Open research questions in Neonatal and fetal brain pathology
50 unresolved questions extracted from the limitations and future-work sections of 630 Neonatal and fetal brain pathology papers in our library. Each links back to the study that raised it.
What the literature leaves open
The mechanisms, multisystem physiology and ontogeny of sustained brain sparing in severe FGR are not well characterised, but advancing this knowledge affords new opportunities to diagnose and manage FGR, and to intervene to prevent adverse consequences.
This secondary analysis of existing data is limited by a small sample size and inconsistent measurements of serum creatinine during NICU admission necessitating use of urine output for AKI diagnosis.
Future studies should focus on multicenter prospective evaluations and the development of standardized, evidence-based guidelines to optimize di- agnostic precision while minimizing radiation exposure in neonates and infants. This bibliometric analysis highlights research trends and identifies gaps in literature.
Additionally, this size and the availability of a full blood cell count from a consistent timepoint establishes a reliable baseline for the 3 SGA groups, and the clinical data recorded ensures that the impact of multiple factors could be investigated.
This review has several strengths. We used a robust approach to identify and summarize etiological studies of social determinants of brain development (MRI) and behavior among pre-school children following preterm birth. The selection criteria excluded studies whose design yielded estimates that lack a causal review included 5 studies (SES-MRI) and interpretation. Our 29 studies (SES-cognition/behavior) examining children who received modern intensive care practices and are growing up in contemporary social circumstances, making their findings relevant to children of today. The study is a comprehensive overview of a growing body of literature linking SES with childhood outcomes; it identifies knowledge gaps and sources of methodological heterogeneity that should be addressed as standards and conventions in research become established. We discuss SES-MRI-behavior putative mechanisms that embed SES in child development. inference. However, Our review has limitations inherent to scoping reviews. It did not include risk-of-bias or quality assessments of the included studies, which limits causal it highlights research areas that would likely benefit from systematic review, for example, the impact of SES on cognition after preterm birth, and it provides information to inform the design of such studies. This review identifies areas that require further empirical studies, for example, the impact of SES on brain development and plasticity in childhood inferred from MRI. KNOWLEDGE GAPS AND FUTURE RESEARCH DIRECTIONS Cognitive, socioemotional and behavioral difficulties are present in about half of preterm children. Preterm birth is also associated 18 A.F. Bonthrone et al. with altered brain growth and maturation as well as brain injury, including white matter injury and intraventricular hemorrhage. However, our understanding of how SES influences different brain and behavioral domains in PTB is incomplete. This review captures the current state of the art regarding the influence of socioeconomic status on brain and behavioral development in pretermborn children up to age 5 years and considers the putative biological mechanisms that link SES to neurodevelopment. Here, we summarized the etiological evidence for associations between SES, brain development inferred from MRI, and early neurodevelopmental outcomes in children born preterm. Robust evidence links SES with cognition, but motor, language and socioemotional domains may also be shaped by social gradients. To further build an evidence base to intervene against the adverse effects of social disadvantage on the lives of children born preterm, we suggest the following research directions: ● Large, longitudinal studies encompassing SES measures, brain imaging, biosamples, and neurodevelopmental outcomes are required to fully characterize effects of SES in PTB across early childhood, to understand the dynamism of SES impacts over time, and to elucidate structure-function relationships.
driven feedback for facing (cid:0) See: Results section in this paper, including Supplement 3 and Supplement 4 Agreed set of 15 recommendations around definitions, aligning data, linkage of data sources, data quality, feasibility of data capture, data-driven feedback mechanisms for professionals, and improving data and data sharing relevant to families (Table 4). ( w h i c h w a s n o t c e r t i f i e d b y p e e r I t i s m a d e r e v i e w ) a v a i l a b e l u n d e r - - a C C B Y N C N D 4 . 0 - I t n e r n a t i o n a l l i c e n s e . i s t h e a u t h o r / f u n d e r , w h o h a s g r a n t e d m e d R x v a i l i c e n s e t o i d s p a y l 22 t h e p r e p r i n t i n p e r p e t u i t y . m e d R x v i p r e p r i n t d o i : h t t p s : / / d o i . o r g / 1 0 . 6 4 8 9 8 / 2 0 2 6 . 0 5 . 0 1 . 2 6 3 5 2 2 0 6 ; t h s i v e r s o n i p o s t e d M a y 7 , 2 0 2 6 . T h e c o p y r i g h t l h o d e r f o r t h s i p r e p r i n t Abbreviations: Maternity Services Data Set (MSDS), Hospital Episode Statistics for Admitted Patient Care (HES APC), the National Neonatal Research Database (NNRD), National Maternity and Perinatal Audit (NMPA). medRxiv preprint doi: https://doi.org/10.64898/2026.05.01.26352206 ; this version posted May 7, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Table 2. Survey participants’ ratings of the importance of clinical indicators and risk factors for understanding potentially avoidable brain injury around the time of birth. N indicates total number of responses.
