This predictive model for preterm birth based on aberrant microRNA expression profile was further improved via implementation of maternal clinical characteristics , and presence of any kind of autoimmune disease ). With this model, 69.81% of pregnancies destined to deliver before 37 gestational weeks were identified with a 10.0% FPR at early stages of gestation. When other clinical variables as well as those mentioned above—such as positive first-trimester screening for early preeclampsia with onset before 34 gestational weeks and/or fetal growth restriction with onset before 37 gestational weeks using the Fetal Medicine Foundation algorithm, as well as positive first-trimester screening for spontaneous preterm birth with onset before 34 gestational weeks using the Fetal Medicine Foundation algorithm—were added to the predictive model for preterm birth, the predictive power was even slightly increased to 71.70% with a 10.0% FPR. Nevertheless, we prefer to keep the first-trimester screening for any type of preterm birth occurring before 37 gestational weeks in the absence of other pregnancy-related complications as simple as possible.The goal of the study was to establish an efficient first-trimester predictive model for any type of preterm birth before 37 gestational weeks (spontaneous preterm birth (PTB) or preterm prelabor rupture of membranes (PPROM)) in the absence of other pregnancy-related complications, such as gestational hypertension, preeclampsia, fetal growth restriction, or small for gestational age. The retrospective study was performed in the period from 11/2012 to 3/2020. Peripheral blood samples were collected from 6440 Caucasian individuals involving 41 PTB and 65 PPROM singleton pregnancies. A control group with 80 singleton term pregnancies was selected on the basis of equal sample-storage time. A combination of only six microRNAs (miR-16-5p, miR-21-5p, miR-24-3p, miR-133a-3p, miR-155-5p, and miR-210-3p; AUC 0.812,  Spontaneous preterm birth (PTB) is characterized as delivery before the completion of 37 gestational weeks induced by regular uterine contractions along with cervical changes. Preterm prelabor rupture of membranes (PPROM) is defined as leakage of amniotic fluid that precedes the onset of labour by at least 2 h ,2,3.An algorithm for the prediction of PTB with onset before 34 gestational weeks in the early stages of gestation exists that is based only on maternal characteristics  combined with previous obstetrics history ,6,7,8,9.Recently, we demonstrated that a set of 12 microRNA biomarkers can predict any type of preterm delivery that is uncomplicated by hypertensive and/or growth-restricted pregnancy disorders. This set of microRNA biomarkers  revealed 52.83% of pregnancies destined to deliver before 37 gestational weeks with a 10.0% FPR in early stages of gestation [p < 0.001, 70.75% sensitivity, 78.75% specificity, cut-off > 0.652, 52.83% of cases with a 10.0% FPR) [Similarly, we have shown that a combination of a minimal number of microRNAs  can also predict any type of preterm delivery before 37 gestational weeks in the absence of other pregnancy-related complications in early stages of gestation with similar discrimination power  in the absence of hypertensive and/or growth-restricted pregnancy disorders or gestational diabetes mellitus. Since other pregnancy-related complications have already been reported to be associated with an altered expression profile for cardiovascular disease-associated microRNAs by our research group ,12,13, fWe were interested in whether the predictive model for any type of preterm birth before 37 gestational weeks (PPROM or PTB) in the absence of other pregnancy-related complications based on an aberrant microRNA expression profile could be further improved via implementation of other maternal clinical characteristics.This study was performed in a retrospective manner for the period from 11/2012 to 3/2020. The peripheral blood was sampled from 6440 singleton Caucasian pregnancies during the first-trimester prenatal screening. A total of 4469 pregnancies had complete medical records. Ultimately, 41 pregnancies were diagnosed as PTBs, and 65 pregnancies were confirmed to have diagnoses of PPROM, among which 29 preterm births occurred before 34 gestational weeks and 77 after 34 gestational weeks. Only those pregnancies that occurred in the absence of other pregnancy-related complications  were involved in the study.n = 80) consisted of normal-term pregnancies and was selected with regard to the equality of gestational age at the time of peripheral blood sampling and the equality of biological sample-storage time.A control group  and of early PE before 34 gestational weeks, FGR before 37 gestational weeks, and PTB before 34 gestational weeks was produced by Astraia Software gmbh, Germany (Astraia Obstetrics Programme), in close collaboration with the Fetal Medicine Foundation (FMF) .n = 106) were predicted to develop early PE before 34 gestational weeks and/or FGR before 37 gestational weeks. In compliance with the ACOG 2018 guidelines [Ten women from the group with preterm pregnancies  were predicted to be at risk of PTB before 34 gestational weeks. The risk of PTB was below the cut-off value of 1:100. Four of these twenty-seven women were simultaneously found to be positive for early PE before 34 gestational weeks and/or FGR before 37 gestational weeks in first-trimester screening. ASA was ultimately given to two of these four women. Simultaneously, 6 out of 80 control term-pregnancies (7.50%) were also identified to be at risk of PTB before 34 gestational weeks.Furthermore, 27 women (25.47% cases) from the group with preterm pregnancies . Reverse transcription was performed with a total reaction volume of 10 µL using miRNA-specific stem loop primers and a TaqMan MicroRNA Reverse Transcription Kit  ,17,18,19MicroRNA gene expression was assessed using the delta-delta Ct method as previously described ,18,19,20∗Power Version 3.1.9.6, Franz Faul, University of Kiel, Germany). To achieve a power of 0.805, 51 cases and 51 controls needed to be tested. Similarly, to achieve a power of 0.902, 70 cases and 70 controls needed to be tested.Initially, power analysis was performed to calculate the minimum sample size required . Afterwards, Benjamini–Hochberg correction was applied.Receiver operating characteristic (ROC) curve analysis was performed for each individual microRNA biomarker to assess the area under the curve (AUC), the cut-off point-associated sensitivity, specificity, positive and negative likelihood ratios , and sensitivity at 90.0% specificity ) .To select microRNA combinations, logistic regression and ROC curve analyses were applied .To assess the detection rate of pregnancies with preterm birth before 37 gestational weeks on the base of a combination of microRNA biomarkers dysregulated in early stages of gestation and maternal clinical characteristics, logistic regression with subsequent ROC curve analyses were again applied .Concerning the microRNA expression studies only, both pilot and validation studies with two independent cohorts of patients were initially performed.n = 65) and PTB (n = 41) were reported [n = 65) and PTB (n = 41). Model validation studies would have been beneficial and desirable but would have required further long-term collection of samples within the framework of routine first-trimester prenatal screening to achieve a sufficient number of cases.Then, experimental microRNA expression data obtained from a larger independent cohort of patients with histories of PPROM , the presence of any kind of autoimmune disease , and positive first-trimester screening for early PE before 34 gestational weeks and/or FGR before 37 gestational weeks using the FMF algorithm, together with positive first-trimester screening for PTB before 34 gestational weeks, represent independent significant risk factors for the subsequent onset of any type of preterm birth before 37 gestational weeks (PTB or PPROM).p < 0.001, 73.58% sensitivity, 88.75% specificity, cut-off > 0.642930). It revealed, in early stages of gestation, 69.81% of pregnancies destined to deliver before 37 gestational weeks with a 10.0% FPR , and the presence of any kind of autoimmune disease ) and six dysregulated microRNA biomarkers  demonstrated very good accuracy for the identification of pregnancies destined to deliver before 37 gestational weeks . It revealed, in early stages of gestation, 66.98% of pregnancies destined to deliver before 37 gestational weeks with a 10.0% FPR , and the presence of any kind of autoimmune disease ) combined with 12 dysregulated microRNA biomarkers  also demonstrated very good accuracy for the identification of pregnancies destined to deliver before 37 gestational weeks . It revealed, in early stages of gestation, 71.70% pregnancies destined to deliver before 37 gestational weeks with a 10.0% FPR , the presence of any kind of autoimmune disease , positive first-trimester screening for early PE before 34 gestational weeks and/or FGR before 37 gestational weeks using the FMF algorithm, and positive first-trimester screening for PTB before 34 weeks of gestation using the FMF algorithm) with six dysregulated microRNA biomarkers  showed the highest possible accuracy for the early identification of pregnancies destined to deliver before 37 gestational weeks . It revealed, in early stages of gestation, 73.58% of pregnancies destined to deliver before 37 gestational weeks with a 10.0% FPR , the presence of any kind of autoimmune disease , positive first-trimester screening for early PE before 34 gestational weeks and/or FGR before 37 gestational weeks using the FMF algorithm, and positive first-trimester screening for PTB before 34 gestational weeks using the FMF algorithm) and 12 dysregulated microRNA biomarkers  also showed the highest possible accuracy for the early identification of pregnancies destined to deliver before 37 gestational weeks  targets.It is also generally accepted that progesterone plays an important role in the maintenance of uterine quiescence until the perinatal period. Progesterone maintains uterine quiescence and reduces uterine contractility through the mediation of multiple actions involving membrane ion channels, expression of receptors and agonists, intracellular cAMP and protein kinase A (PKA) signaling, calcium signaling, and contractile proteins . At the A set of 12 microRNA biomarkers alone  demonstrated similar discrimination power in predicting during early stages of gestation any type of preterm delivery (PTB or PPROM) occurring before 37 gestational weeks in the absence of hypertensive and/or growth-restricted pregnancy disorders or gestational diabetes mellitus as the set of six microRNA biomarkers alone . Both combinations of microRNAs alone were able to predict preterm delivery occurring before 37 gestational weeks in 52.83% of cases with a 10.0% FPR. Therefore, the combination of six microRNAs  was considered sufficient to for implementation as a fundamental variable in a model for the prediction in early stages of gestation of the occurrence of any type of preterm delivery (PTB or PPROM) occurring before 37 gestational weeks in the absence of other pregnancy-related complications, such as GH, PE, FGR, or SGA.The implementation of other essential maternal clinical characteristics in this predictive model, such as maternal age and BMI at early stages of gestation, infertility treatment with assisted reproductive technology, the occurrence of preterm delivery before 37 gestational weeks in previous pregnancy(ies), and the presence of any kind of autoimmune disease, could significantly improve the detection rate of any type of preterm birth (PTB or PPROM) occurring before 37 gestational weeks in the absence of other pregnancy-related complications, such as GH, PE, FGR, or SGA. This model was able to identify 69.81% of cases with a 10.0% FPR at early stages of gestation.The implementation of other variables in this predictive model for preterm birth, such as positive first-trimester screening for early PE with onset before 34 gestational weeks and/or FGR with onset before 37 gestational weeks and positive first-trimester screening for PTB with onset before 34 gestational weeks, both using the FMF algorithm, would be possible but is not necessary. It slightly increased the detection rate to 71.70% of cases with a 10.0% FPR.The novel predictive model for any type of preterm birth (PTB or PPROM) occurring before 37 gestational weeks in the absence of other pregnancy-related complications, such as GH, PE, FGR, or SGA, was based on the combination of the expression profiles of six microRNA  in whole peripheral blood samples and basic maternal clinical characteristics, such as maternal age and BMI at early stages of gestation, infertility treatment with assisted reproductive technology, the occurrence of preterm delivery before 37 gestational weeks in previous pregnancy(ies), and the presence of any kind of autoimmune disease. It was able to predict 69.81% of cases in the early stages of gestation with a 10.0% FPR.The implementation of additional variables in this predictive model, such as positive first-trimester screening for early PE with onset before 34 gestational weeks and/or FGR with onset before 37 gestational weeks and positive first-trimester screening for PTB with onset before 34 gestational weeks, both using the FMF algorithm, increased the detection rate of preterm births to 71.70% of cases with a 10.0% FPR.Consecutive large-scale studies involving other ethnic groups and multiple pregnancies are needed to verify the data resulting from this pilot study. Future work will also involve the use of machine-learning techniques for predicting preterm labor, measurements of heart rate variability, and electrohysterography, a noninvasive procedure to monitor contractions during pregnancy.National patent application—Industrial Property Office, Czech Republic (patent n. PV2021-562).


