Different Time Points Of Pregnancy Research Articles

12328 Multimodal Imaging Reveals Changes In Beta Cell Metabolism And Heterogeneity Throughout Pregnancy

Abstract Disclosure: J.M. Cuala: None. T. Singh: None. C. Deng: None. K. Jayapalan: None. S. Dhawan: None. K. White: None. S. Georgia: None. During pregnancy, a unique, transient metabolic stressor, pancreatic islets adapt by balancing hormone production to maintain tight glucose homeostasis. Maternal insulin demand increases as systemic insulin resistance increases. To keep up with the increase in demand, beta cell functional dynamics change throughout pregnancy, including increasing insulin synthesis and lowering the threshold for glucose-stimulated insulin secretion (GSIS). Failure to adapt can lead to gestational diabetes (GD), a complication in 14% of pregnancies worldwide, feeding into a vicious cycle of impaired function and, eventually, hyperglycemia. Fundamentally, beta cell function is dictated by its metabolism, calcium signaling, and insulin content upon glucose stimulation. To better understand how beta cell maladaptation during pregnancy leads to gestational diabetes, we propose to apply a multidisciplinary approach to integrate novel tools to assess function and metabolism fluctuations throughout normal pregnancy. Using live isolated islets from wild-type C57BL/6 (BL6) and InsCre-gCAMP6f fl/fl (INS-gCAMP) mice, we will measure GSIS and take 4D images using metabolic fluorescence lifetime imaging (FLIM) and confocal microscopy to visualize and quantify metabolic and functional changes at different time points at cellular resolution. We expect functional and metabolic capacity levels to increase during the onset of beta cell remodeling (∼Day 8) and continue to peak throughout pregnancy. In contrast, changes in beta cell heterogeneity become more evident at the peaks of beta cell proliferation and expansion (∼Day 11-14). The proposed study will implement novel techniques to establish beta cell functional and metabolic information within a 3D pancreatic islet context throughout different time points of pregnancy. With this, we will provide greater insight into beta cell biology and its adaptation to metabolic stress to better understand the progression of gestational diabetes, which can then be applied to investigate other cellular adaptive dynamics that affect health and disease. Presentation: 6/2/2024

The associations of pre-pregnancy BMI and gestational weight gain with maternal gut microbiota.

Previous studies reporting the association between gut microbiota dysbiosis and maternal obesity were mostly confined at the phylum level or at postpartum period. This study aimed to investigate the dynamic changes in gut microbial communities associated with maternal obesity at different time points of pregnancy. We performed 16S rRNA gene V3-V4 amplicon sequencing on stool samples from 110 women in all three trimesters and 1-month postpartum. Maternal gut microbial communities associated with maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) were explored. The influence of maternal obesity on gut microbiota trajectories was determined based on longitudinal shifts in community clusters across the trimesters. The richness index of alpha diversity decreased with the progression of pregnancy, particularly in women with excessive GWG. The evenness index in 2nd trimester was found inversely associated with GWG. Various taxonomic differences in 1st trimester were associated with excessive GWG, whereas limited taxonomic differences in 2nd and 3rd trimesters were associated with pre-pregnancy BMI or GWG. Meanwhile, the gut microbiota trajectory with especially depleted genus Faecalibacterium in 1st trimester was associated with excessive GWG (adjusted odds ratio 5.7, 95% confidence interval 1.2-28.1). Moreover, the longitudinal abundances of genus Lachnospiraceae ND3007 group across gestations were depleted in women with overweight/obese pre-pregnancy BMI, while genus Bifidobacterium enriched in women with excessive GWG. Our study shows that dysbiosis of the gut microbiota in early pregnancy may have a significant impact on excess GWG. The abundance of the genus Faecalibacterium in 1st trimester may be a potential risk factor. Clinical trial number: NCT03785093 (https://classic.clinicaltrials.gov/ct2/show/NCT03785093).

Timing of magnetic resonance imaging in pregnancy for outcome prediction in congenital diaphragmatic hernia.

