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.

Characteristics of the cytoplasmic halo during fertilisation correlate with the live birth rate after fresh cleaved embryo transfer on day 2 in minimal ovarian stimulation cycles: a retrospective observational study.

BACKGROUND: Information regarding the influence of cytoplasmic events during fertilisation on the clinical outcome remains limited. The cytoplasmic halo is one of these events. A previous study that used time-lapse technology found an association of the presence and morphokinetics of the cytoplasmic halo with cleavage patterns, development to the blastocyst stage, and the ongoing pregnancy rate after blastocyst transfer. Therefore, the cytoplasmic halo may be a useful predictor of the pregnancy outcome after cleaved embryo transfer. This study evaluated the ability of the cytoplasmic halo to predict a live birth after fresh cleaved embryo transfer on day 2, and sought to identify factors potentially influencing the presence and morphokinetics of the halo. METHODS: A total of 902 embryos cultured in the EmbryoScope+® time-lapse system and subjected to single fresh cleaved embryo transfer were retrospectively analysed. The presence and duration of a cytoplasmic halo were annotated. The initial positions of the pronuclei were also observed. The correlation between the cytoplasmic halo and live birth was evaluated and the association of the cytoplasmic halo with patient, cycle, and embryonic characteristics was determined. RESULTS: Absence of a cytoplasmic halo was associated with a significant decrease in the likelihood of a live birth after fresh cleaved embryo transfer. Prolongation of the halo, especially the duration of central repositioning of cytoplasmic granules, had an adverse impact on the live birth rate. The characteristics of the cytoplasmic halo were not affected by the ovarian stimulation method used, female age, the serum steroid hormone level on the day of trigger, or semen quality. However, the cytoplasmic halo was significantly affected by male age, oocyte diameter, and the initial position of the male pronucleus. CONCLUSIONS: Absence or prolongation of the cytoplasmic halo was negatively correlated with the live birth rate after fresh cleaved embryo transfer. The characteristics of the cytoplasmic halo were strongly associated with oocyte diameter, male age, and the initial position of the male pronucleus. These findings indicate that the characteristics of the cytoplasmic halo can be used to select more competent embryos for transfer at the cleavage stage.

The effect of thyroid autoantibody on assisted reproduction technology outcome in euthyroid women: One center experience.

Thyroid dysfunction is an important factor to cause failure in assisted reproduction technology (ART) procedures. In this study, we recorded the serum level of thyroid autoantibody to fig. out its relationship with the ART outcome. The results showed that the serum concentrations of TSH had a statistically significant increase between the basal level and the levels at time of serum pregnancy test both in women with and without thyroid autoantibody (p= 0.002 and p=0.019, respectively). Additionally, the TSH level increased significantly in thyroid autoantibody-positive group than those in thyroid autoantibody-negative group during controlled ovarian hyper stimulation (COH) process(p = 0.006). The risk of preterm delivery was lower in thyroid autoantibody-negative group. In sum, the present study provided evidence of an association between thyroid autoantibody and preterm delivery in euthyroid women.

Triggering change in stimulation protocols: a matter of oocyte maturation and beyond.

Since the birth of Louise Brown, in vitro fertilization (IVF) stimulation protocols have evolved significantly. One particular area of focus has been the process of final oocyte maturation, during which the oocyte gains competence to support fertilization and early embryonic development up to implantation. The field of human assisted reproductive technology (ART) is witnessing increased utilization of GnRH agonists (GnRHa) as trigger agents, in addition to or instead of the traditionally used human chorionic gonadotropin (hCG). Future translational studies will reveal whether oocyte developmental competence, as reflected in live birth outcomes, are not only non-inferior, but also superior with the use of GnRHa as a trigger for both nuclear and cytoplasmic oocyte maturation.

Mathematical Modeling and Simulation Provides Evidence for New Strategies of Ovarian Stimulation.

