Urinary polycyclic aromatic hydrocarbon metabolites and their association with oxidative stress among pregnant women in Los Angeles.

Background: Polycyclic aromatic hydrocarbons (PAHs) have been linked to adverse birth outcomes, but few epidemiological studies to date have evaluated associations between urinary PAH metabolites and oxidative stress biomarkers in pregnancy. Methods: We measured a total of 7 PAH metabolites and 2 oxidative stress biomarkers (malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG)) in urine samples collected up to three times during pregnancy in 159 women enrolled at antenatal clinics at the University of California Los Angeles during 2016-2019. Using multiple linear regression models, we estimated the percentage change (%) and 95% confidence interval (CI) in 8-OHdG and MDA measured at each sample collection time per doubling of PAH metabolite concentrations. Results: Most PAH metabolites were positively associated with both urinary oxidative stress biomarkers, MDA and 8-OHdG, with stronger associations in early and late pregnancy. Women pregnant with male fetuses exhibited slightly larger increases in both MDA and 8-OHdG in association with PAH exposures in early and late pregnancy. Conclusion: Urinary OH-PAH biomarkers are associated with increases in oxidative stress during pregnancy, especially in early and late pregnancy. Sex differences in associations between PAH exposures and oxidative stress need to be further explored in the future.

Association Between Gestational Diabetes Mellitus and Hypertension: A Systematic Review and Meta-Analysis of Cohort Studies With a Quantitative Bias Analysis of Uncontrolled Confounding.

BACKGROUND: Whether individuals with gestational diabetes (GDM) had an increased risk of hypertension remains unclear. We conducted a systematic literature review and meta-analysis to examine the association between GDM and hypertension and performed a quantitative bias analysis to quantify the impact of uncontrolled confounding due to antenatal psychological stress. METHODS: We searched databases (PUBMED, EMBASE, and Web of Science) through 2022/11. Eligible studies were cohort studies that reported the association of GDM with hypertension. We assessed the risk of bias using the Newcastle-Ottawa Scale for cohort studies. We pooled adjusted risk ratios with 95% CIs using a random effects model. We performed the quantitative bias analysis using the bias formula. RESULTS: We included 15 cohort studies, with a total of 3 959 520 (GDM, 175 378; non-GDM, 3 784 142) individuals. During the follow-up of 2 to 20 years, 106 560 cases of hypertension were reported. We found that GDM was associated with a higher risk of hypertension (pooled risk ratio, 1.78 [95% CI, 1.47, 2.17]). The risk ratio was lower among cohorts assessing incident (1.58 [95% CI, 1.29, 1.95]) than prevalent hypertension (2.60 [95% CI, 2.40, 2.83]). However, other subgroup analyses showed no differences. The quantitative bias analysis revealed that if the uncontrolled confounder of antenatal psychological stress was additionally adjusted, the positive association between GDM and hypertension would attenuate slightly (≤18%) but remains positive. CONCLUSIONS: Limitations of this study included residual confounding and discrepancies in GDM and hypertension ascertainments. Our findings indicate that GDM is positively associated with hypertension after the index pregnancy.

Prevalence of maternal hyperglycemic subtypes by race/ethnicity and associations between these subtypes with adverse pregnancy outcomes: Findings from a large retrospective multi-ethnic cohort in the United States.