This case report documents a rare and unique presentation of an oropharyngeal duplication cyst and subsequent neonatal airway management. A one-day-old premature female presented with postpartum respiratory distress requiring emergent intubation secondary to an oropharyngeal mass of the left tongue. After being stabilized and transferred to an academic center, imaging revealed a cystic lesion that was then marsupialized and drained by the otolaryngology team. Pathology demonstrated mature colonic tissue and was consistent with an enteric duplication cyst. This report highlights the importance of prenatal diagnosis and the potential of a lifesaving ex utero intrapartum treatment (EXIT) procedure. Enteric duplication cysts can be found anywhere along the alimentary canal and are benign congenital heterotopic tissue with two layers of smooth muscle, gastrointestinal, or respiratory epithelium ,2. TheseA one-day-old female born preterm at 33 weeks and six days was transferred to our tertiary referral hospital for evaluation and treatment of an oropharyngeal mass causing airway obstruction. She had been born to a gravida 3 para 3 26-year-old African American female by spontaneous vaginal delivery after she had a premature rupture of membranes and a positive group B Streptococcus culture. Antenatal ultrasound had not been performed during the pregnancy. Surfactant had been administered at the outside hospital; Apgar scores at five and 10 minutes had been 4 and 6, respectively, and the patient had been noted to be in respiratory distress with poor respiratory effort. The patient weighed 2,170 grams. Positive pressure ventilation with a bag valve mask had been initiated and intubation had been attempted, which had led to the discovery of the oropharyngeal mass. A laryngeal mask airway had been immediately placed. The otolaryngology service had then performed direct laryngoscopy and intubation with a 3.0 endotracheal tube utilizing a Parsons laryngoscope. The patient had then been transferred to our facility for further management and care.On arrival, the patient was noted to be hypoglycemic (29 mg/dL). An umbilical catheter was placed for resuscitation and a nasogastric tube was placed for enteral feeding. Ampicillin was given for sepsis prophylaxis. MRI of the oral cavity was performed on day two of life Figures , 1B.Based on the MRI, the radiologist described a large well-circumscribed non-enhancing cystic lesion in the left tongue base and oral cavity measuring up to approximately 3.6 cm. This was thought to represent a dermoid cyst or teratoma or, less likely, an epidermoid cyst or lymphangioma. On day two of the patient's life, the cyst was aspirated and drained at the bedside. A total of 20 mL of mildly cloudy, mucoid cystic contents were aspirated and sent for cytology  that removed an additional 6 mL of hemorrhagic fluid. After reviewing the test results available, the most likely working diagnosis was an oropharyngeal duplication cyst. Sclerotherapy was not recommended. On day 15 of life, the patient was extubated, and the nasogastric tube was removed. On day 16 of life, our pediatric otolaryngologist performed microlaryngoscopy, bronchoscopy, and excision biopsy with marsupialization of the tongue cyst Figures , 5.Attempts were made intraoperatively to separate the cyst wall from the surrounding tongue muscle, but it was noted to be integrated into the underlying muscle. Operative specimens were sent to pathology for histologic examination. The pathology report revealed fragments of the cyst wall composed of the colonic mucosa and the underlying enteric smooth muscle layers, with features most consistent with the diagnosis of an oropharyngeal duplication cyst Figures -6C.The postoperative course was uncomplicated, and the patient was extubated on postoperative day one. Progression to full oral feeding was achieved during the patient’s hospital stay itself. On follow-up examination at two months of age, the patient had a well-healed base of the tongue with only a small area of a possible remnant on the left tongue. No further interventions were necessary as the patient was thriving, feeding orally, and her parents had no other concerns.Enteric duplication cysts are usually detected prenatally or in the first year of life, with variable clinical significance, depending on size, location, and type of mucosal pattern. The nomenclature of enteric duplication cysts includes choristoma, heterotopic gastrointestinal cyst, and enterocystoma . While tThe differential diagnosis for an oral tongue lesion in a neonate remains broad and includes teratoma, cystic hygroma, dermoid cyst, ranula, hemangioma, neuroblastoma, enteric duplication cyst, and thyroglossal duct cyst -12. In aFrom this point onward, the case became a pathologic diagnosis. The pathological diagnostic criterion for enteric duplication cysts is the presence of a smooth muscle layer wall that contains epithelium derived from the alimentary canal and is located along the alimentary tract . PerhapsA comparison of teratomas and enteric duplication cysts is insightful in this discussion, as both were considered potential diagnoses based on the initial MRI findings. Ultimately, the pathological analysis established the final diagnosis of enteric duplication cyst. Part of the difficulty in this diagnosis stemmed from the cyst’s location on the tongue. While the cyst was labeled as the base of the tongue, in actuality, there was not a clear distinction as a cyst residing solely at the base of the tongue. Possible involvement of the ectodermal tissue anterior to the circumvallate papillae could have favored the diagnosis of mature teratoma. Histologically, teratomas are more often seen as having tissue from all three germ cell layers and are composed of disorganized tissue. In comparison, enteric duplication cysts have highly organized tissue and are derived from the endodermal lining . This caIn any congenital malformation, the initial management depends on the hemodynamic and respiratory status of the patient. In cases where respiratory compromise is noted, the first step in the management is establishing an airway. This can be particularly difficult, and in some cases, one may need to use fiberoptic laryngoscopy or tracheostomy if initial measures fail. Airway obstruction can present at birth, or weeks to months after delivery. If oral intubation is unattainable, being prepared for tracheostomy can be lifesaving for newborns as well . Many ofThe EXIT procedure involves maintaining uteroplacental blood flow via cesarean section delivery while attempting to immediately secure the airway. The goal is to achieve partial cesarean delivery of the head, neck, and torso with the advent of uterine-relaxing agents. Uteroplacental bypass time averages 24 minutes, which extends the amount of time able to perform lifesaving airway management . The maiWe reported a rare case of colonic tissue within a base-of-tongue cyst presenting as airway obstruction. The final diagnosis was based on the correlation of clinical, radiological, and histological findings. We believe this case represents a variation of enteric duplication cyst presenting in a rare location in the head and neck that caused airway obstruction and immediate threat to the life of this newborn. Treatment of such cases should be multidisciplinary and coordinated with as much prenatal planning as possible prior to the delivery to ensure a safe, secure airway and definitive treatment of the obstructing mass.


