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Preterm birth is associated with increased risk for a spectrum of neurodevelopmental disabilities. The cerebellum is implicated in a wide range of cognitive functions extending beyond sensorimotor control and plays an increasingly recognized role in brain development. Morphometric studies based on volume analyses have revealed impaired cerebellar development in preterm infants. However, the structural covariance between the cerebellum and cerebral cortex has not been studied during the neonatal period, and the extent to which structural covariance is affected by preterm birth remains unknown. In this study, using the structural MR images of 52 preterm infants scanned at term-equivalent age and 312 full-term controls from the Developing Human Connectome Project, we compared volumetric growth, local cerebellum shape development and cerebello-cerebral structural covariance between the two groups. We found that although there was no significant difference in the overall volume measurements between preterm and full-term infants, the shape measurements were different. Compared with the control infants, preterm infants had significantly larger thickness in the vermis and lower thickness in the lateral portions of the bilateral cerebral hemispheres. The structural covariance between the cerebellum and frontal and parietal lobes was significantly greater in preterm infants than in full-term controls. The findings in this study suggested that cerebellar development and cerebello-cerebral structural covariance may be affected by premature birth.

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INTRODUCTION: Periodic breathing (PB) is considered physiological in the neonatal period and usually disappears in the first months of life. There are few data available on persistent PB after the neonatal period. The objective of this study was to characterize infants born at term with persistent PB after the age of 1 month through polysomnography (PSG) performed during symptoms. METHODS: This retrospective case series included infants born at term between 2012 and 2021, without an underlying disease, who presented with symptoms of persistent PB during a PSG. Persistent PB was defined as more than 1 % of total sleep time (TST) of PB after 1 month of life, and PB was defined as a succession of at least three episodes of central apnea lasting more than 3 s and separated by less than 20 s of normal breathing. RESULTS: A total of 10 infants born at term were included. They underwent PSG for brief resolved unexplained events, desaturation, pauses in breathing, cyanosis, and/or signs of respiratory distress. The percentage of TST spent with PB was 18.1 % before 3 months of age (n = 7), and 4.7 % between 3 and 6 months of age (n = 10). During the first PSG, ≥3 % of desaturation events were observed in 77-100 % of the PB episodes. At the first PSG, nine of the 10 infants had an obstructive apnea-hypopnea index of >10/h and five of 10 infants had a central apnea index of >5/h. Gastroesophageal reflux (GER) was suspected in eight infants. All infants showed improvement in the initial symptoms during the first year of life. CONCLUSION: This study presents cases of persistent and symptomatic PB after 1 month of life in infants born at term. The interesting finding was the presence of obstructive sleep apnea syndrome and/or central apnea syndrome in the majority of children, along with GER.

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Objective: In this study, we investigated the characteristics of the intestinal microbiota of preterm infants, and then analyzed the effects of probiotics supplementation on intestinal microbiota in preterm infants. Methods: This study enrolled 64 infants born between 26 and 32 weeks gestational age (GA) and 22 full-term infants. 34 premature infants received oral probiotic supplementation for 28 days. Stool samples were obtained on the first day (D1) and the 28th day (D28) after birth for each infant. Total bacterial DNA was extracted and sequenced using the Illumina MiSeq Sequencing System, specifically targeting the V3-V4 hyper-variable regions of the 16S rDNA gene. The sequencing results were then used to compare and analyze the composition and diversity index of the intestinal microbiota. Results: There was no significant difference in meconium bacterial colonization rate between premature and full-term infants after birth (p > 0.05). At D1, the relative abundance of Bifidobacterium, Bacteroides, and Lactobacillus in the stool of preterm infants was lower than that of full-term infants, and the relative abundance of Acinetobacter was higher than that of full-term infants. The Shannon index and Chao1 index of intestinal microbiota in preterm infants are lower than those in full-term infants (p < 0.05). Supplementation of probiotics can increase the relative abundance of Enterococcus and Enterobacter, and reduce the relative abundance of Escherichia and Clostridium in premature infants. The Chao1 index of intestinal microbiota decreased in preterm infants after probiotic supplementation (p < 0.05). Conclusion: The characteristics of intestinal microbiota in preterm infants differ from those in full-term infants. Probiotic supplementation can reduce the relative abundance of potential pathogenic bacteria and increase the abundance of beneficial microbiota in premature infants.

