Brain templates for Chinese babies from newborn to three months of age.

The infant brain develops rapidly and this area of research has great clinical implications. Neurodevelopmental disorders such as autism and developmental delay have their origins, potentially, in abnormal early brain maturation. Searching for potential early neural markers requires a priori knowledge about infant brain development and anatomy. One of the most common methods of characterizing brain features requires normalization of individual images into a standard stereotactic space and conduct of group-based analyses in this space. A population representative brain template is critical for these population-based studies. Little research is available on constructing brain templates for typical developing Chinese infants. In the present work, a total of 120 babies from 5 to 89 days of age were included with high resolution structural magnetic resonance imaging scans. T1-weighted and T2-weighted templates were constructed using an unbiased registration approach for babies from newborn to 3 months of age. Age-specific templates were also estimated for babies aged at 0, 1, 2 and 3 months old. Then we conducted a series of evaluations and statistical analyses over whole tissue segmentations and brain parcellations. Compared to the use of population mismatched templates, using our established templates resulted in lower deformation energy to transform individual images into the template space and produced a smaller registration error, i.e., smaller standard deviation of the registered images. Significant volumetric growth was observed across total brain tissues and most of the brain regions within the first three months of age. The total brain tissues exhibited larger volumes in baby boys compared to baby girls. To the best of our knowledge, this is the first study focusing on the construction of Chinese infant brain templates. These templates can be used for investigating birth related conditions such as preterm birth, detecting neural biomarkers for neurological and neurodevelopmental disorders in Chinese populations, and exploring genetic and cultural effects on the brain.

Advances in extracellular vesicles as mediators of cell-to-cell communication in pregnancy.

Cell-to-cell communication mediated by Extracellular Vesicles (EVs) is a novel and emerging area of research, especially during pregnancy, in which placenta derived EVs can facilitate the feto-maternal communication. EVs comprise a heterogeneous group of vesicle sub-populations with diverse physical and biochemical characteristics and originate by specific biogenesis mechanisms. EVs transfer molecular cargo (including proteins, nucleic acids, and lipids) between cells and are critical mediators of cell communication. There is growing interest among researchers to explore into the molecular cargo of EVs and their functions in a physiological and pathological context. For example, inflammatory mediators such as cytokines are shown to be released in EVs and EVs derived from immune cells play key roles in mediating the immune response as well as immunoregulatory pathways. Pregnancy complications such as gestational diabetes mellitus, preeclampsia, intrauterine growth restriction and preterm birth are associated with altered levels of circulating EVs, with differential EV cargo and bioactivity in target cells. This implicates the intriguing roles of EVs in reprogramming the maternal physiology during pregnancy. Moreover, the capacity of EVs to carry bioactive molecules makes them a promising tool for biomarker development and targeted therapies in pregnancy complications. This review summarizes the physiological and pathological roles played by EVs in pregnancy and pregnancy-related disorders and describes the potential of EVs to be translated into clinical applications in the diagnosis and treatment of pregnancy complications.

Histological chorioamnionitis and pathological stages on very preterm infant outcomes.

AIMS: Histological chorioamnionitis (HCA) is a condition linked to preterm birth and neonatal infection and its relationship with various pathological stages in extremely preterm neonates, and with their associated short- and long-term consequences, remains a subject of research. This study investigated the connection between different pathological stages of HCA and both short-term complications and long-term outcomes in preterm infants born at or before 32 weeks of gestational age. METHODS: Preterm infants born at ≤ 32 weeks of gestation who underwent placental pathology evaluation and were followed-up at 18-24 months of corrected age were included. Neonates were classified based on their exposure to HCA and were further subdivided into different groups according to maternal inflammatory responses (MIR) and fetal inflammatory responses (FIR) stages. We compared short-term complications during their hospital stay between the HCA-exposed and -unexposed groups and examined the influence of HCA stages on long-term outcomes. RESULTS: The HCA group exhibited distinct characteristics such as higher rates of premature rupture of membranes > 18 h, reduced amniotic fluid, early-onset sepsis, bronchopulmonary dysplasia and intraventricular haemorrhage (IVH) grades III-IV (P < 0.05). The moderate-severe HCA group displayed lower gestational age, lower birth weight and higher incidence of IVH (grades III-IV) and preterm sepsis compared with the mild HCA group (P < 0.05). After adjusting for confounders, the MIR stages 2-3 group showed associations with cognitive impairment and cerebral palsy (P < 0.05), and the FIR stages 2-3 group also showed poor long-term outcomes and cognitive impairment (P < 0.05). CONCLUSIONS: Moderate-severe HCA was associated with increased early-onset sepsis, severe IVH and poor long-term outcomes, including cognitive impairment and cerebral palsy. Vigilant prevention strategies are warranted for severe HCA cases in order to mitigate poorer clinical outcomes.