The aim of this study was to create a simplistic taxonomy to improve transparency and consistency in, and reduce complexity of, interpreting diffusion tensor imaging (DTI) profiles in white matter disruption. Using a novel strategy of a periodic table of DTI elements, we examined if DTI profiles could demonstrate neural properties of disruption sufficient to characterize white matter changes specific for hydrocephalus vs. non-hydrocephalus, and to distinguish between cohorts of neural injury by their differing potential for reversibility.n = 24 vs. 27, normal pressure hydrocephalus (NPH), n = 16 vs. 9 and Alzheimer's disease (AD), n = 27 vs. 47. We generated DTI profiles from fractional anisotropy (FA) and mean, axial and radial diffusivity measures , and constructed an algorithm to map changes consistently to a periodic table of elements, which fully described their diffusivity and neural properties.DTI datasets from three clinical cohorts representing pathological milestones from reversible to irreversible brain injury were compared to those of healthy controls at baseline, over time and with interventions. The final dataset comprised patients vs. controls in the following groupings: mild traumatic brain injury (mTBI), Mapping tissue signatures to a periodic table of DTI elements rapidly characterized cohorts by their differing patterns of injury. At baseline, patients with mTBI displayed the most preserved tracts. In NPH, the magnitude of changes was dependent on “familial” DTI neuroanatomy, i.e., potential for neural distortion from risk of ventriculomegaly. With time, patients with Alzheimer's disease were significantly different to controls across multiple measures. By contrast, patients with mTBI showed both loss of integrity and pathophysiological processes of neural repair. In NPH, some patterns of injury, such as “stretch/compression” and “compression” were more reversible following intervention than others; these neural profile properties suggested “microstructural resilience” to injury.Using the novel strategy of a periodic table of DTI elements, our study has demonstrated it is possible to distinguish between different cohorts along the spectrum of brain injury by describing neural profile properties of white matter disruption. Further work to contribute datasets of disease toward this proposed taxonomic framework would enhance the translatability of DTI profiles to the clinical-research interface. Restoration of brain functions following injury requires an understanding of the resilience of neural tissue against pathological insults. Currently, we assess white matter tracts for microstructural damage but do not describe them in terms of their potential reversibility. Participants in longitudinal cohort studies and clinical trials undergo baseline imaging to document their structural integrity and functional connectivity. However, they may have white matter injury patterns with differing capacity for neural repair or recovery. Such patients may not exhibit equivalent responses to interventions, including drug therapies or application of novel neuroprostheses. Yet, there is no standard framework to describe cohorts by their differing white matter injuries. This gap in knowledge and such differential potential of patient cohorts are likely to have been major contributors to the failures of promising drug interventions in large-scale clinical trials across acute brain injury and neurodegenerative disease.There is an urgent need to develop more precise imaging biomarkers for correlation with assessments of intervention. In addition, our lack of understanding of how to describe the potential responsiveness of white matter injury has implications for assessing the risks vs. benefits for specific interventions in high-risk groups, such as the elderly population. The emerging field of aging neurosurgery represents such an evolving challenge. Despite the growth of the cohort of patients above 65 years presenting for surgical intervention, a cohesive approach toward a strategy for geriatric surgical needs is lacking. Elderly patients are considered high risk and yet, demonstrate potential for recovery. Specific conditions, such as chronic subdural haematoma, spinal degenerative myeloradiculopathy and hydrocephalus, have excellent results with surgical intervention –3. Good in vivo to characterize the reversibility potential of their neural injury prior to invasive CSF testing.Classically described by Adams et al.  as a triThe study of NPH is confounded by multiple theories of pathogenesis, yet unresolved. However, many major hypotheses streams, such as tissue distortion and vascular ischaemia, converge in white matter dysfunction . Shunt-rperiodic table of DTI elements.” The aims of this study were to (1) examine if DTI profiles could distinguish white matter injury in hydrocephalus vs. non-hydrocephalus and if so, (ii) create a simplified taxonomy of DTI interpretation by using the strategy of a “periodic table of DTI elements.”To address this conundrum, we have previously shown the utility of simplistic ROI-based DTI profiles in an at-risk model of white matter injury in NPH . DTI proWe examined DTI profiles from a cohort of Classic NPH (ClNPH) patients, the purer form of shunt-responsive NPH, and compared them to patients with mild traumatic brain injury  and patients with Alzheimer's disease . The utility of DTI examination has been shown in all three conditions; interpretations of white matter injury patterns are known , 18–23.DTI metrics for the various clinical cohorts mTBI, ClNPH and AD–were obtained from international datasets for which methodology is well-established. Cohort demographics are described in Approval for individual studies was obtained from local or institutional ethics committees. Written informed consent was obtained from all subjects or legal representatives, if appropriate, as required by local ethics committees.2; and image scan time of 7 min 22 s.The mTBI cohort from the University of Malaya was imaged on a 3T MRI scanner  using an eight-channel head coil . The DTI2, along with 4 b-0 images.MRI for the NPH cohort was performed on a 3T Siemens Tim Trio using a 12 channel head matrix radio frequency receive coil . The DTI3; TR = 9,000 ms; scan time = 9 min. Forty-six separate images were acquired for each DTI scan: 5 T2-weighted images with no diffusion sensitization (b0 images) and 41 diffusion-weighted images .The AD cohort from the ADNI were scanned on 3T GE Medical Systems scanners at 14 acquisition sites in North America . DiffusiPre-processing, image registration, and analysis for the mTBI dataset was carried out with FSL and AFNI software packages. Initial preprocessing involved corrections for head movement and eddy currents, brain tissue extraction, and fitting of the diffusion tensor model. The FSL tool fnirt was used for non-linear special registration of each subject to the FMRIB58_FA standard-space image. Predefined ROIs for each individual subject were mapped with the AFNI 3dROIstats tool and median FA, MD, L1, and L2 and 3 values obtained for each tract .In the NPH dataset, the FDT diffusion toolbox in FSL analysis tools was used for eddy current correction and DTI pre- and post-processing. Co-registration of the structural 3D volumetric image and DTI images was performed using SPM5. MPRAGE images were re-sliced to match the DTI image space using the s0 volume . A DTI-based white matter tract atlas was used for anatomical identification of key fiber bundles and ROIs were placed on the structural images and applied to co-registered DTI files .ADNI DTI metrics used in this paper were the UCLA DTI ROI summary measures for ADNIGO and ADNI2. Pre-processing steps for head motion and eddy current correction and removal of non-brain tissue were done using FSL. T1-weighted anatomical images were aligned to a standard brain template; skull-stripped b0 images were aligned and then registered to their respective T1-weighted scans. A study-specific template was created, each individual subject's initial FA map elastically registered to the template, and resulting deformation fields applied to diffusivity maps to align them to the same coordinate space. The mean of all voxels from each of the regions of interest from the atlas were obtained .DTI region of interest (ROI) values for fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (L1), and radial diffusivity L2 and 3) obtained using established methodology were used in this analysis , 24, 25. obtainedWe observed recurring common properties in DTI profiles across the spectrum of brain injury and developed a novel arrangement of white matter injury as a “periodic table of DTI elements” , Table 4t-tests were used to test for differences between clinical cohorts and healthy controls, and paired samples t-tests for changes in clinical cohorts over time. All statistical tests were two-tailed, and significance level was set at p < 0.05.Statistical analyses were conducted using SPSS Statistics Version 23.0 . Data is reported as mean ± standard deviation, unless otherwise stated. Independent samples At baseline, it was possible to distinguish patient cohorts vs. healthy controls in NPH and AD using DTI profiles alone. When comparing differences in AD patients vs. controls, white matter families in the midline, lateral to the ventricles and remote functional tracts showed evidence of oedema , although the cohort at 12 months remained severely disrupted compared to controls at baseline.Using the cohort with AD from ADNI, we found that it was possible to demonstrate the effect of progression of neurodegeneration. At 12 months' follow-up, the white matter changes progressed in all midline, lateral and fronto-temporal tracts tested –4. When 6C, Order III).In NPH, at 6 months, differences driven by radial diffusivity that were highly disproportionate to other measures remained despite intervention (Order VI). This DTI profile was common to all post-operative white matter families, suggesting that it may be a DTI tissue signature of shunted hydrocephalus. In tracts midline to the ventricles, the pattern of distortion/ oedema (Order VI) was not amenable to improvement. However, white matter families with DTI profiles of stretch/oedema, stretch/compression and compression showed improvement in compression  post-surgery  is associated with structural integrity, and therefore, a drop in FA is found in most neurological disorders. This reduction in FA would be consistent with microstructural damage of fibers, such as seen in demyelination and axonal degeneration. However, we have found that in hydrocephalus, FA can be shown to both increase and decrease , 79. For-surgery , 32. Tan-surgery . Convers-surgery . Mechani-surgery , 35, 36.a priori model of at-risk white matter tracts comprising only six key ROIs is sufficient to demonstrate at least three distinct and concurrent patterns of neural distortion , matching findings from our previous work. Using the periodic table, this profile of improvement is described by Order III. Interestingly, by mapping cohorts to the periodic table of elements, it became apparent that, despite differing pre-operative DTI measures, all post-operative hydrocephalus tracts had a DTI profile in common. Order VI, in which FA decrease is driven by highly disproportionate increases in L2 and 3, was also observed by Tan et al. in their young adult hydrocephalic cohort without ventriculomegaly , as well as specific patterns of white matter tracts and their distortions by CSF compartments described in NPH, such as ventriculomegaly and disproportionately enlarged subarachnoid space hydrocephalus (DESH) . Differistortion . DTI pro outcome . Here, alomegaly . This superiodic table of DTI elements, it has been possible to demonstrate where patterns of neural injury diverge, or where they are overlap. The cohorts in Orders VII to VIII of the periodic table match ADNI studies suggesting that ventriculomegaly may be an early imaging signature of AD and/or NPH. The progression in the AD cohort at 12 months toward neuronal degeneration , is consistent with known interpretations of ADNI data; white matter damage in AD follows neurodegenerative staging and progression of disease . The NPH study was approved by the local Research Ethics Committee of the Cambridge Health Authority (LREC: 06/Q0108/330). Individual ADNI sites received approval from their respective governing Institutional Review Boards. The patients/participants provided their written informed consent to participate in this study.NK conceptualized the experimental design. NK, CL, and SS analyzed the data. NK and CL wrote the manuscript, as well as provided visualizations for the data and led revisions of the work. AH contributed to data acquisition, imaging post-processing, and analysis from the UM site. ZC, MC, JP, and VN contributed to the acquisition of data used in this paper and provided comments and suggestions toward improving revisions. All authors reviewed the manuscript.NK was supported by a National Medical Research Council Clinician Scientist Award (MOH-000303-00) and Transition Award (NMRC/TA/0024/2013) and the National Neuroscience Institute RIE2020 Centre Grant Bridging Fund (IRNMR17CBG01). NPH study imaging at the University of Cambridge was funded by a Medical Research Council Programme Grant [Wolfson Brain Imaging Centre Cooperative]. MC and ZC were supported by Revert Project, Interreg France (Channel Manche) England, funded by ERDF. JP has received a National Institute for Health Research Brain Injury Health Technology Cooperative and National Institute for Health Research Senior Investigator Award (2009–2014). MTBI data from the University of Malaya was partially funded by a University Malaya Research Grant  and a High Impact Research Grant of University of Malaya (HIR-UM.C/625/1/HIRMOHE/12).