Executive Functions Rehabilitation in Premature Children Using an Adaptive Motion-Interaction Videogame Platform: A Randomized Controlled Trial.

Background: Premature children are at increased risk of executive functions (EF) deficits and these difficulties persist into adolescence and adulthood, potentially undermining their development and academic achievements. The aim of the present randomized controlled trial (RCT) is to evaluate the efficacy of the Intendu trainer, an adaptive virtual reality platform, at ameliorating EF in preterm children. Methods: A single-center, RCT was conducted. The intervention group was exposed to game session with the Intendu software in addition to the standard of care in use in our center. The main outcome was the proportion of children with a 10-point increase in the processing speed quotient as measured by WPPSI-III after 4 weeks from the baseline assessment. Results: Forty-seven children born before 36 + 5 weeks were randomized to the experimental (n = 24) or control arm (n = 23). Five children were lost to follow-up. Thirteen of 23 children (56%) reached the main outcome in the experimental group and 5 of 19 (26%) in the control group (P = 0.049, per-protocol analysis) with an absolute benefit increase (ABI) of 30% reconfirmed by the intention-to-treat analysis (P = 0.022, ABI of 32%). Conclusion: Intendu brain-trainer showed promising short-term results on EF in pre-term children, however, larger studies with longer periods of follow-up are warranted to better investigate the role of this or similar technology in promoting better EF in preterm children.

Fetal Cerebral Ventriculomegaly: A Narrative Review and Practical Recommendations for Pediatric Neurologists.

Fetal cerebral ventriculomegaly is one of the most common fetal neurological disorders identified prenatally by neuroimaging. The challenges in the evolving landscape of conditions like fetal cerebral ventriculomegaly involve accurate diagnosis and how best to provide prenatal counseling regarding prognosis as well as postnatal management and care of the infant. The purpose of this narrative review is to discuss the literature on fetal ventriculomegaly, including postnatal management and neurodevelopmental outcome, and to provide practice recommendations for pediatric neurologists.

Congenital Cytomegalovirus Infection With Isolated "Minor" Lesions at Fetal Magnetic Resonance Imaging: Long-Term Neurological Outcome.

BACKGROUND: The prognostic relevance of fetal/early postnatal magnetic resonance (MR) imaging (MRI) isolated "minor" lesions in congenital cytomegalovirus (CMV) infection is still unclear, because of the heterogeneity of previously reported case series. The aim of this study was to report the imaging and long-term clinical follow-up data on a relatively large cohort of infected fetuses. METHODS: Among 140 CMV-infected fetuses from a single-center 12-year-long fetal MRI database, cases that showed isolated "minor" lesions at MRI, mainly represented by polar temporal lesions, were selected. MRI features were described, and clinical follow-up information was collected through consultation of medical records and telephone interview to establish the auditory and neurological outcome of each patient. RESULTS: Thirty-six cases were included in the study. The frequency of "minor" lesions increased progressively with ongoing gestational age in cases who underwent serial MR examination; 31% of cases were symptomatic at birth for unilateral altered auditory brainstem response. At long-term clinical follow-up, performed in 35 patients at a mean age of 64.5 months (range: 25 to 138), 43% of patients were asymptomatic and 57% presented with mild/moderate disability including hearing loss (34%), unilateral in all cases but one (therefore classified as severe), and/or minor cognitive and behavioral disorders (49%). CONCLUSIONS: Descriptive analysis of the type and modality of occurrence of "minor" lesions suggests performing serial fetal/postnatal MR examinations not to miss later-onset lesions. Follow-up data from the present cohort, combined with maternal/fetal factors and serologic-laboratory parameters may contribute to improve prenatal and neonatal period counselling skills.

Cobblestone-like brain malformation with a new bi-allelic ADGRG1 (GPR-56) mutation: Fetal imaging-pathology correlation.

