individuals with poor ovarian reserve have a lower likelihood of achieving a live birth using their own oocytes; other forms of therapy (eg, oocyte donation) should be offered. (See "In vitro fertilization: Procedure", section on 'Assessment of ovarian reserve'.)
●Hydrosalpinx – Studies have consistently shown that the presence of a hydrosalpinx is associated with poor IVF outcome: the live birth rate is one-half that of women without hydrosalpinges [29]. Moreover, randomized trials have demonstrated that salpingectomy prior to IVF in women with hydrosalpinges improves pregnancy rates, and therefore should be recommended [30,31]. Hydrosalpingeal fluid may impair establishment of a successful pregnancy by negatively impacting the transferred embryo or endometrial receptivity. These adverse effects may be mediated by mechanical factors, microorganisms, endotoxins, cytokines, lack of nutrients, oxidative stress, and/or the woman's genotype (HOXA10) [32]. Laparoscopic salpingectomy is the preferred approach and cost-effective in this patient population. Other potentially effective approaches include salpingostomy and hysteroscopic tubal occlusion. (See "Female infertility: Reproductive surgery", section on 'Salpingectomy before in vitro fertilization'.)
However, at least one meta-analysis has found evidence of reduced ovarian reserve following salpingectomy. In a meta-analysis of 25 studies comparing women who underwent salpingectomy (one or both tubes) with women who did not have salpingectomy, women who underwent salpingectomy required higher gonadotropin doses, had higher follicle-stimulating hormone (FSH) levels (following bilateral salpingectomy), and had fewer oocytes retrieved [33]. As pregnancy and live birth rates were not reported, it is not known if these differences are clinically important. Given the above data demonstrating improved IVF outcomes after removal of hydrosalpinges, we continue to advise salpingectomy for women with hydrosalpinx who require IVF. We make an effort to avoid interrupting the vascular connection between the uterus and the ovary by removing only the fallopian tube and as little of the broad ligament as possible.
●Tobacco and substance use – Cigarette smoking reduces IVF success rates (fewer ova retrieved) and is associated with numerous adverse effects on general health [34,35]; we recommend smokers be advised to stop smoking. As tobacco exposure, alcohol use, and other substance use (eg, cannabis) can impact the long-term health of the patient and/or offspring, we advise patients avoid these exposures and discuss cessation or counseling options as appropriate.
•(See "Benefits and consequences of smoking cessation" and "Overview of smoking cessation management in adults".)
•(See "Overview of smoking cessation management in adults".)
•(See "Substance use during pregnancy: Overview of selected drugs".)
Minimal or unclear effect
●Leiomyoma – The effect of leiomyomas on IVF depends on their location: submucosal myomas (FIGO types 0 to 2) decrease the chance of success, whereas subserosal myomas (FIGO types 5 to 8) do not appear to have any effect (figure 3). The effect of intramural myomas is unclear. A meta-analysis of 19 observational studies showed a significant decrease in live birth (risk ratio [RR] 0.79, 95% CI 0.70-0.88) and clinical pregnancy rates (RR 0.85, 95% CI 0.77-0.94) in women with noncavity-distorting intramural fibroids compared with those without fibroids [36]. However, no study has yet confirmed that removing them improves outcome [37]. (See "Uterine fibroids (leiomyomas): Treatment overview", section on 'Impact of fibroids on fertility'.)
●Endometrioma and endometriosis – Whether an asymptomatic endometrioma should be removed prior to IVF is controversial; there is no consensus on the optimum approach [38]. We do not routinely resect endometriomas prior to initiating IVF as surgery does not improve outcomes of assisted reproductive technology (ART) and may damage ovarian reserve [39,40]. Women with endometriosis undergoing ART appear to have similar chances of achieving a clinical pregnancy and live birth as women with other causes of infertility [41].
•(See "Female infertility: Treatments", section on 'Endometriosis'.)
●Previous pregnancy history – A previous live birth is associated with higher likelihood of successful IVF, but a history of one or more miscarriages does not substantially reduce the likelihood of success [21].
●Previous unsuccessful IVF cycle – Lack of success in an IVF cycle does not appreciably decrease success rates during subsequent treatment until approximately the fourth IVF cycle [42].