Improving UK data on avoidable perinatal brain injury: consultations and co-creation of recommendations · 2026 · DOIUsing an asynchronous consensus exercise conducted over email, the advisory group and the patient/family representatives shaped and agreed a set of 15 recommendations (Table 4 and Supplement 5).
Improving UK data on avoidable perinatal brain injury: consultations and co-creation of recommendations · 2026 · DOIOur approach enabled the expertise of diverse stakeholders to be mobilised at scale to agree strategic recommendations in an area of pressing need.22,23 While focused on UK perinatal brain injury, the approach and findings may be highly relevant to address data challenges and improvement needs in other maternity and neonatal areas (both in the UK and beyond),17,21,24- 26 though this requires further evaluation. A limitation is that it was not feasible to involve all relevant stakeholders. Convenience sampling for the national survey supported broad inclusion but not full representativeness, while future efforts should engage additional senior UK decision makers beyond those consulted in the multidisciplinary groups. A further technical issue to address is understanding how any updates to, or stronger linkage within, existing datasets may affect the identification of missing items identified in our earlier data dictionary review.22 Finally, we acknowledge that many of the proposed recommendations are aspirational, but also believe that without a clear improvement vision it will be difficult to gain traction and make change over the long-term.
Improving UK data on avoidable perinatal brain injury: consultations and co-creation of recommendations · 2026 · DOIThe development of algorithms for the diagnosis of fetal growth restriction using non-invasive electrocardiography requires further research of the following parameters: SI, TP, AC/DC, LF, LF/HF ratio, QTc duration, QRS complex width, and T/QRS ratio.
Prospects for the study of some electrophysiological parameters in the diagnosis of fetal growth restriction · 2023 · DOIConclusion: Fetal resistance to impending labor hypoxia has not been previously investigated, so values of low fetal resistance to intrauterine hypoxia are still not among the indications for the use of excess oxygen and the choice of Cesarean section to exclude stillbirth and neonatal encephalopathy.
Aerobic Brain Metabolism, Body Temperature, Oxygen, Fetal Oxygen Supply and Fetal Movement Dynamics as Factors in Stillbirth and Neonatal Encephalopathy: Invention Review · 2023 · DOIIn this study, it was determined that HF mostly developed for non-immune reasons, prenatal diagnosis and follow-up were insufficient and the interventions performed in the delivery room were an important factor in predicting mortality in the follow-up of neonates with HF.
Objective: Effect of nutritional support for preterm infants with very low (VLBW) and extremely low body (ELBW) weight with hypoxic damage of the central nervous system (CNS) of varying severity is not well elucidated.
The effects of nutritional support for premature babies with ELBW and VLBW with hypoxic damage to the central nervous system · 2020 · DOIDespite many different clinical studies on the problem of intraventricular hemorrhage, the causes of development, risk factors, as well as prediction of fatal cases in children born prematurely with existing severe IVH remain unclear and debatable.
INTRAVENTRICULAR HEMORRHAGES IN NEONATOLOGY: PREDICTION OF THE LETHAL CASES IN PREMATURE INFANTS · 2019 · DOIHowever, it is quite difficult to diagnose and predict hypoxic-ischemic myocardial injury (HIMI) in the early stages due to the lack of standard diagnostic criteria and sensitive laboratory tests.
DEBATING ISSUES AS TO THE PROGNOSIS AND DIAGNOSIS OF HYPOXIC-ISCHEMIC MYOCARDIAL INJURY BY ASPHYXIA IN NEWBORNS · 2016 · DOIWhile foals with PAS are commonly reported in the literature, the aetiology and underlying pathophysiology are still very poorly understood, with a majority of the information extrapolated from human and animal models.
Brain injury patterns identified on early MRI scans and their relationships to the nature of the hypoglycemic insult and neurodevelopmental outcomes are poorly defined.
Patterns of Cerebral Injury and Neurodevelopmental Outcomes After Symptomatic Neonatal Hypoglycemia · 2008 · DOIFuture research should focus on long-term follow-up, assessing not only survival but also neurodevelopmental outcomes, pulmonary vascular disease progression, and cardiac remodeling.
Targeted neonatal echocardiography-guided management of high flow cerebral vascular malformations: Impact of a multidisciplinary neurohemodynamics team · 2026 · DOIAlthough researchers have no identified abnormalities from cell dosing, the dose-response relationship is poorly characterized, as it remains unclear whether higher doses host greater effects than lower doses. Given the multifactorial cascade of neonatal brain injury events- involving excitotoxicity, oxidative stress, inflammation and cell death-a multimodal approach is likely to provide the greatest benefit/outcomes to neonates, but further research is required. Overall, a development in the optimized delivery methods is a critical area of research that needs to be studied in the future.
