Significant decrease of maternal mitochondria carryover using optimized spindle-chromosomal complex transfer.

Mutations in mitochondrial DNA (mtDNA) contribute to a variety of serious multi-organ human diseases, which are strictly inherited from the maternal germline. However, there is currently no curative treatment. Attention has been focused on preventing the transmission of mitochondrial diseases through mitochondrial replacement (MR) therapy, but levels of mutant mtDNA can often unexpectedly undergo significant changes known as mitochondrial genetic drift. Here, we proposed a novel strategy to perform spindle-chromosomal complex transfer (SCCT) with maximal residue removal (MRR) in metaphase II (MII) oocytes, thus hopefully eliminated the transmission of mtDNA diseases. With the MRR procedure, we initially investigated the proportions of mtDNA copy numbers in isolated karyoplasts to those of individual oocytes. Spindle-chromosomal morphology and copy number variation (CNV) analysis also confirmed the safety of this method. Then, we reconstructed oocytes by MRR-SCCT, which well developed to blastocysts with minimal mtDNA residue and normal chromosomal copy numbers. Meanwhile, we optimized the manipulation order between intracytoplasmic sperm injection (ICSI) and SCC transfer and concluded that ICSI-then-transfer was conducive to avoid premature activation of reconstructed oocytes in favor of normal fertilization. Offspring of mice generated by embryos transplantation in vivo and embryonic stem cells derivation further presented evidences for competitive development competence and stable mtDNA carryover without genetic drift. Importantly, we also successfully accomplished SCCT in human MII oocytes resulting in tiny mtDNA residue and excellent embryo development through MRR manipulation. Taken together, our preclinical mouse and human models of the MRR-SCCT strategy not only demonstrated efficient residue removal but also high compatibility with normal embryo development, thus could potentially be served as a feasible clinical treatment to prevent the transmission of inherited mtDNA diseases.

Strategies to Increase Cervical Cancer Screening With Mailed Human Papillomavirus Self-Sampling Kits: A Randomized Clinical Trial.

Importance: Optimal strategies for increasing cervical cancer screening may differ by patient screening history and health care setting. Mailing human papillomavirus (HPV) self-sampling kits to individuals who are overdue for screening increases adherence; however, offering self-sampling kits to screening-adherent individuals has not been evaluated in the US. Objective: To evaluate the effectiveness of direct-mail and opt-in approaches for offering HPV self-sampling kits to individuals by cervical cancer screening history (screening-adherent and currently due, overdue, or unknown). Design, Setting, and Participants: Randomized clinical trial conducted in Kaiser Permanente Washington, a US integrated health care delivery system. Individuals aged 30 to 64 years with female sex, a primary care clinician, and no hysterectomy were identified through electronic health records (EHRs) and enrolled between November 20, 2020, and January 28, 2022, with follow-up through July 29, 2022. Interventions: Individuals stratified as due (eg, at the time of randomization, these individuals have been previously screened and are due for their next screening in ≤3 months) were randomized to receive usual care (patient reminders and clinician EHR alerts [n = 3671]), education (usual care plus educational materials about screening [n = 3960]), direct mail (usual care plus educational materials and a mailed self-sampling kit [n = 1482]), or to opt in (usual care plus educational materials and the option to request a kit [n = 3956]). Individuals who were overdue for screening were randomized to receive usual care (n = 5488), education (n = 1408), or direct mail (n = 1415). Individuals with unknown history for screening were randomized to receive usual care (n = 2983), education (n = 3486), or to opt in (n = 3506). Main Outcomes and Measures: The primary outcome was screening completion within 6 months. Primary analyses compared direct-mail or opt-in participants with individuals randomized to the education group. Results: The intention-to-treat analyses included 31 355 randomized individuals (mean [SD] age, 45.9 [10.4] years). Among those who were due for screening, compared with receiving education alone (1885 [47.6%]), screening completion was 14.1% (95% CI, 11.2%-16.9%) higher in the direct-mail group (914 [61.7%]) and 3.5% (95% CI, 1.2%-5.7%) higher in the opt-in group (2020 [51.1%]). Among individuals who were overdue, screening completion was 16.9% (95% CI, 13.8%-20.0%) higher in the direct-mail group (505 [35.7%]) compared with education alone (264 [18.8%]). Among those with unknown history, screening was 2.2% (95% CI, 0.5%-3.9%) higher in the opt-in group (634 [18.1%]) compared with education alone (555 [15.9%]). Conclusions and Relevance: Within a US health care system, direct-mail self-sampling increased cervical cancer screening by more than 14% in individuals who were due or overdue for cervical cancer screening. The opt-in approach minimally increased screening. To increase screening adherence, systems implementing HPV self-sampling should prioritize direct-mail outreach for individuals who are due or overdue for screening. For individuals with unknown screening history, testing alternative outreach approaches and additional efforts to document screening history are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT04679675.

Using Protection Motivation Theory to Predict Intentions for Breast Cancer Risk Management: Intervention Mechanisms from a Randomized Controlled Trial.

