Early Intervention in preterm infants modulates LINE-1 promoter methylation and neurodevelopment

ABSTRACTBackgroundEarly life adversity exposure impacts preterm infants’ neurodevelopment and early intervention protocols may modulate neurodevelopmental outcomes.Neuronal genomes are plastic in response to environment and mobile genetic elements, including LINE-1 (L1), are source of brain genomic mosaicism. Maternal care during early life regulates L1 methylation and copy number variations (CNVs) in mice. Here, we sought to identify the effects of maternal care and positive multisensory stimulation (Early Intervention) on L1 methylation and neurodevelopment in preterm infants.MethodsVery preterm infants were randomized to receive Standard Care or Early Intervention. L1 methylation was measured at birth and at hospital discharge. At 12 months infants’ neurodevelopment was evaluated with the Griffiths Scales. L1 methylation and CNVs were measured in mouse brain areas at embryonic and postnatal stages.ResultsWe demonstrated that L1 is hypomethylated in preterm versus term infants at birth. Early Intervention contributes to restore L1 methylation and positively modulates neurodevelopment. We showed that L1 methylation is developmentally-regulated in mice, decreasing in early postnatal life stages, which turns into an increased L1 CNVs specifically in hippocampus and cortex.ConclusionsHere we demonstrated that L1 dynamics can be modulated by Early Intervention, in parallel with ameliorated neurodevelopmental outcomes. We further identified a specific developmental window of the fetal mouse brain, sensitive to early life experience, in which L1 dynamics are fine-tuned contributing to shape the brain genomic landscape.Trail RegistrationclinicalTrial.gov (NCT02983513)FundingItalian Ministry of Health (RC 780/03 2017), University of Milan (DISCCO 2015) and INGM internal funding.

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Early maternal care restores LINE-1 methylation and enhances neurodevelopment in preterm infants

BMC Medicine ◽

10.1186/s12916-020-01896-0 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Camilla Fontana ◽

Federica Marasca ◽

Livia Provitera ◽

Sara Mancinelli ◽

Nicola Pesenti ◽

...

Keyword(s):

Early Intervention ◽

Preterm Infants ◽

Mouse Brain ◽

Maternal Care ◽

Intervention Program ◽

Life Experience ◽

Molecular Networks ◽

Neurodevelopmental Outcomes ◽

Very Preterm Infants ◽

Link Type

Abstract Background Preterm birth affects almost 9–11% of newborns and is one of the leading causes of childhood neurodevelopmental disabilities; the underlying molecular networks are poorly defined. In neurons, retrotransposons LINE-1 (L1) are an active source of genomic mosaicism that is deregulated in several neurological disorders; early life experience has been shown to regulate L1 activity in mice. Methods Very preterm infants were randomized to receive standard care or early intervention. L1 methylation was measured at birth and at hospital discharge. At 12 and 36 months, infants’ neurodevelopment was evaluated with the Griffiths Scales. L1 methylation and CNVs were measured in mouse brain areas at embryonic and postnatal stages. Results Here we report that L1 promoter is hypomethylated in preterm infants at birth and that an early intervention program, based on enhanced maternal care and positive multisensory stimulation, restores L1 methylation levels comparable to healthy newborns and ameliorates neurodevelopment in childhood. We further show that L1 activity is fine-tuned in the perinatal mouse brain, suggesting a sensitive and vulnerable window for the L1 epigenetic setting. Conclusions Our results open the field on the inspection of L1 activity as a novel molecular and predictive approach to infants’ prematurity-related neurodevelopmental outcomes. Trial registration ClinicalTrial.gov (NCT02983513). Registered on 6 December 2016, retrospectively registered.

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FREQUENCY AND IMPLICATIONS OF SEVERE NEONATAL PROTEIN C DEFICIENCY

10.1055/s-0038-1643609 ◽

1987 ◽

Author(s):

M J Manco-Johnson ◽

T C Abshire ◽

L J Jacobson

Keyword(s):