New approaches to ovarian stimulation protocols, such as luteal start, random start or double stimulation, allow for flexibility in ovarian stimulation at different phases of the menstrual cycle. It has been proposed that the success of these methods is based on the continuous growth of multiple cohorts ("waves") of follicles throughout the menstrual cycle which leads to the availability of ovarian follicles for ovarian controlled stimulation at several time points. Though several preliminary studies have been published, their scientific evidence has not been considered as being strong enough to integrate these results into routine clinical practice. This work aims at adding further scientific evidence about the efficiency of variable-start protocols and underpinning the theory of follicular waves by using mathematical modeling and numerical simulations. For this purpose, we have modified and coupled two previously published models, one describing the time course of hormones and one describing competitive follicular growth in a normal menstrual cycle. The coupled model is used to test ovarian stimulation protocols in silico. Simulation results show the occurrence of follicles in a wave-like manner during a normal menstrual cycle and qualitatively predict the outcome of ovarian stimulation initiated at different time points of the menstrual cycle.

Pasado presente y futuro de la estimulación ovárica en el tratamiento de la infertilidad / Past, present and future of ovarian stimulation in infertility treatment

La mejor comprensión de la fisiología reproductiva y la disponibilidad de más y mejores recursos diagnóstico/terapéuticos permiten individualizar la estimulación ovárica y hacerla más efectiva (mejores resultados), eficiente (en menos tiempo y con dosis más bajas), segura (con menos y más leves complicaciones), cómoda (menos molestias y autonomía) y accesible (para más personas, a menores costos). Con tecnología de ADN recombinante se dispone ahora de todas las gonadotrofinas e incluso algunas con formas moleculares modificadas para aumentar la duración de acción y disminuir el número de inyecciones. El esquema más utilizado es el de FSH recombinante junto con antagonistas de GnRH. Hay indicaciones específicas para agregar LH o coadyuvantes como hGH o andrógenos transdérmicos. La estimulación ovárica, además de infertilidad, se usa para la preservación de la fertilidad. Cada vez se implementan más estrategias como acumulación de óvulos, esquemas no convencionales (random start, DuoStim y otros) junto a vitrificación ovular, estudio genético preimplantatorio, transferencias embrionarias diferidas y la investigación continúa. Se pronostican mejoras en un futuro próximo, entre otras antagonistas por vía oral y estudio genético de pacientes para diagnosticar mutaciones o polimorfismos de gonadotrofinas y sus receptores. Aunque ya es factible individualizar la estimulación y volverla más efectiva, segura y amigable, así como ofrecer otras opciones a pacientes de mal pronóstico.

Due to an increased understanding of reproductive physiology and to the availability of more and better diagnostic/therapeutic agents, ovarian stimulation through individualization, has become more effective (improved results), efficient (shorter span and lower doses), safe (less and milder complications), comfortable (less discomfort and dependance) and affordable (for more people at lower cost). All gonadotrophins are now available by recombinant DNA technology, including some modified compounds for specific purposes such as longer action and fewer injections. The most popular ovarian regime uses recombinant FSH and GnRH antagonist. There are precise indications for adding LH or adjuncts like hGH or transdermal androgens. Besides infertility, ovarian stimulation is also indicated for fertility preservation. Strategies like oocyte accumulation, non-conventional stimulation protocols (random start, DuoStim and others), oocyte vitrification, preimplantation genetic testing, freeze-all, deferred embryo transfer for particular cases are becoming popular, and the research still goes on. Future advances like oral GnRH antagonists, and the study of mutations and polymorphisms for gonadotropins and its receptors are foreseen. Today through individualization, ovarian stimulation is safe, effective and friendly, also we can offer good options to bad prognosis patients

