1 5214 102 PRETERM BEHAVIORAL EPIGENETICS: A SYSTEMATIC REVIEW. BEHAVIORAL EPIGENETICS IS REVEALING NEW PATHWAYS THAT LEAD INDIVIDUALS FROM EARLY ADVERSITY EXPOSURES TO LATER-IN-LIFE DETRIMENTAL OUTCOMES. PRETERM BIRTH CONSTITUTES ONE OF THE MAJOR ADVERSE EVENTS IN HUMAN DEVELOPMENT. PRETERM INFANTS ARE HOSPITALIZED IN THE NEONATAL INTENSIVE CARE UNIT (NICU) WHERE THEY ARE EXPOSED TO LIFE-SAVING YET PAIN-INDUCING PROCEDURES AND TO PROTECTIVE CARE. THE APPLICATION OF BEHAVIORAL EPIGENETICS TO THE FIELD OF PRETERM STUDIES (I.E., PRETERM BEHAVIORAL EPIGENETICS, PBE) IS RAPIDLY GROWING AND HOLDS PROMISES TO PROVIDE VALID INSIGHTS FOR RESEARCH AND CLINICAL ACTIVITY. HERE, THE EVIDENCE OF THE EPIGENETIC CORRELATES OF PRENATAL ADVERSITIES, NICU-RELATED ENVIRONMENT AND DEVELOPMENT OF PRETERM INFANTS IS SYSTEMATICALLY REVIEWED. THE FINDINGS SUGGEST THAT A NUMBER OF PRENATAL ADVERSE (E.G., MATERNAL DEPRESSION AND STRESS) AND POST-NATAL (E.G., NICU-RELATED PAIN-RELATED STRESS) EVENTS AFFECT THE DEVELOPMENTAL TRAJECTORIES OF PRETERM INFANTS AND CHILDREN VIA EPIGENETIC ALTERATIONS OF IMPRINTED AND STRESS-RELATED GENES. NONETHELESS, THE POTENTIAL EPIGENETIC VESTIGES OF EARLY CARE AND PROTECTIVE INTERVENTIONS IN NICU HAVE NOT BEEN INVESTIGATED YET AND THIS REPRESENTS A FASCINATING CHALLENGE FOR FUTURE PBE RESEARCH. 2018 2 5961 45 TELOMERE LENGTH IN PRETERM INFANTS: A PROMISING BIOMARKER OF EARLY ADVERSITY AND CARE IN THE NEONATAL INTENSIVE CARE UNIT? PRETERM INFANTS PRESENT AN IMMATURE NEUROBEHAVIORAL PROFILE AT BIRTH, EVEN IN ABSENCE OF SEVERE BRAIN INJURIES AND PERINATAL COMPLICATIONS. AS SUCH, THEY REQUIRE A LONG-LASTING HOSPITALIZATION IN THE NEONATAL INTENSIVE CARE UNIT (NICU), WHICH IS THOUGHT TO GRANT AT-RISK NEWBORNS' SURVIVAL, BUT STILL ENTAILS A NUMBER OF PHYSICAL, PAINFUL, AND SOCIO-EMOTIONAL STRESSORS. HENCE, PRETERM BIRTH AND NICU STAY REPRESENT AN EARLY ADVERSE EXPERIENCE, WHICH HAS BEEN LINKED TO DETRIMENTAL CONSEQUENCES FOR NEUROLOGICAL, NEURO-ENDOCRINAL, BEHAVIORAL, AND SOCIO-EMOTIONAL DEVELOPMENT, AS WELL AS TO DISEASE LATER IN LIFE. RECENT ADVANCES IN THE BEHAVIORAL EPIGENETIC FIELD ARE HELPING US TO UNVEIL THE POTENTIAL MECHANISMS THROUGH WHICH EARLY NICU-RELATED STRESS MAY LEAD TO NEGATIVE DEVELOPMENTAL OUTCOMES. FROM THIS PERSPECTIVE, TELOMERE REGULATION MIGHT BE A KEY PROGRAMMING MECHANISM. TELOMERES ARE THE TERMINAL PORTION OF CHROMOSOMES AND ARE KNOWN TO GET SHORTER WITH AGE. MOREOVER, TELOMERE LENGTH (TL) IS AFFECTED BY THE EXPOSURE TO STRESS DURING EARLY DEVELOPMENT. AS SUCH, TL MIGHT BE AN INNOVATIVE BIOMARKER OF EARLY ADVERSE EXPOSURES IN YOUNG INFANTS AND CHILDREN. UNFORTUNATELY, THERE IS PAUCITY OF STUDIES INVESTIGATING TL IN POPULATIONS OF PRETERM INFANTS AND ITS ASSOCIATION WITH KNOWN NICU-RELATED STRESSORS REMAINS UNEXPLORED. IN THE PRESENT PAPER, THE POTENTIAL RELEVANCE OF TL FOR RESEARCH AND CLINICAL WORK WITH PRETERM INFANTS WILL BE UNDERLINED IN THE LIGHT OF RECENT CONTRIBUTIONS LINKING PROGRESSIVE TELOMERE SHORTENING AND EARLY EXPOSURE TO ADVERSE EXPERIENCES AND STRESSFUL ENVIRONMENTS IN HUMANS. FINALLY, INSIGHTS WILL BE PROVIDED TO GUIDE CLINICALLY RELEVANT TRANSLATIONAL RESEARCH ON TL IN THE FIELD OF VPT BIRTH AND NICU STAY. 2017 3 1235 32 CUMULATIVE PROCEDURAL PAIN AND BRAIN DEVELOPMENT IN VERY PRETERM INFANTS: A SYSTEMATIC REVIEW OF CLINICAL AND PRECLINICAL STUDIES. VERY PRETERM INFANTS MAY MANIFEST NEURODEVELOPMENTAL IMPAIRMENTS, EVEN IN THE ABSENCE OF BRAIN LESIONS. PATHOGENESIS IS COMPLEX AND MULTIFACTORIAL. EVIDENCE SUGGESTS A ROLE OF EARLY ADVERSITIES ON NEURODEVELOPMENTAL OUTCOMES, VIA EPIGENETIC REGULATION AND CHANGES IN BRAIN ARCHITECTURE. IN THIS CONTEXT, WE FOCUSED ON CUMULATIVE PAIN EXPOSURE WHICH PRETERM NEONATES EXPERIENCE IN NEONATAL INTENSIVE CARE UNIT (NICU). WE SYSTEMATICALLY SEARCHED FOR: I) EVIDENCE LINKING PAIN WITH BRAIN DEVELOPMENT AND EXPLORING THE POTENTIAL PATHOGENETIC ROLE OF EPIGENETICS; II) PRECLINICAL RESEARCH SUPPORTING