Preterm Infants ◽

Protein C ◽

Newborn Infants ◽

Postnatal Life ◽

Protein C Deficiency ◽

Term Infants ◽

Severe Respiratory Distress ◽

Thrombotic Risk ◽

Thrombin Activation ◽

Low Levels

The newborn infant has a physiologically low level of protein C which rises very slowly in postnatal life. The frequency and significance of severe neonatal protein C deficiency has not been reported. In this study, protein C levels were measured in 110 newborn infants at the time of birth using functional (amidolytic, Cact) and immunologic (Laurell rocket, Cag) assays. The protein C levels were compared with a marker of thrombin activation (D-dimer fragment of fibrin, +D-D) and infants were subsequently followed for signs and symptoms of thrombosis. Results are summarized below (protein C levels are expressed as U/ml).Thirteen infants had protein C levels compatible with the homozygous deficiency state. Extremely low levels of protein C (<0.20 U/ml) were not found in well term infants and were rarely noted in stable preterm infants. D-D were infrequently present and no thrombosis occurred. Near term infants born with fetal distress frequently showed +D-D but rarely demonstrated extremely low levels of protein C. None of these infants required indwelling arterial catheters and no thromboses occurred. Preterm infants with severe respiratory distress showed lower protein C levels at birth (p <0.01). Although 71% had +D-D, thromboses in these infants were all related to invasive catheterizations. In contrast, the study population of twins demonstrated a high frequency of severe protein C deficiency with negative D-D and frequent thromboses, three of which occurred in the absence of instrumentation. In summary, severe protein C deficiency and thrombin activation are common in sick preterm infants with the risk of thrombosis increased by intravascular catheterization. In contrast, twins with severe protein C deficiency may manifest a thrombotic risk which is independent of thrombin activation or catheterization.

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Magnetic resonance spectroscopy in preterm infants: association with neurodevelopmental outcomes

Archives of Disease in Childhood - Fetal and Neonatal Edition ◽

10.1136/archdischild-2016-311403 ◽

2017 ◽

Vol 103 (3) ◽

pp. F238-F244 ◽

Cited By ~ 7

Author(s):

Reina Hyodo ◽

Yoshiaki Sato ◽

Miharu Ito ◽

Yuichiro Sugiyama ◽

Chikako Ogawa ◽

...

Keyword(s):

White Matter ◽

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Preterm Infants ◽

Normal Development ◽

Resonance Spectroscopy ◽

Neurodevelopmental Outcomes ◽

Term Infants ◽

Equivalent Age ◽

Frontal White Matter

ObjectiveTo compare magnetic resonance spectroscopy (MRS) metabolite ratios in preterm infants at term-equivalent age with those in term infants and to evaluate the association between MRS metabolites and neurodevelopmental outcomes at 18 months corrected age in preterm infants.DesignWe studied infants born at a gestational age <37 weeks and weighing <1500 g during 2009–2013 using MRS at term-equivalent age. Infants with major brain abnormalities were excluded. The ratios of N-acetylaspartate (NAA) to creatine (Cre), NAA to choline-containing compounds (Cho) and Cho to Cre in the frontal white matter and thalamus were measured using multivoxel point-resolved proton spectroscopy sequence. Neurodevelopmental outcomes were assessed at 18 months corrected age.ResultsThirty-three preterm infants and 16 term infants were enrolled in this study. Preterm infants with normal development at 18 months showed significantly lower NAA/Cho ratios in the frontal white matter than term infants. There were no differences in the Cre/Cho ratios between preterm and term infants. At 18 months corrected age, 9 preterm infants with a mild developmental delay showed significantly lower NAA/Cho ratios in the thalamus than 24 preterm infants with normal development.ConclusionsPreterm infants at term-equivalent age showed reduced MRS metabolites (NAA/Cho) compared with term infants. Decreased NAA/Cho ratios in the thalamus were associated with neurodevelopmental delay at 18 months corrected age in preterm infants.

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Exploring Objects With Feet Advances Movement in Infants Born Preterm: A Randomized Controlled Trial

Physical Therapy ◽

10.2522/ptj.20080278 ◽

2009 ◽

Vol 89 (10) ◽

pp. 1027-1038 ◽

Cited By ~ 21

Author(s):

Jill C. Heathcock ◽

James C. (Cole) Galloway

Keyword(s):

