Live birth of chimeric monkey with high contribution from embryonic stem cells.

A formal demonstration that mammalian pluripotent stem cells possess preimplantation embryonic cell-like (naive) pluripotency is the generation of chimeric animals through early embryo complementation with homologous cells. Whereas such naive pluripotency has been well demonstrated in rodents, poor chimerism has been achieved in other species including non-human primates due to the inability of the donor cells to match the developmental state of the host embryos. Here, we have systematically tested various culture conditions for establishing monkey naive embryonic stem cells and optimized the procedures for chimeric embryo culture. This approach generated an aborted fetus and a live chimeric monkey with high donor cell contribution. A stringent characterization pipeline demonstrated that donor cells efficiently (up to 90%) incorporated into various tissues (including the gonads and placenta) of the chimeric monkeys. Our results have major implications for the study of primate naive pluripotency and genetic engineering of non-human primates.

Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn.

BACKGROUND: In early-onset severe hemolytic disease of the fetus and newborn (HDFN), transplacental transfer of maternal antierythrocyte IgG alloantibodies causes fetal anemia that leads to the use of high-risk intrauterine transfusions in order to avoid fetal hydrops and fetal death. Nipocalimab, an anti-neonatal Fc receptor blocker, inhibits transplacental IgG transfer and lowers maternal IgG levels. METHODS: In an international, open-label, single-group, phase 2 study, we assessed treatment with intravenous nipocalimab (30 or 45 mg per kilogram of body weight per week) administered from 14 to 35 weeks' gestation in participants with pregnancies at high risk for recurrent early-onset severe HDFN. The primary end point was live birth at 32 weeks' gestation or later without intrauterine transfusions as assessed against a historical benchmark (0%; clinically meaningful difference, 10%). RESULTS: Live birth at 32 weeks' gestation or later without intrauterine transfusions occurred in 7 of 13 pregnancies (54%; 95% confidence interval, 25 to 81) in the study. No cases of fetal hydrops occurred, and 6 participants (46%) did not receive any antenatal or neonatal transfusions. Six fetuses received an intrauterine transfusion: five fetuses at 24 weeks' gestation or later and one fetus before fetal loss at 22 weeks and 5 days' gestation. Live birth occurred in 12 pregnancies. The median gestational age at delivery was 36 weeks and 4 days. Of the 12 live-born infants, 1 received one exchange transfusion and one simple transfusion and 5 received only simple transfusions. Treatment-related decreases in the alloantibody titer and IgG level were observed in maternal samples and cord blood. No unusual maternal or pediatric infections were observed. Serious adverse events were consistent with HDFN, pregnancy, or prematurity. CONCLUSIONS: Nipocalimab treatment delayed or prevented fetal anemia or intrauterine transfusions, as compared with the historical benchmark, in pregnancies at high risk for early-onset severe HDFN. (Funded by Janssen Research and Development; UNITY ClinicalTrials.gov number, NCT03842189.).

Temperature anomalies undermine the health of reproductive-age women in low- and middle-income countries.

Climate change is expected to undermine population health and well-being in low- and middle-income countries, but relatively few analyses have directly examined these effects using individual-level data at global scales, particularly for reproductive-age women. To address this lacuna, we harmonize nationally representative data from the Demographic and Health Surveys on reproductive health, body mass index (BMI), and temporary migration from 2.5 million adult women (ages 15 to 49) in approximately 109,000 sites across 59 low- and middle-income countries, which we link to high-resolution climate data. We use this linked dataset to estimate fixed-effect logistic regression models of demographic and health outcomes as a function of climate exposures, woman-level and site-level characteristics, seasonality, and regional time trends, allowing us to plausibly isolate climate effects from other influences on health and migration. Specifically, we measure the effects of recent exposures to temperature and precipitation anomalies on the likelihood of having a live birth in the past year, desire for another child, use of modern contraception, underweight (BMI < 18.5), and temporary migration, and subsequently allow for nonlinearity as well as heterogeneity across education, rural/urban residence, and baseline climate. This analysis reveals that exposures to high temperatures increase live births, reduce desire for another child, increase underweight, and increase temporary migration, particularly in rural areas. The findings represent clear evidence that anthropogenic temperature increases contribute to temporary migration and are a significant threat to women's health and reproductive autonomy in low- and middle-income countries.

On the reproductive capabilities of aneuploid human preimplantation embryos.

In IVF cycles, the application of aneuploidy testing at the blastocyst stage is quickly growing, and the latest reports estimate almost half of cycles in the US undergo preimplantation genetic testing for aneuploidies (PGT-A). Following PGT-A cycles, understanding the predictive value of an aneuploidy result is paramount for making informed decisions about the embryo's fate and utilization. Compelling evidence from non-selection trials strongly supports that embryos diagnosed with a uniform whole-chromosome aneuploidy very rarely result in the live birth of a healthy baby, while their transfer exposes women to significant risks of miscarriage and chromosomally abnormal pregnancy. On the other hand, embryos displaying low range mosaicism for whole chromosomes have shown reproductive capabilities somewhat equivalent to uniformly euploid embryos, and they have comparable clinical outcomes and gestational risks. Therefore, given their clearly distinct biological origin and clinical consequences, careful differentiation between uniform and mosaic aneuploidy is critical in both the clinical setting when counseling individuals and in the research setting when presenting aneuploidy studies in human embryology. Here, we focus on the evidence gathered so far on PGT-A diagnostic predictive values and reproductive outcomes observed across the broad spectrum of whole-chromosome aneuploidies detected at the blastocyst stage to obtain evidence-based conclusions on the clinical management of aneuploid embryos in the quickly growing PGT-A clinical setting.