To evaluate the impact of the timing of MRI on the prediction of survival and morbidity in patients with CDH, and whether serial measurements have a beneficial value. This retrospective cohort study was conducted in two perinatal centers, in Germany and Italy. It included 354 patients with isolated CDH having at least one fetal MRI. The severity was assessed with the observed-to-expected total fetal lung volume (o/e TFLV) measured by two experienced double-blinded operators. The cohort was divided into three groups according to the gestational age (GA) at which the MRI was performed (< 27, 27-32, and > 32weeks' gestation [WG]). The accuracy for the prediction of survival at discharge and morbidity was analyzed with receiver operating characteristic (ROC) curves. Multiple logistic regression analyses and propensity score matching examined the population for balance. The effect of repeated MRI was evaluated in ninety-seven cases. There were no significant differences in the prediction of survival when the o/e TFLV was measured before 27, between 27 and 32, and after 32 WG (area under the curve [AUC]: 0.77, 0.79, and 0.77, respectively). After adjustment for confounding factors, it was seen, that GA at MRI was not associated with survival at discharge, but the risk of mortality was higher with an intrathoracic liver position (adjusted odds ratio [aOR]: 0.30, 95% confidence interval [95%CI] 0.12-0.78), lower GA at birth (aOR 1.48, 95%CI 1.24-1.78) and lower o/e TFLV (aOR 1.13, 95%CI 1.06-1.20). ROC curves showed comparable prediction accuracy for the different timepoints in pregnancy for pulmonary hypertension, the need of extracorporeal membrane oxygenation, and feeding aids. Serial measurements revealed no difference in change rate of the o/e TFLV according to survival. The timing of MRI does not affect the prediction of survival rate or morbidity as the o/e TFLV does not change during pregnancy. Clinicians could choose any gestational age starting mid second trimester for the assessment of severity and counseling.

Risk of birth defects in pregnant persons with sleep-disordered breathing during pregnancy.

As many as one in four pregnant women may experience sleep-disordered breathing (SDB) during pregnancy. The same sequelae of SDB, such as insulin resistance and inflammation, have been implicated in the development of certain birth defects. This is a secondary analysis of the SDB substudy of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be study, which included 2106 participants who had a sufficiency sleep study at two visits at different time points in pregnancy. SDB was based on a self-administered home sleep apnea test with data scored by trained, blinded research polysomnologists. SDB was defined as an apnea-hypopnea index (AHI) ≥5. The primary outcome of this analysis was any of the 45 non-chromosomal birth defects included in the National Birth Defects Prevention Network Annual Report. In this cohort, the overall rate of birth defects was 3.1%. The prevalence was similar between those without SDB (3.0%) and those with only mid-pregnancy SDB (3.4%), but was higher in those with early-pregnancy SDB (6.7%). After adjusting for maternal age, chronic hypertension, pregestational diabetes, and body mass index (BMI), there were no statistically significant differences in the risk of birth defects by subject SDB status. Further studies to evaluate the effect of prepregnancy and early-pregnancy SDB on the fetus, as well as the risk of specific birth defects and neonatal outcomes in those with an objectively measured diagnosis of SDB, are still needed.

Cord Blood FGF-21 and GDF-15 Levels Are Affected by Maternal Exposure to Moderate to Severe Anemia and Malaria.