Follicle flushing does not improve live birth and increases procedure time: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To determine whether follicle flushing during oocyte retrieval improves live birth or secondary outcomes in assisted reproductive technology (ART). DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women undergoing ART using autologous gametes. INTERVENTION(S): A systematic search of PubMed, EMBASE, Cochrane Database, and Web of Science for randomized controlled trials comparing follicle flushing to direct aspiration during oocyte retrieval published in English between 1989 to 2020. MAIN OUTCOME MEASURE(S): Live birth as primary outcome, and clinical and ongoing pregnancy, total and mature metaphase II (MII) oocytes retrieved, and operating time as secondary outcomes. RESULT(S): Eleven studies were included totaling 1,178 cases. No difference in live birth was demonstrated between follicle flushing and direct aspiration. Clinical pregnancy and ongoing pregnancy were not improved with flushing. Total oocyte and MII yield were lower with flushing compared with direct aspiration. Procedure time was increased with flushing by 2 minutes in poor responders and 9 minutes in normal responders. Other sensitivity analyses did not demonstrate any changes, except the difference in MII yield was no longer statistically significant. CONCLUSION(S): Follicle flushing during oocyte retrieval increases procedure time and does not improve live birth or secondary ART outcomes. Randomized data do not support the use of follicle flushing as an intervention in ART.

Controlled ovarian stimulation should not be preferred for male infertility treated with intrauterine insemination: a retrospective study.

BACKGROUND: Some studies have stated that intrauterine insemination (IUI) with controlled ovarian stimulation (COS) might increase the pregnancy rate, while others suggest that IUI in the natural cycle (NC) should be the first line of treatment. It remains unclear whether it is necessary to use COS at the same time when IUI is applied to treat isolated male factor infertility. Thus, we aimed to investigate efficacy of IUI with COS for isolated male factor infertility. METHODS: A total of 601 IUI cycles from 307 couples who sought medical care for isolated male factor infertility between January 2010 and February 2020 were divided into two groups: NC-IUI and COS-IUI. The COS-IUI group was further divided into two subgroups according to the number of pre-ovulatory follicles on the day of HCG: cycles with monofollicular development (one follicle group) and cycles with at least two pre-ovulatory follicles (≥ 2 follicles group). The IUI outcomes, including clinical pregnancy, live birth, spontaneous abortion, ectopic pregnancy, and multiple pregnancy rates were compared. RESULTS: The clinical pregnancy, live birth, spontaneous abortion, and ectopic pregnancy rates were comparable between the NC-IUI and COS-IUI group. Similar results were also observed among the NC-IUI, one follicle, and ≥ 2 follicles groups. However, with respect to the multiple pregnancy rate, a trend toward higher multiple pregnancy rate was observed in the COS-IUI group compared to the NC-IUI group (8.7% vs. 0, P = 0.091), and a significant difference was found between the NC-IUI and ≥ 2 follicles group (0 vs. 16.7%, P = 0.033). CONCLUSION: In COS cycles, especially in those with at least two pre-ovulatory follicles, the multiple pregnancy rate increased without a substantial gain in overall pregnancy rate; thus, COS should not be preferred in IUI for isolated male factor infertility. If COS is required, one stimulated follicle and one healthy baby should be the goal considering the safety of both mothers and foetuses.

Does quantity equal quality?-A morphokinetic assessment of embryos obtained from young women with decreased ovarian response to controlled ovarian stimulation.

PURPOSE: To assess oocyte quality in young patients with decreased ovarian response to controlled ovarian stimulation using time-lapse analysis. METHODS: A retrospective cohort study conducted at five medical centers between 2013 and 2017. The "decreased ovarian response" (DOR) group consisted of 241 women who underwent controlled ovarian stimulation with ≤ 5 retrieved oocytes and 519 cultured embryos. The "normal response" (NOR) group consisted of 667 women with ≥ 6 retrieved oocytes resulting in 3633 embryos. Data included annotation of morphokinetic events of embryos cultured in a time-lapse incubator from time of pronuclei appearance to time of starting blastocyst formation (tSB). Comparison was made between morphokinetic parameters of DOR and NOR patients with additional subgroup analysis according to the implantation status. RESULTS: Implantation and clinical pregnancy rates were significantly higher in the NOR group compared with the DOR group (44.5% vs. 31.6% and 51.5% vs. 37.7%, respectively; p < 0.05). Embryos from the DOR group reached the morphokinetic milestones later than embryos obtained from NOR patients. In the DOR group, implanted embryos reached starting blastocyst formation (tSB) faster than embryos which failed to be implanted, however, manifested a protracted course compared with implanted embryos from the NOR group. In a multivariate analysis-decreased ovarian response, nulliparity, number of transferred embryos, and t4, and were predictive for implantation. CONCLUSIONS: The quantitative decrease in ovarian response is associated with reduced oocyte quality, reflected by a slower developmental rate and lower implantation and pregnancy rates.