Livebirth rate after one frozen embryo transfer in ovulatory women starting with natural, modified natural, or artificial endometrial preparation in Viet Nam: an open-label randomised controlled trial.

BACKGROUND: Use of frozen embryo transfer (FET) in in-vitro fertilisation (IVF) has increased. However, the best endometrial preparation protocol for FET cycles is unclear. We compared natural and modified natural cycle strategies with an artificial cycle strategy for endometrial preparation before FET. METHODS: In this randomised, open-label study, we recruited ovulatory women aged 18-45 years at a hospital in Ho Chi Minh City, Viet Nam, who were randomly allocated (1:1:1) to natural, modified natural, or artificial cycle endometrial preparation using a computer-generated random list and block randomisation. The trial was not masked due to the nature of the study interventions. In natural cycles, no oestrogen, progesterone, or human chorionic gonadotropin (hCG) was used. In modified natural cycles, hCG was used to trigger ovulation. In artificial cycles, oral oestradiol valerate (8 mg/day from day 2-4 of menstruation) and vaginal progesterone (800 mg/day starting when endometrial thickness was ≥7 mm) were used. Embryos were vitrified, and then one or two day-3 embryos or one day-5 embryo were warmed and transferred under ultrasound guidance. If the first FET cycle was cancelled, subsequent cycles were performed with artificial endometrial preparation. The primary endpoint was livebirth after one FET. This trial is registered at ClinicalTrials.gov, NCT04804020. FINDINGS: Between March 22, 2021, and March 14, 2023, 4779 women were screened and 1428 were randomly assigned (476 to each group). 99 first FET cycles were cancelled in each of the natural and modified cycle groups, versus none in the artificial cycle group. The livebirth rate after one FET was 174 (37%) of 476 in the natural cycle strategy group, 159 (33%) of 476 in the modified natural cycle strategy group, and 162 (34%) of 476 in the artificial cycle strategy group (relative risk 1·07 [95% CI 0·87-1·33] for natural vs artificial cycle strategy, and 0·98 [0·79-1·22] for modified natural vs artificial cycle strategy). Maternal and neonatal outcomes did not differ significantly between groups, as the power to detect small differences was low. INTERPRETATION: Although the livebirth rate was similar after natural, modified natural, and artificial cycle endometrial preparation strategies in ovulatory women undergoing FET IVF, no definitive conclusions can be made regarding the comparative safety of the three approaches. FUNDING: None.

Buprenorphine versus Methadone for Opioid Use Disorder in Pregnancy.

BACKGROUND: Opioid agonist therapy is strongly recommended for pregnant persons with opioid use disorder. Buprenorphine may be associated with more favorable neonatal and maternal outcomes than methadone, but existing data are limited. METHODS: We conducted a cohort study involving pregnant persons who were enrolled in public insurance programs in the United States during the period from 2000 through 2018 in which we examined outcomes among those who received buprenorphine as compared with those who received methadone. Exposure to the two medications was assessed in early pregnancy (through gestational week 19), late pregnancy (gestational week 20 through the day before delivery), and the 30 days before delivery. Risk ratios for neonatal and maternal outcomes were adjusted for confounders with the use of propensity-score overlap weights. RESULTS: The data source for the study consisted of 2,548,372 pregnancies that ended in live births. In early pregnancy, 10,704 pregnant persons were exposed to buprenorphine and 4387 to methadone. In late pregnancy, 11,272 were exposed to buprenorphine and 5056 to methadone (9976 and 4597, respectively, in the 30 days before delivery). Neonatal abstinence syndrome occurred in 52.0% of the infants who were exposed to buprenorphine in the 30 days before delivery as compared with 69.2% of those exposed to methadone (adjusted relative risk, 0.73; 95% confidence interval [CI], 0.71 to 0.75). Preterm birth occurred in 14.4% of infants exposed to buprenorphine in early pregnancy and in 24.9% of those exposed to methadone (adjusted relative risk, 0.58; 95% CI, 0.53 to 0.62); small size for gestational age in 12.1% and 15.3%, respectively (adjusted relative risk, 0.72; 95% CI, 0.66 to 0.80); and low birth weight in 8.3% and 14.9% (adjusted relative risk, 0.56; 95% CI, 0.50 to 0.63). Delivery by cesarean section occurred in 33.6% of pregnant persons exposed to buprenorphine in early pregnancy and 33.1% of those exposed to methadone (adjusted relative risk, 1.02; 95% CI, 0.97 to 1.08), and severe maternal complications developed in 3.3% and 3.5%, respectively (adjusted relative risk, 0.91; 95% CI, 0.74 to 1.13). Results of exposure in late pregnancy were consistent with results of exposure in early pregnancy. CONCLUSIONS: The use of buprenorphine in pregnancy was associated with a lower risk of adverse neonatal outcomes than methadone use; however, the risk of adverse maternal outcomes was similar among persons who received buprenorphine and those who received methadone. (Funded by the National Institute on Drug Abuse.).