AIMS: With the two-step gestational diabetes mellitus (GDM) screening approach, hyperglycemic subtypes can be identified. We aimed to investigate racial/ethnic differences in the prevalence of hyperglycemic subtypes and to examine the associations between these subtypes and adverse pregnancy outcomes. METHODS: In this retrospective cohort, 11,405 pregnancies were screened using the two-step approach. Hyperglycemic subtypes included: pregnancy-impaired glucose intolerance-I (PIGT-I), PIGT-II, GDM-I (abnormal post-load glucose only), and GDM-II (abnormal fasting & post-load glucose). Modified Poisson regressions with robust error variance were used to estimate age-adjusted prevalence ratios (PR) of hyperglycemic subtypes and multivariable-adjusted risk ratios (RR) of adverse pregnancy outcomes. RESULTS: The prevalence of hyperglycemic subtypes was higher in Asians (PIGT-I: 1.51 [95% confidence interval 1.35-1.69]; PIGT-II: 2.18 [1.78-2.68]; GDM-I: 2.55 [2.10-3.10]; GDM-II: 1.55 [1.08-2.21]) and Hispanics (PIGT-I: 1.32 [1.16-1.50]; PIGT-II: 2.07 [1.67-2.57]; GDM-I: 1.69 [1.35-2.13]; GDM-II: 2.68 [1.93-3.71]) than non-Hispanic Whites (NHW). Despite low GDM prevalence, Japanese and Koreans had higher PIGT prevalence than NHW. PIGT-II was positively associated with hypertensive disorders of pregnancy (1.19 [1.02-1.38]), large-for-gestational age (1.73 [1.37-2.18]), and preterm birth (PB, 1.33 [1.05-1.68]). PIGT-I (1.23 [1.04-1.45]) and GDM-I (1.56 [0.87-1.71]) were positively related to PB. CONCLUSIONS: The prevalence of hyperglycemic subtypes varies by race/ethnicity and they have distinct health implications.

Alpha-1 antitrypsin deficiency and pregnancy complications and birth outcomes: A population-based cohort study in Denmark.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is related to developing lung and liver disease, but no large-scale studies examine its association with birth outcomes. OBJECTIVE: We investigated the risk of pregnancy complications and adverse birth outcomes in mothers and children with AATD. METHODS: Using a large cohort data of Danish mothers and children with AATD from 1973 to 2013 (n = 2,027,229), with 559 cases (305 mothers and 254 children). We conducted Poisson regression to examine associations between alpha-1 antitrypsin deficiency, adverse birth outcomes, and pregnancy complications in mothers and children. RESULTS: AATD was related to term low birth weight [<2500g; Risk Ratio(RR) = 2.04, 95% confidence interval (CI): 1.50-2.79], lowest quartile of abdominal circumference at birth in children of non-smoking mothers (RR = 1.55, 95% CI: 1.14-2.11), delivery via Cesarean-section (RR = 1.59, 95% CI: 1.05-2.40), preterm birth (RR = 1.54, 95% CI: 1.19-2.00) and preeclampsia (RR = 2.64, 95% CI: 1.76-3.94). CONCLUSIONS: This emphasizes the need for mothers with AATD to be monitored closely during pregnancy to reduce the risk of adverse birth outcomes. Routine screening for alpha-1 antitrypsin in pregnancy may be considered among mothers with a pulmonary and liver disease history.

Gestational diabetes mellitus and risk of neurodevelopmental disorders in young offspring: does the risk differ by race and ethnicity?

BACKGROUND: Previous studies examined the associations of gestational diabetes mellitus with autism spectrum disorder and attention deficit hyperactivity disorder. However, the associations between gestational diabetes mellitus and other neurodevelopmental disorders, such as the common speech/language disorder and developmental coordination disorder, are rarely studied, and whether the associations vary by race/ethnicity remains unknown. OBJECTIVE: This study aimed to examine the associations of gestational diabetes mellitus with individual neurodevelopmental disorders in young offspring, and to investigate whether the associations vary by race/ethnicity. STUDY DESIGN: This retrospective cohort study (Glucose in Relation to Women and Babies' Health [GrownB]) included 14,480 mother-offspring pairs in a large medical center in the United States from March 1, 2013 to August 31, 2021. We ascertained gestational diabetes mellitus using the validated ICD (International Classification of Diseases) codes (ICD-9: 648.8x; ICD-10: O24.4x), and identified neurodevelopmental disorders (speech/language disorder, developmental coordination disorder, autism spectrum disorder, and other neurodevelopmental disorders [attention deficit hyperactivity disorder, behavioral disorder, intellectual disability, and learning difficulty]) and their combinations using validated algorithms. We compared the hazard of neurodevelopmental disorders during the entire follow-up period between offspring born to mothers with and without gestational diabetes mellitus using multivariable Cox regression models. RESULTS: Among all mothers, 19.9% were Asian, 21.8% were Hispanic, 41.0% were non-Hispanic White, and 17.3% were of other/unknown race/ethnicity. During the median follow-up of 3.5 years (range, 1.0-6.3 years) after birth, 8.7% of offspring developed at least 1 neurodevelopmental disorder. Gestational diabetes mellitus was associated with a higher risk of speech/language disorder (adjusted hazard ratio, 1.59 [95% confidence interval, 1.07-2.35]), developmental coordination disorder (2.36 [1.37-4.04]), autism spectrum disorder (3.16 [1.36-7.37]), other neurodevelopmental disorders (3.12 [1.51-6.47]), any neurodevelopmental disorder (1.86 [1.36-2.53]), the combination of speech/language disorder and autism spectrum disorder (3.79 [1.35-10.61]), and the combination of speech/language disorder and developmental coordination disorder (4.22 [1.69-10.51]) among offspring born to non-Hispanic White mothers. No associations between gestational diabetes mellitus and any neurodevelopmental disorders or their combinations were observed among offspring born to mothers of other racial/ethnic groups. CONCLUSION: We observed an elevated risk of neurodevelopmental disorders among young offspring born to non-Hispanic White mothers with gestational diabetes mellitus, but not among other racial/ethnic groups.