Anemia and malaria are global health problems affecting >50% of pregnant women in sub-Saharan Africa and are associated with intrauterine growth restriction. The hormones fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) are involved in metabolic regulation and are expressed in the placenta. No studies exist on FGF-21 and GDF-15 responses to exposures of malaria and anemia in pregnancy. Using a prospective, longitudinal pregnancy and birth cohort of women with an average age of 26 years from a rural region in northeastern Tanzania, we examined if FGF-21 and GDF-15 levels in maternal blood at week 33 ± 2 (n = 301) and in cord blood at birth (n = 353), were associated with anemia and malaria exposure at different time points in pregnancy and with neonatal anthropometry. Among mothers at gestation week 33 ± 2, lower FGF-21 levels were observed after exposure to malaria in the first trimester, but not anemia, whereas GDF-15 levels at week 33 ± 2 were not associated with malaria nor anemia. In cord blood, moderate to severe anemia at any time point in pregnancy was associated with higher levels of FGF-21, whereas malaria exposure in the third trimester was associated with lower FGF-21 levels in cord blood. Negative associations were observed between cord blood FGF-21 and GDF-15 levels and neonatal skinfold thicknesses and birthweight. Our results suggest that moderate to severe anemia throughout pregnancy associates with higher FGF-21 levels, and malaria in last trimester associates with lower FGF-21 levels, in the neonates, thereby potentially affecting the future cardiometabolic health of the child.

Measurement of Health-Related Quality of Life from Conception to Postpartum Using the EQ-5D-5LAmong a National Sample of US Pregnant and Postpartum Adults.

During pregnancy, physiological changes occur from conception to birth. We assessed the health-related quality of life (HRQoL) throughout pregnancy and postpartum using the EQ-5D-5L. Between May and July 2021 (wave 1) and December 2021 and April 2022 (wave 2), we conducted a series of cross-sectional, national online surveys of 5250 pregnant and postpartum United States (US) adults. The survey included the EQ-5D-5L, EQ visual analog scale (EQ VAS), items measuring respondents' sociodemographic and health information, last menstrual period, estimated date of delivery, and date of pregnancy end (if postpartum). We examined monthly EQ-5D-5L items, utility values, and EQ VAS scores during pregnancy and postpartum. We used quantile regression adjusted for calendar month of last menstrual period to estimate changes in HRQoL at different time points of pregnancy and postpartum. There was a steady increase in the frequency of respondents reporting health-related problems and a decline in EQ-5D-5L utility values from early pregnancy until the ninth month of pregnancy (β = -0.21; standard error [SE] 0.02; P < 0.001), followed by a 0.10 (SE 0.02; P < 0.001) unit increase in values during the first postpartum month and a stabilization during the remainder of the postpartum period (β = 0.02; SE 0.02; P = 0.214). The median EQ-5D-5L utility value was lowest during the ninth month of pregnancy (median 0.78 [interquartile range 0.30]). HRQoL as measured by EQ-5D-5L varies across pregnancy, indicating progressive declines throughout pregnancy and a return to first trimester values during the first month postpartum. Studies involving HRQoL measurement in pregnant people should account for the stage of pregnancy in their estimates.

Longitudinal profile of sHLA-G during pregnancy and its association with small for gestational age births in North Indian pregnant females: A nested case-control study.

Small for gestational age (SGA) neonates are vulnerable to various long and short-term adverse health consequences. The expression of HLA-G in the placenta is crucial for establishment and maintenance of pregnancy. Its aberrant expression could lead to perturbed immunological interactions in the placenta which could be associated with SGA births. The objective of this study was to assess the difference in the trajectories of soluble HLA-G in maternal sera during pregnancy between women delivering SGA and appropriate for gestational age (AGA) neonates. Soluble HLA-G was estimated in the maternal sera collected at different time points in pregnancy of North-Indian pregnant females delivering SGA (N=23) or AGA (N=17) neonates using sandwich ELISA. Linear mixed models were built and compared to study the association between sHLA-G levels during pregnancy and SGA births. No significant difference was observed in the sHLA-G trajectories during pregnancy in mothers delivering SGA as compared to those delivering AGA (P-value=.5677). A trend towards higher sHLA-G levels at the first trimester of pregnancy (<14weeks of gestation) was observed in mothers delivering SGA neonates (Median=41.71, IQR=21.31-71.38) as compared to those delivering AGA neonates (Median=37.58, IQR=19.05-73.57). During pregnancy, sHLA-G trajectories do not differ significantly between mothers delivering SGA and those delivering AGA neonates. However, sHLA-G trends towards higher levels during early pregnancy in mothers delivering SGA neonates.