Massive perivillous fibrin deposition: Diagnosis, obstetrical features, and treatment.

MPVFD (Massive perivillous fibrin deposition) is placental lesion characterized by extensive massive deposits of fibrin in the intervillous space, extending over at least 25 % of the placental volume. Currently, this pathology can only be detected through histopathological examination of the placenta after a pregnancy has ended. The underlying mechanisms are poorly studied, there is no biomarker available for the diagnosis of MPVFD and treatment protocols are experimental and still lacking. The objective of this study is to systematically review the literature on the associated clinicopathologic features, treatment, and prognosis of MPVFD. We ended up with 17 studies, of these 12 studies were considered relevant for this article and included in the final analysis. All studies reporting MPVFD are retrospective. MPVFD is associated with recurrent miscarriage, intra uterine fetal death (IUFD), intra uterine growth restriction (IUGR) and preterm delivery. The prevalence in pregnancies with a delivery after 22 weeks of gestation was at 1.1 % and even higher to 2.7 % in recurrent early miscarriages. The reported risk of fetal death in MPVFD ranges mainly from 15 to 80 %. Preterm delivery is spontaneous in 50 to 70 % of cases and induced by of a severe intrauterine growth restriction (IUGR) in 30 to 50 % of cases depending on the study. Its causes and treatment are still poorly understood, although several avenues have been explored. This review summarizes current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology, and potential prophylaxis against recurrence in this chronic inflammatory placental syndrome.

A novel technique to estimate intravillous fetal vasculature on routine placenta histologic sections.

Placental histopathologic lesions are dichotomized into "present" or "absent" and have limited inter-rater reliability. Continuous metrics are needed to characterize placental health and function. Tissue sections (N = 64) of human placenta were stained with CD34 antibody and hematoxylin. Proportion of the villous space occupied by fetal vascular endothelium (%FVE; pixels positive for CD34/total pixels) was evaluated for effect sizes associated with pregnancy outcomes, smoking status, and subtypes of lesions (n = 30). Time to fixation>60 min significantly increased the quantification. Large effect sizes were found between %FVE and both preterm birth and intrauterine growth restriction. These results demonstrate proof-of-concept for this vascular estimation.

Multivariate and regional age-related change in basal ganglia iron in neonates.

In the perinatal period, reward and cognitive systems begin trajectories, influencing later psychiatric risk. The basal ganglia is important for reward and cognitive processing but early development has not been fully characterized. To assess age-related development, we used a measure of basal ganglia physiology, specifically brain tissue iron, obtained from nT2* signal in resting-state functional magnetic resonance imaging (rsfMRI), associated with dopaminergic processing. We used data from the Developing Human Connectome Project (n = 464) to assess how moving from the prenatal to the postnatal environment affects rsfMRI nT2*, modeling gestational and postnatal age separately for basal ganglia subregions in linear models. We did not find associations with tissue iron and gestational age [range: 24.29-42.29] but found positive associations with postnatal age [range:0-17.14] in the pallidum and putamen, but not the caudate. We tested if there was an interaction between preterm birth and postnatal age, finding early preterm infants (GA < 35 wk) had higher iron levels and changed less over time. To assess multivariate change, we used support vector regression to predict age from voxel-wise-nT2* maps. We could predict postnatal but not gestational age when maps were residualized for the other age term. This provides evidence subregions differentially change with postnatal experience and preterm birth may disrupt trajectories.

Brain MRI findings and their association with visual impairment in young adolescents born very preterm.