CLINICAL OBSERVATIONAL STUDIES. NINE CLINICAL NEUROIMAGING STUDIES, DURING NEONATAL OR SCHOOL AGE, MOSTLY FROM THE SAME RESEARCH GROUP, REVEALED VOLUME REDUCTION OF WHITE AND GRAY MATTER STRUCTURES IN ASSOCIATION WITH POSTNATAL PAIN EXPOSURE. THREE CONTROLLED ANIMAL STUDIES MIMICKING NICU SETTINGS FOUND INCREASED CELL DEATH OR APOPTOSIS; NEVERTHELESS, ELIGIBLE GROUPS WERE LIMITED IN SIZE. EPIGENETIC MODULATION (SLC6A4 PROMOTER METHYLATION) WAS IDENTIFIED IN ONLY TWO CLINICAL TRIALS. WE CALL FOR ADDITIONAL RESEARCH AND, ALTHOUGH KNOWLEDGE GAPS, WE ALSO POINT OUT THE URGENT NEED OF MINIMIZING PAINFUL PROCEDURES IN NICUS. 2021 4 5216 34 PRETERM BIRTH: LONG TERM CARDIOVASCULAR AND RENAL CONSEQUENCES. BACKGROUND: CARDIOVASCULAR AND CHRONIC KIDNEY DISEASES ARE A PART OF NONCOMMUNICABLE CHRONIC DISEASES, THE LEADING CAUSES OF PREMATURE DEATH WORLDWIDE. THEY ARE RECOGNIZED AS HAVING EARLY ORIGINS THROUGH ALTERED DEVELOPMENTAL PROGRAMMING, DUE TO ADVERSE ENVIRONMENTAL CONDITIONS DURING DEVELOPMENT. PRETERM BIRTH IS SUCH AN ADVERSE FACTOR. RATES OF PRETERM BIRTH INCREASED IN THE LAST DECADES, HOWEVER, WITH THE IMPROVEMENT IN PERINATAL AND NEONATAL CARE, A GROWING NUMBER OF PRETERM BORN SUBJECTS HAS NOW ENTERED ADULTHOOD. CLINICAL AND EXPERIMENTAL EVIDENCE SUGGESTS THAT PRETERM BIRTH IS ASSOCIATED WITH IMPAIRED OR ARRESTED STRUCTURAL OR FUNCTIONAL DEVELOPMENT OF KEY ORGANS/SYSTEMS MAKING PRETERM INFANTS VULNERABLE TO CARDIOVASCULAR AND CHRONIC RENAL DISEASES AT ADULTHOOD. THIS REVIEW ANALYZES THE EVIDENCE OF SUCH CARDIOVASCULAR AND RENAL CHANGES, THE ROLE OF PERINATAL AND NEONATAL FACTORS SUCH AS ANTENATAL STEROIDS AND POTENTIAL PATHOGENIC MECHANISMS, INCLUDING DEVELOPMENTAL PROGRAMMING AND EPIGENETIC ALTERATIONS. CONCLUSION: PRETERM BORN SUBJECTS ARE EXPOSED TO A SIGNIFICANTLY INCREASED RISK FOR ALTERED CARDIOVASCULAR AND RENAL FUNCTIONS AT YOUNG ADULTHOOD. ADEQUATE, SPECIFIC FOLLOW-UP MEASURES REMAIN TO BE DETERMINED. WHILE ANTENATAL STEROIDS HAVE CONSIDERABLY IMPROVED PRETERM BIRTH OUTCOMES, REPEATED THERAPY SHOULD BE CONSIDERED WITH CAUTION, AS ANTENATAL STEROIDS INDUCE LONG-TERM CARDIOVASCULAR AND METABOLIC ALTERATIONS IN ANIMALS' MODELS AND THEIR INVOLVEMENT IN THE ACCELERATED CELLULAR SENESCENCE OBSERVED IN HUMAN STUDIES CANNOT BE EXCLUDED. 2018 5 1755 30 EARLY NUTRITION AND LATER OUTCOMES IN PRETERM INFANTS. THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE IS AN EMERGING AREA OF INTEREST THAT AMALGAMATES MANY AREAS OF SCIENTIFIC STUDIES AND ENCOMPASSES A WIDE RANGE OF DIVERSE DISCIPLINES FROM EPIDEMIOLOGY TO MOLECULAR BIOLOGY. EVIDENCE HAS ACCUMULATED TO SHOW THAT EARLY LIFE EXPERIENCES, BOTH IN UTERO AND IN INFANCY HAVE LONG-TERM EFFECTS ON MANY BODY SYSTEMS. THERE ARE NOW GOOD DATA TO SHOW THAT SUBOPTIMAL IN UTERO GROWTH, ESPECIALLY WHEN COMBINED WITH RAPID GROWTH ACCELERATION IN EARLY POSTNATAL LIFE MAY INCREASE THE RISK OF LATER LIFE METABOLIC DISEASE. THE MECHANISMS ARE COMPLEX BUT LIKELY TO INVOLVE EPIGENETIC MARKS SUCH AS DNA METHYLATION. PRETERM INFANTS FREQUENTLY EXPERIENCE SUBOPTIMAL NUTRIENT INTAKES IN EARLY POSTNATAL LIFE AND EXHIBIT GROWTH FAILURE WITHIN THE NICU. THEY ALSO RECEIVE PRODUCTS THAT MAY NOT PROVIDE EITHER AN OPTIMAL QUANTITY OR QUALITY OF NUTRIENTS. FOLLOW-UP STUDIES HAVE NOW SHOWN MUCH HIGHER RISKS FOR LONG-TERM CHRONIC DISEASE IN CHILDREN AND ADULTS WHO WERE BORN PRETERM. THERE ARE HIGHER LEVELS OF INSULIN RESISTANCE AND ABNORMAL PARTITIONING OF FAT DEPOSITION. THE ONSET OF PUBERTY SEEMS EARLIER, AVERAGE HEIGHT IS LESS AND BLOOD PRESSURE, MEASURES OF VASCULAR HEALTH AND LIPID PROFILES SUGGEST CARDIOVASCULAR HEALTH IS LIKELY TO DIFFER FROM HEALTHY TERM BORN CONTROLS. DESPITE THIS, THERE ARE NO DATA TO SUGGEST AN OVERALL BENEFIT OF LIMITING NUTRIENT INTAKE, OR RESTRICTING GROWTH IN PRETERM INFANTS. THERE ARE STRONG DATA TO SHOW THAT THE PRETERM BRAIN IS EXQUISITELY VULNERABLE TO UNDERNUTRITION, AND THAT SUBOPTIMAL NUTRIENT INTAKES MAY PERMANENTLY AFFECT LATER COGNITIVE ATTAINMENT. A CLINICAL FOCUS ON EARLY NUTRIENT INTAKES AND BREAST MILK PROVISION IS KEY TO OPTIMISING LONG-TERM HEALTH OUTCOMES. 