T2* Mapping of Placental Oxygenation to Estimate Fetal Cortical and Subcortical Maturation.

This cohort study investigates the association between T2* mapping of placental oxygenation and cortical and subcortical fetal brain volumes in typically developing fetuses scanned longitudinally in the third trimester.

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.

Assessing the impact of pregnancy and birth factors on the maternal and infant microbiota.

Background: The microbiota acquired at birth is known to play an intimate role in later life health and disease and has been shown to be affected by the mode of birth. There has been recent interest in microbiota correction by maternal vaginal seeding in Cesarean section-born infants; however, the safety of this practice has been debated. The aim of this study was to assess how other factors, such as timing of sampling, maternal obesity, vaginal Group B Streptococcus colonization (GBS), and antibiotic exposure, affect the maternal and infant microbiota. Methods: Maternal vaginal and saliva samples were collected at three time periods: 35-37 weeks gestation (prenatal), within 24-36 hours after birth (birth), and at ~6 weeks postpartum. Infant saliva and stool samples were collected at ~6 weeks postpartum. 16S rRNA amplicon sequencing was utilized to assess the taxonomic and inferred functional compositions of the bacterial communities from both mothers and infants. Results: Samples from 36 mothers and 32 infants were obtained. Gestational age, breastfeeding, mode of birth, and gravidity were associated with taxonomic alterations in the infant samples, while obesity, antibiotic use, and GBS status were not. Maternal samples were predominantly affected by time, whereby significant alterations including increased microbial diversity were seen at birth and persisted to 6 weeks postpartum. Conclusion: This study provides information on the relationship between health and delivery factors and changes in vaginal and infant microbiota. These results may better direct clinicians and mothers in optimizing the infant microbiota towards health during infancy and later life.

Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling.

Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs.

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.

The impact of maternal diabetes on birth to placental weight ratio and umbilical cord oxygen values with implications for fetal-placental development.

INTRODUCTION: We determined the impact of gestational diabetes (GDM) and pre-existing diabetes (DM) on birth/placental weight and cord oxygen values with implications for placental efficiency and fetal-placental growth and development. METHODS: A hospital database was used to obtain birth/placental weight, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA >34 weeks (N = 69,854). Oxygen saturation was calculated from the cord PO2 and pH data, while fetal O2 extraction was calculated from the oxygen saturation data. The effect of diabetic status on birth/placental weight and cord oxygen values was examined adjusting for covariates. RESULTS: Birth/placental weights were stepwise decreased in GDM and DM compared to non-diabetics with placentas disproportionally larger indicating decreasing placental efficiency. Umbilical vein oxygen was marginally increased in GDM but decreased in DM attributed to the previously reported hyper-vascularization in diabetic placentas with absorbing surface area of capillaries initially increased, but then constrained by increasing distance from maternal blood within the intervillous space. Umbilical artery oxygen was unchanged in GDM and DM, with fetal O2 extraction decreased in DM indicating that fetal O2 delivery must be increased relative to O2 consumption and likely due to increased umbilical blood flow. DISCUSSION: Increased villous density/hyper-vascularization in GDM and DM with placentas disproportionately larger and umbilical blood flow increased, are postulated to normalize umbilical artery oxygen despite increased birth weights and growth-related O2 consumption. These findings have implications for mechanisms signaling fetal-placental growth and development in diabetic pregnancies and differ from that reported with maternal obesity.

Semi-automatic segmentation of the fetal brain from magnetic resonance imaging.

