Sex- and age-based differences in fetal and early childhood hippocampus maturation: a cross-sectional and longitudinal analysis.

The hippocampus, essential for cognitive and affective processes, develops exponentially with differential trajectories seen in girls and boys, yet less is known about its development during early fetal life until early childhood. In a cross-sectional and longitudinal study, we examined the sex-, age-, and laterality-related developmental trajectories of hippocampal volumes in fetuses, infants, and toddlers associated with age. Third trimester fetuses (27-38 weeks' gestational age), newborns (0-4 weeks' postnatal age), infants (5-50 weeks' postnatal age), and toddlers (2-3 years postnatal age) were scanned with magnetic resonance imaging. A total of 133 datasets (62 female, postmenstrual age [weeks] M = 69.38, SD = 51.39, range = 27.6-195.3) were processed using semiautomatic segmentation methods. Hippocampal volumes increased exponentially during the third trimester and the first year of life, beginning to slow at approximately 2 years. Overall, boys had larger hippocampal volumes than girls. Lateralization differences were evident, with left hippocampal growth beginning to plateau sooner than the right. This period of rapid growth from the third trimester, continuing through the first year of life, may support the development of cognitive and affective function during this period.

Default mode network functional connectivity strength in utero and the association with fetal subcortical development.

The default mode network is essential for higher-order cognitive processes and is composed of an extensive network of functional and structural connections. Early in fetal life, the default mode network shows strong connectivity with other functional networks; however, the association with structural development is not well understood. In this study, resting-state functional magnetic resonance imaging and anatomical images were acquired in 30 pregnant women with singleton pregnancies. Participants completed 1 or 2 MR imaging sessions, on average 3 weeks apart (43 data sets), between 28- and 39-weeks postconceptional ages. Subcortical volumes were automatically segmented. Activation time courses from resting-state functional magnetic resonance imaging were extracted from the default mode network, medial temporal lobe network, and thalamocortical network. Generalized estimating equations were used to examine the association between functional connectivity strength between default mode network-medial temporal lobe, default mode network-thalamocortical network, and subcortical volumes, respectively. Increased functional connectivity strength in the default mode network-medial temporal lobe network was associated with smaller right hippocampal, left thalamic, and right caudate nucleus volumes, but larger volumes of the left caudate. Increased functional connectivity strength in the default mode network-thalamocortical network was associated with smaller left thalamic volumes. The strong associations seen among the default mode network functional connectivity networks and regionally specific subcortical volume development indicate the emergence of short-range connectivity in the third trimester.

Cost-effectiveness of noninvasive fetal RhD blood group genotyping in nonalloimmunized and alloimmunized pregnancies.

BACKGROUND: We sought to determine the cost-effectiveness of noninvasive fetal RhD blood group genotyping in nonalloimmunized and alloimmunized pregnancies in Canada. STUDY DESIGN AND METHODS: We developed two probabilistic state-transition (Markov) microsimulation models to compare fetal genotyping followed by targeted management versus usual care (i.e., universal Rh immunoglobulin [RhIG] prophylaxis in nonalloimmunized RhD-negative pregnancies, or universal intensive monitoring in alloimmunized pregnancies). The reference case considered a healthcare payer perspective and a 10-year time horizon. Sensitivity analysis examined assumptions related to test cost, paternal screening, subsequent pregnancies, other alloantibodies (e.g., K, Rh c/C/E), societal perspective, and lifetime horizon. RESULTS: Fetal genotyping in nonalloimmunized pregnancies (at per-sample test cost of C$247/US$311) was associated with a slightly higher probability of maternal alloimmunization (22 vs. 21 per 10,000) and a reduced number of RhIG injections (1.427 vs. 1.795) than usual care. It was more expensive (C$154/US$194, 95% Credible Interval [CrI]: C$139/US$175-C$169/US$213) and had little impact on QALYs (0.0007, 95%CrI: -0.01-0.01). These results were sensitive to the test cost (threshold achieved at C$88/US$111), and inclusion of paternal screening. Fetal genotyping in alloimmunized pregnancies (at test cost of C$328/US$413) was less expensive (-C$6280/US$7903, 95% CrI: -C$6325/US$7959 to -C$6229/US$7838) and more effective (0.19 QALYs, 95% CrI 0.17-0.20) than usual care. These cost savings remained robust in sensitivity analyses. DISCUSSION: Noninvasive fetal RhD genotyping saves resources and represents good value for the management of alloimmunized pregnancies. If the cost of genotyping is substantially decreased, the targeted intervention can become a viable option for nonalloimmunized pregnancies.

