RESUMO
BACKGROUND: Women with obesity and infertility are counseled to lose weight prior to conception and infertility treatment to improve pregnancy rates and birth outcomes, although confirmatory evidence from randomized trials is lacking. We assessed whether a preconception intensive lifestyle intervention with acute weight loss is superior to a weight neutral intervention at achieving a healthy live birth. METHODS AND FINDINGS: In this open-label, randomized controlled study (FIT-PLESE), 379 women with obesity (BMI ≥ 30 kg/m2) and unexplained infertility were randomly assigned in a 1:1 ratio to 2 preconception lifestyle modification groups lasting 16 weeks, between July 2015 and July 2018 (final follow-up September 2019) followed by infertility therapy. The primary outcome was the healthy live birth (term infant of normal weight without major anomalies) incidence. This was conducted at 9 academic health centers across the United States. The intensive group underwent increased physical activity and weight loss (target 7%) through meal replacements and medication (Orlistat) compared to a standard group with increased physical activity alone without weight loss. This was followed by standardized empiric infertility treatment consisting of 3 cycles of ovarian stimulation/intrauterine insemination. Outcomes of any resulting pregnancy were tracked. Among 191 women randomized to standard lifestyle group, 40 dropped out of the study before conception; among 188 women randomized to intensive lifestyle group, 31 dropped out of the study before conception. All the randomized women were included in the intent-to-treat analysis for primary outcome of a healthy live birth. There were no significant differences in the incidence of healthy live births [standard 29/191(15.2%), intensive 23/188(12.2%), rate ratio 0.81 (0.48 to 1.34), P = 0.40]. Intensive had significant weight loss compared to standard (-6.6 ± 5.4% versus -0.3 ± 3.2%, P < 0.001). There were improvements in metabolic health, including a marked decrease in incidence of the metabolic syndrome (baseline to 16 weeks: standard: 53.6% to 49.4%, intensive 52.8% to 32.2%, P = 0.003). Gastrointestinal side effects were significantly more common in intensive. There was a higher, but nonsignificant, first trimester pregnancy loss in the intensive group (33.3% versus 23.7% in standard, 95% rate ratio 1.40, 95% confidence interval [CI]: 0.79 to 2.50). The main limitations of the study are the limited power of the study to detect rare complications and the design difficulty in finding an adequate time matched control intervention, as the standard exercise intervention may have potentially been helpful or harmful. CONCLUSIONS: A preconception intensive lifestyle intervention for weight loss did not improve fertility or birth outcomes compared to an exercise intervention without targeted weight loss. Improvement in metabolic health may not translate into improved female fecundity. TRIAL REGISTRATION: ClinicalTrials.gov NCT02432209.
Assuntos
Infertilidade Feminina/terapia , Infertilidade/complicações , Estilo de Vida , Adulto , Exercício Físico , Feminino , Fertilização , Humanos , Infertilidade Feminina/complicações , Cuidado Pré-Concepcional , Estados Unidos , Redução de Peso , Adulto JovemRESUMO
PURPOSE: The understanding of the role of plasma antioxidant levels in male fertility in the USA is limited. In a secondary analysis of the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial, we sought to determine whether serum levels of vitamin E (α-tocopherol), zinc, and selenium were correlated with semen parameters and couple fertility outcomes. METHODS: This study is a secondary analysis of the MOXI clinical trial. The primary endpoints in this secondary analysis include semen parameters, and DNA fragmentation and clinical outcomes including pregnancy and live birth. Analyses were completed using Wilcoxon's rank-sum test and linear regression models. RESULTS: At baseline, the analysis included plasma labs for vitamin E (n = 131), selenium (n = 124), and zinc (n = 128). All baseline plasma values were in the normal ranges. There was no association between selenium, zinc, or vitamin E levels and semen parameters or DNA fragmentation. Baseline antioxidant levels in the male partners did not predict pregnancy or live birth among all couples. Among those randomized to placebo, baseline male antioxidant levels did not differ between those couples with live birth and those that did not conceive or have a live birth. CONCLUSIONS: Among men attending fertility centers in the USA, who have sufficient plasma antioxidant levels of zinc, selenium, or vitamin E, no association was observed between vitamins and semen parameters or clinical outcomes in couples with male infertility. Higher levels of antioxidants among men with circulating antioxidants in the normal range do not appear to confer benefit on semen parameters or male fertility.