2013 6 2605 23 EPIGENETICS-A POTENTIAL MEDIATOR BETWEEN AIR POLLUTION AND PRETERM BIRTH. PRETERM BIRTH IS A MAJOR CAUSE OF INFANT MORBIDITY AND MORTALITY AND A POTENTIAL RISK FACTOR FOR ADULT CHRONIC DISEASE. WITH OVER 15 MILLION INFANTS BORN PRETERM WORLDWIDE EACH YEAR, PRETERM BIRTH POSES A GLOBAL HEALTH CONCERN. THERE IS A POSSIBLE ASSOCIATION BETWEEN AIR POLLUTION AND PRETERM BIRTH, THOUGH STUDIES HAVE BEEN INCONSISTENT, LIKELY DUE TO VARIATION IN STUDY DESIGN. HOW AIR POLLUTION INDUCES HEALTH EFFECTS IS UNCERTAIN; HOWEVER, STUDIES HAVE REPEATEDLY DEMONSTRATED THE EFFECTS OF AIR POLLUTION ON EPIGENETIC MODIFICATIONS. MORE RECENT EVIDENCE SUGGESTS THAT EPIGENETICS MAY, IN TURN, BE LINKED TO PRETERM BIRTH. DISCOVERY OF ENVIRONMENTALLY MODIFIABLE EPIGENETIC PROCESSES CONNECTED TO PRETERM BIRTH MAY HELP TO IDENTIFY WOMEN AT RISK OF PRETERM BIRTH, AND ULTIMATELY LEAD TO DEVELOPMENT OF NEW PRETERM BIRTH PREVENTION MEASURES. 2016 7 2419 27 EPIGENETIC SIGNATURE OF CHRONIC MATERNAL STRESS LOAD DURING PREGNANCY MIGHT BE A POTENTIAL BIOMARKER FOR SPONTANEOUS PRETERM BIRTH. PRETERM BIRTH IS THE LEADING CAUSE OF MORTALITY IN NEWBORN INFANTS AND CAN LEAD TO SIGNIFICANT NEONATAL MORBIDITIES. SPONTANEOUS PRETERM BIRTH ACCOUNTS FOR AT LEAST 50.0% OF ALL PRETERM BIRTHS. WE ARGUE THAT CHRONIC MATERNAL STRESS LOAD, WHICH IS AN IMPORTANT RISK FACTOR FOR SPONTANEOUS PRETERM BIRTH, COULD BE REPRESENTED BY EPIGENETIC SIGNATURE OF SEVERAL SPECIFIC GENETIC LOCI IN THE MOTHER'S BLOOD. A LITERATURE SEARCH WAS DONE IN PUBMED WITH THE FOLLOWING KEYWORDS: "DNA METHYLATION," "EPIGENETICS," "MATERNAL STRESS" AND "PRETERM BIRTH" FROM YEAR 2000 TO 2017. WE SUGGEST THAT THESE GENETIC LOCI MIGHT BE RELATED TO VULNERABILITY AND HYPERSENSIBILITY OF STRESS RESPONSE DURING PREGNANCY IN WOMEN WITH PRETERM BIRTHS. THE MOTHER'S EPI-GENETIC STRESS BIOPROFILE WAS SUPPOSED TO BE A RESULT OF CHRONIC MATERNAL STRESS LOAD SINCE HER BIRTH. THIS EPIGENETIC BIOPROFILE MIGHT ALSO BE A POTENTIAL BIOMARKER FOR SPONTANEOUS PRETERM BIRTH. DNA METHYLATION CHANGES ARE TISSUE-SPECIFIC AND HUMAN STRESS RESPONSE MANIFESTS MOSTLY THROUGH THE CENTRAL NERVOUS SYSTEM (CNS). NEVERTHELESS, WE FOUND EVIDENCE THAT METHYLATION CHANGES OF DNA ISOLATED FROM BLOOD LEUCOCYTES MIGHT BE A RELIABLE MEASURE OF STRESS-RELATED EPIGENETIC CHANGES THAT OCCUR IN THE CNS. EVALUATING BIOLOGICAL MECHANISMS THROUGH THE DEVELOPMENT OF SIMPLE ASSAYS BASED ON EPIGENETIC CHANGES TO MEASURE CHRONIC STRESS LOADS IN EXPECTANT MOTHERS CAN LEAD TO OUR ABILITY TO PREPARE MORE EFFECTIVE MEASURES FOR THE PREVENTION OF PRETERM BIRTHS, AS WELL AS LEADING TO MORE EFFECTIVE TREATMENT STRATEGIES FOR BOTH EXPECTANT MOTHERS AND THEIR NEWBORNS. 2018 8 2802 30 FETAL AND INFANT ORIGINS OF ASTHMA. PREVIOUS STUDIES HAVE SUGGESTED THAT ASTHMA, LIKE OTHER COMMON DISEASES, HAS AT LEAST PART OF ITS ORIGIN EARLY IN LIFE. LOW BIRTH WEIGHT HAS BEEN SHOWN TO BE ASSOCIATED WITH INCREASED RISKS OF ASTHMA, CHRONIC OBSTRUCTIVE AIRWAY DISEASE, AND IMPAIRED LUNG FUNCTION IN ADULTS, AND INCREASED RISKS OF RESPIRATORY SYMPTOMS IN EARLY CHILDHOOD. THE DEVELOPMENTAL PLASTICITY HYPOTHESIS SUGGESTS THAT THE ASSOCIATIONS BETWEEN LOW BIRTH WEIGHT AND DISEASES IN LATER LIFE ARE EXPLAINED BY ADAPTATION MECHANISMS IN FETAL LIFE AND INFANCY IN RESPONSE TO VARIOUS ADVERSE EXPOSURES. VARIOUS PATHWAYS LEADING FROM ADVERSE FETAL AND INFANT EXPOSURES TO GROWTH ADAPTATIONS AND RESPIRATORY HEALTH OUTCOMES HAVE BEEN STUDIED, INCLUDING FETAL AND EARLY INFANT GROWTH PATTERNS, MATERNAL SMOKING AND DIET, CHILDREN'S DIET, RESPIRATORY TRACT INFECTIONS AND ACETAMINOPHEN USE, AND GENETIC SUSCEPTIBILITY. STILL, THE SPECIFIC ADVERSE EXPOSURES IN FETAL AND EARLY POSTNATAL LIFE LEADING TO RESPIRATORY DISEASE IN ADULT LIFE ARE NOT YET FULLY UNDERSTOOD. CURRENT STUDIES SUGGEST THAT BOTH ENVIRONMENTAL AND GENETIC FACTORS IN VARIOUS PERIODS OF LIFE, AND THEIR EPIGENETIC MECHANISMS MAY UNDERLIE THE COMPLEX ASSOCIATIONS OF LOW BIRTH WEIGHT WITH RESPIRATORY DISEASE IN LATER LIFE. NEW WELL-DESIGNED EPIDEMIOLOGICAL STUDIES ARE NEEDED TO IDENTIFY THE SPECIFIC UNDERLYING MECHANISMS. THIS REVIEW IS FOCUSED ON SPECIFIC ADVERSE FETAL AND INFANT GROWTH PATTERNS AND EXPOSURES, GENETIC SUSCEPTIBILITY, POSSIBLE RESPIRATORY ADAPTATIONS AND PERSPECTIVES FOR NEW STUDIES. 