Vanquishing multiple pregnancy in in vitro fertilization in the United States-a 25-year endeavor.

The practice of in vitro fertilization has changed tremendously since the birth of the first in vitro fertilization infant in 1978. With the success of early in vitro fertilization programs in the United States, there was a substantial rise in twin births nationwide. In the mid-1990s, more than 30% of in vitro fertilization cycles resulted in twin or higher-order multifetal pregnancies. Since that time, we not only have witnessed improvements in laboratory and treatment efficacy but also have seen a dramatic impact on pregnancy outcomes, specifically regarding twin pregnancies. Because the field evolved and the risks of multifetal pregnancies became more salient, in 2019, the rate of twin pregnancies had dropped to <7% of cycles. This improvement was largely because of technical advancements and revised professional guidance: culturing embryos longer before transfer, improved freezing technology, embryo preimplantation genetic testing, and revised professional guidance regarding the number of embryos to transfer. These developments have led to single-embryo transfer becoming the standard of care in most scenarios. We used national in vitro fertilization surveillance data of all autologous in vitro fertilization cycles from 1996 to 2019 to illustrate trends in the following improved outcomes: autologous embryo transfer cycles involving blastocyst-stage embryos, vitrified embryos, preimplantation genetic testing cycles, total number of embryos being transferred per cycle, and single-embryo transfer usage over time. Among deliveries from autologous embryo transfers, we highlighted trends in singleton births over time and proportion of deliveries involving twins, triplets, quadruplets, or greater. The notable progress in reducing the rate of multifetal pregnancies with in vitro fertilization was largely attributed to a series of technical and clinical actions, culminating in an 80% reduction in the incidence of multiple births without a loss in overall treatment effectiveness.

Increased risk of large-for-gestational age birthweight in singleton siblings conceived with in vitro fertilization in frozen versus fresh cycles.

BACKGROUND: Children born from fresh in vitro fertilization (IVF) cycles are at greater risk of being born smaller and earlier, even when limited to singletons; those born from frozen cycles have an increased risk of large-for-gestational age (LGA) birthweight (z-score ≥1.28). This analysis sought to overcome limitations in other studies by using pairs of siblings, and accounting for prior cycle outcomes, maternal characteristics, and embryo state and stage. METHODS: Pairs of singleton births conceived with IVF and born between 2004 and 2013 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database, matched for embryo stage (blastocyst versus non-blastocyst) and infant gender, categorized by embryo state (fresh versus frozen) in 1st and 2nd births (four groups). RESULTS: The data included 7795 singleton pairs. Birthweight z-scores were 0.00-0.04 and 0.24-0.26 in 1st and 2nd births in fresh cycles, and 0.25-0.34 and 0.50-0.55 in frozen cycles, respectively. LGA was 9.2-9.8 and 14.2-15.4% in 1st and 2nd births in fresh cycles, and 13.1-15.8 and 20.8-21.0% in 1st and 2nd births in frozen cycles. The risk of LGA was increased in frozen cycles (1st births, adjusted odds ratios (AOR) 1.74, 95% CI 1.45, 2.08; and in 2nd births when the 1st birth was not LGA, AOR 1.70, 95% CI 1.46, 1.98 for fresh/frozen and 1.40, 1.11, 1.78 for frozen/frozen). CONCLUSIONS: Our results with siblings indicate that frozen embryo state is associated with an increased risk for LGA. The implications of these findings for childhood health and risk of obesity are unclear, and warrant further investigation.

Fertility workups: the times they are a-changin'.

The workup of patients seeking assisted reproductive technology (ART) treatments has been modified by the tremendous improvements in ART efficacy accomplished recently. Moreover, the fact that ART is nowadays also offered to women who are not necessarily infertile-seeking genetic testing of their embryos-lead to important changes in how we investigate ART candidates. All the facets of these changes have been reviewed in the present introduction to this View-and-Review series on modern-day infertility workups.

Predicting personalized cumulative live birth following in vitro fertilization.