PURPOSE: Very preterm birth increases risk for neonatal white matter injury, but there is limited data on to what extent this persists into adolescence and how this relates to ophthalmological outcomes. The aim of this study was to assess brain MRI findings in 12-year-old children born very preterm compared to controls and their association with concurrent ophthalmological outcomes. METHODS: We included 47 children born very preterm and 22 full-term controls (gestational age <32 and >37 weeks, respectively). Brain MRI findings were studied in association with concurrent ophthalmological outcomes at 12-year follow-up. RESULTS: Evans index (0.27 vs 0.25, p<0.001) and a proposed "posterior ventricle index" (0.47 vs 0.45, p=0.018) were increased in children born very preterm. Higher gestational age associated with larger corpus callosum area (ß=10.7, 95%CI 0.59-20.8). Focal white matter lesions were observed in 15 (32%) of very preterm children and in 1 (5%) of full-term controls. Increased posterior ventricle index increased risk for visual acuity ≤1.0 (OR=1.07×1011, 95%CI=7.78-1.48×1021) and contrast sensitivity <0.5 (OR=2.6×1027, 95%CI=1.9×108-3.5×1046). Decreased peritrigonal white matter thickness associated with impaired visual acuity (ß=0.04, 95%CI 0.002-0.07). CONCLUSION: More white matter lesions and evidence of lower white matter volume were found in children born very preterm compared with full-term controls at 12-year follow-up. The association between larger posterior ventricle index and reduced visual acuity and contrast sensitivity suggests disturbances of the posterior visual pathway due to diffuse white matter lesions.

Clinical and Histological Associations of Chronic Inflammatory Lesions in Preterm Placentas: Uncovering the Hidden Dangers.

BACKGROUND: Chronic placental inflammatory lesions (CPIL) include chronic deciduitis (CD), villitis of unknown etiology (VUE), and chronic chorioamnionitis (CCA). The frequency of these lesions and their relationship with various clinicopathological parameters in preterm birth (PTB) is presented. MATERIAL AND METHODS: Preterm placentas from April 2018 to December 2020 were reviewed for presence of CPIL. PTB was classified as spontaneous, indicated, or mixed phenotype. The association of CPIL with clinical parameters like gestational age, birth weight, obstetric complications, and placental parameters like placental dimensions, weight, vascular malperfusion, acute inflammatory lesions, and basal plate myometrial fibers were analyzed. RESULTS: The study included 538 preterm placentas with 54.3% from indicated PTB. CD was more common (28.4%) than VUE (17.8%) and CCA (12.6%). CD showed significant association with VUE and CCA (both P = .0001) and VUE with CCA (P = .0001). CD was more common in indicated PTB (33.8%, P = .002) and associated with lower birth weight (1591 g vs 1705 g, P = .003), lower placental weight (270.7 g vs 296.9 g, P = .004), length (14.2 cm vs 14.8 cm, P = .006), breadth (11.7 cm vs 12.2 cm, P = .007), maternal vascular malperfusion (P = .004), and basal plate myometrial fibers (P = .02). High-grade and multifocal low-grade VUE was associated with reduced placental length (13.9 cm vs 14.6 cm, P = .02)and breadth (11.5 cm vs 12.1 cm, P = .01). CCA did not show any other association. CONCLUSION: CPIL are common in PTB and their coexistence suggested a common pathogenic mechanism. Placental examination is the only definite way to identify as they lack clinical signs and symptoms. The smaller placental size associated with these lesions may suggest alter mechanisms for adverse pregnancy outcomes.

Significant association between circumvallate placenta, placental abruption and acute chorioamnionitis in preterm birth: A 23-year retrospective cohort study.

AIM: circumvallate placenta, placental abruption and acute chorioamnionitis separately are associated with unfavourable clinical outcomes. We aimed to determine the prevalence and define whether an association exists between the three abnormalities. METHODS: 16,042 placenta pathology reports between 1997 and 2020 from a tertiary care centre in the Netherlands were retrospectively analysed. For the statistical analysis, the chi-square test and bootstrapping were used to evaluate an association. RESULTS: In our cohort the prevalence of circumvallate placenta is 2.2 %, placental abruption cases 4.0 % and acute chorioamnionitis 20.6 %. We observed a statistically significant association between all three placental abnormalities: circumvallate placenta, placental abruption and acute chorioamnionitis. In addition, there was also an association between circumvallate placenta and acute chorioamnionitis. CONCLUSION: Our results show that combined presence of circumvallate placenta, placental abruption and acute chorioamnionitis are associated in preterm birth (p = 0.001). A remarkable finding is that the combination of all three abnormalities (circumvallate placenta, placental abruption and acute chorioamnionitis) was not observed in term pregnancies >37 weeks.