2012 9 4797 25 NUTRITIONAL INTERVENTIONS TO IMPROVE BRAIN OUTCOMES IN PRETERM INFANTS. THE LAST 20 YEARS HAVE SEEN DRAMATIC IMPROVEMENTS IN SURVIVAL FOR PRETERM INFANTS IN BOTH HIGH- AND LOW-INCOME SETTINGS. SURVIVAL RATES OF OVER 50% IN INFANTS BORN 16 WEEKS EARLY (24 WEEKS' GESTATION) ARE NOW COMMONPLACE IN WELL-RESOURCED NEONATAL INTENSIVE CARE UNITS. HOWEVER, ENSURING ADEQUATE NUTRIENT INTAKES ESPECIALLY IN THE FIRST FEW DAYS AND WEEKS IS CHALLENGING, AND MANY INFANTS SHOW POOR GROWTH AND NUTRITIONAL STATUS. GOOD NUTRITIONAL MANAGEMENT SHOULD BE SEEN AS THE CORNERSTONE OF GOOD NEONATAL CARE AND IS KEY TO IMPROVING A RANGE OF IMPORTANT OUTCOMES INCLUDING REDUCED RATES OF RETINOPATHY OF PREMATURITY, CHRONIC LUNG DISEASE, NECROTIZING ENTEROCOLITIS (NEC), AND SEPSIS. EQUALLY IMPORTANTLY, IS THAT GOOD NUTRITIONAL STATUS IS ESSENTIAL TO OPTIMIZE BRAIN GROWTH AND DIFFERENTIATION. THERE ARE MULTIPLE POTENTIAL MECHANISMS THAT LINK NUTRITION TO BRAIN OUTCOMES IN PRETERM INFANTS INCLUDING NEEDS FOR TISSUE ACCRETION, ENERGY SUPPLY, SIGNALING ROLES, FUNCTIONAL COMPONENTS IN HUMAN MILK, EPIGENETIC REGULATION, PREVENTION OF NEC AND DISEASE, AND IMPACTS ON THE GUT BRAIN AXES. THIS ARTICLE WILL REVIEW DATA IN SUPPORT OF DIFFERENT MECHANISTIC LINKS FOR THE IMPACT OF NUTRITION ON BRAIN OUTCOMES IN PRETERM INFANTS. 2021 10 2274 24 EPIGENETIC REGULATION AND FETAL PROGRAMMING. FETAL PROGRAMMING ENCOMPASSES THE ROLE OF DEVELOPMENTAL PLASTICITY IN RESPONSE TO ENVIRONMENTAL AND NUTRITIONAL SIGNALS DURING EARLY LIFE AND ITS POTENTIAL ADVERSE CONSEQUENCES (RISK OF CARDIOVASCULAR, METABOLIC AND BEHAVIOURAL DISEASES) IN LATER LIFE. THE FIRST STUDIES IN THIS FIELD HIGHLIGHTED AN ASSOCIATION BETWEEN POOR FETAL GROWTH AND CHRONIC ADULT DISEASES. HOWEVER, ENVIRONMENTAL SIGNALS DURING EARLY LIFE MAY LEAD TO ADVERSE LONG-TERM EFFECTS INDEPENDENTLY OF OBVIOUS EFFECTS ON FETAL GROWTH. ADVERSE LONG-TERM EFFECTS REFLECT A MISMATCH BETWEEN EARLY (FETAL AND NEONATAL) ENVIRONMENTAL CONDITIONS AND THE CONDITIONS THAT THE INDIVIDUAL WILL CONFRONT LATER IN LIFE. THE MECHANISMS UNDERLYING THIS RISK REMAIN UNCLEAR. HOWEVER, EXPERIMENTAL DATA IN RODENTS AND RECENT OBSERVATIONS IN HUMANS SUGGEST THAT EPIGENETIC CHANGES IN REGULATORY GENES AND GROWTH-RELATED GENES PLAY A SIGNIFICANT ROLE IN FETAL PROGRAMMING. IMPROVEMENTS IN OUR UNDERSTANDING OF THE BIOCHEMICAL AND MOLECULAR MECHANISMS AT PLAY IN FETAL PROGRAMMING WOULD MAKE IT POSSIBLE TO IDENTIFY BIOMARKERS FOR DETECTING INFANTS AT HIGH RISK OF ADULT-ONSET DISEASES. SUCH IMPROVEMENTS SHOULD ALSO LEAD TO THE DEVELOPMENT OF PREVENTIVE AND THERAPEUTIC STRATEGIES. 2008 11 585 29 BEHAVIORAL PERINATOLOGY: BIOBEHAVIORAL PROCESSES IN HUMAN FETAL DEVELOPMENT. BEHAVIORAL PERINATOLOGY IS AS AN INTERDISCIPLINARY AREA OF RESEARCH THAT INVOLVES CONCEPTUALIZATION OF THEORETICAL MODELS AND CONDUCT OF EMPIRICAL STUDIES OF THE DYNAMIC TIME-, PLACE-, AND CONTEXT-DEPENDENT INTERPLAY BETWEEN BIOLOGICAL AND BEHAVIORAL PROCESSES IN FETAL, NEONATAL, AND INFANT LIFE USING AN EPIGENETIC FRAMEWORK OF DEVELOPMENT. THE BIOBEHAVIORAL PROCESSES OF PARTICULAR INTEREST TO OUR RESEARCH GROUP RELATE TO THE EFFECTS OF MATERNAL PRE- AND PERINATAL STRESS AND MATERNAL-PLACENTAL-FETAL STRESS PHYSIOLOGY. WE PROPOSE THAT BEHAVIORAL PERINATOLOGY RESEARCH MAY HAVE IMPORTANT IMPLICATIONS FOR A BETTER UNDERSTANDING OF THE PROCESSES THAT UNDERLIE OR CONTRIBUTE TO THE RISK OF THREE SETS OF OUTCOMES: PREMATURITY, ADVERSE NEURODEVELOPMENT, AND CHRONIC