Data-driven insights can transform women's reproductive health.

This perspective explores the transformative potential of data-driven insights to understand and address women's reproductive health conditions. Historically, clinical studies often excluded women, hindering comprehensive research into conditions such as adverse pregnancy outcomes and endometriosis. Recent advances in technology (e.g., next-generation sequencing techniques, electronic medical records (EMRs), computational power) provide unprecedented opportunities for research in women's reproductive health. Studies of molecular data, including large-scale meta-analyses, provide valuable insights into conditions like preterm birth and preeclampsia. Moreover, EMRs and other clinical data sources enable researchers to study populations of individuals, uncovering trends and associations in women's reproductive health conditions. Despite these advancements, challenges such as data completeness, accuracy, and representation persist. We emphasize the importance of holistic approaches, greater inclusion, and refining and expanding on how we leverage data and computational integrative approaches for discoveries so that we can benefit not only women's reproductive health but overall human health.

Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium.

BACKGROUND: Placenta accreta spectrum disorders are associated with severe maternal morbidity and mortality. Placenta accreta spectrum disorders involve excessive adherence of the placenta preventing separation at birth. Traditionally, this condition has been attributed to excessive trophoblast invasion; however, an alternative view is a fundamental defect in decidual biology. OBJECTIVE: This study aimed to gain insights into the understanding of placenta accreta spectrum disorder by using single-cell and spatially resolved transcriptomics to characterize cellular heterogeneity at the maternal-fetal interface in placenta accreta spectrum disorders. STUDY DESIGN: To assess cellular heterogeneity and the function of cell types, single-cell RNA sequencing and spatially resolved transcriptomics were used. A total of 12 placentas were included, 6 placentas with placenta accreta spectrum disorder and 6 controls. For each placenta with placenta accreta spectrum disorder, multiple biopsies were taken at the following sites: placenta accreta spectrum adherent and nonadherent sites in the same placenta. Of note, 2 platforms were used to generate libraries: the 10× Chromium and NanoString GeoMX Digital Spatial Profiler for single-cell and spatially resolved transcriptomes, respectively. Differential gene expression analysis was performed using a suite of bioinformatic tools (Seurat and GeoMxTools R packages). Correction for multiple testing was performed using Clipper. In situ hybridization was performed with RNAscope, and immunohistochemistry was used to assess protein expression. RESULTS: In creating a placenta accreta cell atlas, there were dramatic difference in the transcriptional profile by site of biopsy between placenta accreta spectrum and controls. Most of the differences were noted at the site of adherence; however, differences existed within the placenta between the adherent and nonadherent site of the same placenta in placenta accreta. Among all cell types, the endothelial-stromal populations exhibited the greatest difference in gene expression, driven by changes in collagen genes, namely collagen type III alpha 1 chain (COL3A1), growth factors, epidermal growth factor-like protein 6 (EGFL6), and hepatocyte growth factor (HGF), and angiogenesis-related genes, namely delta-like noncanonical Notch ligand 1 (DLK1) and platelet endothelial cell adhesion molecule-1 (PECAM1). Intraplacental tropism (adherent versus non-adherent sites in the same placenta) was driven by differences in endothelial-stromal cells with notable differences in bone morphogenic protein 5 (BMP5) and osteopontin (SPP1) in the adherent vs nonadherent site of placenta accreta spectrum. CONCLUSION: Placenta accreta spectrum disorders were characterized at single-cell resolution to gain insight into the pathophysiology of the disease. An atlas of the placenta at single cell resolution in accreta allows for understanding in the biology of the intimate maternal and fetal interaction. The contributions of stromal and endothelial cells were demonstrated through alterations in the extracellular matrix, growth factors, and angiogenesis. Transcriptional and protein changes in the stroma of placenta accreta spectrum shift the etiologic explanation away from "invasive trophoblast" to "loss of boundary limits" in the decidua. Gene targets identified in this study may be used to refine diagnostic assays in early pregnancy, track disease progression over time, and inform therapeutic discoveries.

Pregnancy after deceased donor vs living donor kidney transplant: associated obstetric and graft outcomes.