Assuntos
Aborto Espontâneo/epidemiologia , Antioxidantes/análise , Infertilidade Masculina/terapia , Nascido Vivo/epidemiologia , Estresse Oxidativo , Sêmen/metabolismo , Vitaminas/sangue , Adolescente , Adulto , Feminino , Fertilização in vitro/métodos , Humanos , Infertilidade Masculina/sangue , Masculino , Gravidez , Taxa de Gravidez , Análise do Sêmen , Estados Unidos , Adulto JovemRESUMO
Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities. Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. Design, Setting, and Participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019). Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). Main Outcomes and Measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%. Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%). Conclusions and Relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results. Trial Registration: ClinicalTrials.gov Identifier: NCT02152696.
Assuntos
Abortivos não Esteroides/administração & dosagem , Metotrexato/administração & dosagem , Gravidez Ectópica/tratamento farmacológico , Gravidez Ectópica/cirurgia , Conduta Expectante , Aborto Espontâneo , Adulto , Gonadotropina Coriônica/sangue , Terapia Combinada , Dilatação e Curetagem , Feminino , Humanos , Satisfação do Paciente , Gravidez , Ultrassonografia Pré-Natal , Hemorragia UterinaRESUMO
BACKGROUND: The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. METHODS: We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. RESULTS: After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. CONCLUSIONS: In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).
Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Gonadotropinas/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , Nitrilas/uso terapêutico , Indução da Ovulação/métodos , Gravidez Múltipla/estatística & dados numéricos , Triazóis/uso terapêutico , Adolescente , Adulto , Feminino , Humanos , Letrozol , Nascido Vivo/epidemiologia , Gravidez , Taxa de Gravidez , Adulto JovemRESUMO
STUDY QUESTION: Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes? SUMMARY ANSWER: AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study. WHAT IS KNOWN ALREADY: Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed. STUDY DESIGN, SIZE, DURATION: A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight. MAIN RESULTS AND THE ROLE OF CHANCE: Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth). LIMITATIONS, REASONS FOR CAUTION: Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia. STUDY FUNDING/COMPETING INTEREST(S): Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care. TRIAL REGISTRATION NUMBER: Clinical Trials.gov number: NCT01044862.
Assuntos
Alostase/fisiologia , Nascido Vivo/epidemiologia , Nascimento Prematuro/epidemiologia , Estresse Fisiológico/fisiologia , Aborto Espontâneo/epidemiologia , Adulto , Índice de Massa Corporal , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Infertilidade Feminina , Indução da Ovulação/estatística & dados numéricos , Pré-Eclâmpsia/epidemiologia , GravidezRESUMO
BACKGROUND: Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. METHODS: In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period. RESULTS: Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups. CONCLUSIONS: As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).
Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , Nitrilas/uso terapêutico , Síndrome do Ovário Policístico/complicações , Triazóis/uso terapêutico , Adulto , Clomifeno/efeitos adversos , Clomifeno/farmacologia , Método Duplo-Cego , Feminino , Fármacos para a Fertilidade Feminina/efeitos adversos , Fármacos para a Fertilidade Feminina/farmacologia , Humanos , Infertilidade Feminina/etiologia , Estimativa de Kaplan-Meier , Letrozol , Nascido Vivo , Fase Luteal , Masculino , Nitrilas/efeitos adversos , Nitrilas/farmacologia , Ovulação/efeitos dos fármacos , Gravidez , Qualidade de Vida , Triazóis/efeitos adversos , Triazóis/farmacologiaRESUMO
BACKGROUND: While female sexual dysfunction is a frequent occurrence, characteristics in infertile women are not well delineated. Furthermore, the impact of infertility etiology on the characteristics in women with differing androgen levels observed in women with polycystic ovary syndrome and unexplained infertility has not been assessed. OBJECTIVE: The objective of the study was to determine the characteristics of sexual dysfunction in women with polycystic ovary syndrome and unexplained infertility. STUDY DESIGN: A secondary data analysis was performed on 2 of Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Networks clinical trials: Pregnancy in Polycystic Ovary Syndrome Study II and Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. Both protocols assessed female sexual function using the Female Sexual Function Inventory and the Female Sexual Distress Scale. RESULTS: Women with polycystic ovary syndrome had higher weight and body mass index than women with unexplained infertility (each P < .001), greater phenotypic (Ferriman-Gallwey hirsutism score, sebum score, and acne score; each P < .001), and hormonal (testosterone, free testosterone, and dehydroepiandrosterone; each P < .001) evidence of androgen excess. Sexual function scores, as assessed by the Female Sexual Function Inventory, were nearly identical. The Female Sexual Distress Scale total score was higher in women with polycystic ovary syndrome. The mean Female Sexual Function Inventory total score increased slightly as the free androgen index increased, mainly as a result of the desire subscore. This association was more pronounced in the women with unexplained infertility. CONCLUSION: Reproductive-age women with infertility associated with polycystic ovary syndrome and unexplained infertility, despite phenotypic and biochemical differences in androgenic manifestations, do not manifest clinically significant differences in sexual function.
