Predictors of success after in vitro fertilization.

The last few decades have witnessed a rise in the global uptake of in vitro fertilization (IVF) treatment. To ensure optimal use of this technology, it is important for patients and clinicians to have access to tools that can provide accurate estimates of treatment success and understand the contribution of key clinical and laboratory parameters that influence the chance of conception after IVF treatment. The focus of this review was to identify key predictors of IVF treatment success and assess their impact in terms of live birth rates. We have identified 11 predictors that consistently feature in currently available prediction models, including age, duration of infertility, ethnicity, body mass index, antral follicle count, previous pregnancy history, cause of infertility, sperm parameters, number of oocytes collected, morphology of transferred embryos, and day of embryo transfer.

Iatrogenic and demographic determinants of the national plural birth increase.

OBJECTIVE: To study the contribution of ovulation induction and ovarian stimulation, in vitro fertilization (IVF), and unassisted conception to the increase in national plural births in the United States, a significant contributor to adverse maternal and infant health outcomes. DESIGN: National and IVF-assisted plural birth data were derived from the Centers for Disease Control and Prevention's National Vital Statistics System (1967-2021, after introduction of Clomiphene Citrate in the United States) and the National Assisted Reproductive Technology Surveillance System (1997-2021), respectively. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): In addition to IVF-assisted plural births, the contributions of unassisted conception to plural births among women aged <35 and ≥35 years were estimated using plural birth rates from 1949-1966 and a Bayesian logistic model with race and age as independent variables. The contribution of ovulation induction and ovarian stimulation was estimated as the difference between national plural births and IVF-assisted and unassisted counterparts. RESULT(S): From 1967-2021, the national twin birth rate increased 1.7-fold to a 2014 high (33.9/1,000 live births), then declined to 31.2/1,000 live births; the triplet and higher order birth rate increased 6.7-fold to a 1998 high (1.9/1,000 live births), then declined to 0.8/1,000 live births. In 2021, the contribution of unassisted conception among women aged <35 years to the national plural births was 56.1%, followed by ovulation induction and ovarian stimulation (19.5%), unassisted conception among women aged ≥35 years (16.8%), and IVF (7.6%). During 2009-2021, the contribution of ovulation induction and ovarian stimulation has remained stable, the contribution of unassisted conception among women aged <35 and ≥35 years has increased, and the contribution of IVF has decreased. CONCLUSION(S): Ovulation induction and ovarian stimulation are leading iatrogenic contributors to plural births. They are, therefore, targets for intervention to reduce the adverse maternal and infant health outcomes associated with plural births. Maternal age of ≥35 years is a significant contributor to the national plural birth increase.

The history and future of in vitro fertilization in the United States: the complex interrelationships among basic science, human medicine, and politics.

Although much of the foundational basic scientific and clinical research was conducted in the United States, the first in vitro fertilization (IVF) birth occurred in the United Kingdom. Why? For centuries, all research surrounding the field of "reproduction" has elicited bipolar passionate responses by the American public, and the issue of "test tube babies" has been no different. The history of conception in the United States is defined by complex interrelationships among scientists, clinicians, and politically charged decisions by various branches of the US government. With a focus on research in the United States, this review summarizes the early scientific and clinical advances important to the development of IVF and then addresses the potential future developments in IVF. We also consider what future advances are possible in the United States given the current regulations, laws, and funding.

Whither cryopreservation? The landscape gets colder.

The increase in utilization and changing legal landscape has made the field of embryo and gamete cryopreservation fraught with potential future challenges and liabilities. Clinics should be aware of the current state of the science, potential legal ramifications of what is currently routine practice, and long-term ethical implications of our work.

The Future of IVF: The New Normal in Human Reproduction.

Increased demand for in vitro fertilization (IVF) due to socio-demographic trends, and supply facilitated by new technologies, converged to transform the way a substantial proportion of humans reproduce. The purpose of this article is to describe the societal and demographic trends driving increased worldwide demand for IVF, as well as to provide an overview of emerging technologies that promise to greatly expand IVF utilization and lower its cost.

Random antral follicle count performed on any day of the menstrual cycle has the same predictive value as AMH for good ovarian response in IVF cycles.