●Obesity – Compared with patients of normal body mass index (BMI; 18.5 to 24.9 kg/m2), patients with overweight or obesity (BMIs 25 to 29.9 and ≥30 kg/m2, respectively) have lower pregnancy and live birth rates following IVF as well as increased obstetric risks [43]. However, these effects are modest, and patients with obesity should not be denied access to IVF care after appropriate counseling and shared decision-making. While IVF may be offered to patients with obesity, limitations may include BMI cutoffs for different fertility centers due to the patient's elevated risk with anesthesia, as most egg retrievals are performed at outpatient surgical centers. For those not meeting BMI cutoffs, collaboration with the patient and primary care physician is encouraged to optimize BMI to permit IVF with safe egg retrieval.
•Comparison of patients with obesity and patients of normal weight – Large cohort studies report that, compared with individuals with a BMI in the normal range, elevated BMI is associated with a decreased IVF pregnancy and live birth rates as well as higher rates of pregnancy loss, low birth weight, and preterm birth [43-51]. Absolute post-IVF birth rates for patients with obesity range from 23 to 37 percent compared with 32 to 41 percent for normal BMI control patients [45,52,53]. The range of live births for patients with obesity reflects the further lowering of live birth rates with increasing degrees of BMI (eg, BMI of 25 to 29.9 kg/m2, 30 to 34.9, etc) [45].
Specific studies include:
-Clinical pregnancy and live birth – A study of 239,127 fresh IVF cycles reported in the 2008-2010 Society for Assisted Reproductive Technology (SART) databases reported lower clinical pregnancy and live birth rates for patients with obesity (BMI ranges 30 to >50 kg/m2) compared with normal BMI control patients (clinical pregnancy: range 36.6 to 46.7 versus 49.1 percent and live birth rate: range 23.3 to 37.3 versus 40.6 percent) [45].
-Live birth rate and polycystic ovary syndrome (PCOS) subgroup – Meta-analysis of 21 cohort studies including 682,523 cycles published between 2008 and 2017 reported reduced live birth rates for patients with obesity compared with normal-weight patients (27 versus 32 percent, risk ratio 0.85, 95% CI 0.82-0.87) [52]. In subgroup analysis, having a PCOS diagnosis further reduced the post-IVF live birth rate in obese patients compared with normal weight patients (34 versus 44 percent, RR 0.78, 95% CI 0.74-0.82).
-Live birth and other obstetric outcomes – A retrospective study of nearly 500,000 fresh autologous IVF cycles performed between 2008 to 2013 comparing patients with obesity with those of normal BMI reported that patients with obesity had lower intrauterine pregnancy (42 versus 46 percent) and live birth (33 versus 38) rates as well as increased incidence of pregnancy loss (19.6 versus 15.0 percent), low birth weight (singleton pregnancy, 11.3 versus 8.6 percent), and preterm birth (singleton pregnancy, 16.0 versus 10.8 percent) [53].
•BMI range 30 to ≥50 kg/m2 – Increasing obesity appears to further reduce live birth rates and increase pregnancy loss. Other obstetric complications are less impacted by increasing BMI.
-Live birth and pregnancy loss – A database study of 239,127 fresh IVF cycles that separated patients with obesity into five BMI groups (30 to 34.9, 35 to 39.9, 40 to 44.9, 45 to 49.9, or >50 kg/m2) reported decreasing live birth rates with every increase in BMI range (live birth rates of 37.3, 33.4, 29.4, 27.7, and 23.3, respectively), while the rates of pregnancy loss generally increased across the same BMI spectrum (pregnancy loss rates of 14.5, 13.0 12.8, 17.0, and 30.0) [45].
-Comparison by obesity range – Obesity is associated with adverse obstetric outcomes, but the magnitude of the increased risk is modest, and therefore not a reason to decline IVF for most patients.
A retrospective cohort study from a single academic medical center compared patients by BMI groups (BMI 30 to 34.9, 35 to 39.9, 40 to 44.9, 45 to 49.9, and >50 kg/m2); patients with a BMI 30 to 34.9 kg/m2 were the reference [54]. All patients with a BMI ≥40 kg/m2 received pretreatment consults with a maternal-fetal medicine specialist and anesthesiologist. The risks of obstetric complications were generally similar across the groups in adjusted analyses, including pregnancy-associated hypertension, gestational hypertension, preeclampsia, need for induction, operative vaginal delivery, and postpartum hemorrhage, among others. While patients with BMI ≥50 kg/m2 had increased risk of preeclampsia with severe features and shoulder dystocia, the small number of patients (n = 22) in this group limited definitive conclusions.
