Long-term Neurodevelopmental Outcome In Children Research Articles

Short-term neonatal and long-term neurodevelopmental outcome of children born term low birth weight

This study aimed to examine the impact of term LBW on short-term neonatal and long-term neurodevelopmental outcomes in children 5–7 years of age. This is a population-based cohort study that merged national data from the Korea National Health Insurance claims and National Health Screening Program for Infants and Children. The participants were women who gave birth at a gestational age of ≥ 37 weeks between 2013 and 2015 in the Republic of Korea, and were tracked during 2020 for the neurodevelopmental surveillance of their children. Among 830,806 women who gave birth during the study period, 31,700 (3.8%) of their babies weighed less than 2500 g. By Cox proportional hazard analysis, children aged 5–7 years who had LBW were associated with any developmental, motor developmental delay, cognitive developmental delay, autism spectrum, attention deficit hyperactivity disorders, and epileptic and febrile seizures.Children born with term LBW were more vulnerable to neurodevelopmental disorders at 5–7 years of age than those with normal and large birth weights. This study further substantiates counseling parents regarding the long-term outcomes of children being born underweight.

A single-center observational study on long-term neurodevelopmental outcomes in children with tuberous sclerosis complex

BackgroundTuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients.MethodsThis cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation.ResultsThirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset (p < 0.05).ConclusionsThe results emphasized the phenotypic variability of pediatric-onset TSC and the high rate of neurological and neuropsychiatric morbidity. Early-onset refractory epilepsy was associated with impaired cognitive development. Children of all ages with TSC require multidisciplinary long-term care and individual early-intervention programs.

Long-term neurodevelopmental outcome in children born after vacuum-assisted delivery compared with second-stage caesarean delivery and spontaneous vaginal delivery: a cohort study

ObjectiveTo evaluate long-term neurodevelopment in children born after low-or mid-station vacuum-assisted delivery (VAD) compared with children delivered by second-stage caesarean delivery (SSCD) or spontaneous vaginal delivery (SVD).DesignCross-sectional cohort study.SettingTwo delivery...

Umbilical cord blood acid-base analysis at birth and long-term neurodevelopmental outcomes in children: a systematic review and meta-analysis.

Umbilical cord blood acid-base sampling is routinely performed at many hospitals. Recent studies have questioned this practice and the association of acidosis with cerebral palsy. To investigate the associations between the results of umbilical cord blood acid-base analysis at birth and long-term neurodevelopmental outcomes and mortality in children. We searched six databases using the search strategy: umbilical cord AND outcomes. Randomised controlled trials, cohorts and case-control studies from high-income countries that investigated the association between umbilical cord blood analysis and neurodevelopmental outcomes and mortality from 1 year after birth in children born at term. We critically assessed the included studies, extracted data and conducted meta-analyses comparing adverse outcomes between children with and without acidosis, and the mean proportions of adverse outcomes. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations approach. We have very low confidence in the following findings: acidosis was associated with higher cognitive development scores compared with non-acidosis (mean difference 5.18, 95% CI 0.84-9.52; n = two studies). Children with acidosis also showed a tendency towards higher risk of death (relative risk [RR] 5.72, 95% CI 0.90-36.27; n = four studies) and CP (RR 3.40, 95% CI 0.86-13.39; n = four studies), although this was not statistically significant. The proportion of children with CP was 2.39/1000 across the studies, assessed as high certainty evidence. Due to low certainty of evidence, the associations between umbilical cord blood gas analysis at delivery and long-term neurodevelopmental outcomes in children remains unclear.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.