Growth hormone supplementation during ovarian stimulation improves oocyte and embryo outcomes in IVF/PGT-A cycles of women who are not poor responders.

PURPOSE: To determine the effect of human growth hormone (GH) supplementation during ovarian stimulation in women undergoing IVF/PGT-A cycles, who do not meet the Bologna criteria for poor ovarian response (POR). METHODS: This is a retrospective cohort study of 41 women with suboptimal outcomes in their first cycle of IVF/PGT-A including lower than expected number of MII oocytes, poor blastulation rate, and/or lower than expected number of euploid embryos for their age, who underwent a subsequent IVF/PGT-A cycle with the same fixed dose gonadotropin protocol and adjuvant GH treatment. Daily cotreatment with GH started with first gonadotrophin injection. The IVF cycle outcomes were compared between the control and GH cycle using the Wilcoxon-Signed Rank test. RESULTS: The total number of biopsied blastocysts (mean ± SD; 2.0 ± 1.6 vs 3.5 ± 3.2, p = 0.009) and euploid embryos (0.8 ± 1.0 vs 2.0 ± 2.8, p = 0.004) were significantly increased in the adjuvant GH cycle compared to the control cycle. The total number of MII oocytes also trended to be higher in the GH cycle (10.2 ± 6.3 vs 12.1 ± 8.3, p = 0.061). The overall blastulation and euploidy rate did not differ between the control and treatment cycle. CONCLUSION: Our study uniquely investigated the use of adjuvant GH in IVF/PGT-A cycles in women without POR and without a priori suspicion for poor outcome based on their clinical parameters. Our study presents preliminary evidence that GH supplementation in these women is beneficial and is associated with an increased number of blastocysts for biopsy and greater number of euploid embryos for transfer.

A 10-year follow-up on the practice of luteal phase support using worldwide web-based surveys.

BACKGROUND: It has been demonstrated that luteal phase support (LPS) is crucial in filling the gap between the disappearance of exogenously administered hCG for ovulation triggering and the initiation of secretion of endogenous hCG from the implanting conceptus. LPS has a pivotal role of in establishing and maintaining in vitro fertilization (IVF) pregnancies. Over the last decade, a plethora of studies bringing new information on many aspects of LPS have been published. Due to lack of consent between researchers and a dearth of robust evidence-based guidelines, we wanted to make the leap from the bench to the bedside, what are the common LPS practices in fresh IVF cycles compared to current evidence and guidelines? How has expert opinion changed over 10 years in light of recent literature? METHODS: Over a decade (2009-2019), we conducted 4 web-based surveys on a large IVF-specialist website on common LPS practices and controversies. The self-report, multiple-choice surveys quantified results by annual IVF cycles. RESULTS: On average, 303 IVF units responded to each survey, representing, on average, 231,000 annual IVF cycles. Most respondents in 2019 initiated LPS on the day of, or the day after egg collection (48.7 % and 36.3 %, respectively). In 2018, 72 % of respondents administered LPS for 8-10 gestational weeks, while in 2019, 65 % continued LPS until 10-12 weeks. Vaginal progesterone is the predominant delivery route; its utilization rose from 64 % of cycles in 2009 to 74.1 % in 2019. Oral P use has remained negligible; a slight increase to 2.9 % in 2019 likely reflects dydrogesterone's introduction into practice. E2 and GnRH agonists are rarely used for LPS, as is hCG alone, limited by its associated risk of ovarian hyperstimulation syndrome (OHSS). CONCLUSIONS: Our Assisted reproductive technology (ART)-community survey series gave us insights into physician views on using progesterone for LPS. Despite extensive research and numerous publications, evidence quality and recommendation levels are surprisingly low for most topics. Clinical guidelines use mostly low-quality evidence. There is no single accepted LPS protocol. Our study highlights the gaps between science and practice and the need for further LPS research, with an emphasis on treatment individualization.