Quantification of 1.5 T T1 and T2* Relaxation Times of Fetal Tissues in Uncomplicated Pregnancies.

BACKGROUND: Despite its many advantages, experience with fetal magnetic resonance imaging (MRI) is limited, as is knowledge of how fetal tissue relaxation times change with gestational age (GA). Quantification of fetal tissue relaxation times as a function of GA provides insight into tissue changes during fetal development and facilitates comparison of images across time and subjects. This, therefore, can allow the determination of biophysical tissue parameters that may have clinical utility. PURPOSE: To demonstrate the feasibility of quantifying previously unknown T1 and T2* relaxation times of fetal tissues in uncomplicated pregnancies as a function of GA at 1.5 T. STUDY TYPE: Pilot. POPULATION: Nine women with singleton, uncomplicated pregnancies (28-38 weeks GA). FIELD STRENGTH/SEQUENCE: All participants underwent two iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL-IQ) acquisitions at different flip angles (6° and 20°) at 1.5 T. ASSESSMENT: Segmentations of the lungs, liver, spleen, kidneys, muscle, and adipose tissue (AT) were conducted using water-only images and proton density fat fraction maps. Driven equilibrium single pulse observation of T1 (DESPOT1 ) was used to quantify the mean water T1 of the lungs, intraabdominal organs, and muscle, and the mean water and lipid T1 of AT. IDEAL T2* maps were used to quantify the T2* values of the lungs, intraabdominal organs, and muscle. STATISTICAL TESTS: F-tests were performed to assess the T1 and T2* changes of each analyzed tissue as a function of GA. RESULTS: No tissue demonstrated a significant change in T1 as a function of GA (lungs [P = 0.89]; liver [P = 0.14]; spleen [P = 0.59]; kidneys [P = 0.97]; muscle [P = 0.22]; AT: water [P = 0.36] and lipid [P = 0.14]). Only the spleen and muscle T2* showed a significant decrease as a function of GA (lungs [P = 0.67); liver [P = 0.05]; spleen [P < 0.05]; kidneys [P = 0.70]; muscle [P < 0.05]). DATA CONCLUSION: These preliminary data suggest that the T1 of the investigated tissues is relatively stable over 28-38 weeks GA, while the T2* change in spleen and muscle decreases significantly in that period. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Congenital CMV infection presenting with massive intracerebral hemorrhage.

INTRODUCTION: Cytomegalovirus (CMV) is a common intrauterine infection and the developing nervous system is a frequent target, suffering a range of injuries from subclinical to catastrophic. CASE PRESENTATION: A 20-week gestational age fetus was found to have a large echogenic focus in one cerebral hemisphere. Congenital CMV infection was identified by amniocentesis and maternal serology. Postmortem examination of the brain revealed massive intracerebral hemorrhage as the correlate for the sonographic finding. The microscopic examination of the brain was also striking for extensive polymicrogyria, a high burden of CMV, and abundant angiocentric CMV pathology. DISCUSSION AND CONCLUSION: Catastrophic intracerebral hemorrhage has not been previously reported in association with congenital CMV infection. The present case expands the range of potential injuries to the developing brain in congenital CMV infection and raises the possibility of a direct vascular injury.

Noninvasive Fetal RhD Blood Group Genotyping: A Systematic Review of Economic Evaluations.