Mueller matrix imaging for collagen scoring in mice model of pregnancy

Preterm birth risk is associated with early softening of the uterine cervix in pregnancy due to the accelerated remodeling of collagen extracellular matrix. Studies of mice model of pregnancy were performed with an imaging Mueller polarimeter at different time points of pregnancy to find polarimetric parameters for collagen scoring. Mueller matrix images of the unstained sections of mice uterine cervices were taken at day 6 and day 18 of 19-days gestation period and at different spatial locations through the cervices. The logarithmic decomposition of the recorded Mueller matrices mapped the depolarization, linear retardance, and azimuth of the optical axis of cervical tissue. These images highlighted both the inner structure of cervix and the arrangement of cervical collagen fibers confirmed by the second harmonic generation microscopy. The statistical analysis and two-Gaussians fit of the distributions of linear retardance and linear depolarization in the entire images of cervical tissue (without manual selection of the specific regions of interest) quantified the randomization of collagen fibers alignment with gestation time. At day 18 the remodeling of cervical extracellular matrix of collagen was measurable at the external cervical os that is available for the direct optical observations in vivo. It supports the assumption that imaging Mueller polarimetry holds promise for the fast and accurate collagen scoring in pregnancy and the assessment of the preterm birth risk.

Use of Ballistocardiography to Monitor Cardiovascular Hemodynamics in Preeclampsia.

Objective: Pregnancy requires a complex physiological adaptation of the maternal cardiovascular system, which is disrupted in women with pregnancies complicated by preeclampsia, putting them at higher risk of future cardiovascular events. The measurement of body movements in response to cardiac ejection via ballistocardiogram (BCG) can be used to assess cardiovascular hemodynamics noninvasively in women with preeclampsia.Methods: Using a previously validated, modified weighing scale for assessment of cardiovascular hemodynamics through measurement of BCG and electrocardiogram (ECG) signals, we collected serial measurements throughout pregnancy and postpartum and analyzed data in 30 women with preeclampsia and 23 normotensive controls. Using BCG and ECG signals, we extracted measures of cardiac output, J-wave amplitude × heart rate (J-amp × HR). Mixed-effect models with repeated measures were used to compare J-amp × HRs between groups at different time points in pregnancy and postpartum.Results: In normotensive controls, the J-amp × HR was significantly lower early postpartum (E-PP) compared with the second trimester (T2; p = 0.016) and third trimester (T3; p = 0.001). Women with preeclampsia had a significantly lower J-amp × HR compared with normotensive controls during the first trimester (T1; p = 0.026). In the preeclampsia group, there was a trend toward an increase in J-amp × HR from T1 to T2 and then a drop in J-amp × HR at T3 and further drop at E-PP.Conclusions: We observe cardiac hemodynamic changes consistent with those reported using well-validated tools. In pregnancies complicated by preeclampsia, the maximal force of contraction is lower, suggesting lower cardiac output and a trend in hemodynamics consistent with the hyperdynamic disease model of preeclampsia.

Maternal Metabolome in Pregnancy and Childhood Asthma or Recurrent Wheeze in the Vitamin D Antenatal Asthma Reduction Trial.

The in utero environment during pregnancy has important implications for the developing health of the child. We aim to examine the potential impact of maternal metabolome at two different timepoints in pregnancy on offspring respiratory health in early life. In 685 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial, we assessed the prospective associations between maternal metabolites at both baseline (10–18 weeks gestation) and third trimester (32–38 weeks gestation) and the risk of child asthma or recurrent wheeze by age three using logistic regression models accounting for confounding factors. Subgroup analyses were performed by child sex. Among 632 metabolites, 19 (3.0%) and 62 (9.8%) from baseline and third trimester, respectively, were associated with the outcome (p-value < 0.05). Coffee-related metabolites in the maternal metabolome appeared to be of particular importance. Caffeine, theophylline, trigonelline, quinate, and 3-hydroxypyridine sulfate were inversely associated with asthma risk at a minimum of one timepoint. Additional observations also highlight the roles of steroid and sphingolipid metabolites. Overall, there was a stronger relationship between the metabolome in later pregnancy and offspring asthma risk. Our results suggest that alterations in prenatal metabolites may act as drivers of the development of offspring asthma.