Assuntos
Infertilidade Feminina/complicações , Síndrome do Ovário Policístico/complicações , Disfunções Sexuais Fisiológicas/etiologia , Adulto , Androgênios/sangue , Estudos Transversais , Feminino , Humanos , Infertilidade Feminina/sangue , Síndrome do Ovário Policístico/sangue , Disfunções Sexuais Fisiológicas/sangueRESUMO
STUDY QUESTION: Can we build and validate predictive models for ovulation and pregnancy outcomes in infertile women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: We were able to develop and validate a predictive model for pregnancy outcomes in women with PCOS using simple clinical and biochemical criteria particularly duration of attempting conception, which was the most consistent predictor among all considered factors for pregnancy outcomes. WHAT IS KNOWN ALREADY: Predictive models for ovulation and pregnancy outcomes in infertile women with polycystic ovary syndrome have been reported, but such models require validation. STUDY DESIGN, SIZE, AND DURATION: This is a secondary analysis of the data from the Pregnancy in Polycystic Ovary Syndrome I and II (PPCOS-I and -II) trials. Both trials were double-blind, randomized clinical trials that included 626 and 750 infertile women with PCOS, respectively. PPCOS-I participants were randomized to either clomiphene citrate (CC), metformin, or their combination, and PPCOS-II participants to either letrozole or CC for up to five treatment cycles. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: Linear logistic regression models were fitted using treatment, BMI, and other published variables as predictors of ovulation, conception, clinical pregnancy, and live birth as the outcome one at a time. We first evaluated previously reported significant predictors, and then constructed new prediction models. Receiver operating characteristic (ROC) curves were constructed and the area under the curves (AUCs) was calculated to compare performance using different models and data. Chi-square tests were used to examine the goodness-of-fit and prediction power of logistic regression model. MAIN RESULTS AND THE ROLE OF CHANCE: Predictive factors were similar between PPCOS-I and II, but the two participant samples differed statistically significantly but the differences were clinically minor on key baseline characteristics and hormone levels. Women in PPCOS-II had an overall more severe PCOS phenotype than women in PPCOS-I. The clinically minor but statistically significant differences may be due to the large sample sizes. Younger age, lower baseline free androgen index and insulin, shorter duration of attempting conception, and higher baseline sex hormone-binding globulin significantly predicted at least one pregnancy outcome. The ROC curves (with AUCs of 0.66-0.76) and calibration plots and chi-square tests indicated stable predictive power of the identified variables (P-values ≥0.07 for all goodness-of-fit and validation tests). LIMITATIONS, REASONS FOR CAUTION: This is a secondary analysis. Although our primary objective was to confirm previously reported results and identify new predictors of ovulation and pregnancy outcomes among PPCOS-II participants, our approach is exploratory and warrants further replication. WIDER IMPLICATIONS OF THE FINDINGS: We have largely confirmed the predictors that were identified in the PPCOS-I trial. However, we have also revealed new predictors, particularly the role of smoking. While a history of ever smoking was not a significant predictor for live birth, a closer look at current, quit, and never smoking revealed that current smoking was a significant risk factor. STUDY FUNDING/COMPETING INTERESTS: The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD33172, U10 HD38998, U10 HD055936, U10 HD055942, and U10 HD055944; and U54-HD29834. Heilongjiang University of Chinese Medicine Grants 051277 and B201005. R.S.L. reports receiving consulting fees from Euroscreen, AstraZeneca, Clarus Therapeutics, and Takeda, and grant support from Ferring, Astra Zeneca, and Toba. K.R.H. reports receiving grant support from Roche Diagnostics and Ferring Pharmascience. G.C. reports receiving Honorarium and grant support from Abbvie Pharmaceuticals and Bayer Pharmaceuticals. M.P.D. holds equity from Advanced Reproductive Care Inc. and DS Biotech, receives fees from Advanced Reproductive Care Inc., Actamax, Auxogyn, ZSX Medical, Halt Medical, and Neomed, and receives grant support from Boehringer-Ingelheim, Abbott, and BioSante, Ferring Pharmaceuticals, and EMD Serono. H.Z. receives research support from the Chinese 1000-scholar plan. Others report no disclosures other than NIH grant support. TRIAL REGISTRATION NUMBER: PPCOS-I and -II were respectively registered at Clinicaltrials.gov: NCT00719186 and NCT00719186.