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: To evaluate pregnancy and infant outcomes among persons immunized with a cell-based quadrivalent inactivated influenza vaccine (IIV4c) during routine pregnancy care. Design: Prospective observational cohort. Setting: US-based obstetrics/gynecology clinics. Population: Pregnant persons. This US-based, prospective observational cohort study evaluated the safety of quadrivalent inactivated influenza vaccine  in pregnant persons immunized over 3 influenza seasons between 2017 and 2020. Pregnant persons were immunized with IIV4c as part of routine care, after which their health care provides HCPs with all observational data to a single coordinating center. Follow-up data were collected at the end of the second trimester and/or at the time of pregnancy outcome. A scientific advisory committee reviewed the data. Prevalence point estimates were reported with 95% confidence intervals (CIs). Pregnancy outcomes included: live birth, stillbirth, spontaneous abortion, elective termination, and maternal death. Infant outcomes included: preterm birth , low birth weight (<2500 g), or major congenital malformations (MCMs). Of the 665 evaluable participants, 659 (99.1%) had a live birth. No stillbirths (0% [95% CI 0.0–0.6]), 4 spontaneous abortions (1.9% [0.5–4.8]), and 1 elective termination (0.5% [0.0–2.6]) were reported. Among 673 infants, 9.2% (upper 95% CI 11.5%) were born prematurely, 5.8% (upper 95% CI 7.6%) had low birth weight, and 1.9% (upper 95% CI 3.1%) were reported to have an MCM. No maternal deaths were reported. Of the 2 infants who died shortly after birth, one was adjudicated as not related to the vaccine; the other’s cause could not be determined due to maternal loss to follow-up. The prevalence of adverse pregnancy outcomes or preterm birth, low birth weight, or MCMs in newborns was similar in persons vaccinated with IIV4c compared to the rates observed in US surveillance systems. The safety profile of IIV4c in pregnant persons is consistent with previously studied influenza vaccines. Pregnant persons are considered a priority group for seasonal influenza vaccination to prevent influenza-related complications, among other at-risk groups such as older adults, very young children and persons with certain chronic medical conditions ,2,3. PreThe majority of inactivated influenza vaccines, including those evaluated in previous studies with pregnant persons, are produced in embryonated chicken eggs. The viruses within these vaccines are susceptible to selection-induced, adaptive mutations in the viral hemagglutinin protein, which can alter the antigenicity and effectiveness of the vaccines ,14,15,16This US-based, prospective observational cohort study was designed as a pregnancy exposure registry in line with the US Food and Drug Administration (FDA) guidance  and condThis study was conducted in accordance with the Good Pharmacoepidemiology Practices, applicable local regulations, and the Declaration of Helsinki ,29. An IThe study population included pregnant persons residing within the US who were immunized with IIV4c as part of routine care at any time during pregnancy. Participants were enrolled prospectively by obstetric HCPs who had committed to enrolling all eligible persons in their clinic who consented to the study; pregnant persons could also self-enroll during their pregnancies, after which their HCPs provided all pertinent data to the registry , spontaneous abortion , or elective termination. Ectopic pregnancy or molar pregnancy were reported as pregnancy types. Specific events of interest for fetuses/infants included preterm birth (infants born at <37 weeks gestation), low birth weight (<2500 g), or major congenital malformations (MCMs). Outcomes of interest included any major structural or chromosomal defect or a combination of three or more minor birth defects in live-born infants, stillbirths, and fetal losses at any gestational age, which closely resembles the definition used by the Centers for Disease Control and Prevention (CDC) Metropolitan Atlanta Congenital Defects Program (MACDP) . Follow-No separate assessments were required for the study. Outcome data, including gestational age and birth weight, were documented in the participants’ medical records as part of routine care and were provided to the registry coordinating center by participating HCPs  or pregnant persons postpartum. A teratologist who was blinded to the timing of vaccination reviewed all reported congenital malformations, classified them using the MACDP coding system, and provided an opinion regarding the gestational time window during which exposure to IIV4c could have potentially had an impact on the reported birth defect. A scientific advisory committee (SAC) comprised of experts in obstetrics/maternal-fetal medicine, pediatrics, clinical research, infectious disease, epidemiology, and teratology met at least annually to review and classify reported MCMs and review aggregated data on other events of interest and provide an interpretation of the data.n = 200) would be exposed to the vaccine during the first trimester. It would also provide >99% power to detect 2.0-fold increases in preterm birth and low birth weight, which had background prevalences of 11.39% and 8.02%, respectively, at the time the study was designed ) was consistent with the preterm birth rate of 10.23% in the general US population in 2019  33]. Ou. Ou33]. The 2018 US prevalence of low birth weight for all births was 8.28% with a rate of 6.60% reported for singleton births . The poiThe point estimate for the prevalence of MCMs in our study (1.9% [upper 95% CI 3.1%]) was similar to the background prevalence of 2.78% . AlthougPrevious studies have not found evidence that maternal immunization increases the risk of adverse pregnancy outcomes ,9,10,11,Our data add to the overall body of evidence that inactivated influenza vaccines are safe for use in pregnant persons. Ongoing routine monitoring will provide further continuous reassurance.Our findings are consistent with published data from various databases and surveillance systems that monitor the safety of influenza vaccines in pregnant persons. These data support the use of IIV4c for immunization against influenza in this population.


In low‐ and middle‐income countries (LMIC), growth impairment is common; however, the trajectory of growth over the course of the first month has not been well characterised. To describe newborn growth trajectory and predictors of growth impairment, we assessed growth frequently over the first 30 days among infants born ≥2000 g in Guinea‐Bissau, Nepal, Pakistan and Uganda. In this cohort of 741 infants, the mean birth weight was 3036 ± 424 g. For 721 (98%) infants, weight loss occurred for a median of 2 days  following birth until weight nadir was reached 5.9 ± 4.3% below birth weight. At 30 days of age, the mean weight was 3934 ± 592 g. The prevalence of being underweight at 30 days ranged from 5% in Uganda to 31% in Pakistan. Of those underweight at 30 days of age, 56 (59%) had not been low birth weight (LBW), and 48 (50%) had reached weight nadir subsequent to 4 days of age. Male sex , LBW , maternal primiparity  and reaching weight nadir subsequent to 4 days of age  were highly predictive of being underweight at 30 days of age. In this LMIC cohort, country of birth, male sex, LBW and maternal primiparity increased the risk of impaired growth, as did the modifiable factor of delayed initiation of growth. Interventions tailored to infants with modifiable risk factors could reduce the burden of growth impairment in LMIC. In low‐ and middle‐income countries, growth impairment is common; however, the trajectory of growth over the course of the first month has not been well characterized. To describe newborn growth trajectory and predictors of growth impairment, we assessed growth frequently over the first 30 days among infants born ≥2000 grams (g) in Guinea‐Bissau, Nepal, Pakistan, and Uganda. In this cohort, country of birth, male sex, LBW and maternal primiparity increased the risk of impaired growth, as did the modifiable factor of delayed initiation of growth. In our study, 98% of infants initially lost weight after birth before beginning weight gain.Although most infants began weight gain by 2 days of age, those with delayed initiation of weight gain were more likely to be underweight at 30 days of age.Male sex, country of birth, low birth weight, maternal primiparity and delayed initiation of weight gain were predictors of being underweight at 30 days of age and of wasting at 30 days of age. We excluded weights obtained on Day 1 from analysis if they varied by 15% or more from birth weight and weights obtained on Days 2, 3 and 4 if they varied by 10% or more from the prior day's weight. Weights were excluded in this manner from seven infants on Day 1, three infants on Day 2, five infants on Day 3, five infants on Day 4 and four infants on Day 5. We did not exclude any weights obtained on Days 12 or 30 due to a lack of certainty regarding plausible weight change in those time intervals.Infant dietary intake including breastfeeding and any supplementary feeding was assessed at these study visits using an instrument previously validated for breastfeeding infants in the first week of life in LMIC  <−2, length‐for‐age z‐score (LAZ) <−2 and weight‐for‐length z‐score (WLZ) <−2, respectively, and calculated using the WHO Anthro Survey Analyzer  was determined using the WHO definition of birth weight less than 2500 g. Underweight, stunting, and wasting were defined as weight‐for‐age λ) was set to 10 , 75th and 90th percentiles of weight (in g) as a function of time after birth separately for each country to depict weight changes during this period Koenker, . A restrχ2 and Student's t‐test were used for the bivariate analysis of dichotomous and normally distributed continuous variables, respectively; Wilcoxon rank sum test was used for bivariate analysis of continuous variables that were not normally distributed. We used Wald‐based confidence intervals to report the relative risk (RR) of dichotomous outcomes. Modified Poisson regression with robust standard errors was used to determine the relationship between baseline characteristics present at birth and dichotomous outcomes at 30 days of age while adjusting for potential confounders. All analyses were conducted in Stata/IC 16.0 (Stata Corp).To test associations with dichotomous outcomes, 3p = 0.03), and on Day 30 for 10 LBW infants (13%) compared to 39 (6%) non‐LBW infants (p = 0.02). Supplementary