Discussions of obesity in adults, including BMI, are available separately.
•(See "Obesity in adults: Prevalence, screening, and evaluation".)
•(See "Obesity in pregnancy: Complications and maternal management".)
●Paternal age – Increasing paternal age has been associated with altered semen parameters and a small negative impact on live birth rates following IVF, although some data conflict [55-60]. In a meta-analysis of 11 studies including 10,527 egg donation cycles, increasing paternal age was associated with a small, linear decrease in live birth rate, but only for couples with maternal age ≥35 years, which suggests that maternal age remains the more important age-related variable [58].
The effects of advancing paternal age on fertility and pregnancy in general are reviewed in detail separately. (See "Effect of advanced paternal age on fertility and pregnancy".)
●Diet – Healthy dietary patterns have been associated with improved outcomes of fertility treatment, but causation cannot be inferred from observational data [61,62]. Improved outcomes may result from a decrease in pregnancy loss in individuals who adhere to a healthy/Mediterranean diet [63].
●Stress – The impact of stress on IVF outcome is unclear as the data are mixed. A detailed discussion is presented in related content. (See "Psychological stress and infertility" and "Psychological stress and infertility", section on 'Impact of stress on IVF outcome'.)
No proven effect
●Aspirin, acupuncture, heparin – Meta-analyses have not demonstrated a statistical improvement in clinical pregnancy rates with use of aspirin [64-66], acupuncture [67-69], or heparin [70] anytime during the IVF cycle. There are inadequate data to assess the efficacy of prophylactic aspirin on other pregnancy outcomes [71].
●Prednisone – Prednisone does not appear to improve live birth rates for patients with past unsuccessful implantation during IVF. In a double-blind randomized trial comparing oral prednisone with placebo in patients with two or more unsuccessful embryo transfers, the live birth rates were similar for the prednisone and placebo groups (37.8 versus 38.8 percent, respectively; absolute difference -1.0 percent, 95% CI -8.1 to 6.1 percent; relative risk 0.97, 95% CI 0.81-1.17, 714 patients) [72]. Similar between-group outcomes were also reported for biochemical pregnancy, clinical pregnancy, implantation, neonatal complications, congenital anomalies, and mean birthweights. Included patients were <38 years of age at time of oocyte retrieval and underwent frozen-thawed embryo transfer with good-quality embryos.
●Acquired or inherited thrombophilia – Although high-quality data are not available, the presence of anticardiolipin or lupus anticoagulant antibodies alone or one of the common inherited thrombophilias does not appear to adversely impact IVF success rates. The available evidence suggests heparin is not routinely indicated when these women undergo IVF. Indications for heparin prophylaxis once pregnancy is confirmed are discussed separately. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy" and "Inherited thrombophilias in pregnancy".)
●Endometrial thickness – A 2014 meta-analysis of studies of the association between endometrial thickness and IVF outcome concluded endometrial thickness was a poor predictor of pregnancy occurrence after IVF and should not be used as a criterion for cycle cancellation, freezing of all embryos, or refraining from further IVF treatment [73]. Addition of granulocyte-colony stimulating factor for patients with thin endometrial lining who are undergoing IVF does not appear to be helpful [74].
●COVID-19 infection or vaccination – At the onset of the coronavirus disease 2019 (COVID-19) pandemic, concerns were raised that possible cross-reactivity between antibodies to the SARS-CoV-2 spike protein and syncyntin-1, a protein involved in the formation of the syncytiotrophoblast of a developing embryo, could negatively impact female fertility [75]. However, available data report no deleterious effects of either viral infection or vaccination on fertility or IVF cycle outcomes [76-78]. In the largest retrospective cohort study comparing 222 vaccinated patients with 983 unvaccinated patients undergoing controlled ovarian stimulation between February and September 2021, outcomes of ovarian stimulation and embryo transfer were similar for both groups, including fertilization and clinical pregnancy rates [77].