Histologic Remission in Inflammatory Bowel Disease and Female Fertility: A Nationwide Study.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is linked to reduced female fertility, but it is unclear how fertility rates vary by histologic disease activity. METHODS: Nationwide IBD cohort of Swedish women aged 15 to 44 years. We examined fertility rates during periods with vs without histologic inflammation (n = 21,046; follow-up, 1990-2016) and during periods with vs without clinical activity (IBD-related hospitalization, surgery, or treatment escalation) (n = 24,995; follow-up, 2006-2020). Accounting for sociodemographics and comorbidities, we used Poisson regression to estimate adjusted fertility rate ratios (aFRRs) for live births conceived during 12-month periods of histologic inflammation (vs histologic remission) and 3-month periods of clinically active IBD (vs quiescent IBD). RESULTS: During periods with vs without histologic inflammation, there were 6.35 (95% confidence interval [CI], 5.98-6.73) and 7.09 (95% CI, 6.48-7.70) live births conceived per 100 person-years of follow-up, respectively, or 1 fewer child per 14 women with 10 years of histologic inflammation (aFRR, 0.90; 95% CI, 0.81-1.00). In women with histologic inflammation, fertility was similarly reduced in ulcerative colitis (UC) (aFRR, 0.89 [95% CI, 0.78-1.02]) and Crohn's disease (CD) (aFRR, 0.86 [95% CI, 0.72-1.04]). Clinical IBD activity was associated with an aFRR of 0.76 (95% CI, 0.72-0.79) or 1 fewer child per 6 women with 10 years of clinical activity. Fertility was reduced in clinically active UC (aFRR, 0.75 [95% CI, 0.70-0.81]) and CD (aFRR, 0.76 [95% CI, 0.70-0.82]). Finally, among women with clinically quiescent IBD, histologic inflammation (vs histologic remission) was associated with reduced fertility (aFRR, 0.85 [95% CI, 0.73-0.98]). CONCLUSIONS: An association between histologic and clinical activity and reduced female fertility in CD and UC was found. Notably, histologic inflammation was also linked to reduced fertility in women with clinically quiescent IBD.

Pregnancy and Birth Outcomes in Patients With Multidrug-Resistant Tuberculosis Treated With Regimens That Include New and Repurposed Drugs.

Among 43 pregnant women receiving multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment with bedaquiline and/or delamanid, 98% had favorable treatment outcomes. Of 31 continued pregnancies, 81% had live births with no reported malformations, and 68% of neonates had normal birth weights. Effective MDR/RR-TB treatment during pregnancy can improve maternal outcomes without harming neonates.

Racialized inequities in live birth after cancer: A population-based study of 63,000 female adolescents and young adults with cancer.

INTRODUCTION: Fertility after cancer is a top concern for adolescents and young adults with cancer (AYAs) (15-39 years old at diagnosis). The authors characterized live births after cancer by race and ethnicity ("race/ethnicity") in a population-based sample of female AYAs. METHODS: This study used Texas Cancer Registry data linked to birth certificates (1995-2016) to estimate cumulative incidence of live birth, based on first live birth after cancer, and compared differences by race/ethnicity. Proportional subdistribution hazards models were used to estimate associations between race/ethnicity and live birth, adjusted for diagnosis age, cancer type, stage, year, and prior live birth, overall and for each cancer type. RESULTS: Among 65,804 AYAs, 10-year cumulative incidence of live birth was lower among non-Hispanic Black AYAs than other racial/ethnic groups: 10.2% (95% confidence interval [CI], 9.4-10.9) compared to 15.9% (95% CI, 14.1-17.9) among Asian or Pacific Islander, 14.7% (95% CI, 14.2-15.3) among Hispanic, and 15.2% (95% CI, 14.8-15.6) among non-Hispanic White AYAs (p < .01). In the adjusted overall model, Black AYAs were less likely to have a live birth after cancer than all other groups. In adjusted models for each cancer type, live birth was significantly less likely for Black AYAs with gynecologic cancers or lymphomas (compared to White AYAs) or thyroid cancers (compared to Hispanic AYAs). CONCLUSION: Black AYAs are less likely than AYAs of other races/ethnicities to have a live birth after cancer, in contrast to patterns of live birth in the general population. Research and action to promote childbearing equity after cancer are imperative.

Conception and pregnancy among women with a live birth after breast cancer treatment: A survey study of young breast cancer survivors.

BACKGROUND: Breast cancer (BC) is the most common malignancy in women of reproductive age. This study sought to explore the postcancer conception and pregnancy experience of young BC survivors to inform counseling. METHODS: In the Young Women's Breast Cancer Study (NCT01468246), a multicenter, prospective cohort, participants diagnosed at age ≤40 years with stage 0-III BC who reported ≥1 postdiagnosis live birth were sent an investigator-developed survey. RESULTS: Of 119 eligible women, 94 (79%) completed the survey. Median age at diagnosis was 32 years (range, 17-40) and at first postdiagnosis delivery was 38 years (range, 29-47). Most had stage I or II (77%) and HR+ (78%) BC; 51% were nulligravida at diagnosis. After BC treatment, most (62%) conceived naturally, though 38% used assisted reproductive technology, 74% of whom first attempted natural conception for a median of 9 months (range, 2-48). Among women with a known inherited pathogenic variant (n = 20), two underwent preimplantation genetic testing. Of 59 women on endocrine therapy before pregnancy, 26% did not resume treatment. Hypertensive disorders of pregnancy (20%) was the most common obstetrical condition. Nine percent of newborns required neonatal intensive care unit admission and 9% had low birth weight. CONCLUSION: Among women with live births after BC treatment, most conceived naturally and having a history of BC did not appear to negatively impact pregnancy complications, though the high rate of hypertensive disorders of pregnancy warrants further investigation. The prolonged period of attempting natural conception for some survivors suggests the potential need for improved understanding and counseling surrounding family planning goals after BC.