Placental inflammation and pregnancy outcomes: A prospective, observational study in South Asia: The PURPOSe study.

OBJECTIVE: To examine inflammatory lesions in placentas of stillbirths, preterm neonatal deaths and term controls in India and Pakistan. DESIGN: Prospective, observational study. SETTING: Three hospitals in India and a large maternity hospital in Pakistan. POPULATION: The enrolled participants with placentas available for histology evaluation included stillbirths (n = 814), preterm live births who died within 28 days of birth (n = 618) and term live birth controls (n = 201). From this same population, polymerase chain reaction (PCR) analysis for pathogens was performed on 809 stillbirth placentas, 614 neonatal death placentas and the placentas of 201 term controls. Placentas from preterm infants who lived beyond day 28 (n = 1432) were only available from India. METHODS: A prospective observational study of placental inflammatory lesions defined by the Amsterdam criteria and on the same placentas, multiplex PCR evaluation for 75 pathogens using TaqMan Array Cards. MAIN OUTCOME MEASURES: Any placental inflammatory lesions, including chorioamnionitis, funisitis, villitis and intervillitis and their association with various pathogens. RESULTS: In the Indian liveborn preterm infants, placental inflammation of any kind was present in 26.2% of those who died versus 16.6% of those who lived (p = 0.0002). Chorioamnionitis was present in 25.8% of those who died versus 16.3% of those who lived (p = 0.0002) and funisitis was present in 4.1% of those who died versus 1.5% of those who lived, (p = 0.005). Across all three sites, in the placentas of the 201 term controls, 18.9% had any inflammation, 16.9% had chorioamnionitis, 5.5% had funisitis, 0.5% had intervillitis and none had villitis. Overall, for stillbirths, any inflammation was observed in 30.2%, chorioamnionitis in 26.9%, funisitis in 5.7%, intervillitis in 6.0% and villitis in 2.2%. For the neonatal deaths, any inflammation was present in 24.9%, chorioamnionitis in 23.3%, funisitis in 8.1%, intervillitis in 1.9% and villitis in 0.5%. Compared with the placentas of term controls, in neonatal deaths, only chorioamnionitis was significantly increased (23.3% versus 16.9%, p = 0.05). Among stillbirths, the rates of any inflammation, chorioamnionitis, intervillitis and villitis were similar across the birthweight groups. However, funisitis was more common in the placentas of stillborn fetuses weighing 2500 g or more (13.8%) compared with 1.0% for those weighing less than 1000 g and 4.8% for stillborn fetuses weighing 1000-2499 g. In the PCR studies, Ureaplasma spp. were by far the most common pathogens found and generally were more commonly found in association with inflammatory lesions. CONCLUSIONS: Chorioamnionitis was the most common type of placental inflammatory lesion regardless of whether the placentas evaluated were from term controls, stillbirths or neonatal deaths. For stillbirths, inflammation in each inflammation category was more common than in the term controls and significantly more so for any inflammation, chorioamnionitis, intervillitis and villitis. For neonatal deaths, compared with the placentas of term controls, all inflammation categories were more common, but only significantly so for chorioamnionitis. Ureaplasma spp. were the most common organisms found in the placentas and were significantly associated with inflammation.

Comparison of Placental Pathology Reports From Spontaneous Preterm Births Finalized by General Surgical Pathologists Versus Perinatal Pathologist: A Call to Action.