The purpose of this study is to evaluate the direct and indirect effects of a web-based, Protection Motivation Theory (PMT)-informed breast cancer education and decision support tool on intentions for risk-reducing medication and breast MRI among high-risk women. Women with ≥ 1.67% 5-year breast cancer risk (N = 995) were randomized to (1) control or (2) the PMT-informed intervention. Six weeks post-intervention, 924 (93% retention) self-reported PMT constructs and behavioral intentions. Bootstrapped mediations evaluated the direct effect of the intervention on behavioral intentions and the mediating role of PMT constructs. There was no direct intervention effect on intentions for risk-reducing medication or MRI (p's ≥ 0.12). There were significant indirect effects on risk-reducing medication intentions via perceived risk, self-efficacy, and response efficacy, and on MRI intentions via perceived risk and response efficacy (p's ≤ 0.04). The PMT-informed intervention effected behavioral intentions via perceived breast cancer risk, self-efficacy, and response efficacy. Future research should extend these findings from intentions to behavior. ClinicalTrials.gov Identifier: NCT03029286 (date of registration: January 24, 2017).

Does mailing unsolicited HPV self-sampling kits to women overdue for cervical cancer screening impact uptake of other preventive health services in a United States integrated delivery system?

Women overdue for cervical cancer screening often have other preventive care gaps. We examined whether mailing unsolicited human papillomavirus (HPV) self-sampling kits to increase cervical cancer screening impacted receipt of other preventive services women were due for: mammography, colorectal cancer (CRC) screening, influenza vaccination, depression screening, and diabetic HbA1c monitoring. From 2014 to 2016, 16,590 underscreened women were randomized to receive a mailed kit or usual care Pap reminders within Kaiser Permanente Washington. We used logistic regression to estimate odds ratios (ORs) of preventive services receipt within 12-months between the intervention vs. control arms, and within the intervention arm (comparing those returning a kit vs. attending Pap vs. nothing), adjusting models for demographic variables. There were no significant between-arm differences in uptake of any of the preventive services: intervention vs. control: mammography OR = 1.01 (95% confidence interval:0.88-1.17), CRC screening OR = 0.98 (0.86-1.13), influenza vaccination OR = 0.99 (0.92-1.06), depression screening OR = 1.07 (0.99-1.16), HbA1c OR = 0.84 (0.62-1.13). Within the intervention arm, preventive services uptake was higher in women who completed cervical cancer screening vs. did not, with stronger effects for women who attended Pap: Pap vs. nothing: mammography OR = 11.81 (8.11-17.19), CRC screening OR = 7.31 (5.57-9.58), influenza vaccination OR = 2.06 (1.82-2.32), depression screening OR = 1.79 (1.57-2.05), HbA1c OR = 3.35 (1.49-7.52); kit vs. nothing: mammography OR = 2.26 (1.56-3.26), CRC screening OR = 5.05 (3.57-7.14), influenza vaccination OR = 1.67 (1.41-1.98), depression screening OR = 1.09 (0.89-1.33), HbA1c OR = 1.23 (0.57-2.65). Mailing HPV self-sampling kits to underscreened women did not negatively impact uptake of other preventive services. However, overall preventive service uptake was the highest among women who attended in-clinic cervical cancer screening.

The comparison of two different protocols ultra-long versus medroxyprogesterone acetate in women with ovarian endometriosis: a prospective randomized controlled trial.

BACKGROUND: This study aimed to investigate the medroxyprogesterone acetate (MPA) + HMG protocol vs ultra-long gonadotrophin releasing hormone (GnRH) agonist protocol in patients with advanced ovarian endometriosis who received in vitro fertilization (IVF). METHODS: Three hundred patients with advanced ovary endometriosis who underwent IVF were included, and embryological and clinical outcomes were assessed between March 2017 and September 2017. Patients were divided into MPA + HMG group and 1-month ultra-long GnRHa protocol group. RESULTS: Lower hMG dose and shorter medication time were found in the MPA + HMG group than in the GnRHa group (P < 0.05). Follicle to-Oocyte Index was significantly different between MPA + HMG group and GnRHa group (P < 0.001). No differences were found in the ovary response and numbers of mature oocytes, fertilized oocytes and viable embryos. The clinical pregnancy and live birth outcomes were similar between MPA + HMG group and GnRHa group, and these outcomes were independent of fresh or frozen embryo transfer in the GnRHa protocol group. There were no significant differences in the time to embryo transfer, medical cost and adverse effects. CONCLUSION: The number of oocytes retrieved and pregnancy outcomes after MPA + HMG protocol are similar to those after ultra-long GnRHa protocol in women with ovarian endometriosis. MPA + HMG protocol may be an alternative to ultra-long GnRHa protocol for IVF in ovary endometriosis patients. Trial registration The trial was registered in the Chinese Clinical Trial Registry (ChiCTR-INR-17010924) In conclusion, the administration of MPA in COH showed similar number of oocytes retrieved, no premature LH surge, and similar pregnancy and live birth outcomes in patients with advanced ovarian endometriosis undergoing IVF/ICSI as compared to the one-month long protocol. The use of MPA in COH appears to be promising although many questions remain to be elucidated, including the dose and time of progestin priming as well as its possible influence on the oocyte development potential and microenvironment. Given their good tolerability, few metabolic influence, and low cost, progestogens provide a novel alternative to the conventional protocol for patients with endometriosis.

Strengthened luteal phase support for patients with low serum progesterone on the day of frozen embryo transfer in artificial endometrial preparation cycles: a large-sample retrospective trial.