CAnceR IN PreGnancy (CARING) - a retrospective study of cancer diagnosed during pregnancy in the United Kingdom.

BACKGROUND: The incidence of cancer diagnosed during pregnancy is increasing. Data relating to investigation and management, as well as maternal and foetal outcomes is lacking in a United Kingdom (UK) population. METHODS: In this retrospective study we report data from 119 patients diagnosed with cancer during pregnancy from 14 cancer centres in the UK across a five-year period (2016-2020). RESULTS: Median age at diagnosis was 33 years, with breast, skin and haematological the most common primary sites. The majority of cases were new diagnoses (109 patients, 91.6%). Most patients were treated with radical intent (96 patients, 80.7%), however, gastrointestinal cancers were associated with a high rate of palliative intent treatment (63.6%). Intervention was commenced during pregnancy in 68 (57.1%) patients; 44 (37%) had surgery and 31 (26.1%) received chemotherapy. Live births occurred in 98 (81.7%) of the cases, with 54 (55.1%) of these delivered by caesarean section. Maternal mortality during the study period was 20.2%. CONCLUSIONS: This is the first pan-tumour report of diagnosis, management and outcomes of cancer diagnosed during pregnancy in the UK. Our findings demonstrate proof of concept that data collection is feasible and highlight the need for further research in this cohort of patients.

Live Birth with or without Preimplantation Genetic Testing for Aneuploidy.

BACKGROUND: Embryo selection with preimplantation genetic testing for aneuploidy (PGT-A) may improve pregnancy outcomes after initial embryo transfer. However, it remains uncertain whether PGT-A improves the cumulative live-birth rate as compared with conventional in vitro fertilization (IVF). METHODS: In this multicenter, randomized, controlled trial, we randomly assigned subfertile women with three or more good-quality blastocysts to undergo either PGT-A or conventional IVF; all the women were between 20 and 37 years of age. Three blastocysts were screened by next-generation sequencing in the PGT-A group or were chosen by morphologic criteria in the conventional-IVF group and then were successively transferred one by one. The primary outcome was the cumulative live-birth rate after up to three embryo-transfer procedures within 1 year after randomization. We hypothesized that the use of PGT-A would result in a cumulative live-birth rate that was no more than 7 percentage points higher than the rate after conventional IVF, which would constitute the noninferiority margin for conventional IVF as compared with PGT-A. RESULTS: A total of 1212 patients underwent randomization, and 606 were assigned to each trial group. Live births occurred in 468 women (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional-IVF group (absolute difference, -4.6 percentage points; 95% confidence interval [CI], -9.2 to -0.0; P<0.001). The cumulative frequency of clinical pregnancy loss was 8.7% and 12.6%, respectively (absolute difference, -3.9 percentage points; 95% CI, -7.5 to -0.2). The incidences of obstetrical or neonatal complications and other adverse events were similar in the two groups. CONCLUSIONS: Among women with three or more good-quality blastocysts, conventional IVF resulted in a cumulative live-birth rate that was noninferior to the rate with PGT-A. (Funded by the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03118141.).

SARS-CoV-2 infection is detrimental to pregnancy outcomes after embryo transfer in IVF/ICSI: a prospective cohort study.

BACKGROUND: To explore whether SARS-CoV-2 infection affects the pregnancy outcomes of assisted reproductive techniques (ART). METHODS: A prospective cohort study recruited patients for embryo transfer from December 01, 2022, to December 31, 2022. All patients were closely followed up for SARS-CoV-2 infection after embryo transfer. The SARS-CoV-2 "diagnosed group" was defined as RNA or antigen-positive. The SARS-CoV-2 "suspected infection group" was defined as having apparent SARS-CoV-2 symptoms without an RNA or antigen test, while the "uninfected group" was defined as having a negative SARS-CoV-2 RNA or antigen test and no SARS-CoV-2 symptoms. RESULTS: A total of 1330 patients participated in the study, 687 of whom were in the SARS-CoV-2 diagnosed group, 219 in the suspected infection group, and 424 in the uninfected group. There was no significant difference in basic characteristics among the three groups. The clinical pregnancy rate was 68% in the SARS-CoV-2 diagnosed group, 63% in the uninfected group, and 51% in the suspected infection group (P < 0.001). The ongoing pregnancy rate was 58% in the SARS-CoV-2 diagnosed group, 53% in the uninfected group, and 45% in the suspected infection group (P < 0.001). Upon analyzing the factors influencing clinical pregnancy, it was found that suspected infection (odds ratio [OR] 0.618, 95% CI 0.444-0.862, P = 0.005) and the short time (≤ 22 days) between embryo transfer and SARS-CoV-2 infection (OR 3.76, 95% CI 1.92-8.24, P < 0.001) were not conducive to clinical pregnancy. In addition, the concurrent presence of fever and dizziness/headache SARS-CoV-2 symptoms (OR 0.715, 95% CI 0.526-0.972, P = 0.032) decreased the clinical pregnancy rate. However, vaccination administered 2-3 times (OR 1.804, 95% CI 1.332-2.444, P < 0.001) was associated with an improvement in clinical pregnancy rate. CONCLUSIONS: This prospective cohort study shows that SARS-CoV-2 infection in a short period of time after embryo transfer is not conducive to clinical pregnancy. Reproductive physicians should advise patients to avoid SARS-CoV-2 infection shortly after embryo transfer. Meanwhile, women should be encouraged to vaccinate at least 2-3 times before embryo transfer or pregnancy.