Early neurodevelopmental outcomes in children with asymptomatic congenital CMV infection

BackgroundApproximately 85–90% of congenital cytomegalovirus infections (cCMV) are asymptomatic. Few studies have investigated early and long-term neurodevelopmental outcomes in children with asymptomatic cCMV (acCMV), and the data is contradictory. In the present study, we did investigate the effect of cCMV asymptomatic infection on neurological outcomes and in cognitive, language and motor development at 6 months of age.MethodsFifty-six children with cCMV asymptomatic infection were followed for 6 months, as part of a long-term surveillance program, examining their neurological and developmental outcomes. Neurological examination and Bayley-III Scales were performed.ResultsClinical evaluation revealed that early neurological outcomes were essentially normal, with minor neurological deficits (i.e., tone abnormalities) in a subgroup of patients. Bayley-III scores were substantially in the normal range, with 14% showing a score less than 85 (-1SD) in the Motor Scale. Children's neurological and neurodevelopmental outcomes at 6 months of age did not differ according to the trimester of infection.ConclusionsSome infants with cCMV asymptomatic infection may present minor neurological abnormalities in early stages of life. It seems useful to monitor this population for early and late neurodevelopmental sequelae.

Long-term neurodevelopmental outcome in children after antenatal intravenous immune globulin treatment in fetal and neonatal alloimmune thrombocytopenia

Children with fetal and neonatal alloimmune thrombocytopenia face increased risk of intracranial hemorrhage potentially leading to developmental impairment. To prevent intracranial hemorrhage, pregnant women with alloantibodies against fetal platelets are often treated with intravenous immunoglobulin. Intravenous immunoglobulin seems effective in vastly reducing the risk of fetal or neonatal bleeding complications. However, information on long-term neurodevelopment of these children is lacking. This study aimed to evaluate long-term neurodevelopmental outcome in children with fetal and neonatal alloimmune thrombocytopenia who were treated with intravenous immunoglobulin antenatally. An observational cohort study was performed, including children of mothers treated with intravenous immunoglobulin during pregnancy because a previous child was diagnosed with fetal and neonatal alloimmune thrombocytopenia. Children were invited for a follow-up assessment including standardized cognitive and neurologic tests. The parents were asked to complete a behavioral questionnaire and school performance reports. The primary outcome was severe neurodevelopmental impairment, defined as severe cognitive impairment (intelligence quotient <70), cerebral palsy with Gross Motor Function Classification System Level ≥3, bilateral blindness, and/or bilateral deafness (requiring amplification). The secondary outcome was mild to moderate neurodevelopmental impairment, defined as either mild to moderate cognitive impairment (intelligence quotient <85), cerebral palsy with Gross Motor Function Classification System Level ≤2, minor neurologic dysfunction, vision loss, and/or hearing loss. Between 2003 and 2017, 51 children were live-born after antenatal intravenous immunoglobulin treatment. One family moved abroad and was therefore not eligible for inclusion. In total, 82% (41/50) of the eligible cases were included for neurodevelopmental assessment at a median age of 9 years and 8 months. Severe neurodevelopmental impairment was not detected. The incidence of mild to moderate neurodevelopmental impairment was 14% (6/41; 95% confidence interval, 6%-29%). The children's mean cognitive score, behavioral scores, and academic achievement were not different from those observed in the Dutch norm groups. Neuroimaging was performed in 90% (37/41) of cases. Severe intracranial hemorrhage was diagnosed in 2 cases (5%), one antenatally before the start of intravenous immunoglobulin and the other case 1 day after birth. Both cases had a normal neurodevelopmental outcome. The risk of neurodevelopmental impairment in children whose mothers were treated for fetal and neonatal alloimmune thrombocytopenia with antenatal intravenous immunoglobulin is comparable to that reported in the general population.

Attention Deficit Hyperactivity Disorder in Children Born to Patients with Infertility: A Population-Based Cohort Study

Long-term neurodevelopmental outcomes in children conceived to mothers requiring infertility treatment are unknown. We investigated the association between infertility, infertility treatment, and risk of childhood attention deficit disorder (ADHD).

Long-Term Neurodevelopmental Outcome in Children with Congenital Cytomegalovirus Infection: A Prospective Multicenter Cohort Study

Long-Term Neurodevelopmental Outcome in Children with Congenital Cytomegalovirus Infection: A Prospective Multicenter Cohort Study

Long-term neurodevelopmental outcomes of the pump twin in twin reversed arterial perfusion sequence treated by radiofrequency ablation.