Assuntos
Fertilização/fisiologia , Infertilidade Feminina/epidemiologia , Nascido Vivo/epidemiologia , Modelos Teóricos , Ovulação/fisiologia , Síndrome do Ovário Policístico/epidemiologia , Adulto , Feminino , Humanos , Infertilidade Feminina/etiologia , Síndrome do Ovário Policístico/complicações , Prognóstico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
This study aimed to determine whether the use of vaginal Endometrin plus intramuscular progesterone on every third day (VIM) in programmed frozen embryo transfer (FET) is associated with lower pregnancy and live birth rates compared to daily intramuscular progesterone (IM). FET data from a single program were collected between November 2018 and December 2021. A total of 903 FETs were analyzed, including 504 FETs in the IM group, and 399 FETs in the VIM group. Inclusion criteria were women undergoing FETs with either 50 mg daily IM progesterone only (control) or 200 mg Endometrin twice daily plus 50 mg IM progesterone on every third day, with the transfer of a single day 5 or 6 frozen embryo. There were no significant differences in patient age at time of FETs, BMI, endometrial thickness, blastocyst quality, or infertility diagnosis between the groups. The VIM had significantly lower positive hCG and clinical pregnancy rates compared to the IM (60.2% vs 72.0% and 40.6% vs 56.7%, respectively, P = 0.0002 and P < 0.0001). The live birth rate was 36.1% in the VIM, compared to 49.4% in the IM (P < 0.0001). These findings also remained significant when excluding FETs with donor egg (35.9% vs 50.1%, P < 0.0001). This study demonstrated that VIM in FET cycles yields significantly lower pregnancy and live birth rates compared to IM along. IM progesterone alone may be preferable to combined Endometrin and IM progesterone in patients undergoing programmed frozen embryo transfers.
RESUMO
Objective: To determine the reproducibility of the World Health Organization Fifth Edition (WHO5) strict grading methodology by comparing the percentage of morphologically normal sperm (PNS) recorded by the core laboratory with results obtained at the fertility centers participating in a multisite clinical trial. Design: Secondary cohort analysis of data from the Males, Antioxidants, and Infertility trial. Setting: Fertility centers. Patients: Semen values of 171 men participating in a multicenter, double-blind, randomized, placebo-controlled trial evaluating the effect of antioxidants on male fertility. Interventions: Not applicable. Main Outcome Measures: Strict morphology expressed as PNS as determined at each fertility center and the core central laboratory for the same semen sample. Results: No correlation was found in the PNS values for the same semen sample between the core laboratory and fertility center laboratories either as a group or by individual site. Interobserver agreement was similarly low (κ = 0.05 and 0.15) between the core and fertility laboratories as a group for strict morphology, categorized by the WHO5 lower reference limits of 4% and 0, respectively. Moderate agreement was found between the core and 2 individual fertility laboratories for the cutoff value of 0 (κ = 0.42 and 0.57). The remainder of the comparisons demonstrated poor to fair agreement. Conclusions: Strict morphology grading using the WHO5 methodology demonstrated overall poor reproducibility among a cohort of experienced fertility laboratories. This lack of correlation and agreement in the PNS values calls into question the reproducibility, and thereby the potential applicability, of sperm strict morphology testing.
RESUMO
BACKGROUND: Randomized trials of assisted reproductive technology (ART) have been designed for outcomes of clinical pregnancy or live birth and have not been powered for obstetric outcomes such as preeclampsia, critical for maternal and fetal health. ART increasingly involves frozen embryo transfer (FET). Although there are advantages of FET, multiple studies have shown that risk of preeclampsia is increased with FET compared with fresh embryo transfer, and the reason for this difference is not clear. NatPro will compare the proportion of preeclampsia between two commonly used protocols for FET,modified natural and programmed cycle. METHODS: In this two-arm, parallel-group, multi-center randomized trial, NatPro will randomize 788 women to either modified natural or programmed FET and follow them for up to three FET cycles. Primary outcome will be the proportion of preeclampsia in women with a viable pregnancy assigned to a modified natural cycle FET (corpus luteum present) protocol compared to the proportion of preeclampsia in pregnant women assigned to a programmed FET (corpus luteum absent) protocol. Secondary outcomes will compare the proportion of live births and the proportion of preeclampsia with severe features between the protocols. CONCLUSION: This study has a potential significant impact on millions of women who pursue ART to build their families. NatPro is designed to provide clinically relevant guidance to inform patients and clinicians regarding maternal risk with programmed and modified natural cycle FET protocols. This study will also provide accurate point estimates regarding the likelihood of live birth with programmed and modified natural cycle FET. TRIAL REGISTRATION: ClinicalTrials.gov NCT04551807 . Registered on September 16, 2020.