Intracytoplasmic sperm injection versus conventional in vitro insemination in couples with non-male infertility factor in the 'real-world' setting: analysis of the HFEA registry.

BACKGROUND: In assisted reproductive technology (ART), the choice between intracytoplasmic sperm injection (ICSI) and conventional in vitro insemination (IVF) remains a pivotal decision for couples with female or unexplained infertility. The hypothesis that ICSI may not confer significant improvements in live birth rates in the absence of a male infertility factor was explored in this study. METHODS: This was a retrospective collection of data recorded by the Human Fertilisation and Embryology Authority (HFEA) in the UK from 2005 to 2018 and analysed through regression analysis models on both the entire dataset and a matched-pair subset. First fresh ART cycles were analysed according to the insemination technique in order to compare live birth as the main outcome. Cycles were included if complete information regarding infertility cause, female age, number of oocytes retrieved, allocation to ICSI or IVF, and treatment outcome in terms of live birth was available. Matching was performed at a 1:1 ratio between IVF and ICSI cycles according to the cause of infertility, female age, number of oocytes, and year of treatment. RESULTS: This study, based on 275,825 first cycles, revealed that, compared with IVF, ICSI was associated with higher fertilization rates and lower cycle cancellations rates. However, ICSI was associated with a lower chance of implantation and live birth than IVF in cycles with female-only infertility: in the entire dataset, the adjusted odds of having a live birth decreased by a factor of 0.95 (95% CI 0.91-0.99, p = 0.011), while in the matched-pair analyses it decreased by a factor of 0.91 (95% CI 0.86-0.96, p = 0.003) using ICSI compared to IVF. For unexplained infertility cycles, the adjusted odds ratios for live birth in ICSI compared to IVF cycles were 0.98 (95% CI 0.95-1.01) in the entire dataset and 0.97 (95% CI 0.93-1.01) in the matched-pair analysis. CONCLUSIONS: Compared with IVF, ICSI was associated with a reduction in live births when ART was indicated due to female-only factors. Additionally, no significant improvements were associated with the use of ICSI in cycles with unexplained infertility. Our findings impose a critical reevaluation regarding the use of ICSI over IVF for cases with female-only factors and unexplained infertility.

Outcomes in 14 live births resulting from Pegvaliase-treated pregnancies in PKU-affected females.

BACKGROUND: Adults with PKU have difficulty maintaining plasma phenylalanine (Phe) in the range that is safe for neurologic function. Elevated plasma Phe is a risk factor for congenital anomalies and developmental delay in offspring resulting from pregnancies with poor Phe control in women with PKU. Enzyme supplementation with pegvaliase allows adults with PKU to eat an unrestricted diet and have plasma Phe levels in a safe range for pregnancy but pegvaliase has not been approved for use in pregnant females with PKU. We report the results of chart review of 14 living offspring of females affected with PKU who were responsive to pegvaliase and chose to remain on pegvaliase throughout their pregnancy. METHODS: Fourteen pregnancies (one triplet pregnancy) and their offspring were identified at eight PKU treatment centers and medical records from pregnancy and birth were submitted for this study. Institutional Review Board approval was obtained. Responses to a dataset were provided to a single center and analyzed. RESULTS: Six females and eight males were born without congenital anomalies and all offspring had normal growth parameters. While mothers had preexisting comorbidities, no additional comorbidities were reported in the offspring. Four of eleven infants (excluding triplet pregnancies) were delivered preterm (36%), a higher rate than the general population (12%). A single first trimester (eight weeks) miscarriage in a 40y was not counted in this cohort of 14 live born infants. CONCLUSION: This retrospective study suggests that pegvaliase is effective at maintaining safe maternal blood Phe levels during pregnancy without deleterious effects on mother or child. A tendency toward premature birth (4/11; 36%) is higher than expected.

Association between proliferative-to-secretory endometrial compaction and pregnancy outcomes after embryo transfer: a systematic review and meta-analysis.