BACKGROUND: Outside of pregnancy, recipients of a deceased donor kidney transplant experience worse graft and overall survival compared with recipients of a living donor kidney transplant. In pregnancy, it is unknown whether the type of donor graft modifies either graft health in the peripartum period or pregnancy outcomes. OBJECTIVE: This study aimed to define characteristics and outcomes in pregnancy based on donor type in kidney transplant recipients. STUDY DESIGN: This was a retrospective cohort study of adult kidney transplant recipients who received their graft between 2000 and 2019 with a subsequent pregnancy enrolled in the Transplant Pregnancy Registry International. The primary outcome was graft loss within 2 years of delivery. The secondary outcomes included severe maternal morbidity and neonatal composite morbidity. Univariate, multivariable logistic regression, and Cox proportional-hazards models were constructed for statistical analysis, with recipients of a living unrelated donor as the referent. RESULTS: Overall, 638 pregnant patients after kidney transplant had pregnancy outcomes that met our inclusion criteria. Of these patients, 168 (26.3%) received a graft from a deceased donor, 310 (48.6%) received a graft from a living related donor, and 160 (25.1%) received a graft from a living unrelated donor. Recipients of a deceased donor were more likely to be nulliparous, have an unplanned pregnancy, and self-identify as non-White. Moreover, recipients of a deceased donor were more likely to experience urinary tract infections (deceased donor: 21.8%; living related donor: 10.1%; living unrelated donor: 20.6%; P=.018). Severe maternal morbidity (deceased donor: 3.4%; living related donor: 2.8%; living unrelated donor: 7.2%) and neonatal composite morbidity (deceased donor: 8.4%; living related donor: 17.1%; living unrelated donor: 14.4%) did not differ by donor type. Deceased donor transplant was associated with graft loss within 2 years of delivery (deceased donor: 6.7%; living related donor: 3.7%; living unrelated donor: 1.3%; adjusted odds ratio, 7.52; 95% confidence interval, 1.53-60.8) and long-term graft loss from transplant (adjusted hazard ratio, 2.08; 95% confidence interval, 1.10-3.95). CONCLUSION: Although our study demonstrated an association between deceased donor transplant and graft loss after pregnancy, it did not provide evidence that pregnancy itself causes graft loss. Recipients of a deceased donor kidney transplant should not be discouraged from pursuing pregnancy based on their donor type, but these patients should undergo preconception counseling with a discussion of their individualized obstetrical and graft risks, close intrapartum monitoring for infection and hypertensive disease, and continued surveillance for at least 2 years after delivery with a multidisciplinary obstetrics and transplant team.

Associations with spontaneous and indicated preterm birth in a densely phenotyped EHR cohort.

Background: Preterm birth (PTB) is the leading cause of infant mortality and follows multiple biological pathways, many of which are poorly understood. Some PTBs result from medically indicated labor following complications from hypertension and/or diabetes, while many others are spontaneous with unknown causes. Previously, investigation of potential risk factors has been limited by lack of data on maternal medical history and the difficulty of classifying PTBs as indicated or spontaneous. Here, we leverage electronic health record (EHR) data (patient health information including demographics, diagnoses, and medications) and a supplemental curated pregnancy database to overcome these limitations. Novel associations may provide new insight into the pathophysiology of PTB as well as help identify individuals who would be at risk of PTB. Methods: We quantified associations between maternal diagnoses and preterm birth using logistic regression controlling for maternal age and socioeconomic factors within a University of California, San Francisco (UCSF), EHR cohort with 10,643 births ( nterm = 9692, nspontaneous_preterm = 449, nindicated_preterm = 418) and maternal pre-conception diagnosis phenotypes derived from International Classification of Diseases (ICD) 9 and 10 codes. Results: Eighteen conditions significantly and robustly (False Discovery Rate (FDR)<0.05) associated with PTBs compared to term. We discovered known (hypertension, diabetes, and chronic kidney disease) and less established (blood, cardiac, gynecological, and liver conditions) associations. Type 1 diabetes was the most significant overall association (adjusted p = 1.6×10 -14 , adjusted OR = 7 (95% CI 5, 12)), and the odds ratios for the significant phenotypes ranged from 3 to 13. We further carried out analysis stratified by spontaneous vs. indicated PTB. No phenotypes significantly associated with spontaneous PTB; however, the results for indicated PTB largely recapitulated the phenotype associations with all PTBs. Conclusions: Our study underscores the limitations of approaches that combine indicated and spontaneous births together. When combined, significant associations were almost entirely driven by indicated PTBs, although our spontaneous and indicated groups were of a similar size. Investigating the spontaneous population has the potential to reveal new pathways and understanding of the heterogeneity of PTB.