OBJECTIVE: Noninvasive fetal rhesus D (RhD) blood group genotyping may prevent unnecessary use of anti-D immunoglobulin (RhIG) in non-alloimmunized RhD-negative pregnancies and can guide management of alloimmunized pregnancies. We conducted a systematic review of the economic literature to determine the cost-effectiveness of this intervention over usual care. DATA SOURCES: Systematic literature searches of bibliographic databases (Ovid MEDLINE, Embase, and Cochrane) until February 26, 2019, and auto-alerts until October 30, 2020, and of grey literature sources were performed to retrieve all English-language studies. STUDY SELECTION: We included studies done in serologically confirmed non-alloimmunized or alloimmunized RhD-negative pregnancies, comparing costs and effectiveness of the intervention versus usual care. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data from the eligible studies and assessed their methodological quality (risk of bias) using the Quality of Health Economic Studies (QHES) and Drummond tools. We narratively synthesized findings. Our review included 8 economic studies that evaluated non-invasive fetal RhD genotyping followed by targeted RhIG prophylaxis in non-alloimmunized pregnancies. Five studies further considered a subsequent alloimmunized pregnancy. The cost-effectiveness of the intervention versus usual care (e.g., universal RhIG or prophylaxis conditional on results of paternal testing) for non-alloiummunized pregnancies was inconsistent. Two studies indicated greater benefits and lower costs for the intervention, and another 2 suggested a trade-off. In 4 studies, the intervention was less effective and costlier than alternatives. Three studies were determined to be of high quality by both tools. Two of these studies favoured the intervention, and one assessed benefits in quality-adjusted life-years. No study clearly examined the cost-effectiveness of repetitive use of fetal genotyping in multiple non-alloimmunized or alloimmunized pregnancies. The cost of genotyping was the most influential parameter. CONCLUSION: The cost-effectiveness of noninvasive fetal RhD genotyping for non-alloimmunized pregnancies varies between studies. Potential savings from targeted management of alloimmunized pregnancies requires further research.

Water-fat magnetic resonance imaging of adipose tissue compartments in the normal third trimester fetus.

BACKGROUND: Assessment of fetal adipose tissue gives information about the future metabolic health of an individual, with evidence that the development of this tissue has regional heterogeneity. OBJECTIVE: To assess differences in the proton density fat fraction (PDFF) between fetal adipose tissue compartments in the third trimester using water-fat magnetic resonance imaging (MRI). MATERIALS AND METHODS: Water-fat MRI was performed in a 1.5-T scanner. Fetal adipose tissue was segmented into cheeks, thorax, abdomen, upper arms, forearms, thighs and lower legs. PDFF and R2* values were measured in each compartment. RESULTS: Twenty-eight women with singleton pregnancies were imaged between 28 and 38 weeks of gestation. At 30 weeks' gestation (n=22), the PDFF was statistically different between the compartments (P<0.0001), with the highest PDFF in cheeks, followed by upper arms, thorax, thighs, forearms, lower legs and abdomen. There were no statistical differences in the rate of PDFF change with gestational age between the white adipose tissue compartments (P=0.97). Perirenal brown adipose tissue had a different PDFF and R2* compared to white adipose tissue, while the rate of R2* change did not significantly change with gestational age between white adipose tissue compartments (P=0.96). CONCLUSION: Fetal adipose tissue accumulates lipids at a similar rate in all white adipose tissue compartments. PDFF variances between the compartments suggest that accumulation begins at different gestational ages, starting with cheeks, followed by extremities, trunk and abdomen. Additionally, MRI was able to detect differences in the PDFF between fetal brown adipose tissue and white adipose tissue.

Fetal Response to a Maternal Internal Auditory Stimulus.

BACKGROUND: Functional MRI (fMRI) is a noninvasive method to investigate the neural correlates of brain development. Insight into the rapidly developing brain in utero is limited, and fetal fMRI can be used to gain a greater understanding of the developmental process. Fetal brain fMRI is typically limited to resting-state fMRI due to the difficulty to instruct or provide a stimulus to the fetus. Previous studies have employed auditory task fMRI with an external sound stimulus directly on the abdomen of the mother; however, this practice has since been deemed unsafe for the developing fetus. PURPOSE: To investigate a reliable and safe paradigm to study the development of fetal brain networks, we postulated that an internal task, such as the mother's singing, as the auditory stimulus would result in activation in the fetal primary auditory cortex. STUDY TYPE: Cohort. POPULATION: Pregnant women with singleton pregnancies (n = 9; 33-38 weeks gestational age). FIELD STRENGTH/SEQUENCE: All subjects underwent two task-based block design blood oxygen level-dependent (BOLD) at 1.5T or 3T. ASSESSMENT: Each volume was assessed for fetal motion and manually reoriented and realigned to correct for fetal motion. Once the motion was corrected, a gestational age-matched parcellated atlas with regions of interest overlaid onto the activation map was used to determine which regions in the brain had activation during task phases. STATISTICAL TESTS: First Level Analysis. MRI data were analyzed using SPM 12 as a task fMRI. RESULTS: Eight subjects had activation on the right Heschl's gyrus; six fetuses demonstrated activation on the left when exposed to the internal acoustic stimulus. Additionally, activation was found on the right and left middle cingulate cortex (MCC) and the left putamen. DATA CONCLUSION: Maternal singing can be used as an internal stimulus to activate the auditory network and Heschl's gyrus during fetal fMRI. Level of Evidence 2 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2020;52:139-145.