What Does Unexpected Suboptimal Response During Ovarian Stimulation Suggest, an Overlooked Group?

Unlike poor ovarian response, despite being predicted to be normal responders based on their ovarian reserve markers, many patients respond suboptimally to ovarian stimulation. Although we can improve the number of retrieved oocytes by increasing the recombinant FSH dose and adding LH, the effect of suboptimal ovarian response on cumulative live birth rate (CLBR) and offspring safety is unclear. This study focuses on the unexpected suboptimal response during ovulation induction, and its causes and outcomes are analysed for the first time with a large amount of data used to compare the cumulative pregnancy rate (CPR), CLBR and offspring safety of patients with one complete ART cycle with all embryos used. Our analysis included 5218 patients treated with the GnRH agonist long protocol for their first IVF-embryo transfer (ET) cycles. Patients were divided into two groups according to whether the ovarian response was suboptimal. Propensity score matching (PSM) was utilized for sampling at up to 1:1 nearest-neighbour matching with caliper 0.05 to balance the baseline and improve comparability between the groups. Results showed that age, BMI and basal FSH were independent risk factors for slow response; the initial dosage of Gn, FSH on the first day of Gn, and LH on the first day of Gn were independent protective factors for suboptimal response. Suboptimal responders were also more likely to have irregular menses. Regarding the clinical pregnancy rate of the fresh IVF/ICSI-ET cycles, the adjusted results of the two groups were not significantly different. There was no difference in the CPR, CLBR, or offspring safety-related data, such as gestational age, preterm delivery rate, birthweight, birth-height and Apgar Scores between the two groups after PSM. Age-related changes in the number of oocytes retrieved from women aged 20-40 years old between the two groups were different, indicating that suboptimal response in elderly patients suggests a decline in ovarian reserve. Although we can now improve the outcomes of suboptimal responders, it increases the cost to the patients and the time to live birth, which requires further attention.

Live Birth Rate in Patients With Premature Ovarian Insufficiency During Long-Term Follow-Up Under Hormone Replacement With or Without Ovarian Stimulation.

We analyzed data from 466 patients with premature ovarian insufficiency (POI) who wished to have a biological child and were followed up while undergoing hormone replacement (HR) therapy with or without ovarian stimulation (OS) between April 2014 and December 2020. OS was conducted in 6891 cycles in 429 patients (Group OS), whereas only HR (Group HR) was conducted in 1117 cycles in 37 patients. The follicle growth rate was 48.3% (207/429) per patient in Group OS and 5.4% (2/37) in Group HR (p<0.01). There were 51 live births (LBs) in 50 patients during follow-up. In Group OS, the LB rate was 5.8% (47/807) in cycles where in vitro fertilization (IVF) and embryo transfer were attempted (Group IVF), and 1.3% (3/236) in cycles where intrauterine insemination/timed intercourse was attempted (p<0.01). No pregnancies occurred in Group HR. Among the patients in Group IVF, the LB rate was significantly higher in patients aged <35 years at the initiation of follow-up than in patients who started at later ages (p<0.01). Among the cases who achieved an LB, 39 were patients with idiopathic POI (Group IVF-1, n=297) and seven were patients who had undergone surgical treatment for benign ovarian tumors (Group IVF-2, n=50); however, no LBs occurred in patients who had undergone treatment for malignancy (n=17), and only one in patients with chromosomal abnormalities (n=22). The LB rate per case in the patients in Group IVF-1 and those aged <35 years at the start of follow-up (Group IVF-1-a) was 24.1% (26/108), which was higher than those of the other age groups. The LB rate per case in the patients in Group IVF-1-a with <4 years of amenorrhea was 37.3% (19/51), and that in the patients in Group IVF-2 with <4 years of amenorrhea was 21.2% (7/33). These results suggest that infertility treatment is possible in some patients with POI, especially those that can be classified in Group IVF-1-a and Group IVF-2 with <4 years of amenorrhea. Therefore, OS combined with HR therapy should be considered for such patients before attempts at oocyte donation.