Dosing Recommendation Based on the Effects of Different Meal Types on Pexidartinib Pharmacokinetics in Healthy Subjects: Implementation of Model-informed Drug Development Strategy.

Pexidartinib, an oral small molecule inhibitor of the colony-stimulating factor 1 receptor, is approved for treatment of adults with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The original dosing regimen is 400 mg of pexidartinib (2 × 200-mg capsules) twice daily, administered on an empty stomach at least 1 hour before or 2 hours after a meal or snack. Because pexidartinib is likely to be taken over an extended period of time, the ability to take pexidartinib with a meal would simplify timing of administration and potentially improve compliance. Since administering 400 mg of pexidartinib with a low-fat meal increases exposure by ≈60% relative to the fasted state, administering 250 mg of pexidartinib with a low-fat meal (low-fat meal dosing regimen) was predicted to achieve an exposure similar to 400 mg administered during a fasted state (original dosing regimen). Based on clinical trial simulations with two one-sided t-tests and bootstrapping (ie, resampling) analyses, a bioequivalence study (n = 24) would have >90% power to conclude that the original dosing regimen (400 mg fasted twice daily) and the low-fat meal dosing regimen (250 mg with a low-fat meal twice daily) are bioequivalent. This report provides the outcome of the implementation of the model-informed drug development strategy to recommend and justify a low-fat meal dosing regimen for pexidartinib that has the potential to improve patient compliance while maintaining drug exposure.

Emergent prelabor cesarean delivery in solid organ transplant recipients: associated risk factors and outcomes.

BACKGROUND: Pregnancies after solid organ transplant are at a higher risk of antepartum admission and pregnancy complications including cesarean delivery. Emergent prelabor cesarean delivery is associated with increased maternal and neonatal morbidity in other high-risk populations, but its incidence and impact in transplant recipients is not well-understood. OBJECTIVE: This study aimed to characterize the risk factors and outcomes of emergency prelabor cesarean delivery in kidney and liver transplant recipients. STUDY DESIGN: This was a retrospective cohort study of all kidney and liver transplant recipients at >20 weeks gestation enrolled in the Transplant Pregnancy Registry International between 1976 and 2019. Participants admitted antepartum who required emergency prelabor cesarean delivery were compared with those admitted antepartum who underwent nonemergent birth. The primary outcomes were severe maternal morbidity and neonatal composite morbidity. Multivariable logistic regression was conducted for neonatal composite morbidity. RESULTS: Of 1979 births, 181 pregnancies (188 neonates) with antepartum admission were included. 51 pregnancies (53 neonates, 28%) were delivered by emergent prelabor cesarean delivery compared with 130 pregnancies (135 neonates, 72%) admitted antepartum who subsequently did not require emergent delivery. The most common indication for emergent delivery was nonreassuring fetal heart tracing (44 pregnancies /51 emergent deliveries = 86%). Pregnant people who underwent emergent prelabor cesarean delivery were less likely to deliver at a transplant center (37.3% vs 41.5%; P=.04) and had increased rates of chronic hypertension (33.3% vs 16.2%; P=.02). There was no significant difference in severe maternal morbidity (3.9% vs 4.6%; P=.84), though there was an increase in surgical site infection in the emergent prelabor cesarean delivery cohort (3.9% vs 0%; P=.02). Among those with emergent prelabor cesarean delivery, there was a significant increase in neonatal composite morbidity (43.4% vs 19.3%; P<.001) with earlier gestational age at delivery (33.4 vs 34.7 weeks; P=.02), lower birthweight (1899 g vs 2321 g; P<.001), lower birthweight percentile (30.3% vs 40.6%; P=.03), increased neonatal intensive care unit admission (52.8% vs 35.6%; P=.03), and increased neonatal mortality (11.3% vs 1.5%; P=.002). After adjusting for year of conception, race, hypertensive disorders, and fetal malformations, there was a persistent increased risk of neonatal morbidity (adjusted odds ratio, 3.01; 95% confidence interval, 1.50-6.08; P=.002) associated with emergent prelabor cesarean delivery after transplant. CONCLUSION: Almost one-third of kidney and liver transplant recipients admitted antepartum had an emergency prelabor cesarean delivery, and 63% of this cohort delivered outside of a transplant center. Pregnancies after transplantation should involve multidisciplinary transplant-obstetrics collaboration to ensure optimal antepartum disease management, especially for preexisting hypertension, to prevent and mitigate obstetrical and neonatal morbidity in the setting of emergent cesarean delivery.