Placental examination, frequently performed by general surgical pathologists, plays an important role in understanding patient outcomes and explaining the underlying mechanisms leading to preterm birth (PTB). This secondary analysis of a larger study recurrent PTB aimed to compare diagnoses between general surgical pathologists (GSP) and a perinatal pathologist (PP) in preterm placentas examined between 2009 and 2018 at a single institution. Pathology diagnoses were coded into 4 categories (acute inflammation [AI], chronic inflammation, fetal vascular malperfusion, maternal vascular malperfusion) based on original reports for the GSP and second review by the single PP. A total of 331 placentas were included, representing placentas finalized by 17 GSPs. The prevalence of all 4 placental diagnostic categories was higher for the PP, and nearly half (49.2%) of placentas finalized by GSP had no diagnostic findings. Agreement was highest for AI at κ=0.50 (weak agreement). However, there was no agreement for maternal vascular malperfusion (κ=0.063), chronic inflammation (κ=0.0026), and fetal vascular malperfusion (κ = -0.018). Chronic basal deciduitis with plasma cells had the highest false-negative rate (missed in 107 cases by GSP). Villous infarction had the highest false-positive rate (overcalled in 28/41 [68%] cases) with the majority of the "infarcts" representing intervillous thrombi. In conclusion, there is no agreement between GSP and PP when assessing placental pathology other than AI, and weak agreement even for AI. These findings are a call to action to implement educational efforts and structural/organizational changes to improve consistency of placental pathology reporting.

Morphological study of the placenta in deliveries with pre-eclampsia: Results from a prospective, observational study in India and Pakistan (PURPOSe).

OBJECTIVE: To compare placental findings in women with and without pre-eclampsia. DESIGN: The PURPOSe study included women with stillbirths, women with preterm births and women at term as controls. The placenta of each case was evaluated using the Amsterdam criteria. SETTING: Two sites and five tertiary care hospitals of south Asia (Three in India and two in Pakistan). POPULATION: Pregnancies in India and Pakistan with placental histology including women with documented hypertension and documented proteinuria and women with neither hypertension nor proteinuria. METHODS: We compared the placental findings of the two groups using the Amsterdam criteria and further evaluated the placental findings in women with and without pre-eclampsia who had a stillbirth, preterm live birth, or term live birth (control). MAIN OUTCOME MEASURES: The main outcome measures were the frequency of maternal and fetal vascular malperfusion and the frequency of placental inflammation and its components, chorioamnionitis, funisitis, villitis and intervillitis in women with and without pre-eclampsia. RESULTS: A total of 733 women had pre-eclampsia and 2334 women had neither hypertension nor proteinuria. In the placentas of women with pre-eclampsia, 57.3% had maternal vascular malperfusion compared with 37.1% in women without pre-eclampsia (p < 0.0001). There was not a significant difference in the prevalence of fetal vascular hypertension between mothers with (17.1%) and without (14.8%, p = 0.6118) pre-eclampsia. When placentas were classified as 'histologically normal' or not, 61.3% of those from pre-eclamptic pregnancies were classified as abnormal, whereas if there was no pre-eclampsia, only 45.0% were classified as histologically abnormal (p < 0.0001). We also considered rates of placental maternal vascular malperfusion in women with and without pre-eclampsia with stillbirth, preterm neonatal death, and term live birth. In women at term with no pre-eclampsia, 16.7% of the placentas had features of maternal vascular malperfusion. This occurred in 79.9% of women with stillbirths with pre-eclampsia compared with 51.8% of those without pre-eclampsia. Maternal vascular malperfusion was present in 49.7% of preterm live births with pre-eclampsia compared with 33.8% without pre-eclampsia. We also evaluated the inflammatory lesions by whether the mother had or did not have pre-eclampsia. When all inflammatory lesions were considered, women with pre-eclampsia had significantly fewer inflammatory lesions than those women without pre-eclampsia (17.1% versus 23.6% p = 0.001). Each of the specific inflammatory lesions was less common in placentas of women with pre-eclampsia than those with chorioamnionitis (16.1% versus 21.9%, p = 0.004) and funisitis (1.5% versus. 5.1%, p = 0.0004). CONCLUSIONS: Of placental lesions in women with pre-eclampsia, maternal vascular malperfusion was the most common. Inflammatory lesions were less common in women with pre-eclampsia.

Morphological placental findings in women infected with SARS-CoV-2 according to trimester of pregnancy and severity of disease.