Despite the high prevalence and multifactorial nature of brain injury in preterm infants, its precise pathogenesis—as well as specific prevention and treatment protocols—remains insufficiently defined.
Mild hypothermia is a promising treatment for HIE, but its efficacy and safety in newborns are not well established.
Mild hypothermia effects on serum neuroprotection, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and superoxide dismutase (SOD) levels in neonates with hypoxic-ischemic encephalopathy · 2025 · DOIINTRODUCTION: Despite much literature on reference values of acid-base status in umbilical cord blood at birth, there are as yet no studies performed to determine gestational age-dependent references in cord venous blood and no studies on preterm acid-base standards.
Gestational age‐related reference values for Apgar score and umbilical cord arterial and venous <scp>pH</scp> in preterm and term newborns · 2019 · DOIIt remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy.
Clinical Seizures in Neonatal Hypoxic-Ischemic Encephalopathy Have No Independent Impact on Neurodevelopmental Outcome: Secondary Analyses of Data from the Neonatal Research Network Hypothermia Trial · 2010 · DOICONCLUSIONS: Cerebellar hemorrhagic injury in preterm infants is associated with a high prevalence of long-term pervasive neurodevelopment disabilities and may play an important and underrecognized role in the cognitive, learning, and behavioral dysfunction known to affect survivors.
Does Cerebellar Injury in Premature Infants Contribute to the High Prevalence of Long-term Cognitive, Learning, and Behavioral Disability in Survivors? · 2007 · DOIDespite many publications identifying possible predictors of outcome in this population of interest, little is known of the long-term developmental outcome of asphyxiated term neonates.
Possibly this result, which is as pet not fully established quantitatively, is due to mechanical factors such as the fact that skin thickness and hair growth vary more markedly in the cutaneous areas than in so-called mucous membrane reflex- ogenous zones.
Quantified Pressure Stimulation and the Specificity and Generality of Response in Fetal Life · 1939 · DOI
Most-cited papers in Neonatal and fetal brain pathology
- Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants After Necrotizing Enterocolitis · PEDIATRICS · 2005 · 630 citations
- Report of the National Institute of Neurological Disorders and Stroke Workshop on Perinatal and Childhood Stroke · PEDIATRICS · 2002 · 513 citations
- Does Cerebellar Injury in Premature Infants Contribute to the High Prevalence of Long-term Cognitive, Learning, and Behavioral Disability in Survivors? · PEDIATRICS · 2007 · 507 citations
- Patterns of Cerebral Injury and Neurodevelopmental Outcomes After Symptomatic Neonatal Hypoglycemia · PEDIATRICS · 2008 · 425 citations
- Ischemic Perinatal Stroke: Summary of a Workshop Sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke · PEDIATRICS · 2007 · 423 citations
- Antenatal Hydronephrosis as a Predictor of Postnatal Outcome: A Meta-analysis · PEDIATRICS · 2006 · 401 citations
- Fetal Lead Exposure at Each Stage of Pregnancy as a Predictor of Infant Mental Development · Environmental Health Perspectives · 2006 · 312 citations
- Outcome among surviving very low birthweight infants: a meta-analysis. · Archives of Disease in Childhood · 1991 · 264 citations
- Topical Review: Long-Term Developmental Outcome of Asphyxiated Term Neonates · Journal of Child Neurology · 2001 · 162 citations
- Methods of fetal movement counting and the detection of fetal compromise · Journal of Obstetrics and Gynaecology · 2008 · 137 citations
Most recent work
- Use of fetal growth charts in England · The Lancet Obstetrics Gynaecology & Women s Health · 2026
- Improving UK data on avoidable perinatal brain injury: consultations and co-creation of recommendations · medRxiv · 2026
- The Methodological Pitfalls Complicating the Analysis of Early Term Births · Paediatric and Perinatal Epidemiology · 2026
- Artificial Intelligence Dystocia Algorithm (AIDA) for Risk Stratification of Occiput Posterior Fetal Head Position · Journal of Imaging · 2026
- The association between mode of delivery and severe intraventricular hemorrhage in very preterm infants · The Journal of Maternal-Fetal & Neonatal Medicine · 2026
- Cutoffs that Count: Insights into Receiver Operating Characteristic Curves for Cord Blood pH, Lactate, and Base Excess from an Indian Tertiary Centre · Annals of African Medicine · 2026
- Stem Cell-Based Innovations for Neonatal Hypoxic-Ischemic Encephalopathy · Journal of Regenerative Medicine and Biology Research · 2026
- Fetal health state detection method based on parameters efficient ensembling of deep learning · Frontiers in Public Health · 2026
- Peripheral blood cell counts of prematurely born, small for gestational age neonates · Clinical and Experimental Pediatrics · 2026
- Asfixia perinatal: revisão de literatura · Revista ft · 2026
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