Does ovarian stimulation benefit ovulatory women undergoing therapeutic donor insemination?

OBJECTIVE: To compare clinical and ongoing pregnancy after natural cycle (NC) intrauterine insemination (IUI) versus ovarian stimulation (OS) IUI in ovulatory women undergoing therapeutic donor insemination (TDI). DESIGN: Retrospective cohort. SETTING: Single infertility center. PATIENT(S): A total of 76,643 IUI cycles in patients treated with intrauterine insemination were examined. Women undergoing TDI in the absence of diagnosed female factor infertility were included. INTERVENTION(S): NC TDI or OS TDI with either clomiphene citrate or letrozole. MAIN OUTCOME MEASURE(S): Clinical and ongoing pregnancies were analyzed by generalized estimating equations adjusting for age, body mass index, total motile sperm at time of insemination and cycle number. Ongoing multiple gestations were examined as a secondary outcome. RESULT(S): Six thousand one hundred ninety-two TDI cycles from 2,343 patients (711 patients without repeated IUI cycles) met inclusion criteria and were available for analysis (3,837 NC and 2,355 OS). There was no difference in mean age between the two groups (NC, 34.2 years vs. OS, 34.3 years). Probability of clinical and ongoing pregnancy was higher in the OS cohort compared with the NC cohort (OS, 22.4% vs. NC, 18.7% and OS, 15.4% vs. NC, 14.9%, respectively). However, OS significantly increased ongoing multiple gestations (OS, 10.8% vs. NC, 2.4%). CONCLUSION(S): Ovarian stimulation in TDI cycles resulted in a <4% increase in clinical and <1% increase in ongoing pregnancy, and more than fourfold increase in ongoing multiple gestations. Natural cycle IUI should be considered as a first-line treatment for ovulatory women who need donor insemination.

Highly elevated level of antimüllerian hormone associated with preterm delivery in polycystic ovary syndrome patients who underwent ovulation induction.

OBJECTIVE: To determine the relationship between high antimüllerian hormone (AMH) levels and increased preterm delivery risk in populations of women with polycystic ovary syndrome (PCOS) or unexplained infertility undergoing ovulation induction. DESIGN: Secondary analysis of data from two multicenter randomized clinical trials: Pregnancy in Polycystic Ovary Syndrome II (PPCOS II); and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). SETTING: Not applicable. PATIENTS: Live births at ≥24 weeks' gestation from both the PPCOS II (n = 172) and AMIGOS (n = 222) cohorts were evaluated, and those at risk for iatrogenic preterm delivery including placental conditions, fetal growth restriction, multiple gestations, hypertensive diseases of pregnancy, and pre-gestational diabetes were excluded. The final analysis included 118 women with PCOS from the PPCOS II cohort and 146 women with unexplained infertility from the AMIGOS cohort. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Spontaneous preterm delivery. RESULTS: In the PCOS population, median AMH overall was 5.5 ng/dL (interquartile range 2.9-9.3 ng/dL). In all, 62% of participants who delivered preterm had AMH levels above the 75th percentile. When comparing clinical covariates between the preterm and term deliveries, women with PCOS who delivered preterm had notably higher AMH than their term counterparts (11.1 vs. 5.4 ng/mL). In the univariate logistic regression analysis, each unit increase in AMH raised the odds of preterm delivery by 14% (odds ratio 1.14, 95% confidence interval 1.02-1.26). The effect was magnified only after adjusting for age, race, body mass index, smoking status, testosterone, homeostatic model assessment for insulin resistance, and treatment randomization group (adjusted odds ratio 1.25, 95% confidence interval 1.06-1.49). Unlike in the PCOS population, the unexplained infertility cohort had no significant difference in AMH levels between those with or without preterm delivery (2.3 vs. 2.6 ng/mL). CONCLUSIONS: Our findings suggest that women with PCOS and high AMH who conceived after ovulation induction represent a high-risk group for preterm delivery. These data indicate that closer monitoring in the third trimester of pregnancies in PCOS patients with early first trimester AMH levels above 9.3 ng/mL may be warranted. CLINICAL TRIAL REGISTRATION NUMBER: NCT01044862.