Preeclampsia, antihypertensive medication use in pregnancy and risk of childhood cancer in offspring.

PURPOSE: Preeclampsia is a serious pregnancy complication that presents a significant risk to both the mother and the fetus. Preeclampsia and medications associated with its treatment are potentially linked to increased childhood cancer risk. Therefore, we examined the association between preeclampsia, antihypertensive medications, and childhood cancer in offspring. METHODS: Cases (n = 6,420) and controls (n = 160,484) were obtained from Danish national registries. We performed conditional logistic regression analyses to estimate the association between preeclampsia and childhood cancer risk, and examined the effects of antihypertensive medication use in pregnancy in relation to childhood cancer risk in the offspring with adjustment for relevant covariates. RESULTS: We observed an increased risk of acute lymphoblastic leukemia (ALL) among those whose mothers had preeclampsia (OR = 1.36, 95% CI 1.03, 1.79), especially for severe preeclampsia (OR = 2.36, 95% CI 1.37, 4.08). We also estimated an increased cancer risk in children born to mothers who were prescribed diuretics during pregnancy [OR = 2.09, 95% confidence interval (CI) 1.39, 3.14]. Intake of other antihypertensive medications was not associated with childhood cancer (OR = 0.78, 95% CI 0.50, 1.23). Among women who did not take diuretics in pregnancy, preeclampsia was associated with neuroblastoma (OR = 2.22, 95% CI 1.08, 4.55). CONCLUSION: Our findings suggested an increased risk for certain types of cancer in the offspring of mothers with preeclampsia and an increased risk of cancer with diuretic intake during pregnancy.

Maternal dietary patterns and placental outcomes among pregnant women in Los Angeles.

INTRODUCTION: Epidemiological studies have linked prenatal maternal diet to fetal growth, but whether diet affects placental outcomes is poorly understood. METHODS: We collected past month dietary intake from 148 women in mid-pregnancy enrolled at University of California Los Angeles (UCLA) antenatal clinics from 2016 to 2019. We employed the food frequency Diet History Questionnaire II and generated the Healthy Eating Index-2015 (HEI-2015), the Alternate Healthy Eating Index for Pregnancy (AHEI-P), and the Alternate Mediterranean Diet (aMED). We conducted T2-weighted magnetic resonance imaging (MRI) in mid-pregnancy (1st during 14-17 and 2nd during 19-24 gestational weeks) to evaluate placental volume (cm3) and we measured placenta weight (g) at delivery. We estimated change and 95 % confidence interval (CI) in placental volume and associations of placenta weight with all dietary index scores and diet items using linear regression models. RESULTS: Placental volume in mid-pregnancy was associated with an 18.9 cm3 (95 % CI 5.1, 32.8) increase per 100 gestational days in women with a higher HEI-2015 (≥median), with stronger results for placentas of male fetuses. We estimated positive associations between placental volume at the 1st and 2nd MRI and higher intake of vegetables, high-fat fish, dairy, and dietary intake of B vitamins. A higher aMED (≥median) score was associated with a 40.5 g (95 % CI 8.5, 72.5) increase in placenta weight at delivery, which was mainly related to protein intake. DISCUSSION: Placental growth represented by volume in mid-pregnancy and weight at birth is influenced by the quality and content of the maternal diet.