Are pre-pregnancy weight fluctuations and adherence to prenatal nutrition and exercise recommendations related to excessive gestational weight gain?

Women who have an overweight or obese pre-pregnancy body mass index (BMI) may be recommended to lose weight before pregnancy, however the association of preconception weight fluctuations and prenatal adherence to nutrition and exercise recommendations with gestational weight gain (GWG) have not been assessed. One hundred women with a pre-pregnancy BMI ≥ 25.0 kg/m2 who participated in the Nutrition and Exercise Lifestyle Intervention Program (NELIP) were included and stratified as gained weight excessively (n = 47) or not (n = 53) using the 2009 Institute of Medicine GWG guidelines. Participants completed a Weight Health History Questionnaire providing information about weight loss prior to the index pregnancy. Adherence was scored based on meeting six nutrition and exercise goals for the NELIP (/6). More women who gained excessively reported that they had actively tried to lose weight a year before the current pregnancy (61%) than women who did not gain excessively (39%; p = 0.02). Of the women attempting preconception weight loss, those who gained excessively lost more weight (6.7 ± 10.2 kg) than women who did not (2.1 ± 3.8 kg; p = 0.003). Adherence to the NELIP was lower among women who gained excessively (3.3 ± 0.8; 55%) than those who did not (4.4 ± 0.9;73%; p < 0.001). Program adherence (p < 0.001) was related to excessive GWG.

Sequential Introduction of Exercise First Followed by Nutrition Improves Program Adherence During Pregnancy: a Randomized Controlled Trial.

BACKGROUND: Adhering to nutrition and exercise recommendations simultaneously during pregnancy may be challenging. The purpose was to examine adherence to the sequential introduction of nutrition and exercise behaviors during pregnancy in comparison with a simultaneous approach. METHOD: A randomized controlled trial including nutrition and exercise was executed. Using a stratified body mass index (BMI) randomization, participants (n = 88) were allocated to one of three groups at 12-18 weeks gestation. Group A received nutrition and exercise simultaneously. Group B received nutrition first and Group C received exercise first, and the second behavior was added at 25 weeks gestation for both groups. The program included weekly weighing, supervised walking sessions, and/or nutrition counseling. Adherence (primary outcome) was measured by scoring women on meeting the intervention goals (3 nutrition and 3 exercise goals) and converted to a percentage. Secondary health outcomes were gestational weight gain (GWG) and excessive GWG on the program, birthweight, macrosomia (birthweight > 4000 g), and low birthweight (birthweight < 2500 g). RESULTS: Group C (n = 23) had the highest adherence to the program (80.2 ± 14.7%) compared with Groups A (n = 17; 60.9 ± 17.9%) and B (n = 20; 66.8 ± 16.7%; p < 0.05, ηp2 = 0.26). There was a significant effect for gestational weight gain (p < 0.05; ηp2 = 0.10) as Group C gained less weight (7.7 ± 2.2 kg) over Group B (9.8 ± 2.8 kg; p = 0.04), however, not Group A (9.1 ± 3.5, p = 0.35). Non-significant small effects favored Group C for the prevention of EGWG (Cramer's V = 0.13). CONCLUSION: Introducing exercise first followed by nutrition at 25 weeks gestation can improve adherence to multiple behavior change programs and thus have a positive effect on health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02804061.

Labour Progression in Obese Women: Are Women With Increased Body Mass Index Having Unnecessary Cesarean Sections?