•Ovarian stimulation, oocyte retrieval, and fertilization – In adjusted analysis of the above retrospective cohort study, there was no association between vaccination and fertilization rate (β=0.02±0.02), numbers of eggs retrieved (β=0.01±0.57), mature oocytes retrieved (β=0.26±0.47), mature oocytes ratio (β=0.02±0.01), blastulation rate (β=0.02±0.02), or euploid rate (β=0.05±0.03) [77].
•Frozen-thawed embryo transfer – Comparison of 214 vaccinated patients with 733 unvaccinated individuals undergoing single euploid frozen-thawed embryo transfer reported no impact of vaccination on clinical pregnancy (adjusted odds ratio [aOR] 0.79, 95% CI 0.54-1.16), pregnancy (aOR 0.88, 95% CI 0.58-1.33), ongoing pregnancy (aOR 0.90, 95% CI 0.61-1.31), biochemical pregnancy loss (aOR 1.21, 95% CI 0.69-2.14) or clinical pregnancy loss (aOR 1.02, 95% CI 0.51-2.06) [77]. Another study that evaluated frozen embryo transfer outcomes between vaccinated (n = 502) and unvaccinated patients (n = 1589) reported no impact on reproductive outcomes [79]. This study included an analysis on interval between vaccination and embryo transfer as well, with groups being <3 months, 3 to 6 months, and >6 months from their last vaccine.
•Fresh embryo transfer – While the data are mixed as to whether COVID-19 vaccination timing impacts pregnancy outcomes in patients undergoing IVF with fresh embryos, the body of evidence suggests limited impact. Definitive conclusions are further limited by observational data with small sample sizes and use of ongoing pregnancy rates rather than live birth rates in many studies.
-No impact of vaccination or timing – A retrospective cohort study evaluating outcomes in vaccinated (n = 240) and unvaccinated (n = 1343) patients undergoing IVF with fresh embryo transfer reported similar ongoing pregnancy and early pregnancy loss rates between the groups (ongoing pregnancy: 36.3 versus 40.7 percent and pregnancy loss: 15 versus 12 percent) [80]. While the analysis did not compare groups by the time interval between vaccination and IVF start, 27.5 percent of the vaccinated cohort had the vaccine within 30 days of IVF start, 38.4 percent within 31 to 60 days, and 34.1 percent after 61 days. Another retrospective cohort study that compared fresh IVF cycle outcomes for 142 vaccinated and 138 unvaccinated patients reported similar ongoing clinical pregnancy and pregnancy loss rates between the groups (ongoing pregnancy: adjusted odds ratio 0.79, 95% CI 0.48-1.29 and pregnancy loss: aOR, 2.15, 95% CI 0.62-7.47) [78].
-Vaccination appears to impact pregnancy rates – In a study that compared 667 vaccinated patients with 2385 unvaccinated patients undergoing IVF, ongoing pregnancy rates were lower for individuals vaccinated ≤30 days or 31 to 60 days before transfer (12 of 35 patients, adjusted risk ratio [aRR] 0.61, 95% CI 0.33-0.91, and 21 of 58 patients, aRR 0.63, 95% CI 0.42-0.85, respectively) [81]. Data on live birth rates were not available owing to the short duration of study follow-up.
WHAT ARE THE PREGNANCY AND LIVE BIRTH RATES? — The outcome of pregnancies conceived via assisted reproductive technology (ART) has been generally good. However, there are increased risks of multiple gestation, preterm birth, and low birth weight. Pregnancy, maternal, and pediatric outcomes are discussed in detail in related content. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
Background conception rate — When counseling patients regarding pregnancy rates with IVF, it is helpful to understand the baseline (unassisted) conception rates for different populations.
●Spontaneous pregnancy in subfertile patients – In one review of subfertile patients, treatment-independent (ie, unassisted) pregnancy rates over 12 months were 27 percent for patients managed in primary care practice, 12 percent for those referred to infertility specialists, and 2 to 6 percent for patients referred specifically for IVF [37].
●IVF compared with observation – In a trial that randomly assigned patients planning their first IVF cycle to receive either IVF within 90 days or no therapy for 90 days, the live birth rates were significantly higher in the IVF group (29 versus 1 percent) [82].