INTRODUCTION: Placental morphology findings in SARS-CoV-2 infection are considered nonspecific, although the role of trimester and severity of infection are underreported. Therefore, we aimed to investigate abnormal placental morphology, according to these two criteria. METHODS: This is an ancillary analysis of a prospective cohort study of pregnant women with suspected SARS-CoV-2 infection, managed in one maternity, from March 2020 to October 2021. Charting of clinical/obstetric history, trimester and severity of COVID-19 infection, and maternal/perinatal outcomes were done. Placental morphological findings were classified into maternal and fetal circulatory injury and acute/chronic inflammation. We further compared findings with women with suspected disease which tested negative for COVID-19. Diseases' trimester of infection and clinical severity guided the analysis of confirmed COVID-19 cases. RESULTS: Ninety-one placental discs from 85 women were eligible as a COVID-19 group, and 42 discs from 41 women in negative COVID-19 group. SARS-CoV-2 infection occurred in 68.2% during third trimester, and 6.6% during first; 16.5% were asymptomatic, 61.5% non-severe and 22.0% severe symptomatic (two maternal deaths). Preterm birth occurred in 33.0% (one fetal death). Global maternal vascular malperfusion (MVM) were significant in COVID-19 group whether compared with negative COVID-19 tests group; however, fetal vascular malperfusion lesions and low-grade chronic villitis were not. Three placentas had COVID-19 placentitis. Decidual arteriopathy was associated with infection in first/mid trimester, and chorangiosis in asymptomatic infections. DISCUSSION: Placental abnormalities after an infection by COVID-19 were more frequent after first/mid-trimester infections. Extensive placental lesions are rare, although they may be more common upon underlying medical conditions.

Patterns of placental pathology associated with preeclampsia.

INTRODUCTION: Maternal vascular malperfusion (MVM) is commonly observed in early onset preeclampsia, but less prevalent in late onset preeclampsia. The purpose of our analysis was to investigate patterns of placental pathology in preeclampsia. METHODS: Electronic health records for all singleton livebirths from 2009 to 2018 at a single institution with a diagnosis of preeclampsia were obtained. Text searching was used to obtain placental data from pathology reports, including lesions of MVM, fetal vascular malperfusion (FVM), chronic inflammation (CI), and acute inflammation (AI). Placental pathology was compared based on timing of delivery and latent class analysis (LCA) was used to investigate subtypes of preeclampsia based on 22 placental variables. RESULTS: 728 patients were included in the analysis. Prevalence of MVM decreased with advancing gestation (95.4% at <34 weeks, 69.8% at 34-36 weeks, and 50%, ≥37 weeks; p < 0.01). LCA identified five classes based on placental pathology: (1) high grade MVM, (2) CI and FVM, (3) low grade MVM, (4) AI, (5) other. Preterm birth varied across the classes (p < 0.01), with the highest prevalence observed among the classes characterized by MVM (high grade: 87.6%; low grade: 63.0%) and the lowest prevalence among the class characterized by AI (23.5%). DISCUSSION: Placental pathology in preeclampsia differs based on gestational age at delivery with MVM seen in nearly all early onset preeclampsia cases. Latent classes largely grouped by previously defined patterns of placental injury (MVM, CI, FVM, AI), and again revealed the highest likelihood of preterm birth in classes characterized by MVM. Results suggest there may be multiple mechanisms leading to the clinical manifestations of preeclampsia.

Altered gray-to-white matter tissue contrast in preterm-born adults.

AIMS: To investigate cortical organization in brain magnetic resonance imaging (MRI) of preterm-born adults using percent contrast of gray-to-white matter signal intensities (GWPC), which is an in vivo proxy measure for cortical microstructure. METHODS: Using structural MRI, we analyzed GWPC at different percentile fractions across the cortex (0%, 10%, 20%, 30%, 40%, 50%, and 60%) in a large and prospectively collected cohort of 86 very preterm-born (<32 weeks of gestation and/or birth weight <1500 g, VP/VLBW) adults and 103 full-term controls at 26 years of age. Cognitive performance was assessed by full-scale intelligence quotient (IQ) using the Wechsler Adult Intelligence Scale. RESULTS: GWPC was significantly decreased in VP/VLBW adults in frontal, parietal, and temporal associative cortices, predominantly in the right hemisphere. Differences were pronounced at 20%, 30%, and 40%, hence, in middle cortical layers. GWPC was significantly increased in right paracentral lobule in VP/VLBW adults. GWPC in frontal and temporal cortices was positively correlated with birth weight, and negatively with duration of ventilation (p < 0.05). Furthermore, GWPC in right paracentral lobule was negatively correlated with IQ (p < 0.05). CONCLUSIONS: Widespread aberrant gray-to-white matter contrast suggests lastingly altered cortical microstructure after preterm birth, mainly in middle cortical layers, with differential effects on associative and primary cortices.