Assuntos
Criopreservação , Transferência Embrionária , Feminino , Humanos , Nascido Vivo , Estudos Multicêntricos como Assunto , Gravidez , Taxa de Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , Técnicas de Reprodução Assistida , Estudos RetrospectivosRESUMO
BACKGROUND: Hysteroscopy requires accurate collection of unabsorbed distension media to measure patient fluid absorption. We assessed the effectiveness and usability of a novel total capture drape compared with a standard drape during hysteroscopy. METHOD: Simulation trials were followed by an early-phase study to compare fluid-capture efficiency and measures of drape usability during hysteroscopy randomizing the total capture drape compared with a standard drape. EXPERIENCE: Simulation trials indicated complete collection of unabsorbed fluid with the total capture drape and progressive loss of unabsorbed fluid with the standard drape. An early-phase study with 68 women found no statistical difference between groups for the hysteroscopic fluid deficit, but saw fewer cases with lost fluid in the total capture drape compared with the standard drape. Direct observation and focus group data indicated a trend for better capture of unabsorbed fluid with the total capture drape, along with increased usability once surgeons became familiar with correct placement. CONCLUSION: Simulation and early-phase study results are favorable for the total capture drape, demonstrating comparable fluid collection with the standard drape. With repeated use and in-service training, surgeons expressed greater confidence in the accuracy of the hysteroscopic fluid deficit with the total capture drape compared with the standard drape. Design modifications should improve overall usability and fluid-capture efficiency.
Assuntos
Histeroscopia/instrumentação , Campos Cirúrgicos , Adulto , Simulação por Computador , Feminino , Grupos Focais , Humanos , Segurança do Paciente , Estudo de Prova de Conceito , Estudos Prospectivos , Design Centrado no UsuárioRESUMO
OBJECTIVE: To examine the factors associated with increased deoxyribonucleic acid fragmentation index (DFI), evaluate the pregnancy outcomes of men with increased DFI, and compare three independent DFI assays. DESIGN: Secondary analysis. SETTING: Nine US-based fertility centers. PATIENTS: Infertile men (N = 147) with sperm concentration ≤15 × 106/mL, motility ≤40%, or normal morphology ≤4% were enrolled. The female partners were ovulatory, ≤40 years old, and had documented tubal patency. INTERVENTIONS: At a baseline visit, the men provided a semen sample. The couples attempted conception without assistance for 3 months and with ovarian stimulation and intrauterine insemination in the subsequent 3 months. MAIN OUTCOME MEASURES: The DFI was analyzed using the sperm chromatin structure assay (SCSA) with increased DFI defined as >30%. The predictors of increased DFI were determined by a multivariable linear regression model. The pregnancy outcomes were compared using the χ2 test. The independent DFI assays (SCSA, deoxynucleotidyl transferase-mediated dUTP nick end labeling, and Comet) were compared with Pearson and Spearman correlations. RESULTS: The 19% of men with increased DFI were older (36.0 vs. 33.0 years) and had lower total sperm motility (38.2% ± 20.5% vs. 45.2% ± 15.6%). Increased male age was found to be a significant predictor of DFI (0.75, 95% confidence interval [0.06, 1.45]). Increased DFI was not associated with conception or live birth. There was a modest correlation of the deoxynucleotidyl transferase-mediated dUTP nick end labeling assay with the SCSA (r = 0.34) and Comet assay (r = 0.19). CONCLUSIONS: Older age was associated with increased DFI among infertile men. The DFI assays were only weakly correlated, indicating a standard definition of DFI is needed to truly interrogate how sperm deoxyribonucleic acid fragmentation impacts male fertility.
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OBJECTIVE: To determine whether biochemical or clinical markers of androgenic activity predict live birth rate with ovarian stimulation in the unexplained infertility population. DESIGN: Secondary analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. SETTING: Multicenter university-based clinical practices. PATIENT(S): Nine hundred couples with unexplained infertility were included. Women were 18-40 years old with regular menses, a normal uterine cavity, at least one patent fallopian tube, and a male partner with ≥5 million motile sperm. Women were randomized to receive gonadotropin, clomiphene, or letrozole with IUI for four or fewer four treatment cycles. Women were evaluated for biochemical (total testosterone, DHEAS, and free androgen index) and clinical markers of androgenic activity (sebum, acne, and hirsutism). Multivariable logistic regression models adjusting for treatment group, maternal age, and body mass index were performed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was live birth. Secondary outcomes included conception, clinical pregnancy, and pregnancy loss. RESULT(S): When comparing 900 women in the AMIGOS trial based on quartiles of serum TT, women were of younger age, higher body mass index, and higher waist circumference with increasing TT. Increasing quartiles of TT also showed increasing DHEAS and free androgen index values. Serum androgens were not associated with outcomes of live birth, conception, clinical pregnancy, or pregnancy loss. Clinical androgen markers were not associated with pregnancy outcomes. CONCLUSION(S): In a randomized cohort of women with unexplained infertility, biochemical and clinical measures of androgens did not predict live birth rate after ovarian stimulation treatment. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01044862.