Live birth and IVF
●Live birth rates per IVF cycle – On a per-cycle basis, the live birth rate following IVF cycles that reach embryo transfer (ET) exceeds that of unassisted conception in the general population (approaching 45 percent versus 28 percent, absolute rates vary by maternal age) [83-86]. The higher live birth rate with IVF is likely due to the retrieval of multiple oocytes. This allows for the transfer of multiple embryos or betters embryo selection.
●Repetitive IVF cycles – The cumulative pregnancy rate and live birth rate continue to increase when IVF is attempted on a repetitive basis but the increase is not linear [87,88]. For patients initiating IVF to conceive a second child after conceiving the first through IVF, estimated live birth rates range from 61 to 88 percent [89].
●Medical and gynecologic disorders – The cause of infertility affects IVF outcome; the highest live birth rates seen in females with ovulatory dysfunction and lowest in those with diminished ovarian reserve (40 versus 15 percent) [90,91]. Pregnancy outcome after ART may be influenced by underlying conditions as well as the procedure itself. However, stress, both perceived and infertility related, does not appear to impact clinical pregnancy rates following IVF treatment [92]. Medical and gynecologic disorders that impact the probability of pregnancy may also influence pregnancy outcome.
●Race and ethnicity – In the United States, IVF success rates appear to vary by race and ethnicity with non-White women having lower live birth rates compared with White women [21,93]. The reasons for these differences are unclear. Outcomes differences by categories of race/ethnicity likely reflect issues of underlying systemic racism and/or socioeconomic differences rather than true differences in biology.
Unassisted pregnancy after IVF — Unassisted pregnancy after successful or unsuccessful IVF is not a rare occurrence, especially among females with good prognostic factors (young, short-duration infertility, unexplained infertility) [94]. Approximately one in five of couples who become pregnant using IVF subsequently have an unassisted pregnancy [95-99]. In a survey study conducted by mail, among 37 couples with <5 years of infertility, a diagnosis of unexplained infertility, and a female partner <35 years of age, 57 percent became pregnant (95% CI 39-73) without assistance over a median follow-up of seven years after their last IVF attempt [95].
WHAT ARE THE RISKS OF THE IVF PROCEDURE? — The risks of the IVF derive from the procedure itself and any risks that develop during subsequent pregnancy [100].
●Procedure risks – Morbidity and mortality rates directly related to IVF are low. Complications are predominantly due to hormonal stimulation and egg retrieval, and include ovarian hyperstimulation syndrome (OHSS), thromboembolism, infection, abdominal bleeding, adnexal torsion, allergic reaction, and anesthetic complications [101,102].
OHSS is a potentially life-threatening complication of ovulation induction that can occur in the setting of ovulation induction with exogenous gonadotropin therapy or IVF. Its most severe manifestations include massive ovarian enlargement and multiple cysts, hemoconcentration, and third-space accumulation of fluid; these changes rarely lead to renal failure, hypovolemic shock, thromboembolic episodes, acute respiratory distress syndrome, and (rarely) death [101,103,104]. Mild OHSS occurs in approximately 25 percent of patients, although some aspects of hyperstimulation are virtually ubiquitous, and a severe form of OHSS is associated with approximately 0.1 to 0.2 percent of all IVF cycles [105]. The clinical symptoms usually appear 5 to 10 days following the first dose of the ovulatory trigger (human chorionic gonadotropin [hCG]). GnRH antagonist protocols are typically chosen for individuals at higher risk for OHSS in order to utilize a GnRHa trigger, for which the risk of OHSS is close to 0 percent [106]. Dopamine agonists may also be used to decrease OHSS risk in patients undergoing controlled ovarian stimulation for IVF [107].
Pathogenesis, clinical manifestations, diagnosis, treatment, and prevention of OHSS are discussed in detail separately.
•(See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome".)
•(See "Prevention of ovarian hyperstimulation syndrome".)
•(See "Management of ovarian hyperstimulation syndrome".)
●Pregnancy-related risks – If IVF results in pregnancy, the patient is at risk of usual pregnancy-related morbidity and mortality (eg, preeclampsia/eclampsia, hemorrhage, thromboembolism, sepsis, amniotic fluid embolism). Ectopic pregnancy occurs in approximately 1.5 to 2 percent of patients [108,109]. Heterotopic pregnancy increases in incidence to 1 in 100 to 1 in 1000 for IVF-conceived pregnancies compared with in 1 in 3000 to 1 in 30,000 for unassisted pregnancy [110].