Endometrial and placental stem cells in successful and pathological pregnancies.

The endometrium is a dynamic tissue that undergoes extensive remodeling during the menstrual cycle and further gets modified during pregnancy. Different kinds of stem cells are reported in the endometrium. These include epithelial stem cells, endometrial mesenchymal stem cells, side population stem cells, and very small embryonic-like stem cells. Stem cells are also reported in the placenta which includes trophoblast stem cells, side population trophoblast stem cells, and placental mesenchymal stem cells. The endometrial and placental stem cells play a pivotal role in endometrial remodeling and placental vasculogenesis during pregnancy. The dysregulation of stem cell function is reported in various pregnancy complications like preeclampsia, fetal growth restriction, and preterm birth. However, the mechanisms by which it does so are yet elusive. Herein, we review the current knowledge of the different type of stem cells involved in pregnancy initiation and also highlight how their improper functionality leads to pathological pregnancy.

Longitudinal neonatal brain development and socio-demographic correlates of infant outcomes following preterm birth.

Preterm birth results in premature exposure of the brain to the extrauterine environment during a critical period of neurodevelopment. Consequently, infants born preterm are at a heightened risk of adverse behavioural outcomes in later life. We characterise longitudinal development of neonatal regional brain volume and functional connectivity in the first weeks following preterm birth, sociodemographic factors, and their respective relationships to psychomotor outcomes and psychopathology in toddlerhood. We study 121 infants born preterm who underwent magnetic resonance imaging shortly after birth, at term-equivalent age, or both. Longitudinal regional brain volume and functional connectivity were modelled as a function of psychopathology and psychomotor outcomes at 18 months. Better psychomotor functioning in toddlerhood was associated with greater relative right cerebellar volume and a more rapid decrease over time of sensorimotor degree centrality in the neonatal period. In contrast, increased 18-month psychopathology was associated with a more rapid decrease in relative regional subcortical volume. Furthermore, while socio-economic deprivation was related to both psychopathology and psychomotor outcomes, cognitively stimulating parenting predicted psychopathology only. Our study highlights the importance of longitudinal imaging to better predict toddler outcomes following preterm birth, as well as disparate environmental influences on separable facets of behavioural development in this population.

Spontaneous preterm birth with placental maternal vascular malperfusion is associated with cardiovascular risk in the fifth decade of life.

Women with a history of spontaneous preterm birth (SPTB) have a mildly elevated cardiovascular risk (CVR) later in life and women with a history of preeclampsia have a highly elevated CVR. In placentas of women with preeclampsia pathological signs of maternal vascular malperfusion (MVM) are often seen. These signs of MVM are also seen in a substantial part of the placentas of women with SPTB. We therefore hypothesize that in women with a history of SPTB, the subgroup with placental MVM has an elevated CVR. This study is a secondary analysis of a cohort study including women 9-16 years after a SPTB. Women with pregnancy complications known to be associated with CVR were excluded. The primary outcome was hypertension defined as blood pressure ≥ 130/80 mmHg and/or treatment with antihypertensive medication. Secondary outcomes were mean blood pressure, anthropometrics, blood measurements including cholesterol and HbA1c, and creatinine in urine. Placental histology was available in 210 (60.0%) women. MVM was found in 91 (43.3%) of the placentas, most often diagnosed by the presence of accelerated villous maturation. Hypertension was diagnosed in 44 (48.4%) women with MVM and in 42 (35.3%) women without MVM (aOR 1.76, 95% CI 0.98 - 3.16). Women with a SPTB and placental MVM showed significantly higher mean diastolic blood pressure, mean arterial pressure and HbA1c approximately 13 years after delivery, compared to women with a SPTB without placental MVM. We therefore conclude that placental malperfusion in women with a SPTB might differentiate in CVR later in life.