feeding other than formula did not differ between LBW and non‐LBW infants. Neonatal mortality occurred before 30 days of age for three infants .In this cohort, 321 infants were enroled in South Asian (SA) sites, Nepal and Pakistan and 420 in sub‐Saharan African (SSA) sites, Guinea‐Bissau and Uganda. All mothers were breastfeeding at enrolment, and only 3 (0.4%) reported having ceased breastfeeding at 30 days of age. Supplementary formula was reported on the day after birth and on Day 30, respectively, for 0 and 0 infants in Guinea‐Bissau, 1 (0.5%) and 1 (0.5%) infant in Uganda, 3 (3%) and 14 (17%) infants in Nepal, and 82 (37%) and 35 (16.6%) infants in Pakistan. Supplementary feeding other than formula, including milk, tea, soup, alcohol and honey, was reported on the day after birth and on Day 30, respectively, for 0 and 8 (4%) infants in Guinea‐Bissau; 97 (48%) and 34 (17%) infants in Uganda; 0 and 19 (24%) infants in Nepal; and for 45 (20%) and 7 (3%) infants in Pakistan. Overall, formula use was more common among LBW infants, occurring on the day after birth for 15 LBW infants (20%) compared to 73 (11%) non‐LBW infants (3.1p < 0.0005). Consistent with this finding, LBW was more common at SA sites compared to SSA sites . The cohort included 260 (49%) male infants, who weighed 88 g more at birth than females (p = 0.005).Baseline maternal characteristics such as education, marital status, household size and primiparity as well as infant characteristics such as weight and length differed by study site Table . Overall3.2Mean weight at 30 days of age was 3934 ± 592 g (range 2265–5585 g), which corresponded to a WAZ of −0.73 ± 1.1 (range −4.06–2.18). The mean birth length was 48.9 ± 1.9 cm (range 43.5–56 cm), which corresponded to a LAZ of −0.34 ± 1.0 (range −3.11 to 3.23). Mean weight change and mean length change over the first 30 days were 885.2 ± 397 g (29.5 ± 13.5% above birth weight), and 3.85 ± 1.70 cm (1.08 ± 0.3% above birth length), respectively. WLZ was not able to be calculated due to length below 45 cm for 15 infants on the day of birth, 6 infants on Day 12 and 3 infants on Day 30.Weight change over the first 30 days varied substantially by country and ranged from 587 ± 316 g (20.8 ± 11.8% above birth weight) in Pakistan to 1078 ± 313 g (34.6 ± 10.9% above birth weight) in Uganda (Table p < 0.0005). Age at weight gain initiation was highly correlated with change in WAZ over the first 30 days; for each additional day of age at the time of weight gain initiation, WAZ at 30 days of age decreased by −0.20 . In particular, infants who reached weight nadir subsequent to 4 days of age were much more likely to be underweight at 30 days of age with a RR of 5.02  and were also much more likely to be wasted at 30 days of age with a RR of 4.65  (Table Weight loss occurred before weight gain for 721 (98%) infants. Overall, infants lost 5.9 ± 4.3% of their birth weight before weight gain began at a median of 2 (interquartile range 1–4) days after birth , male sex , LBW  and maternal primiparity . In a multivariable analysis examining the relationship between being underweight at 30 days and country and sex while adjusting for birth weight, maternal age and maternal primiparity, the RRs for Guinea‐Bissau, Nepal and Pakistan compared to Uganda were 1.08 , 0.87  and 2.76 , respectively, with male sex and maternal primiparity continuing as strong predictors with RRs of 2.30  and 1.91 , respectively (Table .77, 9.044In this cohort of healthy breastfed infants born in LMIC without respiratory distress or congenital anomaly, the majority of infants who were underweight at 30 days of age had not been low birth weight but rather, had experienced poor initial weight gain. A more pronounced and extended period of initial weight loss before the initiation of weight gain was significantly associated with reduced growth attainment at 30 days of age, suggesting that efforts to promote adequate nutrition in the first few days after birth may reduce the risk of growth impairment. Male infants appear to be particularly vulnerable and were more than twice as likely to be underweight at 30 days of age as defined by the WHO Child Growth Standards. In our study, the risk of being underweight at 30 days of age varied substantially by country. Taken together, results from this study suggest that it may be feasible to identify apparently healthy newborns at higher risk of subsequent growth impairment and develop tailored interventions to improve outcomes.Our findings are consistent with recent literature demonstrating the persistent, strong association of LBW with being underweight throughout early infancy in LMIC and the difficulty establishing healthy growth for this vulnerable LBW population (Benjamin‐Chung et al., Importantly, the slower postnatal weight gain we identified in Nepal and Pakistan appears to have compounded weight disparities present at birth. Factors contributing to differences in birth weight and postnatal weight gain by location could include antenatal care practices, constitutional characteristics and early feeding behaviours. Further research is needed to understand the aetiology of inadequate prenatal and postnatal growth in LMIC.Our study has several limitations. First, validated assessment of gestational age was not available at most of our sites, and caesarean births were rare, so we are unable to report how newborn growth varied by gestational age or delivery method. Since 10.6% of our cohort newborns were LBW, it is likely that the proportion of preterm infants was not insignificant. This is an important limitation because preterm birth influences supplementary feeding practices, time to weight nadir and growth trajectory in the first 30 days (Poulimeneas et al., Our study was able to examine the impact of these variables day‐to‐day in the first days after birth, and our results demonstrate that expeditiously initiating healthy weight gain in the first few days after birth is a crucial component of preventing newborns from being underweight and may be especially important for male infants and those born in SA. Interventions such as early initiation of breastfeeding and early feeding of expressed milk are effective for promoting healthy growth, and breastfeeding counselling and education support packages including early initiation of breastfeeding have been shown to be effective for improving infant growth in LMIC (Ahmadi et al., Valerie J. Flaherman and Susan B. Roberts conceptualised and designed this study. Victoria Nankabirwa, Augusto Braima da Sa, Srijana Dongol, Akina Shrestha, Imran Nisar, Muddassir Altaf, Khushboo Liaquat, Benazir Baloch, Najeeb Rahman, Yasir Shafiq, Shabina Ariff and Fyezah Jehan completed the research. Alvaro Medel Herrero and Eric Schaefer analysed the data, Valerie Flaherman had primary responsibility for writing the manuscript and all authors have read and approved the final manuscript.All authors disclose support from the Bill & Melinda Gates Foundation which funded this research. Dr. Roberts also discloses funding from Danone, S.A., for unrelated work.


Investigation of the basic conditions and disease spectrum in neonatal intensive care unit (NICU) from 2012 to 2020, in the underdeveloped area of Xiangxi, China.N = 16,094) admitted to the NICU of a hospital in the Xiangxi area from 2012 to 2020 were selected for the retrospective study.All newborns (via cesarean delivery (CD). The most prevalent diseases diagnosed in the NICU were jaundice (22.01%), respiratory (18.45%) and neurological diseases (17.54%). Over the 9-year study window, the prevalence of jaundice and cardiovascular diseases increased, while respiratory and neurological diseases became less frequent. The prevalence of the remaining diseases remained unchanged. Prevalence of neonatal diseases is influenced by gender, patient sources, delivery methods, gestational age and birth weight (P < 0.05). The prevalence of neonatal diseases was significantly higher in males, infants born via CD, and in infants of lower gestational age and birth weight.The average male/female ratio was 1.43:1, with 9,482 males and 6,612 females admitted to the NICU. The sample comprised 41.02% premature infants, and 56.52% had been delivered P < 0.05). Newborns of specific gestational age, birth weight and delivery method should be considered “at-risk” and targeted in the formulation of preventive measures. There is a great need to improve the diagnosis and treatment of neonatal diseases—and perinatal health care in general—to ensure improved outcomes for newborns admitted to NICUs in underdeveloped regions.The study contributes in-depth information about infant characteristics in an NICU in an undeveloped region of China. In the past 9 years, the average proportion of premature infants in the NICU decreased to 37.38% in 2020, but this figure remains higher than the Chinese national average of 26.2%. Similarly, the CD rate is higher than the Chinese average. The spectrum of neonatal diseases in the NICU in Xiangxi area is drawn, included jaundice, respiratory and neurological diseases, primarily. Through statistical analysis, it is found that the types and prevalence of neonatal diseases are closely related to different gender, gestational age, patient sources, delivery methods, and birth weight ( The World Health Organization (WHO) reports that neonatal diseases constitute the fifth most common cause of death in the world , causingThe “Healthy China 2030 Plan” reports that China faces new challenges and a changing disease spectrum . StudyinGiven the lack of reports on neonatal diseases in NICUs in China's underdeveloped areas, this study selected all newborns admitted to the NICU of a hospital in Xiangxi over the past 9 years. We retrospectively describe the basic conditions, disease spectrum and factors influencing newborns in the NICU.The Xiangxi area has 17.88 million people, accounting for 27.2% of the total population of Hunan Province of China. Although Xiangxi is the only underdeveloped area in Hunan, a large gap exists in the medical treatment level in this area compared with relatively developed areas. The NICU selected for this study is part of the largest hospital in the Xiangxi area with the highest standard of medical treatment in that region. It is a treatment center for critically-ill newborns, with 11 doctors (two professors and two associate professors) and 38 nursing staff (three associate professors). The NICU has 50 ordinary beds and 10 intensive care rescue beds. Medical equipment used in the unit includes neonatal ventilators, incubators, neonatal jaundice therapeutic devices, monitors, newborn hearing screeners, and hypothermia therapy apparatus, etc. The hospital uses electronic databases to record neonatal status, ensuring data is accurate and credible. The data collected in this hospital were considered to represent the disease spectrum and development of newborn diseases in the Xiangxi area.From 2012 to 2020, there were 25,656 newborns born in this hospital, of which 9,615 (37.33%) were inborn  newborn. After approval by the Ethics Committee, data collection took place using the hospital database. All data were reviewed by two researchers. We undertook a retrospective analysis of all hospitalized newborns in the NICU of a hospital in Xiangxi from 2012 to 2020. A total of 17,206 newborns were initially included in this study. A total of 1,112 cases were excluded . Finally, 16,094 newborns were included [of which 9,615 were inborn  newborn, and 6,479 were outborn  newborn; see Statistical analysis of basic information about NICU newborns was undertaken, including hospitalization number, gender, gestational age, delivery method, birth weight, and patient source. This information was then related to discharge diagnosis, according to the International Statistical Classification of Diseases and Related Health Problems  breakdown and classification of children's diseases see . Then exThe WHO classification of “Global causes of childhood deaths in 2010”  had beent-tests. A P-Value of <0.05 was considered statistically significant.We used SPSS 21.0 software for data sorting and analysis. The enumeration data are expressed by the constituent