ObjectivesTo assess long‐term neurodevelopmental outcomes in children after radiofrequency ablation (RFA) for twin reversed arterial perfusion (TRAP) sequence.MethodsThis cross‐sectional study included children who underwent RFA for the TRAP sequence between 2012 and 2018. We assessed neurodevelopment in children using the Kinder Infant Development Scale, a validated questionnaire. The developmental quotient (DQ) assessed in nine subscales was calculated as the developmental age divided by the chronological age. Neurodevelopmental delay (NDD) was defined as a DQ of <70 points.ResultsIn total, 38 children from 37 pregnancies underwent RFA for the TRAP sequence during the study period; 6 fetuses died in utero. We sent the questionnaire to the parents of the 32 surviving children and obtained answers for 27 (84%). The median age at the assessment was 2 years and 5 months old. The median total DQ was 111 (80–150). Most median DQs in the nine subscales were above 70. The incidence of NDD was 0% (0/27). There were no marked differences in DQ by chorionicity.ConclusionsChildren who survived after RFA for TRAP sequence showed favorable long‐term neurodevelopmental outcomes. Radiofrequency ablation seems to rarely affect fetal neurodevelopment. Pregnant women with TRAP sequence are encouraged to be treated by RFA.

Predictors of long-term neurodevelopmental outcomes of children born extremely preterm

Children born extremely preterm (<28 weeks’ gestation) are at high risk of a range of adverse neurodevelopmental outcomes in later childhood compared with their peers born at term, including cognitive, motor, and behavioral difficulties. These difficulties can be associated with poorer academic achievement and health outcomes at school age. In this review, we discuss several predictors in the newborn period of early childhood neurodevelopmental outcomes including perinatal risk factors, neuroimaging findings and neurobehavioral assessments, along with social and environmental influences for children born extremely preterm. Given the complexity of predicting long-term outcomes in children born extremely preterm, we recommend multi-disciplinary teams in clinical practice to assist in determining an individual child's risk for adverse long-term outcomes and need for referral to targeted intervention, based upon their risk.

Long-term neurodevelopmental outcomes of children with congenital heart defects: A prospective, population-based cohort study (EPICARD)

No population-based prospective cohort study has assessed the neurodevelopmental outcomes of school-aged children with CHD. To assess whether some groups of CHDs, more specifically cyanotic CHD (CCHD) with or without heart failure and non CCHD with heart failure, are at greater risk of adverse neurodevelopmental outcomes at 8 years of age. We used data from the prospective population-based cohort study EPICARD, which included all children with a CHD diagnosed in the prenatal period and up to 1 year of age, between 2005 and 2008 in the greater Paris areas. We looked at the overall intellectual quotient (IQ), and the specific neurocognitive domains. We classified the CHDs based on pathophysiological and clinical management characteristics and compared the outcomes across six groups of CHDs as compared with the control group (minor ventricular septal defects). In order to do so, we used multivariable linear regression models with the Heckman method to account for selection bias due to differential loss to follow-up. From the 1196 eligible patients for the 8-year follow up, 473 (39.5%) completed the neurodevelopmental evaluations. Compared to the control group, children with CCHD with or without heart failure had lower IQ scores, −8.0 ( P < 0.01) and −7.3 ( P = 0.02), respectively. Those with CCHD and non CCHD with heart failure also had lower scores at the language subtest, −1.9 ( P < 0.01) and − 1.4 ( P < 0.01), respectively. CCHD and non CCHD with heart failure and CHD with increased pulmonary blood flow had lower learning and memory scores, −1.36 ( P < 0.01), −1,2 ( P = 0.05) and − 0.9 ( P = 0.04), respectively. CCHD with heart failure had lower scores in the executive functions (inhibition) domain, −1.2 ( P = 0.05) Children with CHD associated with cyanosis and/or heart failure had significantly lower neurodevelopment scores at 8 years of age, both for overall IQ and specific neurocognitive domains.

Long-term neurodevelopment in children born with esophageal atresia: a systematic review.