Parsing brain-behavior heterogeneity in very preterm born children using integrated similarity networks.

Very preterm birth (VPT; ≤32 weeks' gestation) is associated with altered brain development and cognitive and behavioral difficulties across the lifespan. However, heterogeneity in outcomes among individuals born VPT makes it challenging to identify those most vulnerable to neurodevelopmental sequelae. Here, we aimed to stratify VPT children into distinct behavioral subgroups and explore between-subgroup differences in neonatal brain structure and function. 198 VPT children (98 females) previously enrolled in the Evaluation of Preterm Imaging Study (EudraCT 2009-011602-42) underwent Magnetic Resonance Imaging at term-equivalent age and neuropsychological assessments at 4-7 years. Using an integrative clustering approach, we combined neonatal socio-demographic, clinical factors and childhood socio-emotional and executive function outcomes, to identify distinct subgroups of children based on their similarity profiles in a multidimensional space. We characterized resultant subgroups using domain-specific outcomes (temperament, psychopathology, IQ and cognitively stimulating home environment) and explored between-subgroup differences in neonatal brain volumes (voxel-wise Tensor-Based-Morphometry), functional connectivity (voxel-wise degree centrality) and structural connectivity (Tract-Based-Spatial-Statistics). Results showed two- and three-cluster data-driven solutions. The two-cluster solution comprised a 'resilient' subgroup (lower psychopathology and higher IQ, executive function and socio-emotional scores) and an 'at-risk' subgroup (poorer behavioral and cognitive outcomes). No neuroimaging differences between the resilient and at-risk subgroups were found. The three-cluster solution showed an additional third 'intermediate' subgroup, displaying behavioral and cognitive outcomes intermediate between the resilient and at-risk subgroups. The resilient subgroup had the most cognitively stimulating home environment and the at-risk subgroup showed the highest neonatal clinical risk, while the intermediate subgroup showed the lowest clinical, but the highest socio-demographic risk. Compared to the intermediate subgroup, the resilient subgroup displayed larger neonatal insular and orbitofrontal volumes and stronger orbitofrontal functional connectivity, while the at-risk group showed widespread white matter microstructural alterations. These findings suggest that risk stratification following VPT birth is feasible and could be used translationally to guide personalized interventions aimed at promoting children's resilience.

Investigation of secretoneurin as a potential biomarker of brain injury in very preterm infants: A pilot study.

Neurodevelopmental impairment is a significant complication among survivors of preterm birth. To improve outcomes, reliable biomarkers for early detection of brain injury and prognostic assessment are required. Secretoneurin is a promising early biomarker of brain injury in adults and full-term neonates suffering from perinatal asphyxia. Data on preterm infants is currently lacking. The aim of this pilot study was to determine secretoneurin concentrations in preterm infants in the neonatal period, and to assess secretoneurin's potential as a biomarker of preterm brain injury. We included 38 very preterm infants (VPI) born at <32 weeks' gestation in the study. Secretoneurin concentrations were measured in serum samples obtained from the umbilical cord, at 48 hours and 3 weeks of life. Outcome measures included repeated cerebral ultrasonography, magnetic resonance imaging at term-equivalent age, general movements assessment, and neurodevelopmental assessment at a corrected age of 2 years by the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III). In comparison to a term-born reference population, VPI had lower secretoneurin serum concentrations in umbilical cord blood and blood collected at 48 hours of life. When measured at 3 weeks of life, concentrations correlated with gestational age at birth. Secretoneurin concentrations did not differ between VPI with an imaging-based diagnosis of brain injury and those without, but when measured in umbilical cord blood and at 3 weeks of life correlated with and were predictive of Bayley-III motor and cognitive scale scores. Secretoneurin levels in VPI differ from term-born neonates. Secretoneurin seems unsuitable as a diagnostic biomarker of preterm brain injury, but bears some prognostic potential and is worthy of further investigation as a blood-based biomarker of preterm brain injury.