BACKGROUND: Low serum progesterone on the day of frozen embryo transfer (FET) is associated with diminished pregnancy rates in artificial endometrium preparation cycles, but there is no consensus on whether strengthened luteal phase support (LPS) benefits patients with low progesterone on the FET day in artificial cycles. This single-centre, large-sample retrospective trial was designed to investigate the contribution of strengthened LPS to pregnancy outcomes for groups with low progesterone levels on the FET day in artificial endometrium preparation cycles. METHODS: Women who had undergone the first artificial endometrium preparation cycle after a freeze-all protocol in our clinic from 2016 to 2018 were classified into two groups depending on their serum progesterone levels on the FET day. Routine LPS was administered to group B (P ≥ 10.0 ng/ml on the FET day, n = 1261), and strengthened LPS (routine LPS+ im P 40 mg daily) was administered to group A (P < 10.0 ng/ml on the FET day, n = 1295). The primary endpoint was the live birth rate, and the secondary endpoints were clinical pregnancy, miscarriage and neonatal outcomes. RESULTS: The results showed that the clinical pregnancy rate was significantly lower in group A than in group B (48.4% vs 53.2%, adjusted risk ratio (aRR) 0.81, 95% confidence interval (CI) 0.68, 0.96), whereas miscarriage rates were similar between the two groups (16.0% vs 14.7%, aRR 1.09, 95% CI 0.77, 1.54). The live birth rate was slightly lower in group A than in group B (39.5% vs 43.3%, aRR 0.84, 95% CI 0.70, 1.0). Birthweights and other neonatal outcomes were similar between the two groups (P > 0.05). CONCLUSIONS: The results indicated that the serum progesterone level on the FET day was one of the risk factors predicting the chances of pregnancy in artificial endometrium preparation cycles, and strengthened LPS in patients with low progesterone on the FET day might help to provide a reasonable pregnancy outcome in artificial cycles, although further prospective evidence is needed to confirm this possibility.

Quercetin prevents primordial follicle loss via suppression of PI3K/Akt/Foxo3a pathway activation in cyclophosphamide-treated mice.

BACKGROUND: Chemotherapy improves the survival rates of patients with various cancers but often causes some adverse effects, including ovarian damage, characterised by a decrease in primordial follicle stockpiles. Recent studies have revealed that chemotherapy may stimulate the PI3K signalling pathway, thereby resulting in accelerated primordial follicle activation and a decreased ovarian reserve. Quercetin is an inhibitor of the PI3K pathway; however, its protective effects against chemotherapy-induced follicle loss in mice have not been established. In this study, the effects of quercetin in a mouse model of cyclophosphamide-induced ovarian dysfunction were investigated. METHODS: C57BL/6 female mice were used for the study. Paraffin sections of mouse ovaries (n = 30 mice) were stained with haematoxylin and eosin for differential follicle counts. Apoptosis (n = 5 mice per group) was evaluated by TUNEL assay. Immunohistochemical staining for ki67 and Foxo3a (n = 5 mice per group) was performed to evaluate the activation of primordial follicles. The role of the PI3K signalling pathway in the ovaries (n = 45 mice) was assessed by western blotting. RESULTS: Quercetin attenuated the cyclophosphamide-induced reduction in dormant primordial follicles. Analysis of the PI3K/Akt/Foxo3a pathway showed that quercetin decreased the phosphorylation of proteins that stimulate follicle activation in cyclophosphamide-induced ovaries. Furthermore, quercetin prevented cyclophosphamide-induced apoptosis in early growing follicles and early antral follicles, maintained anti-Müllerian hormone levels secreted by these follicles, and preserved the quiescence of the primordial follicle pool, as determined by intranuclear Foxo3a staining. CONCLUSIONS: Quercetin attenuates cyclophosphamide-induced follicle loss by preventing the phosphorylation of PI3K/Akt/Foxo3a pathway members and maintaining the anti-Müllerian hormone level through reduced apoptosis in growing follicles. Accordingly, quercetin is expected to improve fertility preservation and the prevention of endocrine-related side effects of chemotherapy.

Out of reach? Correlates of cervical cancer underscreening in women with varying levels of healthcare interactions in a United States integrated delivery system.

One in five U.S. women with health insurance are underscreened for cervical cancer. We sought to identify whether underscreening correlates differed among women with different levels of health care interaction. Among women age 30-64 years who were members of an integrated U.S. health system, we used 2014-2015 electronic health record data to identify underscreened cases (≥3.4 years since last Papanicolaou (Pap) test, n=3352) and screening-adherent controls (<3.4 years since last Pap test, n=45,359) and extracted data on potential underscreening correlates (demographics, health history, and healthcare utilization). We calculated the odds of underscreening in the total population and by subgroups defined by healthcare visits and online health portal usage in the prior 12 months. Underscreening was associated with older age (50-64 vs. 30-39; odds ratio (OR)=1.6; 95%CI=1.4-1.8), current tobacco use (vs. never use; OR=2.1; 95%CI=1.8-2.2), higher BMI (≥35 kg/m2 vs <25 kg/m2, OR=2.0; 95%CI=1.8-2.3), screening non-adherence for colorectal cancer (OR=5.1; 95%CI=4.6-5.7) and breast cancer (OR=8.1, 95%CI=7.2-9.0), and having no recent visit with their primary care provider (PCP) nor recent health portal use (vs. recent PCP visit and portal use; OR=8.4, 95%CI=7.6-9.4). Underscreening correlates were similar between the total study population and within all healthcare interaction groups. Interaction with the healthcare system is associated with lower odds of underscreening, but sociodemographic and health status correlates are similar regardless of primary care visits or online portal use. These data support the need for additional interventions to reach insured women who remain underscreened for cervical cancer.