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This study compared gut (fecal) microbiota profiles between pre-term and full-term infants, assuming that pre-term infants without feeding intolerance would have gut microbiota similar to those of full-term infants. A total of 13 pre-term infants (gestational age < 37 weeks, birthweight ≤ 2500 g) and 10 full-term infants were included. The pre-term infants were assigned to the feeding tolerance (FT) group (n = 7) if their daily intake exceeded 100 mL/kg/day at two weeks after birth, or the feeding intolerance (FI) group (n = 6). Microbial DNA from weekly fecal samples was analyzed. The microbiota profiles of the pre-term infants and full-term infants were significantly different (p = 0.0001), as well as the FT and FI groups (p = 0.0009). The full-term group had more diversity, with higher concentrations of facultative anaerobes such as Bifidobacteriaceae and Lactobacteriaceae. The FT group's gut microbiota matured over four weeks, with higher levels of digestion-related bacteria, while the FI group had more pathogens. In the FI group, a significant difference was observed between the first and second weeks, with no significant differences noted between the first week and the third or fourth weeks. The delay in the development of the pre-term infants' gut microbiota may be associated with the FI.

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BACKGROUND: We aimed to assess prevalence and clinical characteristics of newborns receiving kidney replacement therapy (KRT). METHODS: We used the National Inpatient Sample (NIS) dataset for the years 2000-2017. Newborns treated with peritoneal dialysis (PD), hemodialysis (HD), and continuous KRT (CKRT) were included. Trend analysis using the Cochran-Armitage test was used to assess prevalence over the years. RESULTS: A total of 64,532,552 hospitalized newborns were included. Among the 4281 infants treated with KRT, 2501 (58.4%) were treated with PD, 997 (23.3%) had HD, and 783 (18.3%) used CKRT. Associated diagnoses included congenital kidney anomalies (37.4% vs. 15% vs. 9.5%), urinary tract anomalies (35% vs. 12.5% vs. 6.3%), and congenital heart disease (68% vs. 25.7% vs. 72.3%). Median length of stay was longest in PD patients (39 days vs. 18 days vs. 26 days), respectively. However, cost of hospitalization was greatest in CKRT patients (US $490,916 vs. US $218,514 vs. US $621,554), respectively. In the entire cohort, 54,424 newborns had acute kidney injury (AKI); of them 16,999 (31%) died. KRT was used in 2,688 (4.9%) of infants with AKI. Over the study period, trends for utilization of PD (from 0.042 to 0.06%) and CKRT (from 0.03 to 0.21%) increased whereas the hemodialysis trend decreased (from 0.021 to 0.013%). CONCLUSIONS: Congenital heart disease (CHD) and congenital anomalies of the kidneys and urinary tract (CAKUT) are the major diagnoses in newborns receiving KRT. Utilization of PD was greater than HD and CKRT. Trends of PD and CKRT utilization increased over time. Less than 5% of infants diagnosed with AKI received KRT.