Early pregnancy imaging predicts ischemic placental disease.

INTRODUCTION: To characterize early-gestation changes in placental structure, perfusion, and oxygenation in the context of ischemic placental disease (IPD) as a composite outcome and in individual sub-groups. METHODS: In a single-center prospective cohort study, 199 women were recruited from antenatal clinics between February 2017 and February 2019. Maternal magnetic resonance imaging (MRI) studies of the placenta were temporally conducted at two timepoints: 14-16 weeks gestational age (GA) and 19-24 weeks GA. The pregnancy was monitored via four additional study visits, including at delivery. Placental volume, perfusion, and oxygenation were assessed at both MRI timepoints. The primary outcome was defined as pregnancy complicated by IPD, with group assignment confirmed after delivery. RESULTS: In early gestation, mothers with IPD who subsequently developed fetal growth restriction (FGR) and/or delivered small-for gestational age (SGA) infants showed significantly decreased MRI indices of placental volume, perfusion, and oxygenation compared to controls. The prediction of FGR or SGA by multiple logistic regression using placental volume, perfusion, and oxygenation revealed receiver operator characteristic curves with areas under the curve of 0.81 (Positive predictive value (PPV) = 0.84, negative predictive value (NPV) = 0.75) at 14-16 weeks GA and 0.66 (PPV = 0.78, NPV = 0.60) at 19-24 weeks GA. DISCUSSION: MRI indices showing decreased placental volume, perfusion and oxygenation in early pregnancy were associated with subsequent onset of IPD, with the greatest deviation evident in subjects with FGR and/or SGA. These early-gestation MRI changes may be predictive of the subsequent development of FGR and/or SGA.

Evaluation of Spatial Attentive Deep Learning for Automatic Placental Segmentation on Longitudinal MRI.

BACKGROUND: Automated segmentation of the placenta by MRI in early pregnancy may help predict normal and aberrant placenta function, which could improve the efficiency of placental assessment and the prediction of pregnancy outcomes. An automated segmentation method that works at one gestational age may not transfer effectively to other gestational ages. PURPOSE: To evaluate a spatial attentive deep learning method (SADL) for automated placental segmentation on longitudinal placental MRI scans. STUDY TYPE: Prospective, single-center. SUBJECTS: A total of 154 pregnant women who underwent MRI scans at both 14-18 weeks of gestation and at 19-24 weeks of gestation, divided into training (N = 108), validation (N = 15), and independent testing datasets (N = 31). FIELD STRENGTH/SEQUENCE: A 3 T, T2-weighted half Fourier single-shot turbo spin-echo (T2-HASTE) sequence. ASSESSMENT: The reference standard of placental segmentation was manual delineation on T2-HASTE by a third-year neonatology clinical fellow (B.L.) under the supervision of an experienced maternal-fetal medicine specialist (C.J. with 20 years of experience) and an MRI scientist (K.S. with 19 years of experience). STATISTICAL TESTS: The three-dimensional Dice similarity coefficient (DSC) was used to measure the automated segmentation performance compared to the manual placental segmentation. A paired t-test was used to compare the DSCs between SADL and U-Net methods. A Bland-Altman plot was used to analyze the agreement between manual and automated placental volume measurements. A P value < 0.05 was considered statistically significant. RESULTS: In the testing dataset, SADL achieved average DSCs of 0.83 ± 0.06 and 0.84 ± 0.05 in the first and second MRI, which were significantly higher than those achieved by U-Net (0.77 ± 0.08 and 0.76 ± 0.10, respectively). A total of 6 out of 62 MRI scans (9.6%) had volume measurement differences between the SADL-based automated and manual volume measurements that were out of 95% limits of agreement. DATA CONCLUSIONS: SADL can automatically detect and segment the placenta with high performance in MRI at two different gestational ages. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

PRENATAL MATERNAL CHARACTERISTICS ASSOCIATED WITH RETINOPATHY OF PREMATURITY.