SummaryBackgroundAlthough the survival rate of esophageal atresia (EA) has increased to over 90%, the risk of functional long-term neurodevelopmental deficits is uncertain. Studies on long-term outcomes of children with EA show conflicting results. Therefore, we provide an overview of the current knowledge on the long-term neurodevelopmental outcome of children with EA.MethodsWe performed a structured literature search in Embase, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google scholar on November 8, 2020 with the keywords ‘esophageal atresia’, ‘long-term outcome’, ‘motor development’, ‘cognitive development’, and ‘neurodevelopment’.ResultsThe initial search identified 945 studies, of which 15 were included. Five of these published outcomes of multiple tests or tested at multiple ages. Regarding infants, one of six studies found impaired neurodevelopment at 1 year of age. Regarding preschoolers, two of five studies found impaired neurodevelopment; the one study assessing cognitive development found normal cognitive outcome. Both studies on motor function reported impairment. Regarding school-agers, the one study on neurodevelopmental outcome reported impairment. Cognitive impairment was found in two out of four studies, and motor function was impaired in both studies studying motor function.ConclusionsLong-term neurodevelopment of children born with EA has been assessed with various instruments, with contrasting results. Impairments were mostly found in motor function, but also in cognitive performance. Generally, the long-term outcome of these children is reason for concern. Structured, multidisciplinary long-term follow-up programs for children born with EA would allow to timely detect neurodevelopmental impairments and to intervene, if necessary.

Long-Term Neurodevelopmental Outcomes of Children with Congenital Heart Defects

To assess whether children with symptomatic congenital heart defects (CHDs) at birth (cyanosis and/or heart failure) are at greater risk of adverse neurodevelopmental outcomes at 8years of age. From a prospective population-based cohort study of newborns with CHDs (EPICARD), we included 473 children with available neurodevelopmental assessments at 8years of age. We grouped the CHD based on symptoms at birth and need for early neonatal intervention. Ventricular septal defects that closed spontaneously within the first year of life were considered the control group. Neurodevelopmental outcomes were assessed using the Kauffman Assessment Battery Test for Children, Second Edition, for IQ (mean 100±15), and the Developmental NEuroPSYchological Assessment Battery, Second Edition, for detailed assessment of specific neurocognitive domains (mean 10±3). Multivariable regression analysis was used to compare the outcomes across the CHD groups after considering potentially confounding variables. Compared with the control group, children with cyanotic CHD without heart failure had lower scores for IQ, -7.2 (95% CI -13.4 to -1.2). Children with noncyanotic CHD with heart failure had lower scores in the specific domains of language -1.5 (95% CI -2.2 to -0.7), and memory and learning -1.3 (95% CI -2.4; -0.3). Those with both cyanotic CHD and heart failure had lower scores for IQ, -7.6 (95% CI -13.5 to -1.8), as well as the specific domains of language and memory and learning, -2.0 (95% CI -2.9 to -1.0) and -1.1 (95% CI -2.3 to -0.1), respectively. Children with symptomatic CHD at birth are at greater risk of adverse neurodevelopmental outcomes at 8years of age, with the greatest risk for those who were born with both cyanosis and heart failure.

Neonatal hypoxic-ischemic encephalopathy diagnosis and treatment: a National Survey in China