OBJECTIVE: To develop in vitro fertilization (IVF) prediction models to estimate the individualized chance of cumulative live birth at two time points: pretreatment (i.e., before starting the first complete cycle of IVF) and posttreatment (i.e., before starting the second complete cycle of IVF in those couples whose first complete cycle was unsuccessful). DESIGN: Population-based cohort study. SETTING: National data from the Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System. PATIENT(S): Based on 88,614 women who commenced IVF treatment using their own eggs and partner's sperm in SART member clinics. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The pretreatment model estimated the cumulative chance of a live birth over a maximum of three complete cycles of IVF, whereas the posttreatment model did so over the second and third complete cycles. One complete cycle included all fresh and frozen embryo transfers resulting from one episode of ovarian stimulation. We considered the first live birth episode, including singletons and multiple births. RESULT(S): Pretreatment predictors included woman's age (35 years vs. 25 years, adjusted odds ratio 0.69, 95% confidence interval 0.66-0.73) and body mass index (35 kg/m2 vs. 25 kg/m2, adjusted odds ratio 0.75, 95% confidence interval 0.72-0.78). The posttreatment model additionally included the number of eggs from the first complete cycle (15 vs. 9 eggs, adjusted odds ratio 1.10, 95% confidence interval 1.03-1.18). According to the pretreatment model, a nulliparous woman aged 34 years with a body mass index of 23.3 kg/m2, male partner infertility, and an antimüllerian hormone level of 3 ng/mL has a 61.7% chance of having a live birth over her first complete cycle of IVF (and a cumulative chance over three complete cycles of 88.8%). If a live birth is not achieved, according to the posttreatment model, her chance of having a live birth over the second complete cycle 1 year later (age 35 years, number of eggs 7) is 42.9%. The C-statistic for all models was between 0.71 and 0.73. CONCLUSION(S): The focus of previous IVF prediction models based on US data has been cumulative live birth excluding cycles involving frozen embryos. These novel prediction models provide clinically relevant estimates that could help clinicians and couples plan IVF treatment at different points in time.

Prior and novel coronaviruses, Coronavirus Disease 2019 (COVID-19), and human reproduction: what is known?

OBJECTIVE: To summarize current understanding of the effects of novel and prior coronaviruses on human reproduction, specifically male and female gametes, and in pregnancy. DESIGN: Review of English publications in PubMed and Embase to April 6, 2020. METHOD(S): Articles were screened for reports including coronavirus, reproduction, pathophysiology, and pregnancy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Reproductive outcomes, effects on gametes, pregnancy outcomes, and neonatal complications. RESULT(S): Seventy-nine reports formed the basis of the review. Coronavirus binding to cells involves the S1 domain of the spike protein to receptors present in reproductive tissues, including angiotensin-converting enzyme-2 (ACE2), CD26, Ezrin, and cyclophilins. Severe Acute Respiratory Syndrome Coronavirus 1 (SARS-CoV-1) may cause severe orchitis leading to germ cell destruction in males. Reports indicate decreased sperm concentration and motility for 72-90 days following Coronavirus Disease 2019 (COVID-19) infection. Gonadotropin-dependent expression of ACE2 was found in human ovaries, but it is unclear whether SARS-Coronavirus 2 (CoV-2) adversely affects female gametogenesis. Evidence suggests that COVID-19 infection has a lower maternal case fatality rate than SARS or Middle East respiratory syndrome (MERS), but anecdotal reports suggest that infected, asymptomatic women may develop respiratory symptoms postpartum. Coronavirus Disease 2019 infections in pregnancy are associated with preterm delivery. Postpartum neonatal transmission from mother to child has been reported. CONCLUSION(S): Coronavirus Disease 2019 infection may affect adversely some pregnant women and their offspring. Additional studies are needed to assess effects of SARS-CoV-2 infection on male and female fertility.

Association of In Vitro Fertilization With Childhood Cancer in the United States.

Importance: In vitro fertilization (IVF) is associated with birth defects and imprinting disorders. Because these conditions are associated with an increased risk of childhood cancer, many of which originate in utero, descriptions of cancers among children conceived via IVF are imperative. Objective: To compare the incidence of childhood cancers among children conceived in vitro with those conceived naturally. Design, Setting, and Participants: A retrospective, population-based cohort study linking cycles reported to the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System from January 1, 2004, to December 31, 2012, that resulted in live births from September 1, 2004, to December 31, 2013, to the birth and cancer registries of 14 states, comprising 66% of United States births and 75% of IVF-conceived births, with follow-up from September 1, 2004, to December 31, 2014. The study included 275 686 children conceived via IVF and a cohort of 2 266 847 children, in which 10 births were randomly selected for each IVF birth. Statistical analysis was performed from April 1, 2017, to October 1, 2018. Exposure: In vitro fertilization. Main Outcomes and Measures: Cancer diagnosed in the first decade of life. Results: A total of 321 cancers were detected among the children conceived via IVF (49.1% girls and 50.9% boys; mean [SD] age, 4.6 [2.5] years for singleton births and 5.9 [2.4] years for multiple births), and a total of 2042 cancers were detected among the children not conceived via IVF (49.2% girls and 50.8% boys; mean [SD] age, 6.1 [2.6] years for singleton births and 4.7 [2.6] years for multiple births). The overall cancer rate (per 1 000 000 person-years) was 251.9 for the IVF group and 192.7 for the non-IVF group (hazard ratio, 1.17; 95% CI, 1.00-1.36). The rate of hepatic tumors was higher among the IVF group than the non-IVF group (hepatic tumor rate: 18.1 vs 5.7; hazard ratio, 2.46; 95% CI, 1.29-4.70); the rates of other cancers did not differ between the 2 groups. There were no associations with specific IVF treatment modalities or indication for IVF. Conclusions and Relevance: This study found a small association of IVF with overall cancers of early childhood, but it did observe an increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility. Continued follow-up for cancer occurrence among children conceived via IVF is warranted.