International standards for fetal brain structures based on serial ultrasound measurements from Fetal Growth Longitudinal Study of INTERGROWTH-21st Project.

To create prescriptive growth standards for five fetal brain structures, measured using ultrasound, in healthy, well-nourished women at low risk of impaired fetal growth and poor perinatal outcome, taking part in the Fetal Growth Longitudinal Study (FGLS) of the INTERGROWTH-21st Project. This was a complementary analysis of a large, population-based, multicenter, longitudinal study. The sample analyzed was selected randomly from the overall FGLS population, ensuring an equal distribution among the eight diverse participating sites and of three-dimensional (3D) ultrasound volumes across pregnancy (range: 15-36 weeks' gestation). We measured, in planes reconstructed from 3D ultrasound volumes of the fetal head at different timepoints in pregnancy, the size of the parieto-occipital fissure (POF), Sylvian fissure (SF), anterior horn of the lateral ventricle, atrium of the posterior horn of the lateral ventricle (PV) and cisterna magna (CM). Fractional polynomials were used to construct the standards. Growth and development of the infants were assessed at 1 and 2 years of age to confirm their adequacy for constructing international standards. From the entire FGLS cohort of 4321 women, 451 (10.4%) were selected at random. After exclusions, 3D ultrasound volumes from 442 fetuses born without a congenital malformation were used to create the charts. The fetal brain structures of interest were identified in 90% of cases. All structures, except the PV, showed increasing size with gestational age, and the size of the POF, SF, PV and CM showed increasing variability. The 3rd , 5th , 50th , 95th and 97th smoothed centiles are presented. The 5th centiles for the POF and SF were 3.1 mm and 4.7 mm at 22 weeks' gestation and 4.6 mm and 9.9 mm at 32 weeks, respectively. The 95th centiles for the PV and CM were 8.5 mm and 7.5 mm at 22 weeks and 8.6 mm and 9.5 mm at 32 weeks, respectively. We have produced prescriptive size standards for fetal brain structures based on prospectively enrolled pregnancies at low risk of abnormal outcome. We recommend these as international standards for the assessment of measurements obtained using ultrasound from fetal brain structures. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Studying social media language changes associated with pregnancy status, trimester, and parity from medical records.

We sought to evaluate whether there was variability in language used on social media across different time points of pregnancy (before, during, and after pregnancy, as well as by trimester and parity). Consenting patients shared access to their individual Facebook posts and electronic medical records. Random forest models trained on Facebook posts could differentiate first trimester of pregnancy from 3 months before pregnancy (F1 score = .63) and from a random 3-month time period (F1 score = .64). Posts during pregnancy were more likely to include themes about family (β = .22), food craving (β = .14), and date/times (β = .13), while posts 3 months prior to pregnancy included themes about social life (β = .30), sleep (β = .31), and curse words (β = .27), and 3 months post-pregnancy included themes of gratitude (β = .17), health appointments (β = .21), and religiosity (β = .18). Users who were pregnant for the first time were more likely to post about lack of sleep (β = .15), activities of daily living (β = .09), and communication (β = .08) compared with those who were pregnant after having a child who posted about others’ birthdays (β = .16) and life events (.12). A better understanding about social media timelines can provide insight into lifestyle choices that are specific to pregnancy.

Normal range of complement components during pregnancy: A prospective study.