The role of Hippo pathway signaling and A-kinase anchoring protein 13 in primordial follicle activation and inhibition.

OBJECTIVE: To determine whether the mechanotransduction and pharmacomanipulation of A-kinase anchoring protein 13 (AKAP13) altered Hippo signaling pathway transcription and growth factors in granulosa cells. Primary ovarian insufficiency is the depletion or dysfunction of primordial ovarian follicles. In vitro activation of ovarian tissue in patients with primary ovarian insufficiency alters the Hippo and phosphatase and tensin homolog/phosphatidylinositol 3-kinase/protein kinase B/forkhead box O3 pathways. A-kinase anchoring protein 13 is found in granulosa cells and may regulate the Hippo pathway via F-actin polymerization resulting in altered nuclear yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif coactivators and Tea domain family (TEAD) transcription factors. DESIGN: Laboratory studies. SETTING: Translational science laboratory. PATIENT(S): None. INTERVENTION(S): COV434 cells, derived from a primary human granulosa tumor cell line, were studied under different cell density and well stiffness conditions. Cells were transfected with a TEAD-luciferase (TEAD-luc) reporter as well as expression constructs for AKAP13 or AKAP13 mutants and then treated with AKAP13 activators, inhibitors, and follicle-stimulating hormone. MAIN OUTCOME MEASURE(S): TEAD gene activation or inhibition was measured by TEAD-luciferase assays. The messenger ribonucleic acid levels of Hippo pathway signaling molecules, including connective tissue growth factor (CTGF), baculoviral inhibitors of apoptosis repeat-containing 5, Ankyrin repeat domain-containing protein 1, YAP1, and TEAD1, were measured by quantitative real-time polymerase chain reaction. Protein expressions for AKAP13, CTGF, YAP1, and TEAD1 were measured using Western blot. RESULT(S): Increased TEAD-luciferase activity and expression of markers for cellular growth were associated with decreased cell density, increased well stiffness, and AKAP13 activator (A02) treatment. Additionally, decreased TEAD-luc activity and expression of markers for cellular growth were associated with AKAP13 inhibitor (A13) treatment, including a reduced expression of the BIRC5 and ANKRD1 (YAP-responsive genes) transcript levels and CTGF protein levels. There were no changes in TEAD-luc with follicle-stimulating hormone treatment, supporting Hippo pathway involvement in the gonadotropin-independent portion of folliculogenesis. CONCLUSION(S): These findings suggest that AKAP13 mediates Hippo-regulated changes in granulosa cell growth via mechanotransduction and pharmacomanipulation. The AKAP13 regulation of the Hippo pathway may represent a potential target for regulation of follicle activation.

Edoxaban Exposure in Patients With Atrial Fibrillation and Estimated Creatinine Clearance Exceeding 100 mL/min.

Edoxaban 60 mg is approved for stroke prevention in patients with atrial fibrillation (AF) not fulfilling any dose-reduction criteria. As edoxaban is partially renally cleared (≈50%), this study compared pharmacokinetics (PK) and pharmacodynamics of edoxaban 60 mg once daily with edoxaban 75 mg once daily in patients with AF with high renal clearance (creatinine clearance > 100 mL/min) over 12 months. Primary PK and pharmacodynamics end points were plasma edoxaban exposure and anti-factor Xa (FXa) concentration. A population PK model estimated edoxaban exposure at steady state. Efficacy and safety outcomes included composites of stroke, transient ischemic attack, systemic embolism, and major and clinically relevant nonmajor bleeding. Of 607 patients, 303 and 304 were randomized to edoxaban 60 and 75 mg, respectively. Edoxaban 75 mg provided ≈25% higher exposure than 60 mg. This increase was accurately depicted in the population PK model; anti-factor Xa concentration correlated with edoxaban exposure. Rates of composite and individual outcomes were similarly low between doses. In conclusion, the 25% increase in edoxaban dose (60-75 mg) resulted in ≈25% exposure increase in the 75-mg group. Higher exposure was not associated with reduced stroke risk in patients with AF with high renal clearance.