Background: Volumetric measurements of fetal brain maturation in the third trimester of pregnancy are key predictors of developmental outcomes. Improved understanding of fetal brain development trajectories may aid in identifying and clinically managing at-risk fetuses. Currently, fetal brain structures in magnetic resonance images (MRI) are often manually segmented, which requires both time and expertise. To facilitate the targeting and measurement of brain structures in the fetus, we compared the results of five segmentation methods applied to fetal brain MRI data to gold-standard manual tracings. Methods: Adult women with singleton pregnancies (n = 21), of whom five were scanned twice, approximately 3 weeks apart, were recruited [26 total datasets, median gestational age (GA) = 34.8, IQR = 30.9-36.6]. T2-weighted single-shot fast spin echo images of the fetal brain were acquired on 1.5T and 3T MRI scanners. Images were first combined into a single 3D anatomical volume. Next, a trained tracer manually segmented the thalamus, cerebellum, and total cerebral volumes. The manual segmentations were compared with five automatic methods of segmentation available within Advanced Normalization Tools (ANTs) and FMRIB's Linear Image Registration Tool (FLIRT) toolboxes. The manual and automatic labels were compared using Dice similarity coefficients (DSCs). The DSC values were compared using Friedman's test for repeated measures. Results: Comparing cerebellum and thalamus masks against the manually segmented masks, the median DSC values for ANTs and FLIRT were 0.72 [interquartile range (IQR) = 0.6-0.8] and 0.54 (IQR = 0.4-0.6), respectively. A Friedman's test indicated that the ANTs registration methods, primarily nonlinear methods, performed better than FLIRT (p < 0.001). Conclusion: Deformable registration methods provided the most accurate results relative to manual segmentation. Overall, this semi-automatic subcortical segmentation method provides reliable performance to segment subcortical volumes in fetal MR images. This method reduces the costs of manual segmentation, facilitating the measurement of typical and atypical fetal brain development.

Highlighting the Mechanistic Relationship Between Perinatal Depression and Preeclampsia: A Scoping Review.

Background: Although there is scientific literature supporting an association between depression and preeclampsia (PE), little is known about the underlying mechanistic pathways that may explain these observed associations. Thus, this study aimed to outline the relationship between depression and PE, and to highlight the underlying cardiovascular and metabolic risk factors that are common to both. Methods: A scoping review of the literature was conducted in Medline, Scopus, and Web of Science. Results: From 706 articles initially identified, 23 articles met the inclusion criteria and were included in this review. Although some studies reported a positive association between PE and postpartum depressive symptoms, challenges comparing different methodologies, measurement instruments and when measurements were administered, and patient populations do not permit a decisive conclusion. In addition, very few studies addressed potential underlying mechanisms that may be contributing to observed associations; thus, a secondary search was conducted to identify cardiovascular and metabolic risk factors that are common to both depression and PE. Conclusion: The cardiovascular and metabolic risk factors (i.e., increased inflammation and oxidative stress and decreased vascular and endothelial function) common to both depression and PE suggest that these factors may contribute as underlying mechanisms in both conditions. These similarities underscore the importance to better understand these mechanisms so preventative and therapeutic strategies could be developed to improve maternal health.

Fetal sex impacts birth to placental weight ratio and umbilical cord oxygen values with implications for regulatory mechanisms.

BACKGROUND: We determined the effect of fetal sex on birth/placental weight and umbilical vein and artery oxygen values with implications for placental efficiency and regulatory mechanisms underlying fetal-placental growth differences. METHODS: A hospital database was used to obtain birth/placental weight, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA > 34 weeks (N = 69,836). Oxygen saturation was calculated from the cord PO2 and pH data, while fractional O2 extraction was calculated from the oxygen saturation data. The effect of fetal sex on birth/placental weight, cord PO2, O2 saturation, and fractional O2 extraction was examined in all patients adjusting for pregnancy and labor/delivery covariates, and in a subset of low-risk patients. RESULTS: Birth/placental weights were lower in females indicating decreased placental efficiency. Umbilical vein oxygen values were higher in females attributed to increased uterine blood flow, while artery oxygen values were lower in females attributed to decreased hemoglobin and umbilical blood flow, and increased oxygen consumption. Fetal O2 extraction was increased in females confirming increased O2 consumption relative to delivery. CONCLUSIONS: Sex-related differences in uterine/umbilical blood flows, placental development, and fetal O2 consumption can be linked to the differences observed in cord oxygen. The lower umbilical artery oxygen in females as a measure of systemic oxygenation signaling growth could account for their decreased birth weights, while slower development in female placentae could account for their lower placental weights, which could be differentially effected contributing to their lower birth/placental weights.