STUDY QUESTION: Does the change in endometrial thickness (EMT) from the end of the follicular/estrogen phase to the day of embryo transfer (ET) determine subsequent pregnancy outcomes? SUMMARY ANSWER: Endometrial compaction from the late-proliferative to secretory phase is not associated with live birth rate (LBR) and other pregnancy outcomes. WHAT IS KNOWN ALREADY: Endometrial compaction has been suggested to be indicative of endometrial responsiveness to progesterone, and its association with ET outcome has been investigated but is controversial. STUDY DESIGN, SIZE, DURATION: A systematic review with meta-analysis was carried out. PubMed, EMBASE, and Web of Science were searched to identify relevant studies from inception to 18 November 2022. The reference lists of included studies were also manually screened for any additional publications. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohort studies comparing ET pregnancy outcomes between patients with and without endometrial compaction were included. A review of the studies for inclusion, data extraction, and quality assessment was performed by two independent reviewers. The effect size was synthesized as odds ratio (OR) with 95% CI using a random-effects model. Heterogeneity and publication bias were assessed by the I2 statistic and Egger's test, respectively. The primary outcome was LBR. Secondary outcomes included biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), miscarriage rate (MR), ongoing pregnancy rate (OPR), and ectopic pregnancy rate (EPR). MAIN RESULTS AND THE ROLE OF CHANCE: Seventeen cohort studies involving 18 973 ET cycles fulfilled the eligibility criteria. The pooled results revealed that there were no significant differences between endometrial compaction and non-compaction groups in LBR (crude OR (cOR) = 0.95, 95% CI 0.87-1.04; I2 = 0%; adjusted OR (aOR) = 1.02, 95% CI 0.87-1.19, I2 = 79%), BPR (cOR = 0.93, 95% CI 0.81-1.06; I2 = 0%; aOR = 0.88, 95% CI 0.75-1.03, I2 = 0%), CPR (cOR = 0.98, 95% CI 0.81-1.18; I2 = 70%; aOR = 0.86, 95% CI 0.72-1.02, I2 = 13%), MR (cOR = 1.09, 95% CI 0.90-1.32; I2 = 0%; aOR = 0.91, 95% CI 0.64-1.31; I2 = 0%), and EPR (cOR = 0.70, 95% CI 0.31-1.61; I2 = 61%). The OPR was marginally higher in crude analysis (cOR = 1.48, 95% CI 1.01-2.16; I2 = 81%) among women with compacted endometrium, but was not evident in adjusted results (aOR = 1.36, 95% CI 0.86-2.14; I2 = 84%). Consistently, the pooled estimate of LBR remained comparable in further subgroup and sensitivity analyses according to the degree of compaction (0%, 5%, 10%, 15%, or 20%), type of ET (fresh, frozen, or euploid only), and endometrial preparation protocol (natural or artificial). No publication bias was observed based on Egger's test. LIMITATIONS, REASONS FOR CAUTION: Although the number of included studies is sufficient, data on certain measures, such as EPR, are limited. The inherent bias and residual confounding were also inevitable owing to the observational study design. Furthermore, inconsistent definitions of pregnancy outcomes may affect the accuracy of our pooled analysis. WIDER IMPLICATIONS OF THE FINDINGS: Given the lack of prognostic value, assessing endometrial compaction or repeated EMT measurement on the day of ET may not be necessary or warranted. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Natural Science Foundation of Jiangxi Province (20224BAB216025), National Natural Science Foundation of China (82260315), and Central Funds Guiding the Local Science and Technology Development (20221ZDG020071). The authors have no conflicts of interest to declare. REGISTRATION NUMBER: CRD42022384539 (PROSPERO).

BlastAssist: a deep learning pipeline to measure interpretable features of human embryos.

STUDY QUESTION: Can the BlastAssist deep learning pipeline perform comparably to or outperform human experts and embryologists at measuring interpretable, clinically relevant features of human embryos in IVF? SUMMARY ANSWER: The BlastAssist pipeline can measure a comprehensive set of interpretable features of human embryos and either outperform or perform comparably to embryologists and human experts in measuring these features. WHAT IS KNOWN ALREADY: Some studies have applied deep learning and developed 'black-box' algorithms to predict embryo viability directly from microscope images and videos but these lack interpretability and generalizability. Other studies have developed deep learning networks to measure individual features of embryos but fail to conduct careful comparisons to embryologists' performance, which are fundamental to demonstrate the network's effectiveness. STUDY DESIGN, SIZE, DURATION: We applied the BlastAssist pipeline to 67 043 973 images (32 939 embryos) recorded in the IVF lab from 2012 to 2017 in Tel Aviv Sourasky Medical Center. We first compared the pipeline measurements of individual images/embryos to manual measurements by human experts for sets of features, including: (i) fertilization status (n = 207 embryos), (ii) cell symmetry (n = 109 embryos), (iii) degree of fragmentation (n = 6664 images), and (iv) developmental timing (n = 21 036 images). We then conducted detailed comparisons between pipeline outputs and annotations made by embryologists during routine treatments for features, including: (i) fertilization status (n = 18 922 embryos), (ii) pronuclei (PN) fade time (n = 13 781 embryos), (iii) degree of fragmentation on Day 2 (n = 11 582 embryos), and (iv) time of blastulation (n = 3266 embryos). In addition, we compared the pipeline outputs to the implantation results of 723 single embryo transfer (SET) cycles, and to the live birth results of 3421 embryos transferred in 1801 cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: In addition to EmbryoScope™ image data, manual embryo grading and annotations, and electronic health record (EHR) data on treatment outcomes were also included. We integrated the deep learning networks we developed for individual features to construct the BlastAssist pipeline. Pearson's χ2 test was used to evaluate the statistical independence of individual features and implantation success. Bayesian statistics was used to evaluate the association of the probability of an embryo resulting in live birth to BlastAssist inputs. MAIN RESULTS AND THE ROLE OF CHANCE: The BlastAssist pipeline integrates five deep learning networks and measures comprehensive, interpretable, and quantitative features in clinical IVF. The pipeline performs similarly or better than manual measurements. For fertilization status, the network performs with very good parameters of specificity and sensitivity (area under the receiver operating characteristics (AUROC) 0.84-0.94). For symmetry score, the pipeline performs comparably to the human expert at both 2-cell (r = 0.71 ± 0.06) and 4-cell stages (r = 0.77 ± 0.07). For degree of fragmentation, the pipeline (acc = 69.4%) slightly under-performs compared to human experts (acc = 73.8%). For developmental timing, the pipeline (acc = 90.0%) performs similarly to human experts (acc = 91.4%). There is also strong agreement between pipeline outputs and annotations made by embryologists during routine treatments. For fertilization status, the pipeline and embryologists strongly agree (acc = 79.6%), and there is strong correlation between the two measurements (r = 0.683). For degree of fragmentation, the pipeline and embryologists mostly agree (acc = 55.4%), and there is also strong correlation between the two measurements (r = 0.648). For both PN fade time (r = 0.787) and time of blastulation (r = 0.887), there's strong correlation between the pipeline and embryologists. For SET cycles, 2-cell time (P < 0.01) and 2-cell symmetry (P < 0.03) are significantly correlated with implantation success rate, while other features showed correlations with implantation success without statistical significance. In addition, 2-cell time (P < 5 × 10-11), PN fade time (P < 5 × 10-10), degree of fragmentation on Day 3 (P < 5 × 10-4), and 2-cell symmetry (P < 5 × 10-3) showed statistically significant correlation with the probability of the transferred embryo resulting in live birth. LIMITATIONS, REASONS FOR CAUTION: We have not tested the BlastAssist pipeline on data from other clinics or other time-lapse microscopy (TLM) systems. The association study we conducted with live birth results do not take into account confounding variables, which will be necessary to construct an embryo selection algorithm. Randomized controlled trials (RCT) will be necessary to determine whether the pipeline can improve success rates in clinical IVF. WIDER IMPLICATIONS OF THE FINDINGS: BlastAssist provides a comprehensive and holistic means of evaluating human embryos. Instead of using a black-box algorithm, BlastAssist outputs meaningful measurements of embryos that can be interpreted and corroborated by embryologists, which is crucial in clinical decision making. Furthermore, the unprecedentedly large dataset generated by BlastAssist measurements can be used as a powerful resource for further research in human embryology and IVF. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Harvard Quantitative Biology Initiative, the NSF-Simons Center for Mathematical and Statistical Analysis of Biology at Harvard (award number 1764269), the National Institute of Heath (award number R01HD104969), the Perelson Fund, and the Sagol fund for embryos and stem cells as part of the Sagol Network. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Pretreatment prediction for IVF outcomes: generalized applicable model or centre-specific model?