OBJECTIVE: This study sought to determine whether obese pregnant women undergo cesarean sections without an adequate trial of labour. This may affect future birth and pregnancy outcomes. METHODS: A retrospective analysis was done on 526 parturients at Victoria Hospital in London, Ontario. Women were categorized according to parity and pre-pregnancy body mass index (BMI; normal weight, BMI 18.5-24.9 kg/m2; obese class II, BMI 35.0-39.9 kg/m2; obese class III, BMI ≥40 kg/m2). Patient charts and partograms were reviewed for labour progression (time at cervical dilation), demographics, and infant outcomes (Canadian Task Force Classification II-2). RESULTS: Obese class II and III primiparous women required an additional 1.62 and 2.67 hours (P = 0.012), respectively, to reach a dilation of 10 cm compared with their normal weight counterparts; obese class II and III multiparous women required an additional 1.25 and 2.05 hours (P = 0.003), respectively. A higher BMI was associated with increased oxytocin use and infant birth weight in primiparous women. Obese women had less gestational weight gain and required more cervical examinations. Cesarean section rates were low for obese parturients (primiparous, 19%; multiparous, 0.8%) and not significantly different among BMI categories. CONCLUSION: This study confirmed published results that labour progresses more slowly as maternal BMI increases. The study was performed in a centre with a specialized BMI pregnancy clinic; thus weight gain adherence, awareness of labour differences, and patient counselling may have contributed to low cesarean section rates. Obstetric care providers should consider differences in maternal BMI in labour progression before undertaking a potentially premature cesarean birth, especially in primiparous women.

Maternal obesity reduces placental autophagy marker expression in uncomplicated pregnancies.

AIM: Obesity has been associated with changes in autophagy and its increasing prevalence among pregnant women is implicated in higher rates of placental-mediated complications of pregnancy such as pre-eclampsia and intrauterine growth restriction. Autophagy is involved in normal placentation, thus changes in autophagy may lead to impaired placental function and development. The aim of this study was to investigate the connection between obesity and autophagy in the placenta in otherwise uncomplicated pregnancies. METHODS: Immunohistochemistry and western blot analysis were done on placental and omental samples from obese (body mass index [BMI] ≥30 kg/m2 ) and normal weight (BMI <25 kg/m2 ) pregnant women with singleton pregnancies undergoing planned Caesarean delivery without labor at term. Samples were analyzed for autophagic markers LC3B and p62 in the peripheral, middle and central regions of the placenta and in omental adipocytes, milky spots and vasculature. RESULTS: As pre-pregnancy BMI increased, there was an increase in both placental and fetal weight as well as decreased levels of LC3B in the central region of the placenta (P = 0.0046). Within the obese patient group, LC3B levels were significantly decreased in the placentas of male fetuses compared to females (P < 0.0001). Adipocytes, compared to milky spots and vasculature, had lower levels of p62 (P = 0.0127) and LC3B (P = 0.003) in obese omenta and lower levels of LC3B in control omenta (P = 0.0071). CONCLUSION: Obesity leads to reduced placental autophagy in uncomplicated pregnancies; thus, changes in autophagy may be involved in the underlying mechanisms of obesity-related placental diseases of pregnancy.

Comparison of modified two-point dixon and chemical shift encoded MRI water-fat separation methods for fetal fat quantification.

BACKGROUND: Fetal fat is indicative of the energy balance within the fetus, which may be disrupted in pregnancy complications such as fetal growth restriction, macrosomia, and gestational diabetes. Water-fat separated MRI is a technique sensitive to tissue lipid content, measured as fat fraction (FF), and can be used to accurately measure fat volumes. Modified two-point Dixon and chemical shift encoded MRI (CSE-MRI) are water-fat separated MRI techniques that could be applied to imaging of fetal fat. Modified two-point Dixon has biases present that are corrected in CSE-MRI which may contribute to differences in the fat measurements. PURPOSE: To compare the measurement of fetal fat volume and FF by modified two-point Dixon and CSE-MRI. STUDY TYPE: Cross-sectional study for comparison of two MRI pulse sequences. POPULATION: Twenty-one pregnant women with singleton pregnancies. FIELD STRENGTH/SEQUENCE: 1.5T, modified two-point Dixon and CSE-MRI. ASSESSMENT: Manual segmentation of total fetal fat volume and mean FF from modified 2-point Dixon and CSE-MRI FF images. STATISTICAL TESTS: Reliability was assessed by calculating the intraclass correlation coefficient (ICC). Agreement was assessed using a one-sample t-test on the fat measurements difference values (modified two-point Dixon - CSE-MRI). The difference scores were tested against a value of 0, which would indicate that the measurements were identical. RESULTS: The fat volume and FF measured by modified two-point Dixon and CSE-MRI had excellent reliability, demonstrated by ICCs of 0.93 (P < 0.001) and 0.90 (P < 0.001), respectively. They were not in agreement, with CSE-MRI giving mean fat volumes 180 mL greater and mean FF 3.0% smaller than modified two-point Dixon. DATA CONCLUSION: The reliability between modified two-point Dixon and CSE-MRI indicates that either technique can be used to compare fetal fat measurements in different participants, but they are not in agreement possibly due to uncorrected biases in modified two-point Dixon. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.