OBJECTIVE: To determine whether the predictive value of AFC for ovarian response to stimulation for IVF depends on the day of the menstrual cycle when ultrasound is performed. METHODS: 410 women undergoing their first IVF cycle were included. All the women had AFC performed twice. The first measurement, random AFC (r-AFC), was performed during the fertility workup whatever the day of their menstrual cycle. Three groups were constituted according to the period of ultrasound performance: at early follicular phase i.e., day 1 to day 6 (eFP-AFC); at mid follicular phase i.e., day 7 to 12 (mFP-AFC) and at luteal phase i.e., day 13 or after (LP-AFC). A second AFC measurement was performed before the start of the ovarian stimulation (SD1-AFC). AMH dosing was done in the early follicular phase. RESULTS: Random AFC (r-AFC) was correlated to AMH (r = 0.69; p<0.001), SD1-AFC (r = 0.75; p<0.001) and number of oocytes retrieved (r = 0.49; p<0.001). When regarding AFC depending on the cycle day group, the correlation with AMH was 0.65, 0.66 and 0.85 for the eFP-AFC, the mFP-AFC and the LP-AFC respectively (all p were <0.001). The ROC analysis showed the same predictive value for good ovarian response (more than 6 oocytes retrieved) for the eFP-AFC, mFP-AFC and LP-AFC (AUC 0.73, 0.75 and 0.84 respectively; p = 0.28). The AUC of r-AFC (0.76) were similar to those of AMH (0.74) and SD1-AFC (0.74) (p = 0.21 and 0.92 respectively). CONCLUSION: AFC is strongly correlated with AMH and highly predictive of good ovarian response during the whole menstrual cycle.

Common practices among consistently high-performing in vitro fertilization programs in the United States: 10-year update.

OBJECTIVE: To evaluate similarities and differences in clinical and laboratory practices among high-performing fertility clinics. DESIGN: Cross-sectional questionnaire study of selected programs. SETTING: Academic and private fertility practices performing in vitro fertilization (IVF). PATIENT(S): Not applicable. INTERVENTION(S): A comprehensive survey was conducted of 13 IVF programs performing at least 100 cycles a year and having high cumulative singleton delivery rates for 2 years. MAIN OUTCOME MEASURE(S): Clinical and laboratory IVF practices. RESULT(S): Although many areas of clinical practice varied among top programs, some commonalities were observed. All programs used a combination of follicle-stimulating hormone and luteinizing hormone for IVF stimulation, intramuscular progesterone in frozen embryo transfer cycles, ultrasound-guided embryo transfers, and a required semen analysis before starting the IVF cycle. Common laboratory practices included vitrification of embryos at the blastocyst stage, air quality control with positive air pressure and high-efficiency particulate air filtration, use of incubator gas filters, working on heated microscope stages, and incubating embryos in a low-oxygen environment, most often in benchtop incubators. CONCLUSION(S): Some areas of consistency in clinical and laboratory practices were noted among high-performing IVF programs that are likely contributing to their success. High-performing programs focused on singleton deliveries. As the field of IVF is rapidly evolving, it is imperative that we share best practices in an effort to improve outcomes from all clinics for the good of our patients.

The altered immunological status of children conceived by assisted reproductive technology.

BACKGROUND: With the increased use of assisted reproductive technology (ART), assessing the potential health risks of children conceived on ART important to public health. Most research in this area has focused on the effects of ART on perinatal, metabolic, and oncological risks in children. Although an increased risk of immune-related diseases has been reported in children born after ART, there are no studies on the immunological status of these children. This study aimed to evaluate the impact of different embryo transfer methods and fertilization strategies on the immune status of the offspring. METHODS: A total of 69 children born to women treated with ART and a matched control group of 17 naturally conceived (NC) children, all aged from 3 to 6 years, were recruited in the reproductive hospital affiliated to Shandong University. The frequency of immune cells in the peripheral blood was assayed using flow cytometry; plasma cytokine levels were determined by multiplex cytokine immunoassay with human cytokine magnetic beads. RESULTS: Compared to children born after natural conception, children born after ART had elevated interferon-γ (IFN-γ) levels, regardless of embryo transfer and fertilization strategies. Children in the fresh-embryo transfer group had significantly higher IL-4 levels and a lower ratio of IFN-γ to IL-4 than those in the NC group ((P = 0.004, 10.41 ± 5.76 pg/mL vs 18.40 ± 7.01 pg/mL, P = 0.023, 1.00 ± 0.48 vs 0.67 ± 0.32, respectively). Similar results were shown in either the in vitro fertilization (IVF) group or the intra-cytoplasmic sperm injection (ICSI) group (P < 0.05 and P = 0.08 for IVF; P < 0.05 and P < 0.05 for ICSI, respectively). These alterations in IL-4 concentrations and the ratio of IFN-γ to IL-4 were statistically significantly correlated with supra-physical E2 (estradiol) levels on the day of hCG administration (R = 0.502, P = 0.017; R = - 0.537, P = 0.010, respectively). Consistently, the frozen embryo transfer did not result in alterations of these immune indicators in the offspring. Overall, there were no significant differences between the ART group and NC group in the frequencies of T cells, B cells, natural killer (NK) cells, CD4+T cells, CD8+T cells, T helper (TH)1 cells, TH17 cells, and regulatory T (Treg) cells and cytokine levels of IL-10 and IL-17a (all P > 0.05). CONCLUSIONS: Immunological alterations existed in children born after the use of ART. The elevated E2 levels before embryo implantation contributed to the increased IL-4 levels in children conceived by fresh embryo transfer. The assessment of immunological alteration is of importance to children conceived by ART for early monitoring and intervention.