Randomized Controlled Trial ◽

Preterm Infants ◽

Controlled Trial ◽

Intervention Strategy ◽

Training Group ◽

Postnatal Life ◽

Testing Session ◽

Term Infants ◽

Randomized Controlled ◽

Movement Training

Background: Previous work has shown that full-term infants who were healthy contacted a toy with their feet several weeks before they did so with their hands and that movement training advanced feet reaching. Certain populations of preterm infants are delayed in hand reaching; however, feet reaching has not been investigated in any preterm population.Objective: The primary purpose of this study was to determine whether preterm infants born at less than 33 weeks of gestational age contacted a toy with their feet at 2 months of corrected age, before doing so with their hands, and whether movement training advanced feet reaching.Design: This study was a randomized controlled trial.Methods: Twenty-six infants born preterm were randomly assigned to receive daily movement training or daily social training. During the 8-week training period, the infants were videotaped in a testing session every other week from 2 to 4 months of age.Results: Both groups contacted the toy with their feet at 2 months of age during the first testing session prior to training, at an age when no infants consistently contacted the toy with their hands. After 8 weeks of training, the movement training group displayed a greater number and longer duration of foot-toy contacts compared with the social training group.Conclusions: These results suggest that movement experiences advance feet reaching as they do for hand reaching. For clinicians, feet-oriented play may provide an early intervention strategy to encourage object interaction for movement impairments within the first months of postnatal life. Future studies can build on these results to test the long-term benefit of encouraging early purposeful leg movements.

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Skin-to-Skin Contact Activates Oxytocin Release and Correlates to Parent Engagement

Developmental Observer ◽

10.14434/do.v12i1.27842 ◽

2019 ◽

Vol 12 (1) ◽

pp. 12

Author(s):

D. Vittner ◽

S. Butler ◽

K. Smith ◽

N. Makris ◽

H. Samra ◽

...

Keyword(s):

Preterm Infants ◽

Parent Engagement ◽

Neurodevelopmental Outcomes ◽

Term Infants ◽

Skin Contact ◽

Interactive Environment ◽

Oxytocin Release ◽

Catch Up ◽

Evidenced Based ◽

Skin To Skin

Over 15 million premature infants are born annually around the world. It has been optimistically yet incorrectly proposed, that healthy preterm infants without major complications eventually catch-up developmentally to term infants. Research shows these preterm infants remain increasingly disadvantaged on many neurodevelopmental outcomes. Parental touch, especially during skin-to-skin contact (SSC) has the potential to reduce the adverse consequences of prematurity. SSC is an evidenced based strategy that increases parental proximity and provides an interactive environment known to enhance infant physiologic stability and aﬀective closeness between parent and infant. Evidence suggests SSC activates oxytocin release in mothers, fathers and infants.

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Impact of emollient therapy for preterm infants in the neonatal period on child neurodevelopment in Bangladesh: an observational cohort study

Journal of Health Population and Nutrition ◽

10.1186/s41043-021-00248-9 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Gary L. Darmstadt ◽

Naila Z. Khan ◽

Summer Rosenstock ◽

Humaira Muslima ◽

Monowara Parveen ◽

...

Keyword(s):

Preterm Infants ◽

Assessment Tool ◽

Neonatal Period ◽

Newborn Infants ◽

Psychomotor Development ◽

Fine Motor ◽

Neurodevelopmental Outcomes ◽

Link Type ◽

Child Neurodevelopment

Abstract Background Topical treatment with sunflower seed oil (SSO) or Aquaphor® reduced sepsis and neonatal mortality in hospitalized preterm infants <33 weeks’ gestational age in Bangladesh. We sought to determine whether the emollient treatments improved neurodevelopmental outcomes during early childhood. Methods 497 infants were randomized to receive SSO, Aquaphor®, or neither through the neonatal period or hospital discharge. 159 infant survivors were enrolled in the longitudinal follow-up study using a validated Rapid Neurodevelopmental Assessment tool and the Bayley Scales of Infant Development II (BSID II) administered at three-monthly intervals for the first year and thereafter at six-monthly intervals. Lowess smoothing was used to display neurodevelopmental status across multiple domains by age and treatment group, and Generalized Estimating Equations (GEE) were used to compare treatment groups across age points. Results 123 children completed at least one follow-up visit. Lowess graphs suggest that lower proportions of children who received massage with either SSO or Aquaphor® had neurodevelopmental delays than control infants in a composite outcome of disabilities. In GEE analysis, infants receiving SSO showed a significant protective effect on the development of fine motor skills [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.86–0.98, p=0.006]. The Psychomotor Development Index (PDI) in the BSID II showed significantly lower disability rates in the Aquaphor group (23.6%) compared to the control (55.2%) (OR 0.21, 95% CI 0.06–0.72, p=0.004). Conclusions Emollient massage of very preterm, hospitalized newborn infants improved some child neurodevelopmental outcomes over the first 2 years of follow-up. Findings warrant further confirmatory research. Trial registration ClinicalTrials.gov (98-04-21-03-2) under weblink https://clinicaltrials.gov/ct2/show/NCT00162747

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Early Biomarkers and Intervention Programs for the Infant Exposed to Prenatal Stress

Current Neuropharmacology ◽

10.2174/1570159x19666210125150955 ◽

2021 ◽

Vol 19 ◽

Author(s):

Marta C. Antonelli ◽

Martin G. Frasch ◽

Mercedes Rumi ◽

Ritika Sharma ◽

Peter Zimmermann ◽

...