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Androgênios/sangue , Infertilidade Feminina/sangue , Infertilidade Feminina/terapia , Técnicas de Reprodução Assistida , Adulto , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Recém-Nascido , Infertilidade Feminina/epidemiologia , Nascido Vivo/epidemiologia , Masculino , Indução da Ovulação/métodos , Indução da Ovulação/estatística & dados numéricos , Gravidez , Resultado da Gravidez/epidemiologia , Taxa de Gravidez , Resultado do TratamentoRESUMO
OBJECTIVE: To determine whether antioxidants improve male fertility, as measured by semen parameters and DNA fragmentation at 3 months and pregnancy resulting in live birth after up to 6 months of treatment, among couples with male factor infertility. DESIGN: Multicenter, double-blind, randomized, placebo-controlled trial with an internal pilot study. SETTING: Nine fertility centers in the United States from December 2015 to December 2018. PATIENT(S): Men (N = 174) with sperm concentration ≤15 million/mL, motility ≤40%, normal morphology ≤4%, or DNA fragmentation >25%, and female partners who were ovulatory, ≤40 years old, and had documented tubal patency. INTERVENTION(S): Males randomly assigned to receive an antioxidant formulation (n = 85) containing 500 mg of vitamin C, 400 mg of vitamin E, 0.20 mg of selenium, 1,000 mg of l-carnitine, 20 mg of zinc, 1,000 µg of folic acid, 10 mg of lycopene daily, or placebo (n = 86). Treatment lasted for a minimum of 3 months and maximum of 6 months, and couples attempted to conceive naturally during the first 3 months and with clomiphene citrate with intrauterine insemination of the female partner in months 4 through 6. MAIN OUTCOME MEASURE(S): Primary outcome was live birth; secondary outcomes included pregnancy within 6 months of treatment. For the internal pilot, the primary outcomes were semen parameters and sperm DNA fragmentation index after 3 months of treatment. RESULT(S): In the Males, Antioxidants, and Infertility (MOXI) study, after 3 months of treatment, the change in sperm concentration differed between the antioxidant group (median -4.0 [interquartile range-12.0, 5.7] million/mL) and placebo group (+2.4 [-9.0, 15.5] million/mL). However, there were no statistically significant differences between the two groups for changes in sperm morphology, motility, or DNA fragmentation. Among the 66 oligospermic men at randomization, sperm concentration did not differ at 3 months between the antioxidant and control groups: 8.5 (4.8, 15.0) million/mL versus 15.0 (6.0, 24.0) million/mL. Of the 75 asthenospermic men, motility did not differ at 3 months: 34% ± 16.3% versus 36.4% ± 15.8%. Among the 44 men with high DNA fragmentation, DNA fragmentation did not differ at 3 months: 29.5% (21.6%, 36.5%) versus 28.0% (20.6%, 36.4%). In the entire cohort, cumulative live birth did not differ at 6 months between the antioxidant and placebo groups: 15% versus 24%. CONCLUSION(S): Antioxidants do not improve semen parameters or DNA integrity among men with male factor infertility. Although limited by sample size, this study suggests that antioxidant treatment of the male partner does not improve in vivo pregnancy or live-birth rates. CLINICAL TRIAL REGISTRATION NUMBER: NCT02421887.