Pregnancy care in solid organ transplant recipients.

Recipients of solid organ transplants who become pregnant represent an obstetrically high-risk population. Preconception planning and effective contraception tailored to the individual patient are critical in this group. Planned pregnancies improve both maternal and neonatal outcomes and provide a window of opportunity to mitigate risk and improve lifelong health. Optimal management of these pregnancies is not well defined. Common pregnancy complications after transplantation include hypertension, preterm birth, infection, and metabolic disease. Multidisciplinary preconception and prepartum management, and counseling decrease complications and benefit the maternal-neonatal dyad.

Mode of Obstetric Delivery in Kidney and Liver Transplant Recipients and Associated Maternal, Neonatal, and Graft Morbidity During 5 Decades of Clinical Practice.

Importance: Rates of cesarean delivery (CD) are increased among transplant recipients. There is a need to define the indications for CD and associated outcomes among transplant recipients to determine the safest mode of obstetric delivery. Objective: To evaluate the association of mode of obstetrical delivery with maternal and neonatal morbidity among pregnant women who have received a kidney or liver transplant. Design, Setting, and Participants: This registry-based retrospective cohort study used data from the Transplant Pregnancy Registry International, which has recruited participants since 1991 from 289 diverse academic and community settings, mainly in North America. Eligible participants were recipients of a kidney or liver transplant who were aged 18 years or older at the time of a live birth at or later than 20 weeks' gestational age and who delivered between 1968 and 2019. The data were analyzed from April 30, 2020, to April 16, 2021. Exposures: Scheduled CD, a trial of labor resulting in CD (TOL-CD), or a TOL resulting in vaginal delivery (TOL-VD). Main Outcomes and Measures: The primary outcomes were severe maternal morbidity and neonatal composite morbidity. Multivariate regression was conducted to calculate odds ratios (ORs) or ß values and 95% CIs with adjustment for differences in maternal comorbidities and gestational age at delivery. Nonmedical indications for CD are those not associated with decreased morbidity or mortality in the obstetric literature. Results: This study included 1865 women, of whom 1435 were kidney transplant recipients and 430 were liver transplant recipients. The age range of the participants was 18 to 48 years; the median body mass index among the participants was in the normal range, and the median transplant-to-conception interval was more than 2 years. Compared with a scheduled CD, a TOL was not associated with increased severe maternal morbidity among kidney transplant recipients (TOL-CD: adjusted odds ratio [aOR], 1.80 [95% CI, 0.77-4.22]; TOL-VD: aOR, 1.22 [95% CI, 0.57-2.62]) (for liver transplant recipients, the numbers were too small for multivariate modeling). In the adjusted model, a TOL was associated with a decrease in neonatal composite morbidity among kidney transplant recipients who underwent TOL-CD (aOR, 0.52; 95% CI, 0.32-0.82) and TOL-VD (aOR, 0.36; 95% CI, 0.24-0.53) and liver transplant recipients who underwent TOL-VD (aOR, 0.41; 95% CI, 0.19-0.87) but not for TOL-CD (aOR, 0.58; 95% CI, 0.21-1.61). The main factors associated with CD after labor were placental abruption (aOR, 12.96; 95% CI, 2.85-59.07) and pregestational diabetes (aOR 5.44; 95% CI, 2.54-11.68). The rate of CD was 51.6% (741 of 1435) among kidney transplant recipients and 41.4% (178 of 430) among liver transplant recipients. In total, 229 of 459 kidney transplant recipients (49.9%) and 50 of 105 liver transplant recipients (47.6%) had scheduled CDs performed for either a nonmedical indication or a repeated indication, although women with these indications are candidates for a TOL. Conclusions and Relevance: In this cohort study, TOL vs a scheduled CD was associated with improved neonatal outcomes among kidney and transplant recipients and not with increased severe maternal morbidity among kidney transplant recipients. These findings may be used to facilitate multidisciplinary decisions regarding the mode of obstetrical delivery.