BackgroundNeonatal hypoxic-ischemic encephalopathy (HIE) affects as many as 100,000 infants each year in China. Therapeutic hypothermia reduces HIE related mortality and long-term neurodevelopmental disabilities. National guidelines for HIE management were published a decade ago. This study aimed to investigate the current status of HIE diagnosis and treatment in China.MethodThis prospective cross-sectional national survey used a questionnaire evaluating practices related to HIE management. Descriptive statistics and Chi-square or Fisher’s exact test were used, and a p-value of < 0.05 was considered significant.ResultsThe 273 hospitals that completed the survey were located in 31 of the 34 provincial districts in China. Eighty-eight percent of the hospitals were Level III hospitals, and 74% treated 10 or more HIE cases annually. Awareness rates of the national guidelines for HIE diagnosis, HIE treatment, and therapeutic hypothermia protocol were 85, 63, and 78%, respectively. Neurological manifestations and blood gas were used as HIE diagnostic criteria by 96% (263/273) and 68% (186/273) of the hospitals, respectively. Therapeutic hypothermia was used in 54% (147/273) of hospitals. The percentage of general hospitals that implemented therapeutic hypothermia (43%, 71/165) was significantly lower than that in maternity and infant hospitals (67%, 49/73) (χ2 = 11.752, p = 0.001) and children’s hospitals (77%, 27/35) (χ2 = 13.446, p < 0.001). Reasons for not providing therapeutic hypothermia included reduction of HIE cases in recent years (39%), high cost of cooling devices and treatment (31%), lack of training (26%), and safety concerns (4%). Among the hospitals that provided therapeutic hypothermia, 27% (39/147) were in full compliance with the recommended protocol. Eighty-one percent (222/273) of the hospitals treated HIE infants with putative neuroprotective agents alone or in combination with cooling. Ninety-one percent of the hospitals had long-term neurodevelopmental follow-up programs for infants with HIE.ConclusionsThere is significant heterogeneity in HIE diagnosis and treatment in China. Therapeutic hypothermia has not become a standard of care for neonatal HIE nationwide. Unproven agents are widely used for HIE treatment. Nationwide standardization of HIE management and dissemination of therapeutic hypothermia represent the opportunities to reduce mortality and improve long-term neurodevelopmental outcomes of children affected by HIE.

Long-term neurodevelopmental outcome after prenatal exposure to maternal hematological malignancies with or without cytotoxic treatment

ABSTRACT Data on the long-term neurodevelopmental outcomes of children exposed to hematological maternal cancer with or without treatment during pregnancy are lacking. A total of 57 children, of whom 33 males and 24 females, prenatally exposed to hematological malignancies and its treatment, were invited for neuropsychological and physical examinations at 18 months, 36 months, 6, 9, 12, 15 and 18 years of age. Oncological, obstetrical, neonatal and follow-up data of these children were collected. Parents were asked to complete questionnaires on their child’s general health, school performances, social situation, behavioral development, executive functioning, and if their child receives supportive care. Non-Hodgkin lymphoma was diagnosed in 35.1%, Hodgkin lymphoma in 28.1%, acute myeloid leukemia in 15.8%, chronic myeloid leukemia in 12.3%, and acute lymphoblastic leukemia in 8.8%. Cognitive development at a median age of 10.7 years was within the normal range. In subgroup analyses of children in early childhood, the gestational age at birth was correlated with the cognitive outcome at a median age of 1.7 years. Scores for language development, intelligence, attention, memory and behavior, as well as clinical neurological and general pediatric examinations were within normal ranges. In subgroup analyses, the need for supportive care in the child was associated with the loss of the mother. Prenatal exposure to hematological maternal malignancies with or without treatment did not affect the neurodevelopment of the child in the long term. Yet, caution is indicated and surveillance of the emotional development of the child is needed, especially when the mother is deceased to cancer.

Neonatal hyperglycaemia is associated with worse neurodevelopmental outcomes in extremely preterm infants

ObjectiveTo assess the associations between neonatal hyperglycaemia and insulin treatment, versus long-term neurodevelopmental outcomes in children born extremely preterm.Design and settingObservational national cohort study (Extremely Preterm Infants in Sweden Study)...

Long-Term Neurodevelopmental Outcome of Children after in Utero Exposure to Chemotherapy