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Preterm and small-for-gestational-age (SGA) infants are more susceptible to vaccine-preventable diseases. To evaluate routine vaccination timeliness in these high-risk groups, a full birth cohort of infants (n = 41,502) born in 2017 and 2018 in Tuscany was retrospectively followed up until 24 months of age. Infants were classified by gestational age (GA) and SGA status. The vaccinations included: hexavalent (HEXA), measles-mumps-rubella, varicella, pneumococcal conjugate (PCV), and meningococcal C conjugate. Time-to-event (Kaplan-Meier) analyses were conducted to evaluate the timing of vaccination according to GA; logistic models were performed to evaluate the associations between GA and SGA with vaccination timeliness. Time-to-event analyses show that the rate of delayed vaccine receipt increased with decreasing GA for all the vaccinations, with a less marked gradient in later vaccine doses. Compared to full-term infants, very preterm infants significantly showed an increased odds ratio (OR) for delayed vaccination in all the vaccinations, while moderate/late preterm infants only showed an increased OR for HEXA-1, HEXA-3, PCV-1, and PCV-3. SGA infants had a significantly higher risk of delayed vaccination only for HEXA-1 and PCV-1 compared to non-SGA infants. In conclusion, vaccinations among preterm and SGA infants showed considerable delay. Tailored public health programs to improve vaccination timeliness are required in these high-risk groups.

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Background: Sepsis is one of the most important causes of morbidity and mortality in the neonatal period, especially in preterms. Diagnosis is difficult because of specific signs and symptoms. The diagnostic gold standard is blood culture, but its sensibility is low. Much effort has been made to identify early, sensitive, and specific diagnostic markers; among these markers particular attention was paid to procalcitonin. However, reference ranges of serum procalcitonin (PCT) shortly after birth have not been sufficiently studied in healthy preterms, and literature is still contradictory. Objectives: The aim of the study is to define PCT age-specific reference ranges in the first 72 h of life in uninfected VLBW preterms. Methods: Serum levels of PCT were assessed for each newborn at birth and every 24 h until the 3rd day of life. The eligible patients were classified into two groups according to their sepsis status. Results: Approximately 343 patients were enrolled; 28 were septic and 315 non-septic. In non-septic infants, 1,015 determinations of PCT values were performed. Our data showed a trend in average value of PCT to increase after birth up to a peak between 24 and 48 h of life and, subsequently, to fall. The average peak value was 15.12 ng/ml achieved at nearly 36 h of life. Conclusion: Our study shows a PCT nomogram of healthy preterms, which is different from the one of term newborns. Data agree with what is reported in literature on the reference ranges and trends of PCT in non-septic preterms shortly after birth.

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Background: Neonatal acute respiratory distress syndrome (ARDS) is a critical clinical disease with high disability and mortality rates. Early identification and treatment of neonatal ARDS is critical. This study aimed to build a perinatal prediction nomogram for early prediction of neonatal ARDS. Methods: A prediction model was built including 243 late-preterm and full-term infants from Daping Hospital in Chongqing, China, hospitalised between Jan 1, 2018 and Dec 31, 2019. 80 patients from the Children's Hospital in Chongqing, China, hospitalised between Jan 1, 2018 and June 30, 2018 were considered for external validation. Multivariate logistic regression was performed to identify independent predictors and establish a nomogram to predict the occurrence of neonatal ARDS. Both discrimination and calibration were assessed by bootstrapping with 1000 resamples. Findings: Multivariate logistic regression demonstrated that mother's education level (odds ratio [OR] 0·478, 95% confidence interval [CI] 0·324-0·704), premature rupture of membrane (OR 0·296, 95% CI 0·133-0·655), infectious disease within 7 days before delivery (OR 0·275, 95% CI 0·083-0·909), hospital level (OR 2·479, 95% CI 1·260-4·877), and Apgar 5-min score (OR 0·717, 95% CI 0·563-0·913) were independent predictors for neonatal ARDS in late-preterm and full-term infants, who experienced dyspnoea within 24 h after birth and required mechanical ventilation. The area under the curve and concordance index of the nomogram constructed from the above five factors were 0·760 and 0·757, respectively. The Hosmer-Lemeshow test showed that the model was a good fit (P = 0.320). The calibration curve of the nomogram was close to the ideal diagonal line. Furthermore, the decision curve analysis demonstrated significantly better net benefit in the model. The external validation proved the reliability of the prediction nomogram. Interpretation: A nomogram based on perinatal factors was developed to predict the occurrence of neonatal ARDS in late-preterm and full-term infants who experienced dyspnoea within 24 h after birth and required mechanical ventilation. It provided clinicians with an accurate and effective tool for the early prediction and timely management of neonatal ARDS. Funding: No funding was associated with this study.