Exposure-response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor.

This analysis was conducted to assess exposure-response relationships for efficacy and safety of pexidartinib in patients with tenosynovial giant cell tumor. Efficacy was assessed categorically by overall response rate (ORR) with Response Evaluation Criteria in Solid Tumors version 1.1 and longitudinally (changes in tumor size and volume). Safety included hepatic parameters (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin). Average pexidartinib concentration (Cavg ) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher Cavg coincided with greater ORR and tumor size reduction, respectively, with smaller joint size having a greater impact. For safety, a significant relationship was observed between Cavg and incidence of ALT-related and AST-related adverse events (AEs). With increased exposure, an increase in efficacy was predicted with near maximum effect at 800 mg/day. Higher initial dose (1000 mg/day) during the first 2 weeks did not improve efficacy. Higher doses were associated with an increased risk of ALT-related and AST-related AEs. These results support the US Food and Drug Administration-approved dose (400 mg two times/day without initial loading dose).

Circulating trophoblast cell clusters for early detection of placenta accreta spectrum disorders.

Placenta accreta spectrum (PAS) is a high-risk obstetrical condition associated with significant morbidity and mortality. Current clinical screening modalities for PAS are not always conclusive. Here, we report a nanostructure-embedded microchip that efficiently enriches both single and clustered circulating trophoblasts (cTBs) from maternal blood for detecting PAS. We discover a uniquely high prevalence of cTB-clusters in PAS and subsequently optimize the device to preserve the intactness of these clusters. Our feasibility study on the enumeration of cTBs and cTB-clusters from 168 pregnant women demonstrates excellent diagnostic performance for distinguishing PAS from non-PAS. A logistic regression model is constructed using a training cohort and then cross-validated and tested using an independent cohort. The combined cTB assay achieves an Area Under ROC Curve of 0.942 (throughout gestation) and 0.924 (early gestation) for distinguishing PAS from non-PAS. Our assay holds the potential to improve current diagnostic modalities for the early detection of PAS.

Exposure-Response Relationships in Patients With HER2-Positive Metastatic Breast Cancer and Other Solid Tumors Treated With Trastuzumab Deruxtecan.

Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer and for HER2-positive metastatic gastric cancer. The approval in breast cancer was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here, we present dose justification for the approved 5.4 mg/kg every-3-weeks (Q3W) dose based on exposure-efficacy evaluated in patients with HER2-positive breast cancer (N = 337) from these 2 trials. Exposure-safety was assessed in patients with all tumor types (N = 639, n = 512 with breast cancer) across 5 trials, including J101 and DESTINY-Breast01. T-DXd doses ranged from 0.8-8.0 mg/kg Q3W; most patients received 5.4 (n = 312) or 6.4 mg/kg (n = 291). For each end point, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T-DXd and released drug. A statistically significant association was observed between intact T-DXd area under the concentration-time curve (AUC) and confirmed objective response rate (ORR; P = 0.028). No significant exposure-response relationships were observed between intact T-DXd or released drug and duration of response or progression-free survival; however, follow-up was limited. All evaluated safety end points demonstrated a significant (P < 0.05) relationship with either intact T-DXd or released drug, with higher adverse event (AE) rates projected at higher exposures. Dose-response projections suggested an increase in ORR (67.5% vs. 62.9%) and toxicity (e.g., grade ≥ 3 all-cause treatment-emergent AEs: 61% vs. 54%) with T-DXd 6.4 vs. 5.4 mg/kg. Results demonstrate the benefit-risk profile at different doses and guide clinicians in the use of the 5.4-mg/kg Q3W dose in patients with HER2-positive metastatic breast cancer.

Differentiating Acute Rejection From Preeclampsia After Kidney Transplantation.