DEGENERATIVE DISEASES IN ADULTHOOD. BASED ON OUR UNDERSTANDING OF THE ONTOGENY OF HUMAN FETAL DEVELOPMENT AND THE PHYSIOLOGY OF PREGNANCY AND FETAL DEVELOPMENT, WE HAVE ARTICULATED A NEUROBIOLOGICAL MODEL OF PRE- AND PERINATAL STRESS. OUR MODEL PROPOSES THAT CHRONIC MATERNAL STRESS MAY EXERT A SIGNIFICANT INFLUENCE ON FETAL DEVELOPMENTAL OUTCOMES. MATERNAL STRESS MAY ACT VIA ONE OR MORE OF THREE MAJOR PHYSIOLOGICAL PATHWAYS: NEUROENDOCRINE, IMMUNE/INFLAMMATORY, AND VASCULAR. WE FURTHER SUGGEST THAT PLACENTAL CORTICOTROPIN-RELEASING HORMONE (CRH) MAY PLAY A CENTRAL ROLE IN COORDINATING THE EFFECTS OF ENDOCRINE, IMMUNE/INFLAMMATORY, AND VASCULAR PROCESSES ON FETAL DEVELOPMENTAL OUTCOMES. FINALLY, WE HYPOTHESIZE THAT THE EFFECTS OF MATERNAL STRESS ARE MODULATED BY THE NATURE, DURATION, AND TIMING OF OCCURRENCE OF STRESS DURING GESTATION. IN THIS PAPER, WE ELABORATE ON THE CONCEPTUAL AND EMPIRICAL BASIS FOR THIS MODEL, HIGHLIGHT SOME RELEVANT ISSUES AND QUESTIONS, AND MAKE RECOMMENDATIONS FOR FUTURE RESEARCH IN THIS AREA. 2002 12 3582 19 IMPACT OF PRENATAL AND EARLY LIFE ENVIRONMENTAL EXPOSURES ON NORMAL HUMAN DEVELOPMENT. THE GLOBAL BURDEN AND PATTERN OF DISEASE HAS CHANGED IN RECENT DECADES, WITH FEWER EARLY CHILDHOOD DEATHS AND LONGER LIVES COMPLICATED BY CHRONIC DISEASE. DISRUPTION OF NORMAL HUMAN GROWTH AND DEVELOPMENT BY ADVERSE ENVIRONMENTAL EXPOSURES, ESPECIALLY DURING FOETAL DEVELOPMENT AND EARLY POSTNATAL LIFE INCREASE LIFE-LONG RISK OF CHRONIC DISEASE. THE DEVELOPMENTAL TIMING AND METHOD OF ADVERSE EXPOSURE DETERMINES THE LIKELY IMPACT ON HEALTH AND DEVELOPMENT. WHILE MANY ORGAN SYSTEMS ARE STRUCTURALLY AND FUNCTIONALLY MATURE AT BIRTH, THE CNS, RESPIRATORY AND IMMUNE SYSTEMS ARE NOT AND UNDERGO PROLONGED PERIODS OF POSTNATAL GROWTH AND DEVELOPMENT. AS SUCH, THESE ORGAN SYSTEMS ARE VULNERABLE TO ADVERSE EFFECTS OF BOTH PRENATAL AND POSTNATAL ENVIRONMENTAL EXPOSURES. WHILE THE PRECISE MECHANISMS UNDERLYING CHRONIC DISEASE ARE UNKNOWN, EPIGENETIC MECHANISMS AND THE INDUCTION OF OXIDATIVE STRESS ARE LIKELY TO BE INVOLVED. AN UNDERSTANDING OF THESE PROCESSES IS NECESSARY TO DEVELOP MITIGATION STRATEGIES AIMED AT REDUCING CHRONIC DISEASE PREVALENCE. 2021 13 4078 26 MATERNAL INFLAMMATION, GROWTH RETARDATION, AND PRETERM BIRTH: INSIGHTS INTO ADULT CARDIOVASCULAR DISEASE. THE "FETAL ORIGIN OF ADULT DISEASE HYPOTHESIS" ORIGINALLY DESCRIBED BY BARKER ET AL. IDENTIFIED THE RELATIONSHIP BETWEEN IMPAIRED IN UTERO GROWTH AND ADULT CARDIOVASCULAR DISEASE RISK AND DEATH. SINCE THEN, NUMEROUS CLINICAL AND EXPERIMENTAL STUDIES HAVE CONFIRMED THAT EARLY DEVELOPMENTAL INFLUENCES CAN LEAD TO CARDIOVASCULAR, PULMONARY, METABOLIC, AND PSYCHOLOGICAL DISEASES DURING ADULTHOOD WITH AND WITHOUT ALTERATIONS IN BIRTH WEIGHT. THIS SO CALLED "FETAL PROGRAMMING" INCLUDES DEVELOPMENTAL DISRUPTION, IMMEDIATE ADAPTATION, OR PREDICTIVE ADAPTATION AND CAN LEAD TO EPIGENETIC CHANGES AFFECTING A SPECIFIC ORGAN OR OVERALL HEALTH. THE INTRAUTERINE ENVIRONMENT IS DRAMATICALLY IMPACTED BY THE OVERALL MATERNAL HEALTH. BOTH PREMATURE BIRTH OR LOW BIRTH WEIGHT CAN RESULT FROM A VARIETY OF MATERNAL CONDITIONS INCLUDING UNDERNUTRITION OR DYSNUTRITION, METABOLIC DISEASES, CHRONIC MATERNAL STRESSES INDUCED BY INFECTIONS AND INFLAMMATION, AS WELL AS HYPERCHOLESTEROLEMIA AND SMOKING. NUMEROUS ANIMAL STUDIES HAVE SUPPORTED THE IMPORTANCE OF BOTH MATERNAL HEALTH AND MATERNAL ENVIRONMENT ON THE LONG TERM OUTCOMES OF THE OFFSPRING. WITH INCREASING RATES OF OBESITY AND DIABETES AND SURVIVAL OF PRETERM INFANTS BORN AT EARLY GESTATIONAL AGES, THE NEED TO ELUCIDATE MECHANISMS RESPONSIBLE FOR PROGRAMMING OF ADULT CARDIOVASCULAR DISEASE IS ESSENTIAL FOR THE TREATMENT OF UPCOMING GENERATIONS. 