The impact of IVF on pregnancy, maternal health, and neonatal development are reviewed in detail separately. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
●Other disadvantages of IVF – Disadvantages of IVF include the high cost, the need for procedures and drugs associated with some risk to the female patient, an increased rate of multiple gestation (which accounts for much of the direct cost of pregnancies conceived via IVF [111]), and, possibly, a slight increase in fetal complications. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
WHAT ARE THE COMPONENTS OF AN IVF CYCLE? — The general components of an IVF cycle are pharmacologic ovarian stimulation (ie, ovulation induction or superovulation), prevention of ovulation during stimulation, ovulatory trigger, oocyte aspiration and fertilization, and embryo transfer (ET). (See "In vitro fertilization: Procedure".)
●Protocol selection – Protocols are typically selected after considering patient factors such as ovarian reserve (anti-müllerian hormone [AMH], antral follicle count [AFC], early follicular follicle-stimulating hormone [FSH] level), age, risk factors for ovarian hyperstimulation syndrome (OHSS), body mass index (BMI), and previous cycle response (if applicable).
•In patients who are anticipated "good responders" (meaning their antral follicle count and AMH levels are high), typically a GnRH antagonist protocol would be chosen to have the option of utilizing a GnRH agonist trigger to minimize OHSS risk. A long GnRH agonist protocol may be used as well.
•In patients with diminished ovarian reserve, or "poor responders," typically the maximum dose of gonadotropins is used in combination with an oral agent like clomiphene citrate or aromatase inhibitors, which harnesses endogenous stores of FSH and luteinizing hormone (LH) that help stimulate follicle growth in addition to the exogenous gonadotropins. In very poor responders (AFC <5, FSH >10 international units/mL, a history of poor response or cycle cancellation), mild stimulation (using a gonadotropin dose <150 international units) may be considered. Clinical data suggest there is no difference in clinical outcomes between mild and traditional stimulation protocols in this patient population.
●Ovarian stimulation – For ovarian stimulation, human menopausal gonadotropin (hMG), FSH, or both [112] is administered in a dose of 150 to 450 (maximum dose) international units/day subcutaneously to stimulate follicular growth [112,113]. Low-dose human chorionic gonadotropin (hCG; diluted hCG) may be used in protocols as well to provide "LH activity" along with the FSH/hMG injections. 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 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.
●Prevention of ovulation
•GnRH antagonist protocol – Stimulation is begun either at the time of menses ("short protocol") or after a variable pretreatment period with oral contraceptives [114]. 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 and the risk of premature ovulation first threatens cycle cancellation. Alternatively, some programs first administer the GnRH antagonist as part of a fixed protocol, starting on a particular cycle day, usually day 6. Daily injections of the antagonist are then continued until hCG administration. One meta-analysis found that, compared with a long GnRH agonist protocol, use of GnRH antagonists reduced the incidence of OHSS by nearly 40 percent (odds ratio [OR] 0.61, 95% CI 0.51-0.72; absolute risk reduction 3 percent), with no difference in the live birth rates (OR 1.02, 95% CI 0.85-1.23) [115].
•GnRH agonist (long) protocol with pituitary suppression – Long protocols have two parts: pituitary suppression followed by ovarian stimulation. Pituitary suppression is begun the cycle prior to the planned ovarian stimulation to prevent a luteinizing hormone (LH) surge before the cohort of stimulated ovarian follicles is mature. The long gonadotropin-releasing hormone (GnRH) agonist protocol is typically chosen for women with good ovarian reserve in an effort to achieve synchronous follicle growth. It is not as commonly used as a GnRH antagonist protocol due to the inability to use a GnRH agonist trigger, which can decrease ovarian hyperstimulation syndrome (OHSS).
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 one approach, common in the United States, either oral contraceptive pills (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). Alternatively, leuprolide acetate can be initiated in the luteal phase of the preceding cycle to avoid stimulating a release of endogenous follicle-stimulating hormone (FSH) and LH since those hormones are relatively low in the luteal phase.
-An alternate approach, commonly used in Europe, is to use a single-depot injection that contains higher doses of the drug [116]. 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.
•GnRH agonist flare (short) protocol
-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 [117].