OBJECTIVE: To evaluate the clinical and laboratory characteristics in pregnancy that differentiate preeclampsia from acute renal allograft rejection and to investigate the maternal, neonatal, and graft sequelae of these diagnoses. METHODS: We conducted a retrospective case-controlled registry study of data abstracted from Transplant Pregnancy Registry International deliveries between 1968 and 2019. All adult kidney transplant recipients with singleton pregnancies of at least 20 weeks of gestation were included. Acute rejection was biopsy proven and preeclampsia was diagnosed based on contemporary criteria. Variables were compared using χ2, Fisher exact, and Wilcoxon rank sum tests as appropriate. Multivariable linear regression was used to analyze preterm birth. Kaplan-Meier curves with log-rank test and Cox proportional hazards model were used to compare graft loss over time. RESULTS: There were 26 pregnant women with biopsy-confirmed acute rejection who were matched by the year they conceived to 78 pregnant women with preeclampsia. Recipients with acute rejection had elevated peripartum serum creatinine levels (73% vs 14%, P<.001), with median intrapartum creatinine of 3.90 compared with 1.15 mg/dL (P<.001). Conversely, only patients with preeclampsia had a significant increase in proteinuria from baseline. Although there were no significant differences in maternal outcomes, graft loss within 2 years postpartum (42% vs 10%) and long-term graft loss (73% vs 35%) were significantly increased in recipients who experienced acute rejection (P<.001 for both). The frequency of delivery before 32 weeks of gestation was 53% with acute rejection and 20% with preeclampsia. After controlling for hypertension and immunosuppressant use, acute rejection was associated with higher frequency of delivery at less than 32 weeks of gestation (adjusted odds ratio 4.04, 95% CI 1.10-15.2). CONCLUSION: In pregnancy, acute rejection is associated with higher creatinine levels, and preeclampsia is associated with increased proteinuria. Acute rejection in pregnancy carries a risk of prematurity and graft loss beyond that of preeclampsia for kidney transplant recipients. FUNDING SOURCE: The Transplant Pregnancy Registry International is supported in part by an educational grant from Veloxis Pharmaceuticals.

Discordant congenital heart defects in monochorionic twins: Risk factors and proposed pathophysiology.

A six-fold increase in congenital heart defects (CHD) exists among monochorionic (MC) twins compared to singleton or dichorionic twin pregnancies. Though MC twins share an identical genotype, discordant phenotypes related to CHD and other malformations have been described, with reported rates of concordance for various congenital anomalies at less than 20%. Our objective was to characterize the frequency and spectrum of CHD in a contemporary cohort of MC twins, coupled with genetic and clinical variables to provide insight into risk factors and pathophysiology of discordant CHD in MC twins. Retrospective analysis of all twins receiving prenatal fetal echocardiography at a single institution from January 2010 -March 2020 (N = 163) yielded 23 MC twin pairs (46 neonates) with CHD (n = 5 concordant CHD, n = 18 discordant CHD). The most common lesions were septal defects (60% and 45.5% in concordant and discordant cohorts, respectively) and right heart lesions (40% and 18.2% in concordant and discordant cohorts, respectively). Diagnostic genetic testing was abnormal for 20% of the concordant and 5.6% of the discordant pairs, with no difference in rate of abnormal genetic results between the groups (p = 0.395). No significant association was found between clinical risk factors and development of discordant CHD (p>0.05). This data demonstrates the possibility of environmental and epigenetic influences versus genotypic factors in the development of discordant CHD in monochorionic twins.

Randomized, Double-Blind Comparison of Half-Dose Versus Full-Dose Edoxaban in 14,014 Patients With Atrial Fibrillation.

BACKGROUND: In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, the lower dose edoxaban regimen (LDER) and the higher dose edoxaban regimen (HDER) were noninferior to well-managed warfarin for stroke prevention in atrial fibrillation. OBJECTIVES: The objective of the present analysis of the ENGAGE AF TIMI-48 trial was to comprehensively compare the net clinical outcome (NCO) of LDER (30 mg once daily, dose reduced to 15 mg in selective patients) versus HDER (60 mg once daily, dose reduced to 30 mg in selective patients). METHODS: This study performed a pre-specified analysis of the ENGAGE AF-TIMI 48 trial, comparing patients on LDER versus HDER. RESULTS: The pre-defined primary NCO (stroke/systemic embolism [SEE], major bleeding, death) was less frequent with LDER (7.26% vs. 8.01%; hazard ratio: 0.90; 95% confidence interval: 0.84 to 0.98; p = 0.014). The secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) and tertiary pre-defined NCOs (stroke, SEE, life-threatening bleeding, or all-cause mortality) were similar between the 2 dosing regimens. Patients randomized to LDER versus HDER had a significantly higher risk of stroke/SEE (2.04% vs. 1.56%; hazard ratio: 1.31; 95% confidence interval: 1.12 to 1.52; p < 0.001). Conversely, major bleeding, intracranial hemorrhage, major gastrointestinal bleeding, and life-threatening bleeding occurred significantly less frequently with LDER compared with those of HDER. These findings were supported by multiple pharmacokinetic findings. CONCLUSIONS: In the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the 2 dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation. (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48]; NCT00781391).