2011 14 6554 27 TRANSGENERATIONAL EFFECTS OF EARLY ENVIRONMENTAL INSULTS ON AGING AND DISEASE INCIDENCE. ADVERSE EARLY LIFE EXPERIENCES ARE MAJOR INFLUENCES ON DEVELOPMENTAL TRAJECTORIES WITH POTENTIALLY LIFE-LONG CONSEQUENCES. PRENATAL OR EARLY POSTNATAL EXPOSURE TO STRESS, UNDERNUTRITION OR ENVIRONMENTAL TOXICANTS MAY REPROGRAM BRAIN DEVELOPMENT AND INCREASE RISK OF BEHAVIOURAL AND NEUROLOGICAL DISORDERS LATER IN LIFE. NOT ONLY EXPERIENCE WITHIN A SINGLE LIFETIME, BUT ALSO ANCESTRAL EXPERIENCE AFFECTS HEALTH TRAJECTORIES AND CHANCES OF SUCCESSFUL AGING. THE CENTRAL MECHANISM IN TRANSGENERATIONAL PROGRAMMING OF A DISEASE MAY BE THE FORMATION OF EPIGENETIC MEMORY. THIS REVIEW EXPLORES TRANSGENERATIONAL EFFECTS OF EARLY ADVERSE EXPERIENCE ON HEALTH AND DISEASE INCIDENCE IN OLDER AGE. FIRST, WE ADDRESS MECHANISMS OF DEVELOPMENTAL AND TRANSGENERATIONAL PROGRAMMING OF DISEASE AND INHERITANCE. SECOND, WE DISCUSS EXPERIMENTAL AND CLINICAL FINDINGS LINKING EARLY ENVIRONMENTAL DETERMINANTS TO ADVERSE AGING TRAJECTORIES IN ASSOCIATION WITH POSSIBLE PARENTAL CONTRIBUTIONS AND SEX-SPECIFIC EFFECTS. THIRD, WE OUTLINE THE MAIN MECHANISMS OF AGE-RELATED FUNCTIONAL DECLINE AND SUGGEST POTENTIAL INTERVENTIONS TO REVERSE NEGATIVE EFFECTS OF TRANSGENERATIONAL PROGRAMMING. THUS, STRATEGIES THAT SUPPORT HEALTHY DEVELOPMENT AND SUCCESSFUL AGING SHOULD TAKE INTO ACCOUNT THE POTENTIAL INFLUENCES OF TRANSGENERATIONAL INHERITANCE. 2020 15 6625 29 UNDERSTANDING RACIAL DISPARITIES OF PRETERM BIRTH THROUGH THE PLACENTA. THE RACIAL DISPARITY ASSOCIATED WITH PRETERM BIRTH IS A PUBLIC HEALTH CONCERN IN THE UNITED STATES. THE PLACENTA IS THE PRINCIPAL METABOLIC, RESPIRATORY, AND ENDOCRINE ORGAN OF THE FETUS AND A KEY ROUTE BY WHICH ENVIRONMENTAL EXPOSURES ARE TRANSMITTED FROM MOTHER TO OFFSPRING. AVAILABLE AT EVERY DELIVERY, IT MAY SERVE AS A MARKER OF DIFFERENCES IN PRENATAL EXPOSURES THAT MANIFEST DIFFERENTLY BY RACE. RECENTLY, WE DESCRIBED DIFFERENCES IN PLACENTAL PATHOLOGY BETWEEN AFRICAN-AMERICAN AND WHITE PRETERM BIRTHS: THE PREVALENCE OF CHRONIC INFLAMMATION WAS HIGHER AMONG AFRICAN-AMERICAN WOMEN'S PLACENTAS COMPARED WITH THOSE OF WHITE WOMEN. SIMILARLY, RACIAL DIFFERENCES HAVE BEEN SHOWN IN PLACENTAL MALPERFUSION AND PLACENTAL WEIGHT. SOCIAL DETERMINANTS SUCH AS POVERTY AND STRESS FROM DISCRIMINATION HAVE BEEN IMPLICATED IN RACIAL DISPARITIES IN PRETERM BIRTH. TO DATE, HOWEVER, THE UNDERLYING BIOLOGICAL MECHANISMS, WHETHER THROUGH INFLAMMATORY, OXIDATIVE STRESS, OR OTHER PATHWAYS INVOLVING EPIGENETIC PROGRAMMING, REMAIN LARGELY UNKNOWN. THE PLACENTA, COMPLEMENTED BY MATERNAL AND UMBILICAL CORD BLOOD BIOMARKERS, MAY PROVIDE IMPORTANT INFORMATION ON THE PERINATAL ENVIRONMENT THAT EXPLAINS THE ORIGINS OF RACIAL DISPARITIES IN PRETERM BIRTH RATES AND SUBSEQUENT HEALTH OUTCOMES. THIS ARTICLE REVIEWS EXISTING LITERATURE AND CURRENT RESEARCH GAPS. OPPORTUNITIES ARE DISCUSSED FOR FUTURE PLACENTAL RESEARCH THAT MAY REVEAL NOVEL MECHANISMS LEADING TO THE DEVELOPMENT OF NEW APPROACHES IN THE PREVENTION AND MANAGEMENT OF PRETERM BIRTH AND ITS OUTCOMES. 2021 16 3664 30 INFANT NEUROBEHAVIORAL DEVELOPMENT. THE TREND TOWARD SINGLE-ROOM NEONATAL INTENSIVE CARE UNITS (NICUS) IS INCREASING; HOWEVER SCIENTIFIC EVIDENCE IS, AT THIS POINT, MOSTLY ANECDOTAL. THIS IS A CRITICAL TIME TO ASSESS THE IMPACT OF THE SINGLE-ROOM NICU ON IMPROVING MEDICAL AND NEUROBEHAVIORAL OUTCOMES OF THE PRETERM INFANT. WE HAVE DEVELOPED A THEORETICAL MODEL THAT MAY BE USEFUL IN STUDYING HOW THE CHANGE FROM AN OPEN-BAY NICU TO A SINGLE-ROOM NICU COULD AFFECT INFANT MEDICAL AND NEUROBEHAVIORAL OUTCOME. THE MODEL IDENTIFIES MEDIATING FACTORS THAT ARE LIKELY TO ACCOMPANY THE CHANGE TO A SINGLE-ROOM NICU. THESE MEDIATING FACTORS INCLUDE FAMILY CENTERED CARE, DEVELOPMENTAL CARE, PARENTING AND FAMILY FACTORS, STAFF BEHAVIOR AND ATTITUDES, AND MEDICAL PRACTICES. MEDICAL OUTCOMES THAT PLAN TO BE MEASURED ARE SEPSIS, LENGTH OF STAY, GESTATIONAL AGE AT DISCHARGE, WEIGHT GAIN, ILLNESS SEVERITY, GESTATIONAL AGE AT ENTERAL FEEDING, AND NECROTIZING ENTEROCOLITIS (NEC). NEUROBEHAVIORAL OUTCOMES INCLUDE THE NICU NETWORK NEUROBEHAVIORAL SCALE (NNNS) SCORES, SLEEP STATE ORGANIZATION AND SLEEP PHYSIOLOGY, INFANT