Defining recurrent implantation failure: a profusion of confusion or simply an illusion?

Recurrent implantation failure (RIF) is a poorly defined clinical scenario marked by failure to achieve pregnancy after multiple embryo transfers. The causes and definitions of implantation failure are heterogeneous, posing limitations on study design as well as the interpretation and application of findings. Recent studies suggest a novel, personalized approach to defining RIF. Here, we review the implantation physiology and definitions of the implantation rate, failure, and RIF.

Novel therapeutic options for treatment of recurrent implantation failure.

Despite the challenges in studying recurrent implantation failure, progress is currently being made in therapeutic options to help those who suffer from recurrent implantation failure. Three of the most promising therapeutic options for recurrent implantation failure include immune therapies such as peripheral blood mononuclear cells, platelet rich plasma and subcutaneous granulocyte-colony stimulating factor.

A review of the pathophysiology of recurrent implantation failure.

Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition-something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.

Do frozen embryo transfers modify the epigenetic control of imprinted genes and transposable elements in newborns compared with fresh embryo transfers and natural conceptions?

OBJECTIVE: To determine whether the epigenetic control of imprinted genes (IGs) and transposable elements (TEs) differs at birth between fresh or frozen embryo transfers and natural conceptions. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): A total of 202 singleton births were divided into three groups: 84 natural pregnancies (controls), 66 in vitro fertilization/intracytoplasmic sperm injection with fresh embryo transfers, and 52 vitro fertilization/intracytoplasmic sperm injection with frozen embryo transfers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Pyrosequencing was used to assess the DNA methylation profiles of three IGs (H19/IGF2:IG-DMR [two sequences], KCNQ1OT1:TSS-DMR, and SNURF:TSS-DMR) and two TEs (LINE-1 and HERV-FRD) in cord blood and placenta. The quantitative reverse transcriptase polymerase chain reaction was used to study the transcription of three IGs (H19, KCNQ1, and SNRPN) and two TEs (LINE-1 and ORF2). RESULT(S): After adjustment, the placental DNA methylation levels of H19/IGF2 were lower in the fresh embryo transfer group than in the control (H19/IGF2-seq1) and frozen embryo transfer (H19/IGF2-seq2) groups. The DNA methylation rate for LINE-1 was lower in placentas from the fresh embryo transfer group than in placentas from the control and frozen embryo transfer groups and for HERV-FRD compared with controls. In cord blood, DNA methylation levels were not significantly associated with the mode of conception. The relative expression of LINE-1 and ORF2 was decreased in both cord blood and placental tissues from fresh embryo transfer conceptions compared with natural conceptions and frozen embryo transfer conceptions. CONCLUSION(S): Compared with natural conceptions and frozen embryo transfers, fresh embryo transfers were associated with methylation and/or transcription changes in some TEs and IGs, mostly in placental samples, which could indicate altered placental epigenetic regulation resulting from ovarian stimulation protocols.

Relationship between semen regurgitation and pregnancy rates with intrauterine insemination.