Value of endometrial thickness change after human chorionic gonadotrophin administration in predicting pregnancy outcome following fresh transfer in vitro fertilization cycles.

PURPOSE: To study whether the change of endometrial thickness (EMT) between the day of human chorionic gonadotrophin (hCG) administration and the day of embryo transfer has any impact on pregnancy outcome in fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. METHODS: This single-center retrospective cohort study included 2620 patients undergoing their first consecutive autologous IVF/ICSI cycles from January 2003 to December 2012. Patients were categorized into three groups based on the percentage change of post-hCG EMT: > 10% decrease, ± 10% plateau and > 10% increase. The primary outcome was live birth rate. RESULTS: Live birth rates were similar in the EMT decrease, plateau and increase groups (27.4% [174/635], 29.7% [300/1010] and 27.6% [269/975]; P = 0.649). Compared with the plateau group, both EMT decrease (crude odds ratio [cOR] 0.89, 95% confidence interval [CI] 0.72-1.11) and increase (cOR 0.90, 95% CI 0.74-1.10) on the day of transfer did not affect the likelihood of live birth. The non-significant association was maintained after controlling for major confounding factors, with the adjusted OR being 0.92 (95% CI 0.73-1.16) and 0.92 (95% CI 0.75-1.13) for the decrease and increase groups, respectively. CONCLUSION: EMT change after hCG administration did not provide significant prognostic information for pregnancy outcome in fresh IVF/ICSI cycles. This finding should offer reassuring information for patients with decreased EMT on the day of embryo transfer while questioning the necessity of EMT re-measurement prior to transfer as a routine practice.

Prior breast density awareness, knowledge, and communication in a health system-embedded behavioral intervention trial.

BACKGROUND: Breast density is an important breast cancer risk factor and a focus of recent national and state health policy efforts. This article describes breast density awareness, knowledge, and communication among participants in a health system-embedded trial with clinically elevated breast cancer risk 1 year before state-mandated density disclosure. METHODS: Trial participants' demographics and prior health history were ascertained from electronic health records. The proportions of women reporting prior breast density awareness, knowledge of density's masking effect, and communication with a provider about their own breast density were calculated using baseline interview data collected from 2017 to 2018. Multiple logistic regression was used to estimate associations between women's characteristics and density awareness, knowledge, and communication. RESULTS: Although the overwhelming majority of participants had heard of breast density (91%) and were aware of breast density's masking effect (87%), only 60% had ever discussed their breast density with a provider. Annual mammography screening was associated with prior breast density awareness (odds ratio [OR], 2.97; 95% confidence interval [CI], 1.29-6.81), knowledge (OR, 2.83; 95% CI, 1.20-6.66), and communication (OR, 2.87; 95% CI, 1.34-6.16) compared with an infrequent or unknown screening interval. Receipt of breast biopsy was also associated with prior knowledge (OR, 1.60; 95% CI, 1.04-2.45) and communication (OR, 1.36; 95% CI, 1.00-1.85). CONCLUSIONS: Breast density awareness and knowledge are high among insured women participating in clinical research, even in the absence of mandated density disclosure. Patient-provider communication about personal density status is less common, particularly among women with fewer interactions with breast health specialists.

Association between peak serum estradiol level during controlled ovarian stimulation and neonatal birthweight in freeze-all cycles: a retrospective study of 8501 singleton live births.