Shorter telomere length of white blood cells is associated with higher rates of aneuploidy among infertile women undergoing in vitro fertilization.

OBJECTIVE: To evaluate whether the telomere length of white blood cells (WBC) and cumulus cells (CC) in an infertile population is associated with ovarian and embryonic performance. DESIGN: Prospective cohort study. SETTING: Academic-affiliated private practice. PATIENTS: A total of 175 infertile women undergoing in vitro fertilization (IVF) at a single center between July 2017 and December 2018. INTERVENTIONS: On the day of oocyte retrieval, genomic DNA was isolated from WBC and CC samples. Telomere length assessment was performed for both tissue types using quantitative real-time polymerase chain reaction. Telomere lengths were normalized using an AluYa5 sequence as an endogenous control, and linear regressions were applied. MAIN OUTCOME MEASURES: This study assessed the relationship between relative telomere length of WBC and CC samples and measures of ovarian and embryonic performance. Specifically, patient age, antimüllerian hormone (AMH) level, peak estradiol (E2) level, number of oocytes retrieved, number of mature (MII) oocytes retrieved, blastulation rate, and aneuploidy rate were assessed. RESULTS: There was a statistically significant relationship between WBC relative telomere length and patient age as well as rates of embryonic aneuploidy, with shorter WBC relative telomere length associated with increasing patient age (P<.01) and higher rates of aneuploidy (P=.01). No statistically significant relationships were observed between WBC relative telomere length and the other outcome measures. No significant associations were noted between CC relative telomere length and any outcomes assessed in this study. CONCLUSION: The relationship between WBC relative telomere length and aneuploidy warrants further investigation, particularly because significant overlap exists between increasing maternal age and rates of embryonic aneuploidy.

Short-term weight change and live birth among women with unexplained infertility and polycystic ovary syndrome undergoing ovulation induction.

OBJECTIVE: To determine if short-term weight change among women with unexplained infertility (UI) and polycystic ovary syndrome (PCOS) undergoing ovulation induction is associated with live birth. DESIGN: Secondary analysis of randomized trials. SETTING: Multicenter fertility trial sites. PATIENT(S): A total of 900 women with UI and 750 women with PCOS. MAIN OUTCOME MEASURE(S): Live birth. INTERVENTION(S): Weight assessment at enrollment and start of up to 4-5 cycles of clomiphene, letrozole, or gonadotropins and intrauterine insemination for women with UI and clomiphene or letrozole with regular intercourse for women with PCOS. RESULT(S): Weight data were available for 856 women with UI and 697 women with PCOS. Mean weight change was -0.2 ± 0.3 kg among women with UI and +2.2 ± 0.2 kg among women with PCOS and did not differ based on treatment allocation. There were 115 women with PCOS (16.4%) who gained ≥3 kg. Increased body mass index and three or more cycles were associated with weight gain in women with PCOS. There was no difference in live birth rate among women with PCOS and ≥3 kg weight gain and women with PCOS who did not gain weight. CONCLUSION(S): Women with PCOS gained an average of 2.2 kg regardless of the medication received, whereas women with UI experienced no short-term weight change during ovulation induction. Weight gain in women with PCOS was not associated with live birth rate.