PURPOSE: Determine whether prenatal maternal characteristics such as sociodemographic characteristics, comorbidities, or pregnancy complications affect retinopathy of prematurity (ROP) development. METHODS: Medical records of 236 mother-infant dyads from our institution were reviewed, only including dyads in which infants were born at 30 weeks gestational age or earlier. The primary outcome measure was the risk of ROP (defined Stage 1 or greater in either eye) and its association with prenatal maternal variables. RESULTS: Maternal Medicaid insurance, smoking during pregnancy, and chorioamnionitis were associated with an increased risk of ROP. For Medicaid insurance and chorioamnionitis, these risks were not appreciably altered by adjustment for potential confounders. CONCLUSION: These results suggest that several prenatal maternal factors may independently affect the risk of ROP in preterm infants. Validation of our findings could aid in the identification of infants at high risk for ROP based on prenatal clinical features.

Utility of In Vivo Magnetic Resonance Imaging Is Predictive of Gestational Diabetes Mellitus During Early Pregnancy.

CONTEXT: Gestational diabetes (GDM) imposes long-term adverse health effects on the mother and fetus. The role of magnetic resonance imaging (MRI) during early gestation in GDM has not been well-studied. OBJECTIVE: To investigate the role of quantitative MRI measurements of placental volume and perfusion, with distribution of maternal adiposity, during early gestation in GDM. METHODS: At UCLA outpatient antenatal obstetrics clinics, ∼200 pregnant women recruited in the first trimester were followed temporally through pregnancy until parturition. Two placental MRI scans were prospectively performed at 14 to 16 weeks and 19 to 24 weeks gestational age (GA). Placental volume and blood flow (PBF) were calculated from placental regions of interest; maternal adiposity distribution was assessed by subcutaneous fat area ratio (SFAR) and visceral fat area ratio (VFAR). Statistical comparisons were performed using the two-tailed t test. Predictive logistic regression modeling was evaluated by area under the curve (AUC). RESULTS: Of a total 186 subjects, 21 subjects (11.3%) developed GDM. VFAR was higher in GDM vs the control group, at both time points (P < 0.001 each). Placental volume was greater in GDM vs the control group at 19 to 24 weeks GA (P = 0.01). Combining VFAR, placental volume and perfusion, improved the AUC to 0.83 at 14 to 16 weeks (positive predictive value [PPV] = 0.77, negative predictive value [NPV] = 0.83), and 0.81 at 19 to 24 weeks GA (PPV = 0.73, NPV = 0.86). CONCLUSION: A combination of MRI-based placental volume, perfusion, and visceral adiposity during early pregnancy demonstrates significant changes in GDM and provides a proof of concept for predicting the subsequent development of GDM.

A Description of the Imaging Innovations for Placental Assessment in Response to Environmental Pollution Study.

OBJECTIVE: The aim of Placental Assessment in Response to Environmental Pollution Study (PARENTs) was to determine whether imaging of the placenta by novel multiparametric magnetic resonance imaging (MRI) techniques in early pregnancy could help predict adverse pregnancy outcomes (APOs) due to ischemic placental disease (IPD). Additionally, we sought to determine maternal characteristics and environmental risk factors that contribute to IPD and secondary APOs. STUDY DESIGN: Potential patients in their first trimester of pregnancy, who agreed to MRI of the placenta and measures of assessment of environmental pollution, were recruited into PARENTs, a prospective population-based cohort study. Participants were seen at three study visits during pregnancy and again at their delivery from 2015 to 2019. We collected data from interviews, chart abstractions, and imaging. Maternal biospecimens (serum, plasma, and urine) at antepartum study visits and delivery specimens (placenta, cord, and maternal blood) were collected, processed, and stored. The primary outcome was a composite of IPD, which included any of the following: placental abruption, hypertensive disease of pregnancy, fetal growth restriction, or a newborn of small for gestational age. RESULTS: In this pilot cohort, of the 190 patients who completed pregnancy to viable delivery, 50 (26%) developed IPD. Among demographic characteristics, having a history of prior IPD in multiparous women was associated with the development of IPD. In the multiple novel perfusion measurements taken of the in vivo placenta using MRI, decreased high placental blood flow (mL/100 g/min) in early pregnancy (between 14 and 16 weeks) was found to be significantly associated with the later development of IPD. CONCLUSION: Successful recruitment of the PARENTs prospective cohort demonstrated the feasibility and acceptability of the use of MRI in human pregnancy to study the placenta in vivo and at the same time collect environmental exposure data. Analysis is ongoing and we hope these methods will assist researchers in the design of prospective imaging studies of pregnancy. KEY POINTS: · MRI was acceptable and feasible for the study of the human placenta in vivo.. · Functional imaging of the placenta by MRI showed a significant decrease in high placental blood flow.. · Measures of environmental exposures are further being analyzed to predict IPD..