STUDY QUESTION: Is there an association between peak serum estradiol (E2) level during controlled ovarian stimulation (COS) and neonatal birthweight in freeze-all cycles? SUMMARY ANSWER: Peak serum E2 level during ovarian stimulation is not associated with neonatal birthweight in freeze-all cycles. WHAT IS KNOWN ALREADY: Supraphysiologic E2 levels during COS have been demonstrated to generate a suboptimal peri-implantation endometrial environment and thus lead to adverse neonatal outcomes in fresh embryo transfer cycles. Previous experimental studies also suggested a potential influence of superovulation on oocyte epigenetic programming, but whether it translates into altered phenotypes of fetal growth and development remains unclear in clinical practice. By segmenting the process of COS and embryo transfer, the freeze-all policy provides a novel model to investigate the sole impact of ovarian stimulation on oocytes after ruling out the effects of hyperestrogenic milieu on endometrium in fresh cycles. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of 8501 patients who underwent their first COS cycles with a freeze-all strategy and delivered live-born singletons in subsequent frozen-thawed embryo transfer cycles from January 2007 to December 2016 at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were categorized into six groups according to E2 level on trigger day in regular increments of 1000 pg/mL: <1000, 1000-1999, 2000-2999, 3000-3999, 4000-4999 and ≥5000 pg/mL. Univariable and multivariable linear regression and logistic regression analysis were performed to assess the independent association between peak E2 level and measures of neonatal birthweight including absolute birthweight, Z-score, low birthweight (LBW) and small-for-gestational age (SGA). MAIN RESULTS AND THE ROLE OF CHANCE: The six groups did not differ significantly in birthweight, Z-score or the incidence of LBW and SGA. Compared with the E2 <1000 pg/mL group, the adjusted mean difference (95% confidence interval [CI]) of stratified higher E2 groups was 17.2 (-31.0-65.5), 12.3 (-35.9-60.5), -4.1 (-51.9-43.7), -0.6 (-48.9-47.8) and -3.6 (-50.0-42.8) g for birthweight, and 0 (-0.11-0.10), 0.02 (-0.08-0.12), 0.04 (-0.06-0.14), -0.01 (-0.11-0.10) and -0.04 (-0.14-0.06) for Z-score, respectively. Regarding the outcomes of LBW and SGA, no increased risks were observed in each E2 category, with the adjusted odds ratio (95% CI) being 1.21 (0.68-2.16), 1.0 (0.58-1.90), 0.90 (0.50-1.63), 0.93 (0.51-1.69) and 1.08 (0.61-1.90) for LBW, and 0.97 (0.58-1.64), 1.06 (0.63-1.77), 0.77 (0.46-1.31), 0.71 (0.41-1.22) and 1.00 (0.60-1.65) for SGA, respectively. LIMITATIONS, REASONS FOR CAUTION: The study was retrospective in design, and other unknown confounding factors may not be included for adjustment. Furthermore, the generalization of the study finding could be limited to some extent by the majority of double cleavage-stage embryo transfer and difference in birthweight reference percentiles between Chinese and other populations. WIDER IMPLICATIONS OF THE FINDINGS: Our observations suggest that the hyperestrogenic milieu during COS does not seem to pose adverse effects on neonatal birthweight after frozen-thawed embryo transfer, which provides reassuring information for high ovarian responders in freeze-all cycles concerning their offspring's health. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Key Research and Development Program of China (SQ2018YFC100163) and National Natural Science Foundation of China (81571397, 81771533). The authors declare no conflict of interest.

Association between endometrial thickness and neonatal outcomes in intrauterine insemination cycles: a retrospective analysis of 1,016 live-born singletons.

BACKGROUND: Decreased endometrial thickness (EMT) has been suggested to be associated with reduced birthweight of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) newborns. Considering the differences in ovarian stimulation degree and laboratory procedures between IVF/ICSI and IUI treatment, we aim to investigate whether EMT has any influence on IUI infant outcomes as well. METHODS: This was a retrospective cohort study of 1016 patients who had singleton livebirths after IUI treatment cycles from January 2008 to December 2018 at a tertiary-care academic medical center in China. Patients were categorized into three groups by the 10th and 90th percentile of peak EMT: ≤7.6, 7.7-13.0 and ≥ 13.1 mm. The primary outcomes of the study were preterm birth (PTB), low birthweight (LBW) and small-for-gestational age (SGA). Multiple regression analyses were performed after controlling for a variety of potential confounders. RESULTS: No significant differences were found among the three groups in gestational age, birthweight and birthweight Z-score. Compared with the EMT 7.7-13.0 mm group, the incidences of PTB, LBW and SGA were 5.5% (adjusted odds ratio [aOR] 0.81, 95% confidence interval [CI] 0.33-2.01), 6.4% (aOR 1.44, 95% CI 0.58-3.58) and 7.3% (aOR 1.21, 95% CI 0.53-2.76) in the EMT ≤7.6 mm group, respectively. Similarly, EMT ≥13.1 mm was not significantly associated with risks of PTB (aOR 0.63, 95% CI 0.24-1.65), LBW (aOR 0.57, 95% CI 0.17-1.95) and SGA (aOR 0.73, 95% CI 0.28-1.92). The odds of other adverse neonatal outcomes, including macrosomia, large-for-gestational age and major congenital malformations, did not show significant differences before and after adjustment in both EMT ≤7.6 and ≥ 13.1 mm groups. CONCLUSIONS: EMT is not independently associated with adverse perinatal outcomes in IUI cycles. This novel finding would provide reassuring information for IUI patients with thin endometrial linings regarding their neonatal health. However, further prospective cohort studies with larger datasets are needed to confirm the conclusion.

Effect of a prior cesarean delivery on pregnancy outcomes of frozen-thawed embryo transfer: A retrospective cohort study in a freeze-all setting.