ProblemThe complement system plays a key role in normal placentation, and delicate regulation of complement system activation is critical for successful pregnancy. Therefore, establishing a normal range of complement components during pregnancy is important for clinical evaluation and research.MethodsWe performed a prospective study to investigate the normal range of complement components in circulation during different stages of pregnancy. Plasma concentrations of complement factor B (CFB), C1q, complement factor H (CFH), C3, C3c, and C4 were measured using an immunoturbidimetric assay; mannan‐binding lectin (MBL), C3a, C5a, and soluble C5b‐9 (sC5b‐9) levels at different time points of pregnancy were determined by enzyme‐linked immunosorbent assay (ELISA).ResultsA total of 733 plasma samples were collected from 362 women with a normal pregnancy and 65 samples from non‐pregnant women. In the first trimester of pregnancy, the levels of CFB, CFH, MBL, C3c, C4, and C3a were 414.5 ± 85.9 mg/L (95% CI for mean: 402.4‐426.6 mg/L), 381.0 ± 89.0 mg/L (95% CI for mean: 368.5‐393.6 mg/L), 4274.5 ± 2752 ng/mL (95% CI for mean: 3881.1‐4656.4 ng/mL), 1346.9 ± 419.8 mg/L (95% CI for mean: 1287.7‐1406.0 mg/L), 357.4 ± 101.8 mg/L (95% CI for mean: 343.0‐371.7 mg/L), and 182.5 ± 150.0 ng/mL (95% CI for mean: 186.9‐229.1 ng/mL), respectively. The levels of C3 and C4 increased gradually throughout pregnancy. The levels of C1q, C5a, and sC5b‐9 in the first and second trimesters were nearly the same as those in non‐pregnant women.ConclusionThe results of this study show that pregnancy itself may influence the plasma levels of complement system components.

Refining the prognosis of fetuses infected with Cytomegalovirus in the first trimester of pregnancy by serial prenatal assessment: a single-centre retrospective study.

To define the predictive value (PV) of known prognostic factors of fetal infection with Cytomegalovirus following maternal primary infection <14weeks of gestation, at different time points of pregnancy: the end of the second trimester; following prenatal magnetic resonance imaging (MRI) at 32weeks of gestation; and using all ultrasound scans performed in the third trimester (US3rdT). A retrospective study. Reference fetal medicine unit. Sixty-two fetuses infected <14weeks of gestation. We defined second-trimester assessment (STA) as the combination of ultrasound findings <28weeks of gestation and fetal platelet count at cordocentesis. Three groups were defined: normal, extracerebral, and cerebral STA. For each group, the PV of STA alone, STA+MRI, and STA+US3rdT were assessed retrospectively. Outcome at birth and at follow-up were reported. The STA was normal, and with extracerebral and cerebral features, in 43.5, 42.0, and 14.5%, respectively. The negative PV of normal STA and MRI for moderate to severe sequelae was 100%. The residual risk was unilateral hearing loss in 16.7% of cases. Of pregnancies with cerebral STA, 44% were terminated. Following extracerebral STA, 48% of neonates were symptomatic and 30% had moderate to severe sequelae. In those cases, the positive and negative PV of MRI for sequelae were 33 and 73%, respectively. STA+US3rdT had a lower negative PV than MRI for symptoms at birth and for moderate to severe sequelae. Any false-positive findings at MRI were mostly the result of hypersignals of white matter. Serial assessment in the second and third trimesters by ultrasound and MRI is necessary to predict the risk of sequelae occurring in 35% of pregnancies following fetal infection in the first trimester of pregnancy. Serial ultrasound prognostic assessment following fetal CMV infection in the 1st trimester is improved by MRI at 32weeks.

Maternal Serum Lipid, Estradiol, and Progesterone Levels in Pregnancy, and the Impact of Placental and Hepatic Pathologies.