•Progestins – An oral progestin can be used for ovulation suppression instead of a GnRH antagonist. Medroxyprogesterone 10 mg daily, either administered daily from stimulation start or administered in a similar fashion to the GnRH antagonist (when the lead follicle is >14 mm or in a fixed protocol) until the day of the trigger. One randomized controlled trial showed noninferiority with regards to oocyte yield and maturity in egg donors utilizing this protocol [118]. A fresh embryo transfer would not be performed when using a progestin during the stimulation process.
●Ovulation triggering
•hCG can be used to trigger ovulation in timing with the egg retrieval (typically timed 35 to 36 hours prior to the procedure). hCG binds the LH receptors and induces the same ovulatory response that occurs during an endogenous LH surge. This type of trigger can be used with any type of stimulation protocol.
•A GnRH agonist trigger can also be used to trigger ovulation in timing with the egg retrieval timed 35 to 36 hours prior to the procedure. The GnRH agonist can only be used in GnRH antagonist protocols, as GnRH receptors are down-regulated in GnRH agonist protocols. The GnRH agonist trigger will induce an endogenous FSH and LH surge to start the ovulatory cascade.
WHEN ARE DONOR OOCYTES USED? — An IVF cycle can use oocytes from the patient undergoing IVF or from a donor. Donated oocytes can be from directed (known) or anonymous donors [119].
Indications — Common indications for using donor oocytes include [119]:
●Advanced reproductive age
●Diminished ovarian reserve of any etiology
●Known or suspected genetic condition that the patient does not want to pass on to offspring
●Poor oocyte or embryo quality or multiple prior unsuccessful attempts at conception with ART
●Hypergonadotropic hypogonadism or premature ovarian insufficiency
●Lack of biologic oocytes (males or trans females)
Donor selection and screening — Various society guidelines are available to guide donor screening and selection as well as management of fertility laboratories [119-124]. Evaluation of a potential oocyte donor includes a complete medical history to screen for active disease and possible heritable disease, psychoeducational evaluation, physical examination, and laboratory testing [119]. In the United States, the Food and Drug Administration (FDA) is responsible for regulating infectious disease testing of all oocyte donors [125,126]. Written documentation of eligibility for donation is required to meet the FDA regulation. Testing must be performed in a laboratory with methodologies that are FDA-approved for donor screening.
Oocyte donation — The processes of ovarian stimulation, oocyte retrieval, and oocyte cryopreservation are the same for autologous and donor oocytes. Oocyte fertilization with resultant embryo formation can be performed with either fresh or frozen-thawed oocytes. Use of fresh donor oocytes may be associated with improved live birth rates, but fresh cycles are also more challenging as they require hormonal synchronization of both the oocyte donor and intended recipient [127].
●(See "In vitro fertilization: Procedure", section on 'IVF cycle'.)
●(See "Fertility preservation: Cryopreservation options", section on 'Oocytes'.)
WHY IS IVF UNSUCCESSFUL?
Etiologies — An IVF cycle can have challenges at any step in the process; the cause may not be identified.
●Problems prior to embryo formation – Follicles may not develop due to diminished ovarian reserve. A mature oocyte may not be retrievable due to technical difficulties. Fertilization failure may be caused by sperm abnormalities or lack of penetration of the zona pellucida, an oocyte activation failure, or a defect in the oocyte.
●Problems after embryo formation – As the majority of IVF cycles result in viable embryos, unsuccessful cycles generally result from lack of embryo implantation. The many factors involved in embryo implantation can be classified into three general categories: embryo quality, endometrial receptivity, and transfer efficiency [128]. Separate maternal factors that can negatively impact implantation include immune factors, thrombophilias, and endometritis.
Examples of potential etiologies of each are listed below, although the impact of some of these conditions is controversial [128,129]:
•Embryo quality:
-Diminished ovarian reserve
-Advanced maternal age
-Suboptimal ovarian stimulation (limits the potential number of embryos formed)
-Suboptimal laboratory culture conditions
-Damage from biopsy or cryopreservation
-Failure to survive thaw
•Abnormal endometrial development or receptivity:
-Poor endometrial development (thin endometrium, altered expression of adhesive molecules)
-Uterine abnormalities (submucosal myomas, uterine septum)
-Unreceptive uterine environment (eg, hydrosalpinges, infection, although IVF cycles are not typically performed in these settings)
•Embryo transfer (ET) efficiency:
-Traumatic ET (eg, use of rigid transfer catheters). However, most practices use soft tip catheters to avoid this issue.