ratio or rate, measurement data by the mean ± standard deviation, and the difference between the two groups was analyzed by the chi-square and A total of 16,094 hospitalized newborns were included in this study, including 9,482 males and 6,612 females. The average male/female ratio was 1.43:1. Average gestational age was 37.14 ± 2.82 weeks (w), and the average birth weight was 2,803.34 ± 728.05 g. The total number of newborns and male/female ratio decreased each year, while the gestational age and birth weight remained stable from year to year .via CD. In 2012, the proportions of VD and CD were 43.26 and 56.74%, respectively. By 2020, the proportions had changed to 35.32 and 64.68%, respectively. Notably, the proportion of CD increased by 7.94% in 9 years. From 2012 to 2020, two delivery methods were recorded: vaginal delivery (VD) and cesarean delivery (CD). A total of 6,965 (43.48%) of infants were delivered naturally (VD); 9,096 (56.52%) Grouped the Xiangxi and inborn newborns of gestation to discuss referral preferences for newborns see , left. Tn = 6,602), which mainly included 35–36+6 weeks late-preterm infants. The highest proportion of preterm infants was noted in 2015 with 56.64% of the sample that year, 19.26% higher than in 2020  were 15.45, 32.99, and 40.97%, respectively see , left.The minimum and maximum birth weight of hospitalized newborns was 330 and 5,530 g. Birth weight was divided into five groups of <1,000, 1,000–1,499, 1,500–2,499, 2,500–3,999, and ≥4,000 g, with the average proportion for each group being 0.37, 4.39, 28.22, 63.10, and 3.91%, respectively. Normal weight infants accounted for most of the newborns (63.10%), followed by low birth weight infants  at 28.22%. The highest proportion of low birth weight infants was seen in 2015, consistent with the highest proportion of preterm infants in that same year , right.In the 9 year period of our study, 9,615 (59.74%) hospitalized newborns were inborn, and 6,479 (40.26%) were outborn see . The proBased on the discharge diagnosis of all hospitalized newborns, The WHO classification of “Global causes of childhood deaths in 2010”   .P < 0.05)  .P < 0.05) in the prevalence of jaundice, respiratory, neurological, cardiovascular, genitourinary system, and genetic diseases among the groups, while the prevalence of blood system diseases, digestive system diseases, electrolyte and acid-base disorders and other diseases were not statistically different for the gender (P > 0.05) (see The chi-square test indicated a significant difference (.05) see .P > 0.05). However, a significant difference between the gestational age groups (P < 0.05) was found for jaundice, asphyxia, respiratory, neurological, cardiovascular, blood system, digestive system, electrolyte and acid-base, infectious, birth injury, eye, ear, throat and nose, skin, endocrine and metabolic, and genetic diseases.P > 0.05) was found between the birth weight groups for genitourinary system diseases. However, significant differences were found between the groups for all the remaining diseases (No significant difference (diseases .P > 0.05). However, significant differences were noted between groups (P < 0.05) for all the remaining diseases, as shown in No significant difference in the prevalence of birth injury disease, eye, ear, throat and nose diseases, endocrine and metabolic diseases, and immune diseases were found among the groups  and the United States (1.05:1) in 2019 . As showInvestigation of the relationship between maternal and neonatal characteristics was beneficial for improving perinatal health care. It could be found that the total number of newborn born in this hospital increased year by year from 2016 in Xiangxi. It was due to the policy implementation of China's “universal two-child policy” in 2016 . This poThe United Nations reported a global rate of 14.6% for low birth weight infants, most of whom are from Asia and Africa . HoweverAnalysis of the disease spectrum in the NICU showed that the most common neonatal diseases are jaundice, respiratory diseases, and neurological diseases, consistent with Wei's  Chinese China's medical treatment level was lower than that of developed countries. It was worth noting that the medical treatment level was more scarce in undeveloped areas. The lowest weight newborn successfully cured could represent the medical treatment level. The PICC technology was first introduced in the Xiangxi area in 2013, and successfully cured one 24 weeks and 650 g newborn in 2019. Which was higher than Gansu  and Changsha  of China, and the United States  . Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.FX was involved in the design, data analysis, and writing of the manuscript. YZ, LC, and RH participated in the data acquisition. QS, Z-yC, and JL was involved in the conceptual framing of the manuscript, review of background literature, and editing of the manuscript. All authors read and approved the final draft.This study was supported by Hunan Provincial Innovation Foundation for Postgraduate (ID: CX20211063), the National Social Science Fund of China (ID: 21XMZ090), and Jishou University School-Level Scientific Research Project (ID: Jdlc2015).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In low-income countries, birth weights for home deliveries are often measured at the nadir when babies may lose up of 10% of their birth weight, biasing estimates of small-for-gestational age (SGA) and low birth weight (LBW). We aimed to develop an imputation model that predicts the ‘true’ birth weight at time of delivery.We developed and applied a model that recalibrates weights measured in the early neonatal period to time=0 at delivery and uses those recalibrated birth weights to impute missing birth weights.This is a secondary analysis of pregnancy cohort data from two studies in Sarlahi district, Nepal.The participants are 457 babies with daily weights measured in the first 10 days of life from a subsample of a larger clinical trial on chlorhexidine (CHX) neonatal skin cleansing and 31 116 babies followed through the neonatal period to test the impact of neonatal massage oil type ).We developed an empirical Bayes model of early neonatal weight change using CHX trial longitudinal data and applied it to the NOMS dataset to recalibrate and then impute birth weight at delivery. The outcomes are size-for-gestational age and LBW.When using the imputed birth weights, the proportion of SGA is reduced from 49% (95% CI: 48% to 49%) to 44% (95% CI: 43% to 44%). Low birth weight is reduced from 30% (95% CI: 30% to 31%) to 27% (95% CI: 26% to 27%). The proportion of babies born large-for-gestational age increased from 4% (95% CI: 4% to 4%) to 5% (95% CI: 5% to 5%).Using weights measured around the nadir overestimates the prevalence of SGA and LBW. Studies in low-income settings with high levels of home births should consider a similar recalibration and imputation model to generate more accurate population estimates of small and vulnerable newborns. A strength of this study is that we developed our model of early neonatal growth using longitudinal data of daily weight change.Another strength is that the data used to develop this model was sampled from a similar population of infants in rural Nepal as was the study used to apply the model; although there may be differences due to secular trends, the median birth weights and neonatal mortality rates of the two studies are similar.A further strength is that both studies included high-quality gestational age and weight measurements taken on a population-representation sample with relatively low levels of missing data.A limitation of the study is that longitudinal data used to build the recalibration model did not have multiples or early neonatal deaths—babies that likely have different early growth patterns—although we are able to impute birth weight for multiples and neonatal deaths in the application model, it was based on measured weights only.Another limitation is that the model may not be generalisable to low-income settings outside of South Asia where prevalence of intrauterine growth restriction is lower.In 2010, 32.4 million babies in low-income and middle-income countries (LMICs) were estimated to be small-for-gestational age (SGA), over a quarter of all live births and these babies had an 83% higher risk of dying the first month of life.nadir or period of minimum neonatal weight), before starting to increase. A systematic review of breastfed, healthy, singleton babies from high-income countries found the nadir of mean weight loss of 7%–8% from birth weight at day 3. Many neonates in these studies had weight loss >7% and up to 10% from birth weight for exclusively breastfed babies.7Along with gestational age, an accurate birth weight measured close to the time of birth is critical for estimating SGA. This is because neonatal weight decreases for the first 2–3 days after birth  to a recalibrated weight at the time of birth and then uses those recalibrated birth weights to impute for babies missing a weight measurement.This was a secondary data analysis of two pregnancy cohort datasets from rural Nepal . The fir10In the CHX trial, a subset of infants (n=457) with first weight measured in the first 6 hours after delivery were purposively sampled for the longitudinal substudy, and then followed for daily weight measurements through the first 10 days of life. Gestational age was calculated using last menstrual period (LMP). Multiples and babies that did not survive the early neonatal period were not included in the CHX subsample of longitudinal data. We selected these data to model early neonatal weight change since it drew from the same population (but earlier timepoint) as the NOMS study.For the NOMS study, women in the study area were visited approximately every 5 weeks and asked about the timing of their LMP. Pregnant women were enrolled throughout the pregnancy  and some women contributed multiple pregnancies to the study data. Birth weight was collected at the first postnatal visit on all surviving liveborn infants. The distribution of visit timing is skewed right since 8% of the babies had their first postnatal visit after day 10 . InformaFor the CHX longitudinal data, we calculated the median and IQR for nadir weight, time in days to reach the nadir and time in days to return to the birth weight in the 10-day period. To make these estimates, we developed a function that extends the predicted weights from time of delivery to a maximum observed time in units of days (within the 10-day period). The function then finds the time in days when the predicted weight achieves its minimum and when the weight returns closest to the birth weight. We plotted a survival curve for probability of return to birth weight within the 10 days. Babies that did not return to their birth weight in the 10-day period were censored.For the NOMS data, we described the sample and analysed the pattern of missing weights and weights taken >72 hours after delivery to determine if babies with missing and non-missing weights differed by preterm status (<37 weeks), survival status through the neonatal period and mother’s parity and educational level.We imputed weight at birth in the NOMS dataset by estimating, then recalibrating from the conditional distribution of each child’s birth weight (weight at t=0) given a single measurement at a known later time t>0 (case 1) or imputing given missing weight (case 2).i at age ti=j.In both cases, the strategy had three steps: (1) use the longitudinal CHX study to estimate the dependence of birth weight on later weights and assume this relationship holds approximately for the NOMS data as well; (2) use the NOMS data to model the dependence of population average weight on age at measurement and other key predictors; (3) integrate (1) and (2) to obtain the optimal linear predictor of birth weights in NOMS given the single weight measurement on each childY is the daily weight for jth of ni for each baby). The fixed effects For the first step, the CHX data were used to fit a linear mixed effect model with the repeated weights as the outcomes .t>0), NOMS.t=0 from the linear mixed effect model, NOMS.G=2×2 variance-covariance matrix of random effects in the linear mixed effects model, chlorhexidine (CHX).