SOCIOECONOMIC STATUS AND ADVERSE BIRTH OUTCOMES: A POPULATION-BASED CANADIAN SAMPLE.

This study assessed the strength of the association between socioeconomic status (SES) and low birth weight (LBW) and preterm birth (PTB) in Southwestern Ontario. Utilizing perinatal and neonatal databases at the London Health Science Centre, maternal postal codes were entered into a Geographic Information System to determine home neighbourhoods. Neighbourhoods were defined by dissemination areas (DAs). Median household income for each DA was extracted from the latest Canadian Census and linked to each mother. All singleton infants born between February 2009 and February 2014 were included. Of 26,654 live singleton births, 6.4% were LBW and 9.7% were PTB. Top risk factors for LBW were: maternal amphetamine use, chronic hypertension and maternal marijuana use (OR respectively: 17.51, 3.18, 2.72); previously diagnosed diabetes, maternal narcotic use and insulin-controlled gestational diabetes predicted PTB (OR respectively: 17.95, 2.69, 2.42). Overall, SES had little impact on adverse birth outcomes, although low maternal education increased the likelihood of a LBW neonate (OR: 1.01).

Clinical Research With Pregnant Women: Perspectives of Pregnant Women, Health Care Providers, and Researchers.

Limited clinical research with pregnant women has resulted in insufficient data to promote evidence-informed prenatal care. Charmaz's constructivist grounded theory methodology was used to explore how research with pregnant women would be determined ethically acceptable from the perspectives of pregnant women, health care providers, and researchers in reproductive sciences. Semistructured interviews were conducted with a purposive sample of 12 pregnant women, 10 health care providers, and nine reproductive science researchers. All three groups suggested the importance of informed consent and that permissible risk would be very limited and complex, being dependent on the personal benefits and risks of each particular study. Pregnant women, clinicians, and researchers shared concerns about the well-being of the woman and her fetus, and expressed a dilemma between promoting research for evidence-informed prenatal care while securing the safety in the course of research participation.

Hyperpolarized [1-(13) C]pyruvate MRI for noninvasive examination of placental metabolism and nutrient transport: A feasibility study in pregnant guinea pigs.

PURPOSE: To test the feasibility of hyperpolarized [1-(13) C]pyruvate magnetic resonance imaging (MRI) for noninvasive examination of guinea pig fetoplacental metabolism and nutrient transport. MATERIALS AND METHODS: Seven pregnant guinea pigs with a total of 30 placentae and fetuses were anesthetized and scanned at 3T. T1 -weighted (1) H images were obtained from the maternal abdomen. An 80 mM solution of hyperpolarized [1-(13) C]pyruvate (hereafter referred to as pyruvate) was injected into a vein in the maternal foot. Time-resolved 3D (13) C images were acquired starting 10 seconds after the beginning of bolus injection and every 10 seconds after to 50 seconds. The pregnant guinea pigs were recovered after imaging. Regions of interest (ROIs) were drawn around the maternal heart and each placenta and fetal liver in all slices in the (1) H images. These ROIs were copied to the (13) C images and were used to calculate the sum of the pyruvate and lactate signal intensities for each organ. The signal intensities were normalized by the volume of the organ and the maximum signal in the maternal heart. RESULTS: No adverse events were observed in the pregnant guinea pigs and natural pupping occurred at term (∼68 days). Pyruvate signal was observed in all 30 placentae, and lactate, a by-product of pyruvate metabolism, was also observed in all placentae. The maximum pyruvate and lactate signals in placentae occurred at 20 seconds. In addition to the observation of pyruvate and lactate signals in the placentae, both pyruvate and lactate signals were observed in all fetal livers. The maximum pyruvate and lactate signals in the fetal livers occurred at 10 seconds and 20 seconds, respectively. CONCLUSION: This work demonstrates the feasibility of using hyperpolarized [1-(13) C]pyruvate MRI to noninvasively examine fetoplacental metabolism and transport of pyruvate in guinea pigs. Hyperpolarized (13) C MRI may provide a novel method for longitudinal studies of fetoplacental abnormalities.

Decorin over-expression by decidual cells in preeclampsia: a potential blood biomarker.