Simple SummaryFacing cancer diagnosis during pregnancy constitutes a truly complex and challenging situation for both the patients and the physicians. Cancer diagnosis in a period of hope and joy is an unendurable situation that may affect the psychosocial functioning of the mother, causing depression, anxiety, self-blame, and social isolation. At the same time, a moral dilemma evolves among medical professionals; what is best for the mother in terms of immediate chemotherapy may have detrimental effects on the fetus, and conversely, delaying therapy and protecting the fetus may have a negative impact on the mother as the tumor progresses. Solid data on the safety profile or risks of anti-cancer agents and on the long-term neurodevelopmental outcome of children after in utero exposure to chemotherapy may provide both the patients and the physicians the information necessary for shared decision making when cancer is diagnosed during pregnancy.Pregnancy-related cancer management represents a real challenge for both the patients and the physicians. The long-term neurodevelopmental outcome of children in utero exposed to chemotherapeutic agents has only recently been addressed. This review aims to systematically integrate and highlight all existing data from the literature regarding the effect of prenatal exposure to chemotherapy on fetal brain growth and child development. All eligible studies are based on validated neurodevelopmental testing scales (e.g., Bayley Scales of Infant Development, Wechsler Preschool and Primary Scale of Intelligence) and/or well-defined questionnaires. Our systematic review including 17 studies demonstrates that no major consequences on the neurodevelopment of children after in utero exposure to anti-cancer drugs have been reported; nevertheless, longer and more thorough follow-up with large-scale multicenter prospective studies is certainly required in order to draw firm conclusions.

Fetal Exposure to MR Imaging: Long-Term Neurodevelopmental Outcome.

Very few studies have investigated long-term neurodevelopment of children exposed to MR imaging antenatally. Thus, the purpose of our study was to evaluate long-term neurodevelopmental outcomes of children exposed to MR imaging during pregnancy. We conducted a historical prospective cohort study in a single tertiary medical center. Women exposed to 1.5T noncontrast MR imaging for maternal or fetal indications were matched to unexposed controls. Long-term neurodevelopmental outcomes were evaluated of their children, 2.5 to 6 years of age, according to the Vineland-II Adaptive Behavior Scale. The Vineland-II Adaptive Behavior Scale assesses communication, daily living skills, socialization, and motor skills. A composite score summarizes these 4 domains. A total of 131 exposed women matched our inclusion criteria and were included in the study group, and 771 unexposed women, in the control group. No difference was identified in the Vineland-II Adaptive Behavior Scale composite score between the children of the study and control groups (mean, 110.79 versus 108.18; P = .098). Differences were also not observed between the children of the 2 groups in 3 of the 4 questionnaire domains: communication (108.84 versus 109.10; P = .888), daily living skills (109.51 versus 108.28; P = .437), and motor skills (105.09 versus 104.42; P = .642). However, the socialization score was favorable for the study group (112.98 versus 106.47; P < .001). Exposure to 1.5T noncontrast MR imaging during pregnancy had no harmful effects on long-term neurodevelopmental outcomes. This study contributes to understanding the safety of MR imaging during pregnancy.

Creative music therapy to promote brain function and brain structure in preterm infants: A randomized controlled pilot study.

Cognitive and neurobehavioral problems are among the most severe adverse outcomes in very preterm infants. Such neurodevelopmental impairments may be mitigated through nonpharmacological interventions such as creative music therapy (CMT), an interactive, resource- and needs-oriented approach that provides individual social contact and musical stimulation. The aim was to test the feasibility of a study investigating the role of CMT and to measure the short- and medium-term effects of CMT on structural and functional brain connectivity with MRI. In this randomized, controlled clinical pilot feasibility trial, 82 infants were randomized to either CMT or standard care. A specially trained music therapist provided CMT via infant-directed humming and singing in lullaby style. To test the short-term effects of CMT on brain structure and function, diffusion tensor imaging data and resting-state functional imaging data were acquired. Clinical feasibility was achieved despite moderate parental refusal mainly in the control group after randomization. 40 infants remained as final cohort for the MRI analysis. Structural brain connectivity appears to be moderately affected by CMT, structural connectomic analysis revealed increased integration in the posterior cingulate cortex only. Lagged resting-state MRI analysis showed lower thalamocortical processing delay, stronger functional networks, and higher functional integration in predominantly left prefrontal, supplementary motor, and inferior temporal brain regions in infants treated with CMT. This trial provides unique evidence that CMT has beneficial effects on functional brain activity and connectivity in networks underlying higher-order cognitive, socio-emotional, and motor functions in preterm infants. Our results indicate the potential of CMT to improve long-term neurodevelopmental outcomes in children born very preterm.