Circulating extracellular vesicles exhibit a differential miRNA profile in gestational diabetes mellitus pregnancies.

We undertook a prospective temporal study collecting blood samples from consenting pregnant women, to test the hypothesis that circulating extracellular vesicles (EVs) carrying specific non-coding microRNA signatures can underlie gestational diabetes mellitus (GDM). To test this hypothesis, miRNA cargo of isolated and characterized EVs revealed contributions from the placenta and differential expression at all three trimesters and at delivery between pregnant and non-pregnant states. Many miRNAs originate from the placental-specific chromosome 19 microRNA cluster (19MC) and chromosome 14 microRNA cluster (14MC). Further a positive correlation emerged between third trimester and at delivery EVs containing miRNAs and those expressed by the corresponding post-parturient placentas (R value = 0.63 to 0.69, p value = 2.2X10-16), in normal and GDM. In addition, distinct differences at all trimesters emerged between women who subsequently developed GDM. Analysis by logistic regression with leave-one-out-cross validation revealed the optimal combination of miRNAs using all the circulating miRNAs (miR-92a-3p, miR-192-5p, miR-451a, miR-122-5p), or using only the differentially expressed miRNAs (has-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-100-5p and hsa-miR-125a-3p) in GDM during the first trimester. As an initial step, both sets of miRNAs demonstrated a predictive probability with an area under the curve of 0.95 to 0.96. These miRNAs targeted genes involved in cell metabolism, proliferation and immune tolerance. In particular genes of the P-I-3-Kinase, FOXO, insulin signaling and glucogenic pathways were targeted, suggestive of placental connectivity with various maternal organs/cells, altering physiology along with pathogenic mechanisms underlying the subsequent development of GDM. We conclude that circulating EVs originating from the placenta with their miRNA cargo communicate and regulate signaling pathways in maternal organs, thereby predetermining development of GDM.

The systemic inflammatory landscape of COVID-19 in pregnancy: Extensive serum proteomic profiling of mother-infant dyads with in utero SARS-CoV-2.

While pregnancy increases the risk for severe COVID-19, the clinical and immunological implications of COVID-19 on maternal-fetal health remain unknown. Here, we present the clinical and immunological landscapes of 93 COVID-19 mothers and 45 of their SARS-CoV-2-exposed infants through comprehensive serum proteomics profiling for >1,400 cytokines of their peripheral and cord blood specimens. Prenatal SARS-CoV-2 infection triggers NF-κB-dependent proinflammatory immune activation. Pregnant women with severe COVID-19 show increased inflammation and unique IFN-λ antiviral signaling, with elevated levels of IFNL1 and IFNLR1. Furthermore, SARS-CoV-2 infection re-shapes maternal immunity at delivery, altering the expression of pregnancy complication-associated cytokines, inducing MMP7, MDK, and ESM1 and reducing BGN and CD209. Finally, COVID-19-exposed infants exhibit induction of T cell-associated cytokines (IL33, NFATC3, and CCL21), while some undergo IL-1ß/IL-18/CASP1 axis-driven neonatal respiratory distress despite birth at term. Our findings demonstrate COVID-19-induced immune rewiring in both mothers and neonates, warranting long-term clinical follow-up to mitigate potential health risks.