STUDY QUESTION: What was the performance of different pretreatment prediction models for IVF, which were developed based on UK/US population (McLernon 2016 model, Luke model, Dhillon model, and McLernon 2022 model), in wider populations? SUMMARY ANSWER: For a patient in China, the published pretreatment prediction models based on the UK/US population provide similar discriminatory power with reasonable AUCs and underestimated predictions. WHAT IS KNOWN ALREADY: Several pretreatment prediction models for IVF allow patients and clinicians to estimate the cumulative probability of live birth in a cycle before the treatment, but they are mostly based on the population of Europe or the USA, and their performance and applicability in the countries and regions beyond these regions are largely unknown. STUDY DESIGN, SIZE, DURATION: A total of 26 382 Chinese patients underwent oocyte pick-up cycles between January 2013 and December 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: UK/US model performance was externally validated according to the coefficients and intercepts they provided. Centre-specific models were established with XGboost, Lasso, and generalized linear model algorithms. Discriminatory power and calibration of the models were compared as the forms of the AUC of the Receiver Operator Characteristic and calibration curves. MAIN RESULTS AND THE ROLE OF CHANCE: The AUCs for McLernon 2016 model, Luke model, Dhillon model, and McLernon 2022 model were 0.69 (95% CI 0.68-0.69), 0.67 (95% CI 0.67-0.68), 0.69 (95% CI 0.68-0.69), and 0.67 (95% CI 0.67-0.68), respectively. The centre-specific yielded an AUC of 0.71 (95% CI 0.71-0.72) with key predictors including age, duration of infertility, and endocrine parameters. All external models suggested underestimation. Among the external models, the rescaled McLernon 2022 model demonstrated the best calibration (Slope 1.12, intercept 0.06). LIMITATIONS, REASONS FOR CAUTION: The study is limited by its single-centre design and may not be representative elsewhere. Only per-complete cycle validation was carried out to provide a similar framework to compare different models in the sample population. Newer predictors, such as AMH, were not used. WIDER IMPLICATIONS OF THE FINDINGS: Existing pretreatment prediction models for IVF may be used to provide useful discriminatory power in populations different from those on which they were developed. However, models based on newer more relevant datasets may provide better calibrations. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China [grant number 22176159], the Xiamen Medical Advantage Subspecialty Construction Project [grant number 2018296], and the Special Fund for Clinical and Scientific Research of Chinese Medical Association [grant number 18010360765]. TRIAL REGISTRATION NUMBER: N/A.

Intra-patient analysis of individual weight gain or loss between IVF cycles: cycle now and transfer later.