MOTHER FEEDING INTERACTION SCORES, AND PAIN SCORES. PRELIMINARY FINDINGS ON THE SAMPLE OF 150 PATIENTS IN THE OPEN-BAY NICU SHOWED A "BASELINE" OF EFFECTS OF FAMILY CENTERED CARE, DEVELOPMENTAL CARE, PARENT SATISFACTION, MATERNAL DEPRESSION, AND PARENTING STRESS ON THE NEUROBEHAVIORAL OUTCOMES OF THE NEWBORN. THE SINGLE-ROOM NICU HAS THE POTENTIAL TO IMPROVE THE NEUROBEHAVIORAL STATUS OF THE INFANT AT DISCHARGE. NEUROBEHAVIORAL ASSESSMENT CAN ASSIST WITH EARLY DETECTION AND THEREFORE PREVENTATIVE INTERVENTION TO MAXIMIZE DEVELOPMENTAL OUTCOME. WE ALSO PRESENT AN EPIGENETIC MODEL OF THE POTENTIAL EFFECTS OF MATERNAL CARE ON IMPROVING INFANT NEUROBEHAVIORAL STATUS. 2011 17 1766 28 EARLY-LIFE EXPERIENCES AND THE DEVELOPMENT OF ADULT DISEASES WITH A FOCUS ON MENTAL ILLNESS: THE HUMAN BIRTH THEORY. IN MAMMALS, EARLY ADVERSE EXPERIENCES, INCLUDING MOTHER-PUP INTERACTIONS, SHAPE THE RESPONSE OF AN INDIVIDUAL TO CHRONIC STRESS OR TO STRESS-RELATED DISEASES DURING ADULT LIFE. THIS HAS LED TO THE ELABORATION OF THE THEORY OF THE DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE, IN PARTICULAR ADULT DISEASES SUCH AS CARDIOVASCULAR AND METABOLIC DISORDERS. IN ADDITION, IN HUMANS, AS STATED BY MASSIMO FAGIOLI'S HUMAN BIRTH THEORY, BIRTH IS HEALTHY AND EQUAL FOR ALL INDIVIDUALS, SO THAT MENTAL ILLNESS DEVELOP EXCLUSIVELY IN THE POSTNATAL PERIOD BECAUSE OF THE QUALITY OF THE RELATIONSHIP IN THE FIRST YEAR OF LIFE. THUS, THIS REVIEW FOCUSES ON THE IMPORTANCE OF PROGRAMMING DURING THE EARLY DEVELOPMENTAL PERIOD ON THE MANIFESTATION OF ADULT DISEASES IN BOTH ANIMAL MODELS AND HUMANS. CONSIDERING THE OBVIOUS DIFFERENCES BETWEEN ANIMALS AND HUMANS WE CANNOT SYSTEMATICALLY MOVE FROM ANIMAL MODELS TO HUMANS. CONSEQUENTLY, IN THE FIRST PART OF THIS REVIEW, WE WILL DISCUSS HOW ANIMAL MODELS CAN BE USED TO DISSECT THE INFLUENCE OF ADVERSE EVENTS OCCURRING DURING THE PRENATAL AND POSTNATAL PERIODS ON THE DEVELOPMENTAL TRAJECTORIES OF THE OFFSPRING, AND IN THE SECOND PART, WE WILL DISCUSS THE ROLE OF POSTNATAL CRITICAL PERIODS ON THE DEVELOPMENT OF MENTAL DISEASES IN HUMANS. EPIGENETIC MECHANISMS THAT CAUSE REVERSIBLE MODIFICATIONS IN GENE EXPRESSION, DRIVING THE DEVELOPMENT OF A PATHOLOGICAL PHENOTYPE IN RESPONSE TO A NEGATIVE EARLY POSTNATAL ENVIRONMENT, MAY LIE AT THE CORE OF THIS PROGRAMMING, THEREBY PROVIDING POTENTIAL NEW THERAPEUTIC TARGETS. THE CONCEPT OF THE HUMAN BIRTH THEORY LEADS TO A COMPREHENSION OF THE MENTAL ILLNESS AS A PATHOLOGY OF THE HUMAN RELATIONSHIP IMMEDIATELY AFTER BIRTH AND DURING THE FIRST YEAR OF LIFE. 2017 18 1779 36 EDITORIAL: MATERNAL INFLAMMATION DURING PREGNANCY: A MODIFIABLE PATHWAY TOWARD IMPROVING OFFSPRING SOCIOEMOTIONAL OUTCOMES IN CHILDHOOD AND ADOLESCENCE. CHILDHOOD PSYCHOPATHOLOGY IS A WELL-ESTABLISHED PREDICTOR OF POOR ADULT LIFE-COURSE OUTCOMES INCLUDING LOWER RATES OF EDUCATIONAL ATTAINMENT AND REDUCED FAMILY INCOME, WITH A TOTAL ECONOMIC LOSS OF $2.1 TRILLION IN THE UNITED STATES.(1) GIVEN THIS HIGH LEVEL OF INDIVIDUAL AND SOCIETAL BURDEN, MUCH EFFORT HAS BEEN DEVOTED TO IDENTIFYING THE MODIFIABLE RISK FACTORS THAT CONFER RISK FOR PSYCHIATRIC DISORDERS DURING EARLY CHILDHOOD. INDEED, NUMEROUS ASPECTS OF EARLY LIFE ADVERSITY, SUCH AS SOCIOECONOMIC DISADVANTAGE, STRESSFUL/TRAUMATIC LIFE EVENTS, AND DISRUPTED PARENT-CHILD RELATIONSHIPS, DEMONSTRATE STRONG ASSOCIATIONS WITH SOCIOEMOTIONAL PROBLEMS AND PSYCHIATRIC DISORDERS INTO ADOLESCENCE.(2) HOWEVER, THE UNDERLYING BIOLOGICAL MECHANISMS THAT ALSO CONTRIBUTE TO THIS RISK TRAJECTORY REMAIN LESS WELL UNDERSTOOD. ONE PROPOSED BIOLOGICAL MECHANISM THAT IS RAPIDLY GAINING MOMENTUM IN THE FIELD OF DEVELOPMENTAL PSYCHOPATHOLOGY CONCERNS EXCESSIVE IMMUNE SYSTEM ACTIVATION AND/OR PROINFLAMMATORY RESPONSES IN THE ORIGINS OF HEALTH AND DISEASE.(3) OF PARTICULAR INTEREST IS THE PRENATAL PERIOD, REPRESENTING A WINDOW OF VULNERABILITY IN WHICH PRENATAL EXPOSURES PREPARE OR PROGRAM THE FETUS FOR THE EXPECTED POSTNATAL ENVIRONMENT.