σ2=residual variance from the linear mixed effects model, CHX.iZ=i×2n random effects design matrix where ni is the number of ages which are being used to predict the birth weight, here ni=1 and i=, NOMS.i=[ZiGt(Zi)]v1,2=covariance of the linear combination of the random effects that contribute to the birth weight prediction, NOMS, CHX.t in hours on: a smooth function of maternal age and education in years, the neonate’s survival status by day of age, infant sex, an indicator of preterm birth and whether the birth was a multiple or singleton, and whether it was the mother’s first birth (parity) using a linear mixed effect model (Y is the estimated weight for a ith woman’s jth pregnancy that resulted in a live birth with a measured weight). Neonatal survival status was defined as a liveborn death in the first 28 days of life with the reference being children who survived the neonatal period (28 days after birth) or alive at the time they were lost to follow-up. We used this model to obtain the estimated weight i at their measurement time t and their predicted birth weight t=0 , we applied the relationship between birth weight and subsequent weights derived in step (1) to the NOMS observed and predicted weights to obtain an improved prediction  of the NOMS infant’s birth weights . We geneWe used these recalibrated weights to impute for infants with missing weight data (case 2). We fit a random forest model to the recalibrated birth weight dataset with baby’s gender, gestational age at delivery, multiple/singleton, neonatal survival status and maternal parity, education and age. Using this model, we then imputed birth weight for babies with no weights measured and randomly generated a m=5 dataset for imputation. Infants with missing parity, survival status, maternal age/education, gestational age, singleton/multiples or sex data were excluded from the imputation. All modelling for case 1 and case 2 were performed in R.11We generated appropriate-for-gestational age (AGA) (10th–90th centiles), SGA (<10th centile) and LGA (>90th centile) using Intergrowth-21 standards extrapolated up to 22+0 to 44+6 weeks GA  .The patients and public were not involved in the design, conduct, reporting or dissemination of this research. Accurately measuring the health and nutritional status of infants is important to clinicians, researchers and families in Nepal, however, we did not seek the public’s priorities, experience or preferences when designing this research question. We did not contact the original participants in the two studies used in this secondary data analysis.The median birth weight in the CHX trial (training data) was 2726 (IQR 2490–2976) . The medAkaike Information Criterion  were on average 50 g higher than the measured weights  and on average 131 g higher on days 1–3 . During Using the imputed birth weights, we found differences in the SGA prevalence compared with weights taken within 72 hours after delivery . SGA preThe sensitivity analysis showed no changes in baby gender or term or preterm delivery, except for very preterm. The proportion of babies born at 28–32 weeks increased significantly (95% CI not overlapping) using the imputed dataset. Also, the neonatal mortality rate increased 109% from 16 deaths to 33 per 1000 live births . Among tBirth weights measured during the nadir bias estimates of SGA, LGA and low birth weight status. Our recalibration model pulled the weights back to t=0 at delivery, increasing the weights measured at the nadir, and decreasing weights measured after the nadir as the baby begins to surpass birth weight. The imputation also generated birth weight estimates for babies missing a measured weight, many of whom were early neonatal deaths and/or very preterm babies who died before the first postnatal study visit. In this dataset, these factors resulted in a reduced prevalence of small, vulnerable newborns. The proportion of babies with SGA is reduced by a relative 10% and low birth weight by a relative 11% when using the recalibrated and imputed birth weights.et al modelled neonatal weight loss among full term, breastfed, singleton Portuguese infants with weight measured within 96 hours.Fonseca In the first week after delivery, there is evidence that infants follow a broadly consistent pattern of weight change. Weight loss 2–3 days postnatally is primarily due to loss of water weight as the cardiopulmonary system readapts for life outside the womb.The main strength of this study is that we had a very large dataset with a relatively small proportion of missing covariates. In both the CHX and NOMS studies, we have high-quality gestational age at birth and weight was measured on a population-representative sample. The two studies were conducted in the same geographic area, from the same study site, and were managed by the same research organisation, the Nepal Nutritional Intervention Study Sarlahi. Another strength of this study is we were able to use daily, longitudinal weights to build the model of early neonatal growth.One limitation is the differences between the two datasets. Difference in timing of data collection: CHX 2002–2005) vs NOMS (2010–2017). Babies born during the NOMS data collection may have a different weight change pattern compared with babies born in CHX trial due to secular trends in maternal health and nutritional status. The per cent of women delivering at home has declined from CHX to NOMS, primarily due to the cash incentive programme in Nepal that pays women to deliver in a facility.02–2005 v9All infants in the CHX subsample of longitudinal weights survived through the neonatal period and were singleton births. This is an important difference in the underlying population of the two samples (CHX vs NOMS) since multiples typically have lower birth weight and very SGA/preterm/low birthweight babies are more likely to die in the few days after delivery. The imputed and measured mean birth weights by survival status were similar, among the babies with non-missing birth weight, indicating that the imputation model performed well .Another limitation is that the birth weights are not missing at random in NOMS. More than half the infants died in the NOMS study before their weight could be measured, and more preterm babies did not have a weight measurement . We found a higher proportion of very preterm babies in the sample with the imputed birth weights and a much higher neonatal mortality rate . We founUsing weights measured at or around the nadir—as typically occurs during community-based studies due to the logistics of quickly transporting data collection teams—overestimates the prevalence of SGA and low birth weight. We found a lower prevalence when using birth weight imputed to the time of delivery compared with weight taken within 72 hours postdelivery in a sample of deliveries in rural Nepal—an area where less than half of women deliver at facilities, high levels of exclusive breast feeding and only half of babies are born with an appropriate weight for gestational age. Other studies using birthweight measurements taken from infants born at home should consider a similar imputation model to generate more accurate SGA/low birthweight status at the population level.Overall, more research on improving estimates of SGA is needed. This model may be generalisable to other South Asian LMIC countries but may not be in LMICs with lower SGA prevalence, such as sub-Saharan Africa. Cohort studies with birthweight measurements should consider measuring longitudinal, early neonatal weight change since data in more diverse settings are needed, especially if a similar birthweight recalibration and imputation is planned. A recalibration model may also be clinically useful to better discriminate smaller babies, improving specificity of care. Finally, we note this model is restricted to live births since neither study measured weights on stillbirths. It would be culturally inappropriate to ask families to retain the fetal remains until study staff could arrive for weight measurement. However, IUGR may be an important cause of fetal death in this area and excluding stillbirths will likely underestimate the prevalence of SGA. Our study could not address this but including stillbirths in global estimates is critical to understanding the burden of IUGR and further work is needed to determine whether stillbirth weights may be imputed.


We investigated subcortical volumes in 2-to-6 week old infants exposed to antenatal maternal depression (AMD) from a South African birth cohort.Several studies have reported enlarged amygdala and smaller hippocampus volumes in children and adolescents exposed to maternal depression. It is unclear whether similar volumetric differences are detectable in the infants’ first weeks of life, following exposure AMD was measured with the Beck Depression Inventory 2nd edition (BDI-II) at 28–32 weeks gestation. T2-weighted structural images were acquired during natural sleep on a 3T Siemens Allegra scanner. Subcortical regions were segmented based on the University of North Carolina neonatal brain atlas. Volumetric estimates were compared between AMD-exposed (BDI-II ⩾ 20) and unexposed (BDI-II < 14) infants, adjusted for age, sex and total intracranial volume using analysis of covariance.N = 49) compared to unexposed infants (N = 75) for the right amygdala  and bilateral caudate nucleus . A significant AMD-by-sex interaction was found for the hippocampus  = 4.80, p = 0.030; right: F = 5.16, p = 0.025), reflecting greater volume in AMD-exposed females , but not males.Larger volumes were observed in AMD-exposed (in utero. Female infants might exhibit volumetric changes that are not observed in male infants. The potential mechanisms underlying these early volumetric differences, and their significance for long-term child mental health, require further investigation.Volumetric differences in subcortical regions can be detected in AMD-exposed infants soon after birth, suggesting structural changes may occur  It has  in life . Multipl in life . Rapid n in life , and the in life . AlthougMultiple structural imaging studies found evidence for larger amygdala volumes and smaller hippocampal volumes in adolescents exposed to maternal depression earlier in their childhood . For theDepression in pregnant women frequently persists after childbirth . The difThis study aimed to advance understanding of the link between AMD exposure and early brain development using data from a South African longitudinal birth cohort. The aims were: 1) to assess whether enlarged amygdala and smaller hippocampal volumes, as previously observed in children and adolescents after maternal depression exposure, can already be detected in 2–6 week old infants that were exposed to AMD in a LMIC setting; 2) to explore whether additional volumetric differences are present in other subcortical brain regions, in particular in the basal ganglia and thalamus; 3) to examine the hypothesis that regional brain volumes associated with AMD exposure, in particular for the amygdala and hippocampus, vary as a function of infant sex. Finally, possible associations between the severity of AMD exposure and subcortical volumes were investigated.22.1The Drakenstein Child Health Study (DCHS) is a longitudinal birth cohort investigating the early life determinants of child health in two low-resource communities located in the Western Cape, South Africa . PregnanThe full DHCS cohort consisted of 1137 expectant mothers who gave birth to 1143 infants . Here, dThe DCHS was approved by the University of Cape Town, Faculty of Health Sciences, Human Research Ethics Committee . Written informed consent was obtained from the mothers on behalf of herself and her infant at enrolment, and again at the start of the neuroimaging session. All study procedures were carried out in accordance with the Declaration of Helsinki .2.2Maternal depression was measured with the Beck Depression Inventory II BDI-II;  at an an2.3Antenatal exposure to harmful substances may confound the association between infant subcortical brain volumes and antenatal maternal depression . Alcohol2.4Gestational age at birth (in