INTRODUCTION: The association between the mode of previous delivery and subsequent success of assisted reproductive treatment has been poorly understood. By mitigating the detrimental effect of supraphysiologic estradiol levels on endometrial receptivity, a freeze-all strategy provides a novel model to investigate the sole impact of a prior cesarean delivery (CD) on embryo transfer outcomes. MATERIAL AND METHODS: This single-center retrospective cohort study included 2660 patients who underwent their first frozen-thawed embryo transfer cycles after a freeze-all policy from January 2013 to December 2018. Patients with a history of live birth by CD were assigned to the CD group, and those with only vaginal delivery (VD) were categorized into the VD group. The primary outcome measure was live birth. Baseline characteristics of the two groups were balanced by propensity score matching in a ratio of 1:1. Univariate and multivariate logistic regression analyses were performed using the after-matching data. RESULTS: Compared with the VD group, the rates of clinical pregnancy (38.3% vs 44.5%; P = .005) and live birth (27.5% vs 33.4%; P = .003) were significantly lower in women with a history of CD. When adjusted for a number of major confounding factors, the negative association between a prior CD and frozen-thawed embryo transfer success was maintained, with the adjusted odds ratio (OR) being 0.80 (95% CI 0.66-0.96) and 0.78 (95% CI 0.63-0.95) for clinical pregnancy and live birth, respectively. Furthermore, a CD history conferred a marginally increased risk of early miscarriage (crude OR 1.48, 95% CI 1.04-2.11; adjusted OR 1.47, 95% CI 1.01-2.14), whereas the odds of multiple and ectopic pregnancy did not show significant differences before and after adjustment. CONCLUSIONS: A prior CD was associated with a decreased chance of live birth and an increased risk of early miscarriage in frozen-thawed embryo transfer cycles.

Effect of Switching from a Progestin-Primed Ovarian Stimulation Protocol to a Modified Ultra-Long Protocol Among Women Who Had 1 Progestin-Primed Ovarian Stimulation (PPOS) Failure Verses Those Who Had 2 PPOS Failures.

BACKGROUND There is little research on whether normoresponsive patients who produced poor-quality embryos once verses those who produced poor-quality embryos twice when using a single COH protocol should change to a different controlled ovarian hyperstimulation (COH) protocol. MATERIAL AND METHODS In this retrospective study, we enrolled 108 patients with 1 PPOS failure who chose to continue receiving the progestin-primed ovarian stimulation (PPOS) protocol (n=61) versus those who decided to switch to the modified ultra-long protocol (n=47). We also enrolled 131 normoresponsive patients with 2 PPOS failures who chose to continue receiving the PPOS protocol (n=60) versus those who decided to switch to the modified ultra-long protocol (n=71) in the third cycle. RESULTS We found no significant difference in clinical outcomes of patients with 1 PPOS failure who continued using the PPOS protocol verses those who switched to the modified ultra-long protocol in the second cycle, expect for a lower cancelation rate (4.3% vs. 16.4%). However, the patients with 2 PPOS failures had significantly more good-quality embryos (0.9 vs. 0.4), more viable embryos (1.8 vs. 0.9), lower cancelation rates (18.3% vs. 53.3%), and higher pregnancy rates per aspirated cycle (26.8% vs. 10.0%) when switching to the modified ultra-long protocol compared to those who decided to continue receiving the PPOS protocol (P<0.05). Furthermore, the odds of clinical pregnancy (odds ratio [OR] 5.997, 95% confidence interval [CI] 1.476-24.361, P=0.01) were positively associated with switching to the COH protocol in the third cycle. CONCLUSIONS For normoresponsive patients with poor-quality embryos when using the PPOS protocol, switching to the modified ultra-long protocol after having 2 PPOS failures was associated with better ART outcomes.

Cross-linked hyaluronan gel to improve pregnancy rate of women patients with moderate to severe intrauterine adhesion treated with IVF: a randomized controlled trial.

PURPOSE: To evaluate whether the cross-linked hyaluronan (cHA) gel can improve the clinical pregnancy rate of patients with moderate to severe intrauterine adhesion (IUA) who underwent operative hysteroscopy followed by embryo transfer. METHODS: Women with moderate to severe IUA desiring to undergo embryo transfer were recruited in this randomized controlled trial. The patients were randomized on the day of receiving hysteroscopy. The control group received standard hysteroscopy, while cHA gel was applied to the treatment group at the end of hysteroscopy and 5-7 days after operation. All patients were expected to undergo in vitro fertilization (IVF)/intracytoplasmic sperm injection and frozen-thawed embryo transfer (FET). RESULTS: A total of 306 patients were enrolled in this study, of which 202 were assigned to the treatment group and 104 to the control group. Both the clinical pregnancy rate (26.3% [49/186] vs. 15.3% [13/85], P = 0.045), the implantation rate (17.7% [57/322] vs. 9.8% [15/153], P = 0.025), and the endometrial thickness on the day of embryo transfer (7.97 ± 1.37 vs. 7.50 ± 0.60 mm, P < 0.001) were significantly higher in the treatment group compared to the control group. In addition, histological assessment of the paired endometrial tissues collected before and after operation revealed a relatively higher number of tubular glands after operation (15.1 ± 13.2 vs. 28.8 ± 30.4, P = 0.166). CONCLUSIONS: To conclude, the application of cHA gel in patients with moderate to severe IUA during hysteroscopy can improve the quality of endometrium and uterine receptivity and consequently enhance the clinical pregnancy rate after IVF/CSI and FET.

The ovulation trigger-OPU time interval of different ovarian protocols in ART: a retrospective study.