STUDY QUESTION: What is the impact of clinically significant weight change on outcomes related to IVF cycle performance? SUMMARY ANSWER: While individual weight loss did not significantly impact ovarian response to stimulation or other cycle outcome parameters in our study, some positive associations were found for individual weight gain. WHAT IS KNOWN ALREADY: The role of weight-change in patients undergoing IVF has been largely studied by comparing weight loss in different cohorts of patients stratified by a static BMI. Specifically, obesity has been extensively studied in relation to its negative effects on assisted or unassisted conception outcomes and ovulatory function. Previous research has shown conflicting results, while BMI, which is commonly used as a marker of obesity, may not accurately reflect the underlying factors affecting fertility in obese patients. STUDY DESIGN, SIZE, DURATION: This study utilized a retrospective within-patient repeated measurement analysis design to assess the impact of weight change on IVF outcomes in cycles where all embryos were cryopreserved at the blastocyst stage for transfer at a later date. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at an academically affiliated fertility center. The data included 961 women who underwent at least two IVF cycles between December 2014 and June 2020, with documented short-term weight gain (n = 607) or weight loss (n = 354) within 1 year from their initial IVF cycle. Multivariable generalized estimating equations (GEE) and generalized linear mixed models (GLMM) were employed to assess associations between weight change and outcomes across cycles. MAIN RESULTS AND THE ROLE OF CHANCE: The multivariable models indicated that weight loss did not show any significant associations with the numbers of oocytes retrieved, or mature oocytes, the fertilization rate or the blastulation rate. However, weight gain demonstrated a minor positive association with the number of oocytes retrieved in both GEE models (coefficient: 0.01, 95% CI: 0.00-0.01) and GLMM models (0.01, 95% CI: 0.01-0.00). There was also a potential increase in the fertilization rate with weight gain, as indicated by a positive coefficient in both GEE models (coefficient: 0.01, 95% CI: 0.00-0.02) and GLMM models (coefficient: 0.01, 95% CI: 0.00-0.01). However, the association between weight gain and the embryo blastulation rate was not statistically significant in any model. LIMITATIONS, REASONS FOR CAUTION: This study focused on cycle performance parameters instead of reproductive outcomes, which restricted our ability to evaluate the impact of weight change on cumulative live birth rates. Additionally, the study did not account for variables such as stimulation protocols, potentially introducing confounding factors and limiting the generalizability of the results. WIDER IMPLICATIONS OF THE FINDINGS: Although obesity is associated with adverse obstetrical risks, there is less evidence of adverse reproductive outcomes in IVF cycles. We therefore recommend that an IVF cycle should not be delayed due to weight, so that the patient is not adversely affected by increasing age. The IVF cycle should aim to freeze all embryos, so that embryo transfer can then occur after weight loss, so as to limit the recognized obstetrical risks. STUDY FUNDING/COMPETING INTEREST(S): The study was not funded and there were no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Morphological quality on Day 3 affects the pregnancy outcomes of low-quality euploid blastocysts: a retrospective cohort study.

STUDY QUESTION: Does the morphological quality on Day 3 influence the pregnancy outcomes of euploid blastocysts? SUMMARY ANSWER: The morphological quality on Day 3 affects the clinical pregnancy rate (CPR) and live birth rate (LBR) of low-quality euploid blastocysts. WHAT IS KNOWN ALREADY: The morphological grading of Day 3 embryos affects the pregnancy outcome of cleavage-stage embryos and is an excellent indicator to predict embryo development potential. However, it is still unclear whether morphological quality on Day 3 is associated with pregnancy outcomes of the euploid blastocyst. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study comprised 1275 patients who received single euploid blastocyst transfer between January 2016 and August 2021 at a tertiary teaching hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were grouped into two groups according to the morphological grading on Day 3 of transferred blastocysts: high-quality (HQ, including Grades I and II) Day 3 embryos and low-quality (LQ, Grade III) Day 3 embryos. The primary outcomes were CPR and LBR. Interactions of development days (Day 5 and Day 6) and morphological quality (high- and low-quality) of blastocysts with morphological quality of Day 3 embryos on pregnancy outcomes were tested in the stratified analysis and logistic regression models. The multivariate logistic regression analysis was conducted to investigate the independent effect of the morphological quality of Day 3 embryos on pregnancy outcomes after adjusting for potentially confounding factors. MAIN RESULTS AND THE ROLE OF CHANCE: The CPR and LBR of the HQ Day 3 embryos group were statistically higher than those of the LQ Day 3 embryos group (CPR: 59.73% versus 49.70%, respectively, P = 0.015; LBR: 49.73% versus 41.21%, respectively, P = 0.041). The development days of blastocysts did not exhibit a multiplicative interaction with the morphological quality of Day 3 embryos on the CPR (P for interaction = 0.648) and LBR (P for interaction = 0.925). The morphological quality of blastocysts exhibits a multiplicative interaction with the morphological quality of Day 3 embryos on the CPR (P for interaction = 0.020) and LBR (P for interaction = 0.012). After adjusting for potential confounders, the HQ Day 3 embryo group was positively associated with the CPR (adjusted odds ratio (aOR): 2.10, 95% CI: 1.31-3.36, P = 0.002) and LBR (aOR: 1.97, 95% CI: 1.20-3.25, P = 0.008) of LQ blastocysts. However, the morphological quality on Day 3 was not significantly associated with the CPR (aOR: 0.95, 95% CI: 0.58-1.55, P = 0.835) and LBR (aOR: 0.86, 95% CI: 0.53-1.40, P = 0.550) of HQ blastocysts. LIMITATIONS, REASONS FOR CAUTION: Selection and confounding bias introduced by the retrospective design cannot be completely eliminated in this study, although multivariable logistic analysis was conducted to adjust for potential confounders. Also, some subgroups had small sample sizes, which may reduce statistical power. Moreover, participants in our study only received single euploid blastocyst transfer, and whether the results could apply to blastocysts with unknown ploidy status is unclear. WIDER IMPLICATIONS OF THE FINDINGS: This study found that the morphological quality on Day 3 was significantly associated with the CPR and LBR of LQ blastocysts; Therefore, when only LQ euploid blastocysts are available for transfer, blastocysts derived from HQ Day 3 embryos are recommended. STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.