Lipids and steroid hormones are closely linked. While cholesterol is the substrate for (placental) steroid hormone synthesis, steroid hormones regulate hepatic lipid production. The aim of this study was to quantify circulating steroid hormones and lipid metabolites, and to characterize their interactions in normal and pathological pregnancies with a focus on hepatic and placental pathologies. A total of 216 serum samples were analyzed. Group A consisted of 32 patients with uncomplicated pregnancies who were analyzed at three different time-points in pregnancy (from the first through the third trimester) and once post partum. Group B consisted of 36 patients (24th to 42nd week of gestation) with pregnancy pathologies (IUGR n = 10, preeclampsia n = 13, HELLP n = 6, intrahepatic cholestasis n = 7) and 31 controls with uncomplicated pregnancies. Steroid profiles including estradiol, progesterone, and dehydroepiandrosterone were measured by GC-MS and compared with lipid concentrations. In Group A, cholesterol and triglycerides correlated positively with estradiol (cholesterol ρ = 0.50, triglycerides ρ = 0.57) and progesterone (ρ = 0.49, ρ = 0.53) and negatively with dehydroepiandrosterone (ρ = - 0.47, ρ = - 0.38). Smoking during pregnancy affected estradiol concentrations, leading to lower levels in the third trimester compared to non-smoking patients (p < 0.05). In Group B, cholesterol levels were found to be lower in IUGR pregnancies and in patients with HELLP syndrome compared to controls (p < 0.05). Steroid hormone concentrations of estradiol (p < 0.05) and progesterone (p < 0.01) were lower in pregnancies with IUGR. Lipid and steroid levels were affected most in IUGR pregnancies, while only minor changes in concentrations were observed for other pregnancy-related disorders. Each of the analyzed entities displayed specific changes. However, since the changes were most obvious in pregnancies complicated by IUGR and only minor changes were observed in pregnancies where patients had impaired liver function, our data suggests that placental rather than maternal hepatic function strongly determines lipid and steroid levels in pregnancy.

Coexpression of TrkB and PD-L1 on human placenta

Objective: We performed comprehensive miRNA and gene expression profiling of maternal peripheral blood natural killer (pNK) cells during pregnancy. Methods: Samples of pNK cells at different time points of pregnancy (first, second, and third trimester of gestation, and postdelivery) were obtained from healthy pregnant females with their informed consent. We performed real-time PCR-based array analysis to examine the expression levels of 756 miRNAs in maternal pNK cells using TaqMan Array MicroRNA Cards. Moreover, we performed DNA microarray analysis of gene expression levels in firstand third-trimester pNK cells using Agilent Microarray Kits. Results: PCR-based array analysis showed transfer of placentaderivedmiRNAs [chromosome19miRNAcluster (C19MC)miRNAs] into maternal pNK cells occurred during pregnancy. Rapid clearance of C19MC miRNAs also occurred in pNK cells after delivery. DNA microarray analysis identified NK cell function-related genes (e.g., KIR genes) that were differentially expressed between firstand third-trimester pNK cells. Conclusions: Maternal pNK cells may adjust to different gestational conditions via the uptake of exogenousmiRNAs (e.g., C19MC miRNAs) during pregnancy.

Analysis of miRNA-mRNA expression profiles in maternal peripheral blood natural killer cells during pregnancy

Objective: We performed comprehensive miRNA and gene expression profiling of maternal peripheral blood natural killer (pNK) cells during pregnancy. Methods: Samples of pNK cells at different time points of pregnancy (first, second, and third trimester of gestation, and postdelivery) were obtained from healthy pregnant females with their informed consent. We performed real-time PCR-based array analysis to examine the expression levels of 756 miRNAs in maternal pNK cells using TaqMan Array MicroRNA Cards. Moreover, we performed DNA microarray analysis of gene expression levels in firstand third-trimester pNK cells using Agilent Microarray Kits. Results: PCR-based array analysis showed transfer of placentaderivedmiRNAs [chromosome19miRNAcluster (C19MC)miRNAs] into maternal pNK cells occurred during pregnancy. Rapid clearance of C19MC miRNAs also occurred in pNK cells after delivery. DNA microarray analysis identified NK cell function-related genes (e.g., KIR genes) that were differentially expressed between firstand third-trimester pNK cells. Conclusions: Maternal pNK cells may adjust to different gestational conditions via the uptake of exogenousmiRNAs (e.g., C19MC miRNAs) during pregnancy.