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Antioxidantes/farmacologia , Infertilidade Masculina/tratamento farmacológico , Adulto , Antioxidantes/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Inseminação Artificial Homóloga , Masculino , Indução da Ovulação/métodos , Projetos Piloto , Gravidez , Taxa de Gravidez , Estados UnidosRESUMO
OBJECTIVE: To study the development of children conceived from non-IVF infertility treatments consisting of gonadotropins, clomiphene, or letrozole. DESIGN: Prospective cohort study. SETTING: U.S. academic health centers. PATIENT(S): Children of women with polycystic ovary syndrome who conceived with letrozole (LTZ) or clomiphene (CC) in the PPCOS II study or women with unexplained infertility (AMIGOS study) who conceived with LTZ, CC, or gonadotropin (GN). INTERVENTION(S): Longitudinal annual follow-up from birth to age 3. MAIN OUTCOME MEASURE(S): Scores from Ages and Stages Developmental Questionnaire (ASQ), MacArthur-Bates Communicative Development Inventory (MCDI), and annual growth. RESULT(S): One hundred eighty-five children from 160 families participated in at least one follow-up evaluation from the two infertility trials. Most multiple gestations in the follow-up study resulted from GN treatment (n = 14) followed by CC (n = 6) and LTZ (n = 3). There were no significant differences among the three groups at any time point with respect to abnormal scores on the ASQ. On the MCDI Words and Gestures, the LTZ group scored significantly higher than the GN group for most items (phrases, early gestures, later gestures, and total gestures). Children in the CC group scored significantly higher than the GN group for the later gestures and total gestures items. CONCLUSION(S): Differences in growth and cognitive developmental rates among children conceived with first-line infertility therapies, including LTZ, are relatively minor and likely due to differences in multiple pregnancy rates.
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Comportamento Infantil , Desenvolvimento Infantil , Clomifeno/uso terapêutico , Fármacos para a Fertilidade/uso terapêutico , Gonadotropinas/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , Letrozol/uso terapêutico , Indução da Ovulação , Adulto , Fatores Etários , Pré-Escolar , Clomifeno/efeitos adversos , Cognição , Feminino , Fertilidade , Fármacos para a Fertilidade/efeitos adversos , Seguimentos , Gestos , Gonadotropinas/efeitos adversos , Humanos , Lactente , Infertilidade Feminina/epidemiologia , Infertilidade Feminina/fisiopatologia , Letrozol/efeitos adversos , Nascido Vivo , Masculino , Indução da Ovulação/efeitos adversos , Síndrome do Ovário Policístico/epidemiologia , Gravidez , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema de Registros , Resultado do Tratamento , Estados Unidos/epidemiologia , Aumento de PesoRESUMO
OBJECTIVE: The objective of the study was to determine the efficacy of a novel "stair-step" clomiphene protocol in women with polycystic ovarian syndrome (PCOS) who do not respond to 50 mg clomiphene. STUDY DESIGN: This was a retrospective analysis at an academic fertility center. The stair-step protocol is performed as follows: 50 mg clomiphene for 5 days, ultrasonography on days 11-14. If unresponsive, immediately begin 100 mg clomiphene for 5 days and repeat ultrasound in 1 week. If still unresponsive, begin 150 mg clomiphene for 5 days and repeat the ultrasound in 1 week. Stair-step cycles were compared with published historical clomiphene outcomes for women who were nonresponsive. RESULTS: The time to ovulation was 32-53 days less with the stair-step protocol compared with a traditional regimen. The dose-dependent ovulation rate was 64% at 100 mg with the stair-step protocol compared with 22% with a traditional regimen. CONCLUSION: It is not necessary to induce menses before increasing clomiphene doses in nonresponsive PCOS patients.
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Clomifeno/administração & dosagem , Fármacos para a Fertilidade Feminina/administração & dosagem , Infertilidade Feminina/tratamento farmacológico , Ovulação/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Infertilidade Feminina/diagnóstico por imagem , Menstruação , Oligomenorreia/diagnóstico por imagem , Oligomenorreia/tratamento farmacológico , Síndrome do Ovário Policístico/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia , Adulto JovemRESUMO
CONTEXT: It is generally assumed that delayed endometrial development observed in luteal phase deficiency (LPD) is the result of abnormally low progesterone (P) levels. This hypothesis has never been tested by direct experiment. OBJECTIVE: Our objective was to evaluate the effects of P concentrations on human endometrium. DESIGN AND SETTING: A randomized trial was conducted at an academic medical center. SUBJECTS: Twenty-nine healthy, ovulatory 18- to 35-yr-old women participated. INTERVENTION: Endometrial samples were obtained from women in natural cycles and two groups of experimentally modeled cycles. Women undergoing modeled cycles were treated with GnRH agonist and a fixed physiological dose of transdermal estradiol, followed by randomization to 10 or 40 mg daily im P administration to achieve either normal circulating luteal P or 4-fold lower P concentrations, the latter representing an experimental model of LPD. MAIN OUTCOME MEASURES: Tissue specimens, obtained after 10 days of P exposure, were analyzed by histological dating, immunohistochemistry, immunoblot, and real-time quantitative RT-PCR (qRT-PCR). RESULTS: Histological dating of endometrium, immunohistochemistry for endometrial integrins, and qRT-PCR analysis for nine putative functional markers showed no differences between the three groups. Preliminary data from Western analysis suggest that some proteins may be affected by low serum P concentrations. CONCLUSIONS: Histological endometrial dating does not reflect circulating P concentrations and cannot serve as a reliable bioassay of the quality of luteal function. Assessment of selected functional markers by either immunohistochemistry or qRT-PCR is similarly insensitive to decreased circulating P. Preliminary evidence suggests that abnormally low luteal phase serum P concentrations may have important functional consequences not otherwise detected.