OBJECTIVE: To evaluate the relationship between semen regurgitation and intrauterine insemination (IUI) outcomes. We hypothesized that clinical pregnancy rates and live birth rates would be reduced when regurgitation occurred. DESIGN: Retrospective cohort study. SETTING: A university-based reproductive endocrinology and infertility clinic. PATIENT(S): Retrospective review of 1,957 IUI cycles performed on 660 patients between July 2007 and May 2012. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was live birth. Secondary outcomes were positive serum pregnancy result and clinical pregnancy. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a cluster-weighted generalized estimating equations method to estimate modified Poisson regression models with robust standard errors to account for multiple IUI cycles in the same patient. RESULT(S): Live birth rates were similar in IUI cycles with and without regurgitation (6.3% vs. 6.8%, respectively, RR = 0.82, 95% CI [0.53-1.26]). Clinical pregnancy rates in the presence or absence of regurgitation were 10.5% vs. 10.0% (RR = 0.99, 95% CI [0.73-1.35]). Positive serum pregnancy tests after IUI did not differ by regurgitation status (15.0% vs. 15.4%, RR = 0.97, 95% CI [0.75-1.24]). Results were unchanged when adjusted for covariates (age, race and ethnicity, body mass index, duration of infertility, medication, infertility diagnosis, total motile count, and method of sperm preparation). CONCLUSION(S): The presence of regurgitation during the IUI procedure is not related to pregnancy outcome.

Time associations between U.S. birth rates and add-Ons to IVF practice between 2005-2016.

Until 2010, the National Assisted Reproductive Technology Surveillance System (NASS) report, published annually by the Center for Disease Control and Prevention (CDC), demonstrated almost constantly improving live birth rates following fresh non-donor (fnd) in vitro fertilization (IVF) cycles. Almost unnoticed by profession and public, by 2016 they, however, reached lows not seen since 1996-1997. We here attempted to understand underlying causes for this decline. This study used publicly available IVF outcome data, reported by the CDC annually under Congressional mandate, involving over 90% of U.S. IVF centers and over 95% of U.S. IVF cycles. Years 2005, 2010, 2015 and 2016 served as index years, representing respectively, 27,047, 30,425, 21,771 and 19,137 live births in fnd IVF cycles. Concomitantly, the study associated timelines for introduction of new add-ons to IVF practice with changes in outcomes of fnd IVF cycles. Median female age remained at 36.0 years during the study period and center participation was surprisingly stable, thereby confirming reasonable phenotype stability. Main outcome measures were associations of specific IVF practice changes with declines in live IVF birth rates. Time associations were observed with increased utilization of "all-freeze" cycles (embryo banking), mild ovarian stimulation protocols, preimplantation genetic testing for aneuploidy (PGT-A) and increasing utilization of elective single embryo transfer (eSET). Among all add-ons, PGT-A, likely, affected fndIVF most profoundly. Though associations cannot denote causation, they can be hypothesis-generating. Here presented time-associations are compelling, though some of observed pregnancy and live birth loss may have been compensated by increases in frozen-thawed cycles and consequential pregnancies and live births not shown here. Pregnancies in frozen-thawed cycles, however, represent additional treatment cycles, time delays and additional costs. IVF live birth rates not seen since 1996-1997, and a likely continuous downward trend in U.S. IVF outcomes, therefore, mandate a reversal of current outcome trends, whatever ultimately the causes.

More blastocysts are produced from fewer oocytes in ICSI compared to IVF - results from a sibling oocytes study and definition of a new key performance indicator.

BACKGROUND: Which fertilization method, between ICSI and IVF in split insemination treatments, has the highest clinical efficiency in producing clinically usable blastocyst? METHODS: 211 infertile couples underwent split insemination treatments for a non-severe male factor. 1300 metaphase II (MII) oocytes were inseminated by conventional IVF and 1302 MII oocytes were micro-injected with the same partner's semen. Embryo development until blastocyst stage on day V and clinical outcomes were valuated trough conventional key performance indicators (KPI), and new KPIs such as blastocyst rate per used MII oocytes and the number of MII oocytes to produce one clinically usable blastocyst from ICSI and IVF procedures. RESULTS: The results were  globally analyzed and according to ovarian stimulation protocol, infertility indication, and female age. The conventional KPI were online with the expected values from consensus references. From global results, 2.3 MII oocyte was needed to produce one clinically usable blastocyst after ICSI compared to 2.9 MII oocytes in IVF. On the same way, more blastocysts for clinical use were produced from fewer MII oocytes in ICSI compared to IVF in all sub-groups. CONCLUSIONS: In split insemination treatments, the yield of clinically usable blastocysts was always superior in ICSI compared to IVF. The new KPI "number of needed oocytes to produce one clinically usable embryo" tests the clinical efficiency of the IVF laboratory.