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.

Gestational age impacts birth to placental weight ratio and umbilical cord oxygen values with implications for the fetal oxygen margin of safety.

BACKGROUND: We determined the impact of gestational age (GA) from near term to term to post-term on birth/placental weight ratio and cord oxygen values with implications for placental transport efficiency for oxygen, fetal O2 consumption relative to delivery or fractional O2 extraction, and oxygen margin of safety. MATERIALS AND METHODS: A hospital database was used to obtain birth/placental weight ratios, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA > 34 completed weeks (N = 69,852). Oxygen saturation was calculated from the cord PO2 and pH data, while fractional O2 extraction was calculated from the oxygen saturation data. The effect of GA grouping on birth/placental weight ratio, cord PO2, O2 saturation, and fractional O2 extraction values, was examined in all patients adjusting for pregnancy and labor/delivery covariates, and in a subset of low-risk patients. RESULTS: Birth/placental weight ratio and umbilical venous O2 values increased with advancing GA, supporting the conjecture of increasing placental transport efficiency for oxygen. However, umbilical arterial O2 values decreased while fractional O2 extraction increased with successive GA groupings, indicating that fetal O2 consumption must be increasing relative to delivery. CONCLUSIONS: Fetal O2 consumption can be seen as ever 'outgrowing' O2 delivery over the last weeks of pregnancy and leading to a continued lowering in systemic oxygen levels. While this lowering in oxygen may trigger feedback mechanisms with survival benefit, the 'oxygen margin of safety' will also be lowered increasing perinatal morbidity and mortality which appear to be hypoxia related.

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.

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.

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.

Acetaminophen in late pregnancy and potential for in utero closure of the ductus arteriosus-a pharmacokinetic evaluation and critical review of the literature.

Acetaminophen has become a novel treatment option for patent ductus arteriosus closure in premature infants. This raises concerns about whether acetaminophen should be avoided in late pregnancy, similar to nonsteroidal anti-inflammatory drugs, because of the risk of in utero ductus arteriosus closure. This article critically evaluated the literature reporting an association between acetaminophen use and in utero ductus arteriosus closure and provided a comparative pharmacokinetic analysis of fetal acetaminophen exposure in pregnancy vs drug levels in neonates, with the goal of making an expert recommendation regarding its safety. Here, 1 prospective cohort study and 12 case reports and series evaluating the risk of premature ductus arteriosus closure with prenatal acetaminophen use were reported and overall do not suggest causation. Pharmacokinetic studies showed that acetaminophen fetal transplacental exposures are well below the levels shown to close the ductus arteriosus in neonates. Short-term use of acetaminophen in the third trimester of pregnancy poses a negligible risk of premature ductus arteriosus closure and can still be considered safe in the third trimester of pregnancy at recommended doses.

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.

Translating developmental origins of health and disease in practice: health care providers' perspectives.

Currently, there is limited knowledge on how health care providers perceive and understand the Developmental Origins of Health and Disease (DOHaD), which may impact how they inform patients and their families throughout the perinatal period. This qualitative descriptive study explored if and how health care providers counsel on in utero programming and future health outcomes with parents, both preconception and during pregnancy. One-on-one, semi-structured interviews were conducted with 23 health care providers from varying health disciplines including obstetrics and gynaecology, midwifery, paediatrics, endocrinology and internal medicine. Audiotaped interviews were transcribed verbatim and analysed using inductive thematic analysis. Three themes were identified: Knowledge about DOHaD, Counselling on DOHaD in Practice Settings and Impact of DOHaD on Health. Health care providers not only expressed excitement over the potential health benefits of DOHaD counselling but also indicated barriers to knowledge translation, including a lack of knowledge among providers and a disconnect between basic scientists and practitioners. All health care providers expressed concerns on how and when to introduce the concept of DOHaD when counselling patients and called for the development of practice guidelines. Counselling on DOHaD needs to be framed in a way that is empowering, minimising the potential of coercion and guilt. More interaction and collaboration are needed between health care providers and researchers to identify strategies to support knowledge translation generated from DOHaD research into practice settings.