-Inaccurate placement of the embryos (eg, lack of ultrasound guidance)
Repeated unsuccessful cycles — Embryo quality is typically the limiting factor for patients with repeated unsuccessful IVF cycles. This is particularly true for females with a normal uterine cavity, adequate endometrial development, and straightforward ET. IVF cycles can be repeated and success can eventually be achieved in the majority of patients. No data-driven limit to the number of cycle attempts has been established. Repeat cycles do not appear to increase maternal cancer risk. (See "Assisted reproductive technology: Pregnancy and maternal outcomes", section on 'Risk of cancer'.)
However, patients with poor prognosis may choose to undergo IVF with donor eggs to increase their success. There is no standardized number of unsuccessful IVF cycles that prompts clinicians to advise patients to proceed with donor oocytes. Variables that inform the decision to use donor oocytes include patient age, ovarian reserve, prognosis, and financial constraints. (See "Evaluation and management of infertility in females of advancing age", section on 'Donor oocytes'.)
Further diagnostic evaluation and treatment of couples with repeated failure of implantation of good-quality embryos may be indicated but is beyond the scope of this topic review. For patients with recurrent unsuccessful implantation after IVF, hysteroscopy does not appear to improve the live birth rate [130,131].
RESOURCES FOR PATIENTS AND CLINICIANS — In the United States, over 450 fertility clinics provide verified data on the outcomes of all assisted reproductive technology (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
●United States 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".)
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
●Terminology – In vitro fertilization (IVF) refers to a complex 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. The European Society for Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Endocrinology (ASRM) have released terminology guidelines in an attempt to standardize language for patients, clinicians, and researchers. (See 'Terminology' above.)
●Uses of IVF – While IVF is mainly used to overcome multiple types of infertility, the technique is also used in clinical situations that desire preimplantation genetic testing (PGT), parenthood for individuals or same-sex couples, and balanced family planning, among other uses. (See 'Why is IVF used?' above.)
●Candidates – Anyone who cannot conceive without IVF is considered a candidate for this treatment. Same-sex couples or single individuals may use IVF to allow for gamete donation or gestational surrogacy. Patients with significant comorbidities, such as cardiac or pulmonary disease, may not be healthy enough to undergo ovarian stimulation and oocyte retrieval, although the procedure is relatively simple and only minimally invasive. (See 'Who is a candidate?' above.)
●Components of IVF cycle – The general components of an IVF cycle are pharmacologic ovarian stimulation (ie, ovulation induction or superovulation), suppression of premature ovulation, oocyte aspiration, fertilization, and embryo transfer. (See "In vitro fertilization: Procedure".)
●Factors that impact IVF success – The major determinant of the success of IVF is the biologic age of the individual who is donating the oocytes. Factors that limit IVF success include poor ovarian reserve, presence of hydrosalpinx, and smoking or tobacco use. (See 'What factors impact IVF success?' above.)
●Pregnancy and live birth rates – On a per-cycle basis, the live birth rate following IVF cycles that reach embryo transfer (ET) exceeds that following unassisted conception in the general population (approaching 40 percent versus 28 percent). The higher live birth rate with IVF is likely due to the retrieval of multiple oocytes. This allows for the transfer of multiple embryos or betters embryo selection.
●Pregnancy outcome – Pregnancies conceived via assisted reproductive technology (ART) generally have a good outcome. However, there are increased risks of multiple gestation, preterm birth, low birth weight, abnormal placentation, ectopic pregnancy, and hypertensive disorders of pregnancy.
•(See "Assisted reproductive technology: Pregnancy and maternal outcomes".)
•(See "Assisted reproductive technology: Infant and child outcomes".)
●Unsuccessful IVF cycle – An IVF cycle can have challenges at any step in the process; problems can occur before or after embryo formation. In some cases, the cause may not be identified. Embryo quality is typically the limiting factor for patients with repeated unsuccessful IVF cycles. (See 'Why is IVF unsuccessful?' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Richard Paulson, MD, MS, who contributed to earlier versions of this topic review.
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