BACKGROUND AND PURPOSE: Autosomal recessive cobblestone-like cortical malformation of the brain, with no eye or muscle involvement, has been reported in patients with biallelic mutations in ADGRG1 (formerly GPR56) and in other brain surface defects (eg, variants in COL3A1). We reported the intra-uterine brain MRI (iu-MRI), post-mortem MRI (pm-MRI), and neuropathology findings of a new ADGRG1 mutation in a fetus at early gestation. Imaging findings were compared with those of the sibling harboring the same mutation, to provide insights about the evolving morphology of such malformation. METHODS: A 21-week fetus underwent iu-MRI for a suspected cortical anomaly on ultrasound. After the MRI results, the termination of the pregnancy was carried out. A pm-MRI scan and autopsy were performed. A neuropathology-imaging correlation was achieved. The 5-year old sibling affected by developmental impairment also underwent a brain MRI. Both subjects underwent a genetic investigation. RESULTS: Two patterns of abnormality of the cerebral surface were identified on both fetal MRI: one at the vertex resembling a cobblestone-cortex due to neuronal overmigration into the subarchnoid space and the other in the occipital areas resembling polymicrogyria. These details closely matched the neuropathology findings. MRI findings of the sibling consisted of typical ADGRG1/GPR56-related brain findings showing a polymicrogyric-like cortex, also reported as bilateral frontal-parietal polymicrogyria. A flattened pons and small cerebellar vermis were present in both cases. Genetic testing demonstrated a novel homozygous variant c.1484T>C in the c gene in both cases. CONCLUSION: Our findings provide further evidence of the overlap of ADGRG1/GPR56-related brain dysgenesis with cobblestone-like cortical malformation of the brain.

Maternal pandemic-related stress during pregnancy associates with infants' socio-cognitive development at 12 months: A longitudinal multi-centric study.

BACKGROUND: Prenatal maternal stress is a key risk factor for infants' development. Previous research has highlighted consequences for infants' socio-emotional and cognitive outcomes, but less is known for what regards socio-cognitive development. In this study, we report on the effects of maternal prenatal stress related to the COVID-19 pandemic on 12-month-old infants' behavioral markers of socio-cognitive development. METHODS: Ninety infants and their mothers provided complete longitudinal data from birth to 12 months. At birth, mothers reported on pandemic-related stress during pregnancy. At infants' 12-month-age, a remote mother-infant interaction was videotaped: after an initial 2-min face-to-face episode, the experimenter remotely played a series of four auditory stimuli (2 human and 2 non-human sounds). The auditory stimuli sequence was counterbalanced among participants and each sound was repeated three times every 10 seconds (Exposure, 30 seconds) while mothers were instructed not to interact with their infants and to display a neutral still-face expression. Infants' orienting, communication, and pointing toward the auditory source was coded micro-analytically and a socio-cognitive score (SCS) was obtained by means of a principal component analysis. RESULTS: Infants equally oriented to human and non-human auditory stimuli. All infants oriented toward the sound during the Exposure episode, 80% exhibited any communication directed to the auditory source, and 48% showed at least one pointing toward the sound. Mothers who reported greater prenatal pandemic-related stress had infants with higher probability of showing no communication, t = 2.14 (p = .035), or pointing, t = 1.93 (p = .057). A significant and negative linear association was found between maternal prenatal pandemic-related stress and infants' SCS at 12 months, R2 = .07 (p = .010), while adjusting for potential confounders. CONCLUSIONS: This study suggests that prenatal maternal stress during the COVID-19 pandemic might have increased the risk of an altered socio-cognitive development in infants as assessed through an observational paradigm at 12 months. Special preventive attention should be devoted to infants born during the pandemic.

Fetal Hydrothorax Treated with Pleuro-Amniotic Shunting: Fetal and Maternal Complications and Long-Term Outcomes.

INTRODUCTION: We aimed to identify maternal and fetal complications and investigate postnatal and long-term outcomes of fetal hydrothorax (FHT) treated with pleuro-amniotic shunting (shunt). METHODS: Single-center retrospective observational cohort of shunt cases performed from 2000 to 2021. Risk factors for maternal complications, fetal demise, neonatal death (NND), and postnatal outcomes were identified. RESULTS: Out of 88 cases, 70 (79.5%) were complicated by hydrops, with an average gestational age (GA) at diagnosis of 27 weeks (range 16-34). In 16 cases, definitive etiology of FHT was identified; five cases of Noonan syndrome and three cases of monogenic disorders diagnosed by whole-exome sequencing (EPHB4, VEGFR3, RASA1). Shunt was performed at an average GA of 28 weeks (20-34), with a dislodgement in 10 cases (11.4%). Maternal: Complications occurred in three cases; survival rate was 76.1% (67/88). Follow-up data were available for 57/67 (85.1%) children. Incidence of severe neurodevelopmental impairment and pneumopathy (broncho dysplasia, persistent pulmonary hypertension of newborn, and asthma) was 5.3% and 8.8%, respectively. Post-treatment persistence of hydrops, FHT associated with genetic syndromes, and GA at birth were risk factors for fetal demise, NND, and postnatal complications. CONCLUSION: In truly isolated FHT, whenever indicated, pleuro-amniotic shunting is a safe procedure associated with good survival rate and long-term outcome.