PURPOSE: To explore the trends of oocyte and pregnancy outcomes over the ovulation trigger-OPU (oocyte pickup) time interval in four mainly used COH protocols. METHODS: This retrospective study was conducted between January 2013 and July 2018. The IVF/ICSI cycles of the patients with normal ovarian reserve were included. The number of total patients was 4673, which consisted of long agonist protocol (n = 819), short agonist protocol (n = 1703), mild stimulation protocol (n = 1627), and GnRH antagonist protocol (n = 524). The primary outcome was mature oocyte rate. RESULTS: The ovulation trigger-OPU time interval and COH protocol were related to cycles with > 80% MII oocytes. Four protocols showed apparently different trends of retrieved oocyte rate and mature oocyte rate over the ovulation trigger-OPU time interval, and the long agonist protocol had the most delayed time interval than other three COH protocols in retrieving more than 60% oocytes (35.4-39.6 h vs. 34.6-38.6 h vs. 32.5-37.5 h vs. 33.8-37.7 h) and getting more than 80% mature oocytes (35.0-39.7 h vs. 36.0-37.7 h vs. 34.1-35.5 h vs. 34.5-36.3 h). And the adjusted odds ratio (OR) of the cumulative live birth rate (CLBR) (OR 1.360, 95% Confidence Interval (CI) 1.156-1.549, P < 0.05) significantly increased with the trigger-OPU time interval in the long agonist protocol. CONCLUSIONS: For getting more and mature oocytes, the ovulation trigger-OPU time intervals should be gradually prolonged from the mild stimulation protocol, the GnRH antagonist protocol, and the short protocol to the long agonist protocol. And the prolonged ovulation trigger-OPU time interval in the long agonist protocol brings higher live birth rate (LBR) and CLBR.

Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing in vitro fertilization/intracytoplasmic sperm injection: A prospective randomized controlled trial.

OBJECTIVE: To compare the endocrinological profiles, cycle characteristics and pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) with or without clomiphene citrate (CC) supplementation in normal ovulatory women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN: Prospective randomized controlled study. PATIENT(S): A total of 320 infertile women undergoing IVF/ICSI. Medroxyprogesterone acetate (MPA) and human menopausal gonadotropin (hMG) were simultaneously administered on menstrual cycle day 3. The women were randomized into 2 equal groups with or without CC supplementation. MEASURES: The primary outcome measure was the percentage of women with profound pituitary suppression (luteinizing hormone [LH] <1.0 IU/L on the trigger day). The secondary outcomes were endocrinological profiles, cycle characteristics and pregnancy outcomes. RESULTS: The percentage of women with profound pituitary suppression was significantly lower in the study group (hMG + MPA + CC) than in the control group (hMG + MPA) (1.9% vs 33.1%, P < .001). The mean LH level during controlled ovarian stimulation (COS) was higher in the study group than in the control group (P < .001), but none of the patients in either group exhibited a premature LH surge. The doses of Gn in the study group were significantly lower than those in the control group (1334.06 ± 212.53 IU vs 1488.28 ± 325.08 IU, P < .001). The number of oocytes retrieved was similar between the 2 groups (10.03 ± 5.97 vs 10.34 ± 7.52, P > .05). No significant differences were observed in either the number of viable embryos or the pregnancy outcomes between the 2 groups. CONCLUSION(S): Clomiphene citrate is an effective adjuvant to alleviate pituitary suppression in the PPOS protocol; however, it has no impact on clinical outcomes.

New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF/ICSI cycles.

STUDY QUESTION: Can dydrogesterone (DYG) be used as an alternative progestin in a progesterone primed ovarian stimulation (PPOS) protocol? SUMMARY ANSWER: DYG can be used as an appropriate alternative progestin in a PPOS protocol. WHAT IS KNOWN ALREADY: PPOS is a new ovarian stimulation regimen based on a freeze-all strategy that uses progestin as an alternative to a GnRH analog for suppressing a premature LH surge during the follicular phase. Medroxyprogesterone acetate (MPA) has been successfully used as an adjuvant to gonadotrophin in the PPOS protocol. However, the use of MPA may lead to stronger pituitary suppression and thus may require a higher dosage of hMG and a longer duration of ovarian stimulation than that of conventional ovarian stimulation protocol. STUDY DESIGN SIZE, DURATION: A prospective RCT including 516 patients was performed between November 2015 and November 2016. Computerized randomization was conducted to assign participants at a 1:1 ratio into two treatment groups: an hMG + DYG group (260 patients) or an hMG + MPA group (256 patients) followed by IVF or ICSI with the freeze-all strategy. One cycle per patient was included. The primary outcome of the trial was the number of oocytes retrieved. The sample size was chosen to detect a difference of two oocytes with a power of 90%. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients under 36 years of age with normal ovarian reserve who were undergoing their first IVF/ICSI procedure due to tubal factor infertility were randomized into two groups based on the oral progestin protocol used: hMG co-treatment with DYG (hMG + DYG) or hMG co-treatment with MPA (hMG + MPA). The different progestin was simultaneously administered at the beginning of menstrual cycle 3 (MC3). Oocyte maturation was co-triggered by administration of a GnRH agonist and hCG. All viable embryos from both protocols were cryopreserved for later transfer. Only the first frozen embryo transfer (FET) cycle was included in our study. The embryological and clinical outcomes were measured. MAIN RESULTS AND THE ROLE OF CHANCE: Basic characteristics, such as age, BMI and infertility duration, in both groups were comparable. There was no significant difference in the number (mean ± SD) of oocytes retrieved [10.8 ± 6.3 for the hMG + DYG group versus 11.1 ± 5.8 for the hMG + MPA group, P = 0.33] or the oocyte retrieval rate [74.3 ± 19.6% for the hMG + DYG group versus 75.0 ± 19.5% for the hMG + MPA group, P = 0.69] between the groups. The viable embryo rate per oocyte retrieved did not differ between the two groups [odds ratio (OR): 1.08, 95% CI: 0.97-1.21, P = 0.16]: 37.4% (1052/2815) for the hMG + DYG group versus 35.6% (1009/2837) for the hMG + MPA group. During the whole process of ovarian stimulation, the mean LH level in the hMG + DYG group was always higher than that in the hMG + MPA group (P < 0.001); however, no patient from either group experienced a premature LH surge. In addition, no patients experienced moderate or severe ovarian hyperstimulation syndrome during the ovarian stimulation. No significant difference was found in the clinical pregnancy rate of the first FET cycle between the two groups (OR: 0.82, 95% CI: 0.56-1.21, P = 0.33): 57.6% for the hMG + DYG group (125/217) versus 62.3% for the hMG + MPA group (132/212). LIMITATIONS REASONS FOR CAUTION: The patients and physician were not blinded to the study. Further, a large proportion of patients were still pregnant at the end of the clinical trial, therefore live birth rates were not observed in the follow-up period. The dose-effectiveness of DYG administration was not addressed in the trial design. WIDER IMPLICATIONS OF THE FINDINGS: DYG, which exhibits no or only weak inhibition of ovulation in normal dosage, can serve as an hMG adjuvant during ovarian stimulation. This finding suggests the possibility of a new application of DYG: as an appropriate alternative progestin for a PPOS protocol in IVF. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by The National Nature Science Foundation of China (Grant no. 81503603), Shanghai Three-year Plan on Promoting TCM Development (Grant no. ZY3-LCPT-2-2006) and the Natural Science Foundation of Shanghai (Grant nos. 15401932700 and 15ZR1424900). None of the authors declare any conflict of interest. TRIAL REGISTRATION NUMBER: Chictr.org.cn: ChiCTR-IPR-15007251. TRIAL REGISTRATION DATE: Chictr.org.cn: 22 October 2015. DATE OF FIRST PATIENT'S ENROLLMENT: 1 November 2015.