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Endométrio/crescimento & desenvolvimento , Endométrio/fisiologia , Leuprolida/farmacologia , Fase Luteal/fisiologia , Doenças Uterinas/induzido quimicamente , Doenças Uterinas/fisiopatologia , Administração Cutânea , Adolescente , Adulto , Relação Dose-Resposta a Droga , Endométrio/efeitos dos fármacos , Endométrio/patologia , Estradiol/administração & dosagem , Feminino , Fármacos para a Fertilidade Feminina/administração & dosagem , Fármacos para a Fertilidade Feminina/farmacologia , Humanos , Leuprolida/administração & dosagem , Fase Luteal/sangue , Fase Luteal/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Progesterona/administração & dosagem , Progesterona/sangue , Progesterona/farmacologia , Doenças Uterinas/sangue , Doenças Uterinas/patologiaRESUMO
Context: Women with polycystic ovary syndrome (PCOS) have increased risk for pregnancy complications, possibly related to pre-existing obesity and excessive gestational weight gain (GWG). Objectives: To assess the contributions of diagnosis and preconception weight on GWG and perinatal outcomes. Research Design and Methods: Prospective cohort study of singleton pregnancies in PCOS (n = 164) and ovulatory controls (n = 176) from infertility treatment. Main Outcome Measures: GWG, birthweight, pregnancy complications. Results: From preconception baseline, normal-weight women with PCOS gained 2.3 pounds more during the first trimester (95% CI, 0.3 to 4.3; P = 0.02), and by the end of the second trimester, 4.2 pounds more than controls (95% CI, 0.7 to 7.7; P = 0.02). Women who were overweight with PCOS gained significantly more weight than did controls by the end of the second trimester (5.2 pounds; 95% CI, 0.2 to 10.2; P = 0.04), whereas women with obesity and PCOS and control women had similar weight gain throughout pregnancy. Within normal-weight, overweight, and obese groups, prevalence of pre-eclampsia and gestational diabetes did not differ between the PCOS and control groups, nor was there a difference in birthweight. Preconception body mass index (BMI) was significantly associated with GWG; for every 1-kg/m2 increase in preconception BMI, GWG decreased by 0.62 pounds (95% CI, -0.85 to -0.40; P < 0.001). Conclusions: Women with PCOS who are of normal weight or are overweight before conception experience more GWG than do ovulatory controls. Within normal-weight, overweight, and obese groups, rates of perinatal complications do not significantly differ between women with PCOS and controls. Preconception BMI is the strongest predictor of GWG.
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Diabetes Gestacional/epidemiologia , Ganho de Peso na Gestação/fisiologia , Obesidade/complicações , Síndrome do Ovário Policístico/complicações , Pré-Eclâmpsia/epidemiologia , Adulto , Peso ao Nascer/fisiologia , Índice de Massa Corporal , Estudos de Casos e Controles , Diabetes Gestacional/metabolismo , Diabetes Gestacional/fisiopatologia , Feminino , Humanos , Obesidade/metabolismo , Obesidade/fisiopatologia , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Prevalência , Estudos ProspectivosRESUMO
The incidence of subclinical hypothyroidism (SCH) in pregnancy was classically thought to be low; however, with new definition of normal TSH range in pregnancy, there has been an increase in the percentage of women who meet classification for SCH. The diagnosis of SCH is important not only for monitoring for maternal conversion to overt hypothyroidism, but also for identifying obstetric and neonatal outcomes related to SCH. Although there have been proven associations between maternal overt hypothyroidism and adverse obstetric and neonatal outcomes, there has been conflicting data on the correlation between SCH and these outcomes. Recent data from a meta-analysis found an increased risk of pregnancy loss, placental abruption, premature rupture of membranes, and neonatal death for women with SCH compared to euthyroidism in pregnancy. Research studies have not demonstrated a distinct benefit from treatment of SCH, and the professional societies are divided on their recommendations for treating SCH. Additionally, universal screening of SCH is controversial at present.