National survey of the Society for Assisted Reproductive Technology membership regarding insurance coverage for assisted reproductive technologies.

OBJECTIVE: To assess the attitudes of Society for Assisted Reproductive Technology (SART) members regarding expanding insurance coverage for patients seeking assisted reproductive technologies (ART) and identify some of the factors that may influence such attitudes. DESIGN: An anonymous online 14-question survey of SART membership; 1,556 surveys were sent through the SART Research Portal from June to December 2017. Questions were incremental in scope, beginning with expanding insurance coverage for ART for vulnerable populations (e.g., fertility preservation for cancer, couples with same recessive gene, fertility preservation for transgender individuals) to extending coverage to include patients who were uninsured for ART. Additional questions assessed attitudes about assuming some fiscal responsibility if mandated insurance were contingent on elective single-embryo transfer (eSET) and lower charges in anticipation of increased number of cases. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Specific response to 14 survey questions. RESULT(S): The overall response rate was 43.4% (675/1,556). A large majority (>95%) favored insurance for fertility preservation for cancer patients and for avoidance of genetic disorders; 62.3% were supportive of infertility insurance coverage for transgender patients; 78% supported expanding insurance for the broadest segment of the general uninsured population; 76.7% supported expanding insurance contingent on eSET; and 51.3% would consider expanding insurance contingent on lowering charge per cycle in general, but only 23% responded as to what lower charge would be acceptable. Three of four factors were shown by multivariable logistic regression to be predictive of attitudes willing to expand insurance: practice setting (academic > hybrid > private), practicing in a mandated state, and higher annual volume of cases (>500 cycles); these had significant increased adjusted odds ratios ranging from 1.7 to 2.9. A fourth factor, the professional role one had in the practice, was not found to be of significant predictive value. CONCLUSION(S): The great majority of respondents were supportive of expanding insurance for specific segments of vulnerable populations with special needs and for the population who are presently uninsured. Furthermore, the majority of respondents would consider expanding insurance coverage contingent on age-appropriate eSET but have concerns about reduced reimbursement. Those most likely to be willing to expand insurance are those who practice in an academic setting or a mandated state and/or have a high annual volume of cases.

Society for Assisted Reproductive Technology and assisted reproductive technology in the United States: a 2016 update.

The Society for Assisted Reproductive Technology (SART) was established within a few years of assisted reproductive technology (ART) in the United States, and has not only reported on the evolution of infertility care, but also guided it toward improved success and safety. Moving beyond its initial role as a registry, SART has expanded its role to include quality assurance, data validation, practice and advertising guidelines, research, patient education and advocacy, and membership support. The success of ART in this country has greatly benefited from SART's role, as highlighted by a series of graphs. SART continues to set the standard and lead the way.

Modest follicle-stimulating hormone elevations in younger women: warn but don't disqualify.

Markers of quantitative defects in egg production (low ovarian reserve) have often been used to exclude patients from treatment, even when egg quality is apt to be satisfactory. Women younger than 38 years of age with modest FSH elevations (10-15 or even 20 IU/L) have acceptable pregnancy rates despite their limited production of eggs ("quality matters more than quantity") and so should be given the opportunity to try IVF.

Progress we can be proud of: U.S. trends in assisted reproduction over the first 20 years.

OBJECTIVE: Documentation of the significant progress of assisted reproductive technology (ART) therapy in the United States. DESIGN: Tabulation of data from the annual published reports of ART activity in the United States for the years 1985 through 1999. SETTING: ART centers in the United States that report their results to the Centers for Disease Control and Prevention (CDC) via the Society for Assisted Reproductive Technology (SART). PATIENT(S): The annual reports included 647,208 cycles of treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The number of clinics and cycles, and the rates of pregnancy, delivery, miscarriage, and multiple pregnancy were examined. Practice trends were also examined. RESULT(S): The number of clinics and cycles has grown steadily. The 155,661 clinical pregnancies led to 128,608 births and 177,745 babies born. The advent of intracytoplasmic sperm injection (ICSI) and the fall of GIFT and zygote intrafallopian transfer (ZIFT) are noted. Pregnancy rates have risen steadily in all therapies, and the number of deliveries of triplets or more has declined dramatically in the most recent reporting years. CONCLUSION(S): Over the years, ART therapies have steadily become more effective, with notable reductions in multiple pregnancies, the ability to avoid laparoscopy (for egg retrieval and in some cases tubal transfers), and effective therapy for serious sperm, egg, and uterine problems, none of which was true in the early years. This has occurred owing to the dedication and ingenuity of practitioners, and, notably, without federal regulation of clinical practice.

Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience, 1996-1998.

OBJECTIVE: To evaluate the role of recipient age on the outcome of donor egg cycles. DESIGN: Retrospective cohort study of aggregated national cycles of donor egg therapy that are collected by Society for Assisted Reproductive Technology and the Centers for Disease Control and Prevention. SETTING: Assisted reproductive technology centers in the United States that report their results to the Centers for Disease Control and Prevention by way of the Society for Assisted Reproductive Technology. PATIENT(S): Recipients of embryos (17,339 cycles) derived from donated eggs between 1996 and 1998. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of implantation, clinical intrauterine pregnancy, pregnancy loss, and delivery based on the age of the recipient. RESULT(S): Success of donor egg therapy was remarkably constant among recipients aged 25 years through those in their late forties. At higher ages, declining rates of implantation, clinical pregnancy, and delivery were seen, along with small increases of pregnancy loss. During the course of the 3 years studied, fewer embryos were transferred and higher rates of implantation were observed. CONCLUSION(S): The success of donor egg therapy is unaffected by recipient age up to the later 40s, after which they begin to decline. Although recipient age per se is likely to be the major cause of this effect, other factors may contribute to this observation.

Follicle-stimulating hormone and estradiol levels independently predict the success of assisted reproductive technology treatment.

OBJECTIVE: To evaluate the relationship between early follicular phase levels of FSH and E(2) and outcomes of therapy with assisted reproductive technologies (ART). DESIGN: Retrospective cohort study. SETTING: ART centers in the United States. PATIENT(S): Women receiving 19,682 ART procedures performed in 135 clinics. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of clinical pregnancy, live birth delivery, and high ovarian response (>/=10 oocytes retrieved after stimulation). RESULT(S): The ratio of each FSH or E(2) value to the respective upper limit of normal value for the clinic was computed. Within each age group, rates of pregnancy, live birth, and high ovarian response decreased linearly as FSH levels increased. For example, among women 35 years of age and younger, pregnancy rates (PR) ranged from 41.1% (FSH ratio 0-0.5) to 18.5% (FSH ratio >2.0). The three outcomes exhibited a similar downward trend as E(2) ratios increased. When both hormone ratios were elevated, outcomes were least favorable. These relationships remained statistically significant after we adjusted for diagnosis, number of embryos transferred, previous births, previous ART therapy, and use of GIFT, zygote intrafallopian transfer (ZIFT), intracytoplasmic sperm injection (ICSI), or assisted hatching. CONCLUSION(S): The FSH and E(2) ratios predict ART success independent of age and other clinical prognostic factors.

Why we may abandon basal follicle-stimulating hormone testing: a sea change in determining ovarian reserve using antimüllerian hormone.

Antimüllerian hormone is the most informative serum marker of ovarian reserve currently available and should be considered an important part of any contemporary reproductive medicine practice. It is both more convenient and informative than basal FSH and can be assessed at any point in the cycle. It is the most useful serum method of determining ovarian reserve, which guides pretreatment counseling, choice of infertility treatment, and avoidance of ovarian hyperstimulation. The future role of basal FSH testing is in doubt.

Gonadotropin-releasing hormone agonist pretreatment did not decrease postoperative adhesion formation after abdominal myomectomy in a randomized control trial.

OBJECTIVE: To determine if 3 months of preoperative gonadotropin-releasing hormone agonist (GnRH-a) treatment decreases postoperative uterine adhesions after open abdominal surgery for the removal of uterine fibroids. DESIGN: Prospective, randomized, clinical study. SETTING: A tertiary care medical center. PATIENT(S): Women of reproductive age with symptomatic uterine fibroids not amenable to hysteroscopic removal. INTERVENTION(S): Twenty patients underwent an initial abdominal myomectomy followed by a second-look laparoscopy for evaluating uterine adhesions after random allocation to groups receiving either GnRH analog or placebo for 3 months before the initial surgery. MAIN OUTCOME MEASURE(S): Adhesion formation between treatment groups and by incision number and aggregate length. RESULT(S): Presurgical GnRH-a treatment did not decrease adhesion formation compared with placebo. For every additional centimeter of incision length, the total adhesion area over the uterine serosal surface increased by 0.55 cm(2). The number of myomas removed and the number of incisions were positively correlated with total adhesion area. CONCLUSION(S): Preoperative treatment with GnRH-a for 3 months before open abdominal myomectomy did not decrease postoperative uterine adhesions. Following the standards of good surgical technique, adhesions are minimized with fewer and smaller incisions.