Strategies to reduce multiple pregnancies during medically assisted reproduction.

Multiple birth rates after fertility treatment are still high in many countries. Multiple births are associated with increased rates of preterm birth and low birth weight babies, in turn increasing the risk of severe morbidity for the children. The multiple birth rates vary in different countries between 2% and 3% and up to 30% in some settings. Elective single-embryo transfer, particularly in combination with frozen-embryo transfer and milder stimulation in ovulation induction/intrauterine insemination, to avoid multifollicular development is an effective strategy to decrease the multiple birth rates while still achieving acceptable live-birth rates. Although this procedure is used successfully in many countries, it ought to be implemented broadly to improve the health of the children. One at a time should be the normal routine.

Differences in perceived stress during ovarian stimulation between women with infertility and those pursing oocyte cryopreservation.

OBJECTIVE: To determine whether the purpose of ovarian stimulation (oocyte cryopreservation [OC] versus in vitro fertilization (IVF) is associated with perceived stress before or after ovarian stimulation; and whether perceived stress is associated with ovarian stimulation outcomes. DESIGN: Prospective cohort study. SETTING: Academic practice. PATIENTS: Women undergoing their first ovarian stimulation cycle as part of a randomized clinical trial, the Learning from Online Video Education (LOVE) study (NCT02979990). INTERVENTIONS: Questionnaire before and after ovarian stimulation. MAIN OUTCOME MEASURES(S): Perceived stress scale (PSS) scores before and after stimulation. The number of oocytes collected was a secondary measure. RESULTS: After adjustment for age, income, race, education, financial assistance, and fertility diagnosis, the indication for treatment (IVF vs. OC) was a significant predictor of pretreatment PSS scores. IVF participants had higher pretreatment scores (18.01 ± 6.43) than did OC participants (15.62 ± 5.61). Posttreatment PSS scores did not differ between the two groups. IVF participants experienced a decrease of 0.85 ± 2.34 points in PSS scores after treatment, whereas OC participant scores were stable over time. The trajectory of PSS scores differed between the two groups and neared significance. Financial support was a significant predictor of pretreatment and posttreatment PSS scores for the entire cohort. Neither pretreatment nor posttreatment PSS was predictive of the number oocytes collected. CONCLUSION: Compared with OC patients, IVF patients have higher stress levels, which decrease after ovarian stimulation. Perceived stress does not affect oocyte yield.

Effect of pretreatment oral contraceptives on fresh and cumulative live birth in vitro fertilization outcomes in ovulatory women.

OBJECTIVE: To evaluate the impact of oral contraceptives (OC) on live birth rate (LBR) following a fresh embryo transfer and cumulative live birth rate (cLBR) in normal ovulatory women undergoing in vitro fertilization (IVF). DESIGN: Retrospective cohort study. SETTING: Reproductive center. PATIENTS: A total of 3,110 normo-ovulatory women aged 20-40 years undergoing IVF either using or not using OC pretreatment in their first autologous cycle. INTERVENTION(S): Patients initiated gonadotropins for their IVF cycle either after a spontaneous menses or following OC pretreatment, which was at the discretion of the provider or according to patients preference. MAIN OUTCOME MEASURE(S): The primary outcomes were LBR after fresh transfer (fLBR) and cLBR. RESULTS: fLBR was significantly lower in women using OC compared to those not (42.6% vs. 52.8%). Although LBR after frozen embryo transfer cycles were similar (42.7% vs. 41.1%), cLBR was significantly lower in women using OC (62.8% vs. 67.6%). Multivariate logistic and COX regression analysis adjusting for baseline characteristics demonstrated that IVF cycle synchronization with OC was significantly associated with a lower fLBR (adjusted odds ratio 0.73, 95% confidence interval 0.62-0.86) and cLBR (adjusted hazard ratio 0.89, 95% confidence interval 0.80-0.98). CONCLUSIONS: Pretreatment OC use is associated with a reduction in fLBR and cLBR.