Carbon Monoxide Inhibits Cytochrome P450 Enzymes CYP3A4/2C8 in Human Breast Cancer Cells, Increasing Sensitivity to Paclitaxel.

Paclitaxel (PTX) is a first-line treatment in breast cancer, though resistance develops quickly and frequently. Cytochrome P450 enzymes CYP3A4 and CYP2C8, which metabolically inactivate PTX in hepatic tissue, are overexpressed in malignant breast tissues. CYP3A4 expression correlates with PTX therapy failure and poor outcomes, though no direct evidence of CYP3A4 contributing to PTX sensitivity exists. Because CYP3A4/2C8 is susceptible to carbon monoxide (CO)-mediated inhibition and CO (a gaseous signaling molecule) has previously exhibited drug-sensitizing effects in cancer cells, we hypothesized that CO-mediated inhibition of CYP3A4/2C8 could lead to enhanced drug sensitivity. Using a photo-activated CO-releasing molecule, we have assessed the ability of CO to alter the pharmacokinetics of PTX in breast cancer cells via inhibition of CYP3A4/2C8 and determined that CO does enhance sensitivity of breast cancer cells to PTX. Inhibition of CYP3A4/2C8 by CO could therefore be a promising therapeutic strategy to enhance PTX response in breast cancer.

Cell-free DNA Methylation and Transcriptomic Signature Prediction of Pregnancies with Adverse Outcomes.

Although analysis of maternal plasma cell-free content has been employed for screening of genetic abnormalities within a pregnancy, limited attention has been paid to its use for the detection of adverse pregnancy outcomes (APOs) based on placental function. Here we investigated cell-free DNA and RNA content of 102 maternal and 25 cord plasma samples. Employing a novel deconvolution methodology, we found that during the first trimester, placenta-specific DNA increased prior to the subsequent development of gestational diabetes with no change in patients with preeclampsia while decreasing with maternal obesity. Moreover, using cell-free RNA sequencing, APOs revealed 71 differentially expressed genes early in pregnancy. We noticed the upregulation of S100A8, MS4A3, and MMP8 that have been already associated with APOs but also the upregulation of BCL2L15 and the downregulation of ALPL that have never been associated with APOs. We constructed a classifier with a positive predictive ability (AUC) of 0.91 for APOs, 0.86 for preeclampsia alone and 0.64 for GDM. We conclude that placenta-specific cell-free nucleic acids during early gestation provide the possibility of predicting APOs prior to the emergence of characteristic clinical features.

Maternal Optical Coherence Tomography Angiography Changes Related to Small for Gestational Age Pregnancies.

Purpose: To study maternal retinal changes in pregnancies that resulted in a small for gestational age (SGA) infant. Methods: Pregnant women with SGA infants at birth and age-matched pregnant women with appropriate for gestational age (AGA) infants at birth (controls) were enrolled. All subjects underwent spectral domain optical coherent tomography angiography (OCTA) imaging using a 10° × 10° scan pattern centered on the fovea. Vessel density (VD) and vessel length density (VLD) of the superficial capillary plexus (SCP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP) were analyzed and compared between the two groups. Results: Twelve eyes of eight subjects with SGA infants and 64 eyes of 44 age-matched subjects with AGA infants were included in this study. There was no significant difference in chronic hypertension (P = 1.0), gestational hypertension (P = 1.0), type 1/2 diabetes (P = 1.0), gestational diabetes (P = 0.97), or preeclampsia (P = 0.50) between the SGA group and AGA group. There were significant increases in both VD and VLD in the SCP and ICP layers when comparing the SGA group with the AGA group (P < 0.05). Conclusions: In this pilot study, subjects with SGA infants had increases in selective retinal vasculature layers that may represent systemic perfusion changes compensating for placental insufficiency. Translational Relevance: Additional assessment of maternal retinal changes in pregnancy using OCTA could prove the technology useful as a biomarker of fetal morbidity.

Characterization of Uterine Motion in Early Gestation Using MRI-Based Motion Tracking.