Prenatal maternal stress during the COVID-19 pandemic and infant regulatory capacity at 3 months: A longitudinal study.

The COVID-19 pandemic is a global traumatic experience for citizens, especially during sensitive time windows of heightened plasticity such as pregnancy and neonatal life. Pandemic-related stress experienced by mothers during pregnancy may act as an early risk factor for infants' regulatory capacity development by altering maternal psychosocial well-being (e.g., increased anxiety, reduced social support) and caregiving environment (e.g., greater parenting stress, impaired mother-infant bonding). The aim of the present longitudinal study was to assess the consequences of pandemic-related prenatal stress on infants' regulatory capacity. A sample of 163 mother-infant dyads was enrolled at eight maternity units in northern Italy. They provided complete data about prenatal stress, perceived social support, postnatal anxiety symptoms, parenting stress, mother-infant bonding, and infants' regulatory capacity at 3 months of age. Women who experienced emotional stress and received partial social support during pregnancy reported higher anxious symptoms. Moreover, maternal postnatal anxiety was indirectly linked to the infants' regulatory capacity at 3 months, mediated by parenting stress and mother-infant bonding. Dedicated preventive interventions should be delivered to mothers and should be focused on protecting the mother-infant dyad from the detrimental effects of pandemic-related stress during the COVID-19 healthcare emergency.

Fetal Neurology: From Prenatal Counseling to Postnatal Follow-Up.

Brain abnormalities detected in fetal life are being increasingly recognized. Child neurologists are often involved in fetal consultations, and specific fetal neurology training has been implemented in many countries. Pediatric neurologists are asked to examine the data available and to contribute to the definition of the long-term outcomes. Ventriculomegaly, posterior fossa malformations, and agenesis/dysgenesis of corpus callosum are among the most common reasons for antenatal neurological consultations. Fetuses with central nervous system and extra-CNS anomalies should ideally be managed in secondary/tertiary hospitals where obstetricians who are experts in fetal medicine and pediatric specialists are available. Obstetricians play a critical role in screening, performing detailed neurosonography, and referring to other specialists for additional investigations. Clinical geneticists are frequently asked to propose diagnostic tests and counsel complex fetal malformations whose phenotypes may differ from those during postnatal life. Advances in fetal MRI and genetic investigations can support the specialists involved in counseling. Nevertheless, data interpretation can be challenging, and it requires a high level of expertise in a multidisciplinary setting. Postnatally, child neurologists should be part of an integrated multidisciplinary follow-up, together with neonatologists and pediatricians. The neurodevelopmental outcomes should be assessed at least up to school age. Children should be evaluated with formal tests of their gross motor, cognitive, language, fine motor/visuo-perceptual skills, and their behavior. In this perspective, fetal neurology can be regarded as the beginning of a long journey which continues with a prolonged, structured follow-up, support to the families, and transition to adult life. A review of the most common conditions is presented, along with the long-term outcomes and a proposal of the neurodevelopmental follow-up of children with CNS malformation which are diagnosed in uterus.

Post-partum Women's Anxiety and Parenting Stress: Home-Visiting Protective Effect During the COVID-19 Pandemic.