weeks) was recorded through ultrasound measurements when available and otherwise was based on measurements of fundal height or self-reported last menstrual period. Birth weight (in kilograms) was obtained at birth at the central hospital where deliveries took place. Maternal age at birth was calculated from maternal and infant dates of birth. All expectant mothers received HIV testing as per national guidelines and infected women were started on antiretroviral therapy if not already on treatment. HIV-exposed infants were tested for HIV using polymerase chain reaction tests at 6 weeks of age . Materna2.5MR images were acquired on a 3 T Siemens Magnetom Allegra MRI scanner  at the Cape Universities Brain Imaging Centre (CUBIC), Tygerberg, Cape Town. Infants were swaddled, fed, and thereafter imaged during natural sleep (without sedation). Earplugs and mini-muffs were used for double ear protection, and the head coil was loaded with a wet clay inlay. Sagittal 3D T2-weighted images were acquired with scan parameters: TR = 3500 ms; TE = 354 ms; FOV = 160 × 160 mm; 128 slices; voxel size = 1.3 × 1.3 × 1.0 mm. The sequence took 5 min. 41 s. to acquire. Images were successfully obtained in 183 infants (scan success rate: 77.5%). More information is provided in earlier publications .T2-weighted images were brain-extracted  using FSThe automated anatomical labelling atlas AAL;  was prev2.6t-tests or chi-square tests where appropriate. In the main analysis, volumes of the twelve subcortical regions were compared between AMD-exposed and unexposed infants using one-way analysis of variance including infant sex, age at scan and intracranial volume (ICV) as covariates, taking possible group differences in global brain size into account. Considering the different socio-environmental characteristics associated with clinic site, the main analysis was repeated including clinic site as additional covariate. Furthermore, the analysis was repeated replacing clinic site with maternal age, education level (low: only primary versus high: any secondary education), alcohol exposure and smoking exposure covariates. This last model was estimated to gain insight into specific variables that may confound the identified group differences. Any descriptive variables that demonstrated significant group differences, as well as gestational age at birth, were additionally adjusted for in supplemental analyses. Since depression-related volumetric alterations may differ as a function of child sex, AMD-by-sex interactions were tested for the pre-defined hippocampus and amygdala regions of interest (ROIs), and for other regions that reached significance in the main analysis. For illustrative purposes, analyses of AMD exposure stratified by infant sex were conducted for a priori ROIs. Finally, linear associations between subcortical volumes and depression severity were examined in the full MRI subsample, also including 16 infants with mild AMD exposure (BDI-II between 14 and 19) that passed quality control, in a post-hoc analysis.Maternal and infant characteristics were compared between AMD-exposed and unexposed groups with two-sample a priori hypotheses for the hippocampus and amygdala, group differences in these ROIs were considered statistically significant at uncorrected p < 0.05. For the other subcortical regions that were explored, results for each model were evaluated against q < 0.05 adjusted for eight multiple comparisons according to the Benjamini-Hochberg false-discovery rate (FDR) correction , whereas alcohol use was similar across the groups . In this DCHS imaging subsample, AMD exposure differed per clinic site. The majority of expectant mothers with AMD attended TC Newman (67.3%), and the majority of mothers without AMD attended Mbekweni . Maternal HIV infection was less prevalent in the AMD-exposed group . Despite the selective inclusion of healthy infants, birth weight was considerably lower in AMD-exposed infants . More sample details are provided in Data from 49 AMD-exposed and 75 AMD-unexposed infants were included for analysis. Expectant mothers with AMD experienced moderate-to-severe depressive symptoms . However, only one mother with depressive symptoms reported antidepressant medication use  at enrolment. Antenatal tobacco use was more prevalent in the AMD exposed compared to unexposed group  = 10.58, p = 0.001; right: mean difference = +3.54%, F = 6.94, p = 0.010) and right amygdala volumes  = 4.36, p = 0.039) compared to unexposed infants. There was no significant group difference for the left amygdala  = 1.76, p = 0.187). Adjusted regional volumes are presented in The minimally adjusted model, which included infant age at scan, sex and ICV as covariates, revealed volumetric differences in p = 0.005; right hippocampus: mean difference = +3.18%, p = 0.024; right amygdala: mean difference = +1.94 %, p = 0.046). After full adjustment for maternal characteristics, the hippocampal differences slightly gained in magnitude , whereas significance was lost for the right amygdala . Of note, none of the added maternal characteristics were significantly associated with right amygdala volume . Two sensitivity analyses separately excluding infants exposed to maternal HIV infection and infants born late preterm (<37 weeks gestation) and two supplemental analyses including birth weight and gestational age at birth as additional covariates demonstrated robustness of effects  = 12.49, p = 0.001; right caudate: mean difference = +6.09%, F = 13.55, p < 0.001). Moreover, the volumetric differences remained significant after adjustment for clinic site  and maternal characteristics . The thalamus, pallidum and putamen did not show significant group differences in volume at any level of adjustment  = 4.80, p = 0.030; right: F = 5.16, p = 0.025). Hereafter, analyses stratified by sex demonstrated a significant enlargement in AMD-exposed compared to unexposed female infants  = 15.22, p = 0.001; right hippocampus: mean difference = +6.47%, F = 12.73, p = 0.010). No significant differences in hippocampal volume were found in male infants (left: p = 0.576 and right: p = 0.882). Moreover, no significant AMD-by-sex interactions were detected for the amygdala or caudate  = 5.06, p = 0.028), whereas no significant difference was present in male infants (p = 0.510). a priori ROIs according to AMD exposure groups, separately for female and male infants.A significant AMD-by-sex interaction was observed bilaterally for the hippocampus  and bilateral caudate volumes . Moreover, EPDS scores showed positive associations with bilateral amygdala , left hippocampus , and bilateral caudate volumes . Full results are presented in AMD severity as measured with the BDI-II was positively associated with left hippocampus (4This study in South African infants aged 2–6 weeks detected enlarged right amygdala and bilateral hippocampus volumes in AMD-exposed compared to unexposed infants. In an exploratory analysis of other subcortical regions, robust evidence was found for an enlargement of the bilateral caudate nucleus in AMD-exposed infants. The direction of effect for the hippocampus was unexpected, in light of the smaller volumes previously observed after maternal depression exposure in childhood. As hypothesized, the regional brain volumes associated with AMD exposure varied as a function of infant sex: enlarged hippocampal volumes were apparent in females but not males exposed to AMD. However, no significant interactions with infant sex were observed for the amygdala and caudate nucleus. Furthermore, no significant associations between severity of AMD exposure and subcortical volumes were found. Taken together, the findings confirm that volumetric differences in subcortical regions can be detected in AMD-exposed infants soon after birth in a LMIC setting.a priori amygdala and hippocampus ROIs build on findings from two previous birth cohort studies. The first study reported an atypical amygdala microstructure that was most pronounced in the right amygdala for AMD-exposed compared to unexposed neonates (The findings of enlarged total grey matter volumes of neonates . Consistneonates . Of noteneonates . Even thWhen comparing the present findings to volumetric differences observed in older children exposed to maternal depression, a mostly consistent direction of effect is observed for the amygdala but not the hippocampus . It is pa priori ROIs, the caudate nucleus was newly implicated in the context of AMD exposure. Whereas the caudate is not the most consistently implicated subcortical brain region in the neurobiology of depression, meta-analyses of adult depressed patients (In addition to the patients  and two patients  have idepatients . A recenpatients . Here, wThree subcortical brain regions were found to have a larger volume in AMD-exposed infants 2–6 weeks after birth, when taking total intracranial volume into account. The consistent direction of effect at this developmental stage, as well as the slight attenuation of effect size when adjusting for antenatal and birth variables, suggests that specifically antenatal exposure to AMD influences early brain development. Genetic risk for depression would be less likely to explain the complete set of findings, given the inconsistent direction of effects compared to volumetric differences in depressed patients and individuals with a family history of depression (including postnatal maternal depression; see The present study was characterized by several notable strengths. The DCHS is a longitudinal birth cohort with extensive psychosocial characterization and this allowed us to rigorously adjust our group comparisons for possible confounding variables, including maternal substance use. MRI scans were obtained in young infants at 2–6 weeks of age, limiting the confounding effects of unmeasured postnatal exposures. Finally, we present the first investigation of early brain development after AMD exposure in a LMIC population. The relatively high prevalence of clinically relevant AMD symptoms and also of poverty-related stressors also see  in the cHowever, our findings need to be interpreted with recognition of the study limitations. AMD was measured at a single timepoint in late pregnancy and therefore findings may not generalize to AMD exposure earlier in pregnancy. Mild overestimation of BDI-II severity scores may occur due to somatic symptoms associated with pregnancy (for example, see in utero. These volumetric differences were most pronounced in female infants, especially for the hippocampus, and this could be indicative of an increased sensitivity to the effects of stress on the intra-uterine environment in female infants. The functional significance of the structural differences remains to be determined, most importantly their predictive value for subsequent problems in child mental health. More research is needed to delineate the neurodevelopmental trajectories of volumetric differences in subcortical brain regions after AMD exposure, and their underlying mechanisms, in LMIC settings.In conclusion, greater volumes of subcortical brain regions were detected in South African AMD-exposed compared to unexposed infants soon after birth, suggesting structural changes may occur Nynke A. Groenewold: Conceptualization, Data curation, Formal analysis, Funding acquisition, Visualization, Writing – original draft. Catherine J. Wedderburn: Conceptualization, Formal analysis, Visualization, Writing – review & editing. Jennifer A. Pellowski: Conceptualization, Methodology, Writing – review & editing. Jean-Paul Fouché: Conceptualization, Methodology, Writing – review & editing. Liza Michalak: Data curation, Writing – review & editing. Annerine Roos: Investigation, Writing – review & editing. Roger P. Woods: Methodology, Writing – review & editing. Katherine L. Narr: Methodology, Writing – review & editing. Heather J. Zar: Conceptualization, Funding acquisition, Resources, Writing – review & editing. Kirsten A. Donald: Conceptualization, Project administration, Investigation, Funding acquisition, Writing – review & editing. Dan J. Stein: Conceptualization, Supervision, Funding acquisition, Resources, Writing – review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.