Magnetic resonance imaging (MRI) is a promising non-invasive imaging technique that can be safely used to study placental development and function. However, studies of the human placenta performed by MRI are limited by uterine motion and motion in the uterus during MRI remains one of the major limiting factors. Here, we aimed to investigate the characterization of uterine activity during MRI in the second trimester of pregnancy using MRI-based motion tracking. In total, 46 pregnant women were scanned twice (first scan between 14 and 18 weeks and second scan between 19 and 24 weeks), and 20 pregnant subjects underwent a single MRI between 14 and 18 weeks GA, resulting in 112 MRI scans. An MRI-based algorithm was used to track uterine motion in the superior-inferior and left-right directions. Uterine contraction and maternal motion cases were separated by the experts, and unpaired Wilcoxon tests were performed within the groups of gestational age (GA), fetal sex, and placental location in terms of the overall intensity measures of the uterine activity. In total, 22.3% of cases had uterine contraction during MRI, which increased from 18.6% at 14-18 weeks to 26.4% at 19-24 weeks GA. The dominant direction of the uterine contraction and maternal motion was the superior to the inferior direction during early gestation.

Diminished viability of human ovarian cancer cells by antigen-specific delivery of carbon monoxide with a family of photoactivatable antibody-photoCORM conjugates.

Carbon monoxide (CO)-releasing antibody conjugates were synthesized utilizing a photoactivatable CO-releasing molecule (photoCORM) and mouse monoclonal antibodies linked by a biotin-streptavidin system. Different monoclonal antibodies raised against different surface-expressed antigens that are implicated in ovarian cancer afforded a family of antibody-photoCORM conjugates (Ab-photoCORMs). In an immunosorbent/cell viability assay, Ab-photoCORMs accumulated onto ovarian cancer cells expressing the target antigens, delivering cytotoxic doses of CO in vitro. The results described here provide the first example of an "immunoCORM", a proof-of-the-concept antibody-drug conjugate that delivers a gaseous molecule as a warhead to ovarian cancer.

Human Placenta Blood Flow During Early Gestation With Pseudocontinuous Arterial Spin Labeling MRI.

BACKGROUND: Noninvasive measurement of placental blood flow is the major technical challenge for predicting ischemic placenta (IPD). Pseudocontinuous arterial spin labeling (pCASL) MRI was recently shown to be promising, but the potential value in predicting the subsequence development of IPD is not known. PURPOSE: To derive global and regional placental blood flow parameters from longitudinal measurements of pCASL MRI and to assess the associations between perfusion-related parameters and IPD. STUDY TYPE: Prospective. POPULATION: Eighty-four women completed two pCASL MRI scans (first; 14-18 weeks and second; 19-24 weeks) from prospectively recruited 118 subjects. A total of 69 subjects were included for the analysis, of which 15 subjects developed IPD. FIELD STRENGTH/SEQUENCE: 3T/T2 -weighted half-Fourier single-shot turbo spin-echo (HASTE) and pCASL. ASSESSMENT: Four perfusion-related parameters in the placenta were derived: placenta volume, placental blood flow (PBF), high PBF (hPBF), and relative hPBF. The longitudinal changes of the parameters and their association with IPD were tested after being normalizing to the 16th and 20th weeks of gestation. STATISTICAL TESTS: Comparisons between two gestational ages within subjects were performed using the paired Wilcoxon tests, and comparisons between normal and IPD groups were performed using the unpaired Wilcoxon tests. RESULTS: The difference between the first and second MRI scans was statistically significant for volume (156.6 cm3 vs. 269.7 cm3 , P < 0.001) and PBF (104.9 ml/100g/min vs. 111.3 ml/100g/min, P = 0.02) for normal subjects, indicating an increase in pregnancy with advancing gestation. Of the parameters tested, the difference between the normal and IPD subjects was most pronounced in hPBF (278.1 ml/100g/min vs. 180.7 ml/100g/min, P < 0.001) and relative hPBF (259.1% vs. 183.2%, P < 0.001) at 16 weeks. DATA CONCLUSION: The high perfusion-related image parameters for IPD were significantly decreased from normal pregnancy at 14-18 weeks of gestation. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;51:1247-1257.