OBJECTIVES: The COVID-19 pandemic resulted in a particularly adverse and stressful environment for expecting mothers, possibly enhancing feelings of anxiety and parenting stress. The present work assesses mothers' anxiety levels at delivery and parenting stress after 3 months as moderated by home-visiting sessions. METHODS: Women (n = 177) in their second or third trimester of pregnancy during the COVID-19 lockdown were enrolled in northern Italy and split into those who did and did not receive home visits. After 3 months, the association between anxiety at delivery and parenting stress was assessed with bivariate correlations in the whole sample and comparing the two groups. RESULTS: Higher anxiety at birth correlated with greater perceived stress after 3 months. Mothers who received at least one home-visiting session reported lower parenting stress at 3 months than counterparts who did not receive home visits. CONCLUSIONS FOR PRACTICE: The perinatal period is a sensitive time window for mother-infant health, especially during a critical time like the COVID-19 pandemic. We suggest that home-visiting programs could be beneficial during global healthcare emergencies to promote maternal well-being after delivery.

Is Brain-Derived Neurotropic Factor Methylation Involved in the Association Between Prenatal Stress and Maternal Postnatal Anxiety During the COVID-19 Pandemic?

Background: The COVID-19 pandemic is a collective trauma that may expose susceptible individuals to high levels of stress. Pregnant women represent a high-risk population, considering that pregnancy is a period of heightened neuroplasticity and susceptibility to stress through epigenetic mechanisms. Previous studies showed that the methylation status of the BDNF gene is linked with prenatal stress exposure. The goals of this study were (a) to assess the association between pandemic-related stress and postnatal anxiety and (b) to investigate the potential role of maternal BDNF methylation as a significant mediator of this association. Methods: In the present study, we report data on the association among pandemic-related stress during pregnancy, maternal BDNF methylation, and postnatal anxiety symptoms. Pandemic-related stress and postnatal anxiety were assessed through self-report instruments. BDNF methylation was estimated in 11 CpG sites in DNA from mothers' buccal cells. Complete data were available from 108 mothers. Results: Results showed that pandemic-related stress was associated with an increased risk of postnatal anxiety, r = 0.20, p < 0.05. CpG-specific BDNF methylation was significantly associated with both prenatal pandemic-related stress, r = 0.21, p < 0.05, and postnatal maternal anxious symptoms, r = 0.25, p = 0.01. Moreover, a complete mediation by the BDNF CpG6 methylation emerged between pandemic-related stress during pregnancy and postnatal maternal anxiety, ACME = 0.66, p < 0.05. Conclusion: These findings suggest that BDNF epigenetic regulation by pandemic-related stress might contribute to increase the risk of anxiety in mothers. Policymakers should prioritize the promotion of health and wellbeing in pregnant women and mothers during the present healthcare emergency.

Epilepsy Course and Developmental Trajectories in STXBP1-DEE.

Background and Objectives: Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy. Methods: Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE. Results: Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course. Discussion: The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.

Pediatric Moyamoya Disease and Syndrome in Italy: A Multicenter Cohort.

Background: Moyamoya is a rare progressive cerebral arteriopathy, occurring as an isolated phenomenon (moyamoya disease, MMD) or associated with other conditions (moyamoya syndrome, MMS), responsible for 6-10% of all childhood strokes and transient ischemic attacks (TIAs). Methods: We conducted a retrospective multicenter study on pediatric-onset MMD/MMS in Italy in order to characterize disease presentation, course, management, neuroradiology, and outcome in a European country. Results: A total of 65 patients (34/65 women) with MMD (27/65) or MMS (38/65) were included. About 18% (12/65) of patients were asymptomatic and diagnosed incidentally during investigations performed for an underlying condition (incMMS), whereas 82% (53/65) of patients with MMD or MMS were diagnosed due to the presence of neurological symptoms (symptMMD/MMS). Of these latter, before diagnosis, 66% (43/65) of patients suffered from cerebrovascular events with or without other manifestations (ischemic stroke 42%, 27/65; TIA 32%, 21/65; and no hemorrhagic strokes), 18% (12/65) of them reported headache (in 4/12 headache was not associated with any other manifestation), and 26% (17/65) of them experienced multiple phenotypes (≥2 among: stroke/TIA/seizures/headache/others). Neuroradiology disclosed ≥1 ischemic lesion in 67% (39/58) of patients and posterior circulation involvement in 51% (30/58) of them. About 73% (47/64) of patients underwent surgery, and 69% (45/65) of them received aspirin, but after diagnosis, further stroke events occurred in 20% (12/61) of them, including operated patients (11%, 5/47). Between symptom onset and last follow-up, the overall patient/year incidence of stroke was 10.26% (IC 95% 7.58-13.88%). At last follow-up (median 4 years after diagnosis, range 0.5-15), 43% (26/61) of patients had motor deficits, 31% (19/61) of them had intellectual disability, 13% (8/61) of them had epilepsy, 11% (7/61) of them had behavioral problems, and 25% (13/52) of them had mRS > 2. The proportion of final mRS > 2 was significantly higher in patients with symptMMD/MMS than in patients with incMMS (p = 0.021). Onset age <4 years and stroke before diagnosis were significantly associated with increased risk of intellectual disability (p = 0.0010 and p = 0.0071, respectively) and mRS > 2 at follow-up (p = 0.0106 and p = 0.0009, respectively). Conclusions: Moyamoya is a severe condition that may affect young children and frequently cause cerebrovascular events throughout the disease course, but may also manifest with multiple and non-cerebrovascular clinical phenotypes including headache (isolated or associated with other manifestations), seizures, and movement disorder. Younger onset age and stroke before diagnosis may associate with increased risk of worse outcome (final mRS > 2).