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The gross motor development of a typically developing infant is a dynamic process, the intra-individual variability of which can be investigated through longitudinal assessments. Changes in gross motor development vary, according to the interaction of multiple sub-systems within the child, environment, task setting, and experience or practice of movement. At present, studies on environmental factors that influence gross motor development in full-term infants over time are limited. The main aim of this study was to investigate environmental factors affecting intra-individual variability from birth to 13 months. The gross motor development of 41 full-term infants was longitudinally assessed every month from the age of 15 days using the Alberta Infant Motor Scale. Parents were interviewed monthly about environmental factors during childcare. Infants showed fluctuations in the percentile of gross motor development, and no systematic pattern was detected. The total mean range of gross motor percentile was 65.95 (SD = 15.74; SEM = 2.28). The percentiles of gross motor skills over the 14 assessments ranged from 36 to 93 percentile points. Factors that were significantly associated with the gross motor development percentile were the use of a baby walker (Coef. = -8.83, p ≤ 0.0001) and a baby hammock (Coef. = 7.33, p = 0.04). The use of baby hammocks could increase the gross motor percentile by 7.33 points. Although the usage of a baby walker is common practice in childcare, it may cause a decrease in the gross motor percentile by 8.83 points according to this study. In conclusion, healthy full-term infants exhibited a natural variability in gross motor development. Placing infants in a baby walker during the first year of age should be approached with caution due to the risk of delayed gross motor development.

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Human milk oligosaccharides, proteins, such as lactoferrin, and bacteria represent just some of the bioactive components of mother's breast milk (BM). Bacteriophages (viruses that infect bacteria) are an often-overlooked component of BM that can cause major changes in microbial composition and metabolism. BM bacteriophage composition has been explored in term and healthy infants, suggesting vertical transmission of bacteriophages occurs between mothers and their infants. Several important differences between term and very preterm infants (<30 weeks gestational age) may limit this phenomenon in the latter. To better understand the link between BM bacteriophages and gut microbiomes of very preterm infants in health and disease, standardised protocols are required for isolation and characterisation from BM. In this study, we use isolated nucleic acid content, bacteriophage richness and Shannon diversity to validate several parameters applicable during bacteriophage isolation from precious BM samples. Parameters validated include sample volume required; centrifugal sedimentation of microbes; hydrolysis of milk samples with digestive enzymes; induction of temperate bacteriophages and concentration/purification of isolated bacteriophage particles in donor milk (DM). Our optimised method enables characterisation of bacteriophages from as little as 0.1 mL BM. We identify viral families that were exclusively identified with the inclusion of induction of temperate bacteriophages (Inoviridae) and hydrolysis of milk lipid processes (Iridoviridae and Baculoviridae). Once applied to a small clinical cohort we demonstrate the vertical transmission of bacteriophages from mothers BM to the gut of very preterm infants at the species level. This optimised method will enable future research characterising the bacteriophage composition of BM in very preterm infants to determine their clinical relevance in the development of a healthy preterm infant gut microbiome.