Comparison of the Efficacy and Safety Outcomes of Edoxaban in 8040 Women Versus 13 065 Men With Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial.

BACKGROUND: Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men. METHODS: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis-defined major bleeding (safety). RESULTS: In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P<0.001). Treatment with edoxaban in women resulted in greater peak edoxaban concentration and inhibition of endogenous factor Xa in comparison with men, resulting in similar endogenous factor Xa activity between the sexes 2 to 4 hours after dose. Treatment with higher-dose edoxaban regimen (versus warfarin) resulted in similar reduction in the risk of stroke/systemic embolic events (women: hazard ratio [HR], 0.87 [0.69-1.11], men: HR, 0.87 [0.71-1.06]; P-interaction=0.97) and major bleeding (women: HR, 0.74 [0.59-0.92], men: HR, 0.84 [0.72-0.99]; P-interaction=0.34) in women and men. However, women assigned to higher-dose edoxaban regimen experienced greater reductions in hemorrhagic stroke (HR, 0.30 [95% CI, 0.15-0.59] versus HR, 0.70 [95% CI, 0.46-1.06]), intracranial bleeding (HR, 0.20 [95% CI, 0.10-0.39] versus HR, 0.63 [95% CI, 0.44-0.89]), and life-threatening or fatal bleeding (HR, 0.25 [95% CI, 0.15-0.42] versus HR, 0.72 [95% CI, 0.54-0.96]) than men (each P-interaction<0.05). CONCLUSIONS: Despite many differences in baseline characteristics between women and men and higher baseline endogenous factor Xa levels in women, the intensity of anticoagulation achieved with edoxaban between the sexes was similar. Treatment with higher-dose edoxaban regimen resulted in an even greater reduction in hemorrhagic stroke and several serious bleeding outcomes in women than in men, whereas the efficacy profile was similar between sexes.

Concentration-QTc analysis of quizartinib in patients with relapsed/refractory acute myeloid leukemia.

PURPOSE: This analysis evaluated the relationship between concentrations of quizartinib and its active metabolite AC886 and QT interval corrected using Fridericia's formula (QTcF) in patients with relapsed/refractory acute myeloid leukemia (AML) treated in the phase 3 QuANTUM-R study (NCT02039726). METHODS: The analysis dataset included 226 patients with AML. Quizartinib dihydrochloride was administered as daily doses of 20, 30, and 60 mg. Nonlinear mixed-effects modeling was performed using observed quizartinib and AC886 concentrations and time-matched mean electrocardiogram measurements. RESULTS: Observed QTcF increased with quizartinib and AC886 concentrations; the relationship was best described by a nonlinear maximum effect (Emax) model. The predicted mean increase in QTcF at the maximum concentration of quizartinib and AC886 associated with 60 mg/day was 21.1 ms (90% CI, 18.3-23.6 ms). Age, body weight, sex, race, baseline QTcF, QT-prolonging drug use, hypomagnesemia, and hypocalcemia were not significant predictors of QTcF. Hypokalemia (serum potassium < 3.5 mmol/L) was a statistically significant covariate affecting baseline QTcF, but no differences in ∆QTcF (change in QTcF from baseline) were predicted between patients with versus without hypokalemia at the same quizartinib concentration. The use of concomitant QT-prolonging drugs did not increase QTcF further. CONCLUSION: QTcF increase was dependent on quizartinib and AC886 concentrations, but patient factors, including sex and age, did not affect the concentration-QTcF relationship. Because concomitant strong cytochrome P450 3A (CYP3A) inhibitor use significantly increases quizartinib concentration, these results support the clinical recommendation of quizartinib dose reduction in patients concurrently receiving a strong CYP3A inhibitor. CLINICAL TRIAL REGISTRATION: NCT02039726 (registered January 20, 2014).