Breast cancer screening outreach effectiveness: Mammogram-specific reminders vs. comprehensive preventive services birthday letters.

We compared the effectiveness of two outreach strategies on timely mammography adherence: a mammogram-specific reminder letter (sent just before a woman was due) to a birthday letter (addresses multiple preventive services and not timed around due dates). We evaluated screening mammography adherence following 79,848 mammogram-specific and 151,626 birthday letters mailed between 2002 and 2012 to women aged 40-74years enrolled in Kaiser Permanente Washington. Screening mammogram adherence was specifically tied to due date and was evaluated separately by age group and up-to-date or overdue status at the time of mailing. We used generalized estimating equations to account for correlation between repeated observations, to model the odds of screening mammography adherence by letter type. Among women up-to-date, adherence following birthday letters was 22-76% lower compared to the mammogram-specific reminders, with the greatest decreases in adherence in women aged 70-74. Birthday letters were more effective at activating screening uptake among some subgroups of overdue women aged 50-69 and most overdue women aged 70-74, but universally low adherence rates were observed in overdue women. Increasing number of recommended services for women aged 50-74 who were up-to-date resulted in 12-17% lower mammography adherence, but had no effect in women aged 40-49 or in overdue women. Birthday letters are less effective than mammogram-specific reminder letters at prompting women to undergo timely breast cancer screening, particularly among women up-to-date with screening. Birthday letters may be effective at increasing overall preventive care; however, supplemental outreach may be needed around the due date to increase timely preventive services receipt.

Comparative effectiveness of two outreach strategies for cervical cancer screening.

OBJECTIVE: Test-specific reminder letters can improve cancer screening adherence. Little is known about the effectiveness of a reminder system that targets the whole person by including multiple screening recommendations per letter. METHODS: We compared the effectiveness of a Pap-specific reminder letter sent 27months after a woman's last Pap, to a reminder letter that included up to seven preventive service recommendations sent before a woman's birthday ("birthday letter") on Pap smear adherence from a natural experiment occurring in routine clinical care. Participants included 82,016 women from Washington State who received 72,615 Pap-specific letters between 2003 and 2007 and 100,218 birthday letters between 2009 and 2012. We defined adherence as having a Pap test within a six month window around the Pap test due date. Using logistic regression, we calculated adjusted odds ratios (OR) for adherence with 95% confidence intervals (CI) following the birthday letter with 1-2 recommendations, 3-5 recommendations, and 6-7 recommendations compared to the Pap-specific letter. All analyses were stratified by whether a woman was up-to-date or overdue for screening at the time she received a letter. RESULTS: Adjusted ORs showed reduced adherence following the birthday letter compared with the Pap-specific letter for up-to-date women whether the letter had 1-2 recommendations (OR=0.37, 95%CI=0.36-0.39), 3-5 recommendations (OR=0.44, 95%CI=0.42-0.45), or 6-7 recommendations (OR=0.36, 95%CI=0.32-0.40). We noted no difference in Pap-test adherence between letter types for overdue women. CONCLUSIONS: In conclusion, for women regularly adherent to screening, an annual birthday letter containing reminders for multiple preventive services was less effective at promoting cervical cancer screening compared with a Pap-specific letter.