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This is a narrative review on the role of biomarkers in the diagnosis of neonatal sepsis. We describe the difficulties to obtain standardized definitions in neonatal sepsis and discuss the limitations of published evidence of cut-off values and their sensitivities and specificities. Maternal risk factors influence the results of inflammatory markers as do gestational age, the time of sampling, the use of either cord blood or neonatal peripheral blood, and some non-infectious causes. Current evidence suggests that the use of promising diagnostic markers such as CD11b, CD64, IL-6, IL-8, PCT, and CRP, either alone or in combination, might enable clinicians discontinuing antibiotics confidently within 24-48 h. However, none of the current diagnostic markers is sensitive and specific enough to support the decision of withholding antibiotic treatment without considering clinical findings. It therefore seems to be justified that antibiotics are often initiated in ill term and especially preterm infants. Early markers like IL-6 and later markers like CRP are helpful in the diagnosis of neonatal sepsis considering the clinical aspect of the neonate, the gestational age, maternal risk factors and the time (age of the neonate regarding early-onset sepsis) of blood sampling.

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[This corrects the article DOI: 10.3389/fimmu.2021.703009.].

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OBJECTIVES: To elucidate breastfeeding patterns, the reasons for stopping exclusive breastfeeding, and the sociodemographic characteristics associated with exclusive breastfeeding of full-term infants during the 6 months after discharge from a neonatal unit in China. METHODS: This cross-sectional study included mothers of full-term infants who were discharged from the 40-bed neonatal unit (level IIA) of a tertiary hospital in Hunan province, China between August 2019 and September 2020. Information on breastfeeding patterns was collected through telephone interviews with the mothers 6 months after their infants had been discharged from the neonatal unit. Binary logistic regression was used to determine the factors associated with exclusive breastfeeding. RESULTS: This study included 489 mother-infant dyads. At 6 months after discharge, 51.5% of mothers were exclusively breastfeeding, 29.0% of mothers were partially breastfeeding, and 19.4% of mothers were not breastfeeding. The most common reason for stopping breastfeeding was "poor milk supply" (81.2%). Factors associated with exclusive breastfeeding included multiparity, exclusive breastfeeding before the hospitalization, providing breast milk to the hospitalized infant, and a high level of maternal education. CONCLUSIONS: In the Chinese culture, mothers who experienced multiparity and higher-level education were more likely to breastfeed their infants to 6 months after discharge from the neonatal unit. In addition, infants who were exclusively breastfed before and during hospitalization were also more likely to be exclusively breastfed after discharge. The results will help inform future research aimed at identifying interventions to reduce early breastfeeding cessation.

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As visual perception development proceeds rapidly after birth, early detection of developmental maturity is required. Healthy infants do not have many opportunities for visual perception evaluation, so a reliable evaluation method is necessary. This retrospective study included 276 healthy full-term infants <24 months of age using the Preverbal Visual Assessment (PreViAs) questionnaire, which measures scores of subdivided age-groups for the global scores and 4 domains: visual attention (VA), visual communication (VC), visual-motor coordination (VMC), and visual processing (VP). Through this study, reference values and cutoff scores of the PreViAs questionnaire were presented, reliability was secured, and potential influencing factors of the PreViAs scores were analyzed. Using Cronbach's α coefficient, the global scores were 0.938, 0.781 for VA, 0.660 for VC, 0.874 for VMC, and 0.942 for VP. The internal consistency of the questionnaire was high in the global scores and 3 domains (VA, VMC, and VP). In infants under 12 months, the global scores and the VA, VMC, and VP domains showed positive association with gestational age, whereas the VC domain correlated with sex: which was found to be greater for females (p < 0.05). In those 12 month and above, no clinical factors were significantly associated with the PreViAs scores in all domains. The PreViAs questionnaire is a useful tool for visual assessment of healthy full-term infants under 24 months of age, suggesting reference values and cutoff scores according to age, and estimating the maturation age for visual perception development of each domain.

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OBJECTIVE: We investigated the relationship between gross motor abilities and sensory processing in typically developing children. METHOD: Participants included children aged 18 to 36 months (N = 48). All participants were full-term infants. We assessed gross motor abilities based on the Gross Motor Function Measure (GMFM), and sensory processing characteristics based on the Infant/Toddler Sensory Profile (ITSP). The gross motor ability index was calculated using GMFM score which was estimated from the age. Pearson's product moment correlation coefficients were used to examine the relationships between the gross motor ability indexes and ITSP section scores. RESULTS: Our findings showed that gross motor ability may be related to oral sensory processing. The children who were more responsive to oral sensory processing tended to exhibit gross motor abilities below the standard for that age. CONCLUSION: Gross motor abilities were related with sensory processing, especially oral sensory processing, in children aged 18 to 36 months.