Cognitive, Behavioral and Socioemotional Development in a Cohort of Preterm Infants at School Age: A Cross-Sectional Study.

More than 50% of children who survive prematurity have an atypical course of development at school age, as environmental demands become more demanding. This study examines the effects of preterm birth on the cognitive, behavioral and socioemotional development of 185 children at ages five and seven years. Weaknesses were found in attention, working memory, processing speed and the ability to correctly interpret emotions at both ages five and seven. Significant correlations were found in regression and moderation models. These findings suggest that school-age children who were preterm infants are at increased risk of exhibiting impairments in several developmental domains that may affect their overall quality of life.

School-Age Outcome of Fetuses with Isolated Complete Septum Pellucidum Agenesis at Prenatal Magnetic Resonance Imaging.

OBJECTIVE: To the best of our knowledge, there have not been studies to address the issue of long-term follow-up of patients with prenatal diagnosis of isolated complete septum pellucidum agenesis (SPA). The aim of this study was to acquire information about the school-age outcome of such patients as a resource for counseling parents receiving this prenatal finding. METHODS: From a large fetal magnetic resonance (MR) database, we selected only those cases with isolated complete SPA as confirmed by two senior pediatric neuroradiologists in consensus; we then gathered information from the parents of those children who had reached the school age. RESULTS: None among the 12 cases (mean age at follow-up: 8.7 years, range: 6-13 year) of the resulting final cohort presented visual or stature deficits; only one required special teaching assistance in school. All other 11 children resulted without any notable academic issue. CONCLUSION: Our report may provide information of practical value about the school-age outcome of fetuses detected by prenatal MR imaging to carry isolated complete SPA.

Prenatal Diagnosis and Neurodevelopmental Outcome in Isolated Cerebellar Hypoplasia of Suspected Hemorrhagic Etiology: a Retrospective Cohort Study.

Data about the neurological prognosis of isolated cerebellar hypoplasia in utero are scant and inconsistent. In this monocentric retrospective study, we describe the neurodevelopmental outcomes in a series of children with isolated cerebellar hypoplasia of presumably hemorrhagic origin prenatally detected with fetal magnetic resonance imaging (fMRI). We retrospectively reviewed the charts of all the pregnant women who were referred for a neurological consultation, diagnosed with fetal encephalic malformation/disruption between 2010 and 2020 in the Fetal Therapy Unit of our institution. Fetal MRI (fMRI) was performed in all the pregnancies. Fetuses with cerebellar hypoplasia presumably of hemorrhagic origin were selected for the study. Fetuses exposed to alcohol or with additional malformations in other cerebral or body areas were excluded. All the infants received the postpartum follow-up care adopted in our center, including post-natal MRI, serial neurological examinations, standardized neurodevelopmental tests, and regular parental interviews. Cognitive functions were tested with GRIFFITHS II, WPPSI-III, and WISC-IV according to the child's age. A total of 14 pregnant women out of 479 fetal consultations were eligible and included in the study group. In 57% of cases, the etiology of the hemorrhage was unknown. In 21% of cases, it was attributed to a blood transfusion, while in the remaining ones, it was attributed to maternal predisposing factors. Among the survivors, two infants were excluded for prematurity, and two were lost to follow-up. Ten patients were thus included in the study. Six patients had normal neurodevelopment and cognition, and three presented mild-moderate neurological signs, i.e., mild dyspraxia and visuoperceptual impairment. Only one child had a severe outcome, i.e., autism spectrum disorder. The cerebellum is particularly vulnerable to disruptions throughout its prolonged development. Extreme caution must be used in prenatal counseling considering that in the acute phase, lesion extension and vermis involvement can be overestimated with fMRI. In cases of uncertainty, performing an additional fMRI could be advisable after 4-8 weeks. However, in our series, infants with isolated cerebellar hypoplasia tended to have a favorable prognosis. Nevertheless, a long-term follow-up is needed and should include a postnatal brain MRI, serial neurological examinations, and neurodevelopmental tests at least up to school age.