Systems biology evaluation of cell-free amniotic fluid transcriptome of term and preterm infants to detect fetal maturity.

BackgroundAmniotic fluid (AF) is a proximal fluid to the fetus containing higher amounts of cell-free fetal RNA/DNA than maternal serum, thereby making it a promising source for identifying novel biomarkers that predict fetal development and organ maturation. Our aim was to compare AF transcriptomic profiles at different time points in pregnancy to demonstrate unique genetic signatures that would serve as potential biomarkers indicative of fetal maturation.MethodsWe isolated AF RNA from 16 women at different time points in pregnancy: 4 from 18 to 24 weeks, 6 from 34 to 36 weeks, and 6 from 39 to 40 weeks. RNA-sequencing was performed on cell-free RNA. Gene expression and splicing analyses were performed in conjunction with cell-type and pathway predictions.ResultsSample-level analysis at different time points in pregnancy demonstrated a strong correlation with cell types found in the intrauterine environment and fetal respiratory, digestive and external barrier tissues of the fetus, using high-confidence cellular molecular markers. While some RNAs and splice variants were present throughout pregnancy, many transcripts were uniquely expressed at different time points in pregnancy and associated with distinct neonatal co-morbidities (respiratory distress and gavage feeding), indicating fetal immaturity.ConclusionThe AF transcriptome exhibits unique cell/organ-selective expression patterns at different time points in pregnancy that can potentially identify fetal organ maturity and predict neonatal morbidity. Developing novel biomarkers indicative of the maturation of multiple organ systems can improve upon our current methods of fetal maturity testing which focus solely on the lung, and will better inform obstetrical decisions regarding delivery timing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0138-5) contains supplementary material, which is available to authorized users.

Tim-4 Promotes Tolerance at the Fetomaternal Interface.

Objective: Acceptance of the fetus expressing allogeneic paternal antigens by the mother is a physiologic model of transplantation tolerance. The T-cell immunoglobulin domain and mucin domain (Tim) family members Tim-1, Tim-2, Tim-3, and Tim-4, are a group of newly described molecules with important immunological functions. Tim-4 has been shown to bind with phosphatidylserine (PtdSer) on apoptotic cells thereby facilitating their clearance, we explored if Tim-4 plays a role in maintaining tolerance at the fetomaternal interface (FMI). Study Design: An established fully allogeneic (CBAxB6) mating experimental setup was used. Pregnant mice were treated with a blocking anti-Tim-4 mAb or control Ig. Resorption of embryos at day 11.5 of pregnancy and litter size at term in treated versus control mice was determined. Placenta, uterus and draining LN were collected at different time points of pregnancy and macrophage, dendritic cells, myeloid derived suppressor cells (MDSCs) and T and B cell populations were characterized and compared between anti-Tim-4 and control groups. Results: Tim-4 is expressed on macrophages, myeloid derived suppressor cells (MDSCs) and on DCs at the uteroplacental interface. We examined whether treatment with anti-Tim-4 antibody would lead to an increase in apoptotic cells. Tim-4 blockade did not result in an increase in apoptosis of any of the immune cells. Further, Tim-4 expressing uterine macrophages and DCs isolated from pregnant anti-Tim-4 treated mice were not defective in phagocytosis of apoptotic cells. Alloreactive CD4, CD8 T cells and B cells were increased following anti-Tim-4 treatment with a decrease in B but not T regulatory cells. Collectively, this data suggest that Tim-4-PtdSer interaction is not a dominant contributor to tolerance at FMI and that Tim-4, via its interaction with a different receptor possibly Tim-1 leads to costimulation. Conclusion: Our data demonstrate that Tim-4 expressing immune cells play a critical in fetomaternal tolerance in vivo by affecting the pool of alloreactive T and B cells.

The placental expression of Human Leukocyte Antigen HLA-F and HLA-E in early normal placentation

The placental expression of Human Leukocyte Antigen HLA-F and HLA-E in early normal placentation