Keyword(s):

Early Intervention ◽

Intervention Strategy ◽

Adult Life ◽

Intervention Programs ◽

Postnatal Life ◽

Healthy Children ◽

Neurodevelopmental Outcomes ◽

Epigenetic Biomarkers ◽

Functional Development ◽

Hypothalamic Pituitary Axis

Functional development of affective and reward circuits, cognition and response inhibition later in life exhibits vulnerability periods during gestation and early childhood. Extensive evidence supports the model that exposure to stressors in the gestational period and early postnatal life increases an individual's susceptibility to future impairments of functional development. Recent versions of this model integrate epigenetic mechanisms of the developmental response. Their understanding will guide the future treatment of the associated neuropsychiatric disorders. A combination of non-invasively obtainable physiological signals and epigenetic biomarkers related to the principal systems of the stress response, the Hypothalamic-Pituitary axis (HPA) and the Autonomic Nervous System (ANS), are emerging as the key predictors of neurodevelopmental outcomes. Such electrophysiological and epigenetic biomarkers can prove to timely identify children benefiting most from early intervention programs. Such programs should ameliorate future disorders in otherwise apparently healthy children. The recently developed Early Family-Centered Intervention Programs aim to influence the care and stimuli provided daily by the family and improving parent/child attachment, a key element for healthy socio-emotional adult life. Although frequently underestimated, such biomarker-guided early intervention strategy represents a crucial first step in the prevention of future neuropsychiatric problems and in reducing their personal and societal impact.

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Late Preterm Infants Have Worse 24-Month Neurodevelopmental Outcomes Than Term Infants

PEDIATRICS ◽

10.1542/peds.2009-3598d ◽

2011 ◽

Vol 127 (3) ◽

pp. peds.2009-3598d-peds.2009-3598d

Keyword(s):

Preterm Infants ◽

Late Preterm ◽

Neurodevelopmental Outcomes ◽

Term Infants ◽

Late Preterm Infants

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Maturation of the preterm gastrointestinal tract can be defined by host and microbial markers for digestion and barrier defense

Scientific Reports ◽

10.1038/s41598-021-92222-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jannie G. E. Henderickx ◽

Romy D. Zwittink ◽

Ingrid B. Renes ◽

Richard A. van Lingen ◽

Diny van Zoeren-Grobben ◽

...

Keyword(s):

Enzyme Activity ◽

Gastrointestinal Tract ◽

Preterm Infants ◽

Early Life ◽

Growth And Development ◽

Stress Proteins ◽

Term Infants ◽

Gastrointestinal Barrier ◽

Related Proteins ◽

Single Center Observational Study

AbstractFunctionality of the gastrointestinal tract is essential for growth and development of newborns. Preterm infants have an immature gastrointestinal tract, which is a major challenge in neonatal care. This study aims to improve the understanding of gastrointestinal functionality and maturation during the early life of preterm infants by means of gastrointestinal enzyme activity assays and metaproteomics. In this single-center, observational study, preterm infants born between 24 and 33 weeks (n = 40) and term infants born between 37 and 42 weeks (n = 3), who were admitted to Isala (Zwolle, the Netherlands), were studied. Enzyme activity analyses identified active proteases in gastric aspirates of preterm infants. Metaproteomics revealed human milk, digestive and immunological proteins in gastric aspirates of preterm infants and feces of preterm and term infants. The fecal proteome of preterm infants was deprived of gastrointestinal barrier-related proteins during the first six postnatal weeks compared to term infants. In preterm infants, bacterial oxidative stress proteins were increased compared to term infants and higher birth weight correlated to higher relative abundance of bifidobacterial proteins in postnatal week 3 to 6. Our findings indicate that gastrointestinal and beneficial microbial proteins involved in gastrointestinal maturity are associated with gestational and postnatal age.

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