BACKGROUND: Decorin, a leucine-rich proteoglycan that is produced by decidual cells, limits invasion and endovascular differentiation of extravillous trophoblast cells during early placentation by binding to multiple tyrosine kinase receptors, in particular, vascular endothelial growth factor receptor-2. OBJECTIVE: Because many studies have reported an association between poor trophoblast invasion and endovascular differentiation with preeclampsia, the studies reported here tested (1) whether decorin over-expression in the chorionic villi and/or basal decidua is associated with preeclampsia and, if so, (2) whether this association results in a hypoinvasive placenta, and (3) whether elevated plasma decorin concentration in the second trimester is a predictive biomarker for preeclampsia. STUDY DESIGN: Decorin messenger RNA expression was measured with quantitative polymerase chain reaction at the tissue level and with in situ hybridization at the cellular level using (35)S-labeled antisense complimentary RNA probe in placentas from healthy control subjects and subjects with preeclampsia (14 each, 23-40 weeks of gestation). Tissue sections of the same placentas were also immunostained for decorin protein. A decorin over-expressing human endometrial stromal cell line was tested for invasion-regulatory effects on an invasive first-trimester extravillous trophoblast cell line HTR-8/SVneo plated in cocultures that were separated by a semipermeable membrane. Furthermore, we conducted retrospective measurements of plasma decorin levels during the second trimester (15-18 weeks of gestation) in a cohort of 28 body mass index-matched pairs of control subjects and subjects with preeclampsia before the onset of clinical disease. RESULTS: First, decorin messenger RNA expression at the cellular level measured with in situ hybridization exhibited profoundly higher expression levels in basal plate decidual cells within the placentas from preeclamptic subjects than those from control subjects at all gestational ages, whereas no difference between the 2 subject groups was noted in villus mesenchymal cells. Similarly decorin messenger RNA expression at the tissue level in chorionic villi (primarily resulting from fetally derived mesenchymal cells) did not differ significantly between control and preeclampsia placentas. These findings were validated with immunostaining for decorin protein. Second, knocking down decorin gene in a decorin over-expressing endometrial cell line (used as an in vitro surrogate of decorin over-expressing decidual cells) in cocultures with extravillous trophoblast cells abrogated its invasion-restraining actions on trophoblast cells, which indicated paracrine contribution of decorin over-expressing decidua to the poor trophoblast invasiveness in situ. Finally, retrospective measurement of plasma decorin levels during the second trimester in 28 body mass index-matched pairs of control subjects and subjects with preeclampsia revealed elevated plasma decorin levels in all subjects with preeclampsia in all body mass index groups. A receiver operating characteristic curve analysis revealed strong diagnostic performance of plasma decorin in the prediction of preeclampsia status. Although there was no significant gestational age-related change in decorin levels during the second trimester in control or subjects with preeclampsia, we found that plasma decorin had a significant inverse relationship with body mass index or bodyweight. CONCLUSION: We conclude that decorin over-expression by basal decidual cells is associated with hypoinvasive phenotype and poor endovascular differentiation of trophoblast cells in preeclampsia and that elevated plasma decorin concentration is a potential predictive biomarker for preeclampsia before the onset of clinical signs.

Implications of Applying Minimal Risk Standards in Clinical Research to Information Provision in Prenatal and Pre-conception Care.

BACKGROUND: There have long been minimal risk thresholds beneath which risks may not need to be discussed in clinical research. This threshold concept may be applied to clinical practice. Our research explored application of minimal risk standards in research regulations to providing information in prenatal and pre-conception care. METHODS: A case study approach applied minimal risk standards in research regulations to prenatal and pre-conception care with respect to the risks of excess alcohol consumption, folic acid insufficiency, exposure to phthalate plasticizers, and exposure to brominated flame retardants (BFRs). RESULTS: Excess alcohol consumption and folic acid insufficiency were found to be above the minimal risk standards as outlined in research regulations, while exposure to phthalates and BFRs requires more evidence to determine whether they are above minimal risk. However, applying the minimal risk standard based on the daily life of a healthy adult or a fetus in a healthy pregnant woman, phthalates and BFRs are at the minimal risk threshold regardless of their potential harm since all pregnant women may be exposed to these chemicals in their daily life. Nevertheless, if there is demonstration of sufficient evidence of harm, they may be above minimal risk if such harm can be reduced by individual choice to avoid exposure. CONCLUSION: The minimal risk concept in research regulations as applied to clinical practice may be useful to help clinicians and professional organizations determine what risks need be discussed in prenatal and pre-conception care.