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BACKGROUND: Movements towards midline are part of the age-adequate motor repertoire of infants. They develop contemporaneously to general movements, changing from occasional simple contact to proper midline motor patterns. AIM: The aim of this study is to describe the ontogeny of movements towards midline in full term healthy infants. STUDY DESIGN: Parents were asked to record their infant every second week, from term age to 22 weeks post-term. SUBJECTS: 25 healthy full-term infants. RESULTS: Three main epochs of development were detected: in the first one, between birth and 4 weeks post-term, movements towards midline were occasional, apparently due to the dominant flexed posture of elbow and knees and the adducted posture of shoulders and hips. In the second epoch, from 4 to 8 weeks, the limbs movements towards midline markedly decreased. In the third one, after 8 weeks, movements towards midline increased again in frequency, first appearing in lower limbs then in upper limbs, first solely as contact and thereafter as manipulation. A temporal overlapping with the occurrence of intermittent or continual fidgety movements was detected. CONCLUSIONS: Movements towards midline progressively change, through a defined timeline, in full term healthy infants. The increased knowledge about the normal age-adequate motor repertoire can help physicians in clinical assessment of high risk infants.

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AIM: Separating infants and their parents after a Caesarean section is still the routine care worldwide. This study investigated three caregiving models on the wakefulness and physiological parameters of full-term infants after an elective Caesarean section. METHODS: Newborn infants born in a Chilean public hospital in 2009-12 were randomised to three groups: cot, fathers' arms or skin-to-skin contact with their father. They were assessed at 15-minute intervals, from 45 to 120 minutes after the Caesarean section. Their physiological parameters were measured, and their wakefulness was assessed using the Neonatal Behavioural Assessment Scale. RESULTS: We studied 95 infant (53% girls) born at a mean gestational age of 38.9 ± 0.9 weeks. Heart rates were significantly higher in the skin-to-skin than cot or fathers' arms groups and showed greater stability over time. Wakefulness was initially higher in the skin-to-skin group, but there were no significant differences by the end of the observation. There were no differences between the groups in peripheral oxygen saturation. Skin-to-skin contact had no negative impact on the infants. CONCLUSION: The skin-to-skin group showed some advantages over the cot and fathers' arms groups when it came to establishing stable physiological parameters and wakefulness. This approach should be supported during mother-infant separation.

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Preterm birth is one of the main health problems encountered in the neonatal period, especially because it is also the first cause of death in the critical 1st month of life and the second in children under 5 years of age. Not only preterm birth entails short term health risks due to low weight and underdeveloped organs, but also increases the risk of suffering from non-transmissible diseases in the long term. To date, it is known that medical conditions and lifestyle factors could increase the risk of preterm birth, but the molecular mechanisms that control this process remain unclear. Luteolysis, increased inflammation or oxidative stress have been described as possible triggers for preterm birth and, in some cases, the cause of dysbiosis in preterm neonates. Several murine models have been developed to shed light into the mechanistic of preterm birth but, for the most part, are inflammation-based labor induction models and the offspring health readouts are mainly limited to survival and weight. Using a set of SWISS-CD1 mice born prematurely we analyzed inflammation and gut permeability parameters compared with term pups at weaning age. Overall, preterm mice presented higher systemic inflammation and gastrointestinal tract permeability. In this perspective article, we discuss the recent discoveries on preterm birth and the necessity of non-inflammatory murine models to really understand these phenotypes and be able to design strategies to prevent the sequels of this traumatic event in neonates.