Depression and Anxiety in Mothers Who Were Pregnant During the COVID-19 Outbreak in Northern Italy: The Role of Pandemic-Related Emotional Stress and Perceived Social Support.

The COVID-19 pandemic is a collective trauma that is threatening citizens' mental health resulting in increased emotional stress, reduced social support, and heightened risk for affective symptoms. The present study aimed to investigate the effects of antenatal pandemic-related emotional stress and perceived social support on the symptoms of depression and anxiety of mothers who were pregnant during the initial COVID-19 outbreak in northern Italy. A sample of 281 mothers was enrolled at eight maternity units in the first hotspot region of the COVID-19 outbreak in northern Italy. Participants filled out online questionnaires assessing the direct or indirect exposure to the SARS-CoV-2 virus, pandemic-related stress, perceived social support, as well as symptoms of depression and anxiety. Depressive and anxious symptomatology was above clinical concern, respectively, in 26 and 32% of the respondents. Mothers who reported no exposure to SARS-CoV-2 during pregnancy and those who reported at least one direct or indirect exposure did not differ in terms of affective symptoms. Continuous scores and risk for severe depression and anxiety were positively associated with prenatal pandemic-related emotional stress and negatively linked with perceived social support during pregnancy. Women who become mothers during the COVID-19 emergency may be at high risk for affective problems. Dedicated preventive programs are needed to provide adequate preventive support and care for maternal mental health during and after the COVID-19 pandemic.

Hidden pandemic: COVID-19-related stress, SLC6A4 methylation, and infants' temperament at 3 months.

The COVID-19 pandemic represents a collective trauma that may have enduring stress effects during sensitive periods, such as pregnancy. Prenatal stress may result in epigenetic signatures of stress-related genes (e.g., the serotonin transporter gene, SLC6A4) that may in turn influence infants' behavioral development. In April 2020, we launched a longitudinal cohort study to assess the behavioral and epigenetic vestiges of COVID-19-related prenatal stress exposure in mothers and infants. COVID-19-related prenatal stress was retrospectively assessed at birth. SLC6A4 methylation was assessed in thirteen CpG sites in mothers and infants' buccal cells. Infants' temperament was assessed at 3-month-age. Complete data were available from 108 mother-infant dyads. Greater COVID-19-related prenatal stress was significantly associated with higher infants' SLC6A4 methylation in seven CpG sites. SLC6A4 methylation at these sites predicted infants' temperament at 3 months.

Neuroimaging and neurodevelopmental outcome after early fetal growth restriction: NEUROPROJECT-FGR.

BACKGROUND: Adverse neurodevelopmental outcomes and MRI alterations are reported in infants born after fetal growth restriction (FGR). This study evaluates the additional role of FGR over prematurity in determining brain impairment. METHODS: Retrospective observational study comparing 48 FGR and 36 appropriate for gestational age infants born between 26 and 32 weeks' gestation who underwent a cerebral MRI at term equivalent age. Exclusion criteria were twins, congenital anomalies, and findings of overt brain lesions. Main outcomes were total maturation score (TMS) and cerebral areas independently measured by two neuro-radiologists and Griffiths or Bayley scale III scores at median age of 2 years. RESULTS: TMS was not significantly different between the groups. Inner calvarium and parenchyma's areas were significantly smaller in FGR cases. There were no significant differences in the average quotient scores. A positive correlation between parenchyma area and cognitive score was found (r = 0.372, p = 0.0078) and confirmed after adjusting for sex, gestational age, and birth weight (p = 0.0014). Among FGR, the subgroup with umbilical arterial Doppler velocimetry alterations had significantly worse gross motor scores (p = 0.005). CONCLUSIONS: FGR plays additional role over prematurity in determining brain impairment. An early structural dimensional MRI evaluation may identify infants who are at higher risk. IMPACT: Fetal growth-restricted infants showed smaller cerebral parenchymal areas than preterm controls. There is a positive correlation between the parenchyma area and the cognitive score. These results highlight the already known link between structure and function and add importance to the role of a structural dimensional MRI evaluation even in the absence of overt brain lesions.

Measuring the Outcomes of Maternal COVID-19-related Prenatal Exposure (MOM-COPE): study protocol for a multicentric longitudinal project.

INTRODUCTION: COVID-19 is a highly infectious respiratory disease that rapidly emerged as an unprecedented epidemic in Europe, with a primary hotspot in Northern Italy during the first months of 2020. Its high infection rate and rapid spread contribute to set the risk for relevant psychological stress in citizens. In this context, mother-infant health is at risk not only because of potential direct exposure to the virus but also due to high levels of stress experienced by mothers from conception to delivery. Prenatal stress exposure associates with less-than-optimal child developmental outcomes, and specific epigenetic mechanisms (eg, DNA methylation) may play a critical role in mediating this programming association. METHODS AND ANALYSIS: We present the methodological protocol for a longitudinal, multicentric study on the behavioural and epigenetic effects of COVID-19-related prenatal stress in a cohort of mother-infant dyads in Northern Italy. The dyads will be enrolled at 10 facilities in Northern Italy. Saliva samples will be collected at birth to assess the methylation status of specific genes linked with stress regulation in mothers and newborns. Mothers will provide retrospective data on COVID-19-related stress during pregnancy. At 3, 6 and 12 months, mothers will provide data on child behavioural and socioemotional outcomes, their own psychological status (stress, depressive and anxious symptoms) and coping strategies. At 12 months, infants and mothers will be videotaped during semistructured interaction to assess maternal sensitivity and infant's relational functioning. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee (Pavia). Results will be published in peer-reviewed journals and presented at national and international scientific conferences. TRIAL REGISTRATION NUMBER: NCT04540029; Pre-results.

Incidence of Cerebral Injury in Monochorionic Twin Survivors after Spontaneous Single Demise: Long-Term Outcome of a Large Cohort.

OBJECTIVES: To evaluate incidence of cerebral injury and outcome in a large series of monochorionic (MC) twin survivors after spontaneous single fetal demise. METHODS: Retrospective analysis of all MC pregnancies with single fetal demise diagnosed at, or referred to, the Fetal Therapy Unit "U. Nicolini," V. Buzzi Children's Hospital, Milan, Italy, from 2004 to 2015. Survivors evaluation protocol included detailed ultrasound (US) of intracranial anatomy, Doppler investigation of peak systolic velocity in the middle cerebral artery (MCA-PSV), and magnetic resonance (MR). Data were collected on pregnancy characteristics, postnatal brain scan, and MR and neurological follow-up. RESULTS: Seventy-eight consecutive MC pregnancies were analyzed. Median gestational age (GA) at single fetal demise was 22 weeks (range 15-36); median interval between single demise and live birth was 105 days (range 1-175), with a median GA at birth of 36 weeks (range 23-41). Prenatal MR was performed in 57 of 78 cases (73%). Cerebral injury affected 14/78 (18%) co-twins, 2 of whom were born immediately after single demise, with postnatal diagnosis of cerebral injury; of the other 12 fetuses that were studied before birth, 10 had a prenatal diagnosis of lesion both with US and MR, one only with MR, and in one case, a grade III intraventricular hemorrhage was reported only after delivery, which occurred at 25 weeks, 5 weeks after the single demise. Signs of fetal anemia (MCA-PSV value above 1.55 MoM) were related to a higher risk of prenatal cerebral injury; cases with postnatal diagnosis of lesion were delivered at lower GA. CONCLUSIONS: Cerebral injury affects 18% of co-twin survivors after single fetal demise in MC twin pregnancies, and evaluation and follow-up of these cases can improve detection rate of such damage.