(3-5) MORE SPECIFICALLY, FETAL PROGRAMMING POSITS THAT THE EFFECTS OF MATERNAL ADVERSITY DURING PREGNANCY ARE, AT LEAST IN PART, TRANSMITTED TO THE FETUS VIA MULTIPLE RELATED PATHWAYS INCLUDING CHRONIC MATERNAL INFLAMMATION AND/OR OVERACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, RESULTING IN ABERRANT MATERNAL-FETAL IMMUNE/GLUCOCORTICOID SYSTEMS AND DOWNSTREAM EPIGENETIC ALTERATIONS IN THE DEVELOPING FETUS. TOGETHER, THESE FACTORS WORK TO INCREASE THE SUSCEPTIBILITY OF OFFSPRING TO ADVERSITY IN THE POSTNATAL ENVIRONMENT AND, IN TURN, ENHANCE RISK FOR PSYCHIATRIC DISORDERS.(3-6) HOWEVER, MUCH OF THE EXISTING LITERATURE IS BASED ON PRECLINICAL ANIMAL MODELS WITH COMPARATIVELY FEWER CLINICAL STUDIES.(3) AS SUCH, THERE REMAINS A PAUCITY OF LARGE, PROSPECTIVELY DESIGNED CLINICAL STUDIES EXAMINING MATERNAL PROINFLAMMATORY CONDITIONS DURING PREGNANCY IN RELATION TO PSYCHOPATHOLOGY IN OFFSPRING. AS PART OF THE LANDMARK NATIONAL INSTITUTES OF HEALTH-FUNDED ECHO (ENVIRONMENTAL INFLUENCES ON CHILD HEALTH OUTCOMES) CONSORTIUM, THE STUDY BY FRAZIER ET AL.(7) REPRESENTS ONE OF THE LARGEST INVESTIGATIONS LINKING PERINATAL MATERNAL PROINFLAMMATORY CONDITIONS WITH CO-OCCURRING PSYCHIATRIC SYMPTOMS IN CHILDREN AND ADOLESCENTS. 2023 19 1911 29 ENVIRONMENT IN CHILDREN'S HEALTH: A NEW CHALLENGE FOR RISK ASSESSMENT. IN THE LAST FEW YEARS, MANY STUDIES HAVE FOCUSED ON THE EFFECTS OF ENVIRONMENTAL CONTAMINANT EXPOSURE DURING THE PRENATAL PERIOD OR INFANCY AS PREDICTORS OF HEALTH OUTCOMES IN THE FUTURE. IN THESE TIME WINDOWS, DUE TO THEIR RAPID GROWTH, AND PHYSIOLOGIC AND METABOLIC DEVELOPMENT, WE CAN OBSERVE A HIGHER VULNERABILITY TO THE EFFECTS OF ENVIRONMENT, WITH RESPECT TO ADULTHOOD. THE EVIDENCE OF POSSIBLE INFLUENCES, PARTLY MEDIATED BY EPIGENETIC MECHANISMS, INVOLVE NEUROBEHAVIORAL RESPONSES AND IMMUNE, ENDOCRINE, AND RESPIRATORY SYSTEMS, ACTING DIRECTLY ON THE CHILD OR INDIRECTLY WHEN MEDIATED BY PLACENTAL TRANSFER OR BREAST FEEDING. IN PARTICULAR, DUE TO A GREATER INTAKE OF AIR, FOOD, AND FLUIDS RELATIVE TO BODY WEIGHT, CRAWLING BEHAVIORS AND SHORT STATURE, THE RISK OF EXCESSIVE EXPOSURE IS GREATER IN CHILDREN. HOWEVER, DATA ON THE LONG-TERM IMPLICATIONS OF EARLY EXPOSURES ARE SCARCE. ADDITIONALLY, SO THAT PHYSICIANS AND INSTITUTIONS FOR CHILD CARE AND ASSISTANCE OF PREGNANT WOMEN CAN TAKE ACTIONS TO COUNTERACT THE EFFECTS OF CHEMICAL POLLUTION (I.E., BY EDUCATIONAL OPPORTUNITIES), A RISK ASSESSMENT PERSPECTIVE THAT RESPONDS TO THE BIOCOMPLEXITY OF THE HUMAN BEING IS NEEDED. THE PRESENT PAPER PROVIDES AN OVERVIEW OF PHYSIOLOGIC AND BEHAVIORAL CHARACTERISTICS DURING THE PERINATAL PERIOD AND IN CHILDHOOD, SUGGESTING IN A MORE INTEGRATED WAY, THE NEED OF A NEW RISK-ASSESSMENT APPROACH TO MANAGING CHRONIC DISEASE IN PEDIATRIC PATIENTS. 2021 20 1229 25 CRITICAL WINDOWS: EXPLORING THE ASSOCIATION BETWEEN PERINATAL TRAUMA, EPIGENETICS, AND CHRONIC PAIN. CHRONIC PAIN IS HIGHLY PREVALENT AND BURDENSOME, AFFECTING MILLIONS OF PEOPLE WORLDWIDE. ALTHOUGH IT EMERGES AT ANY POINT IN LIFE, IT OFTEN MANIFESTS IN ADOLESCENCE. GIVEN THAT ADOLESCENCE IS A UNIQUE DEVELOPMENTAL PERIOD, ADDITIONAL STRAINS ASSOCIATED WITH PERSISTENT AND OFTEN IDIOPATHIC PAIN LEAD TO SIGNIFICANT LONG-TERM CONSEQUENCES. WHILE THERE IS NO SINGULAR CAUSE FOR THE CHRONIFICATION OF PAIN, EPIGENETIC MODIFICATIONS THAT LEAD TO NEURAL REORGANIZATION MAY UNDERPIN CENTRAL SENSITIZATION AND SUBSEQUENT MANIFESTATION OF PAIN HYPERSENSITIVITY. EPIGENETIC PROCESSES ARE PARTICULARLY ACTIVE DURING THE PRENATAL AND EARLY POSTNATAL YEARS. WE DEMONSTRATE HOW EXPOSURE TO VARIOUS TRAUMAS, SUCH AS INTIMATE PARTNER VIOLENCE WHILE IN UTERO OR ADVERSE CHILDHOOD EXPERIENCES, CAN SIGNIFICANTLY INFLUENCE EPIGENETIC REGULATION WITHIN THE BRAIN AND IN TURN MODIFY PAIN-RELATED PROCESSES. WE PROVIDE COMPELLING EVIDENCE THAT THE BURDEN OF CHRONIC PAIN IS LIKELY INITIATED EARLY IN LIFE, OFTEN BEING TRANSMITTED FROM MOTHER TO OFFSPRING. WE ALSO HIGHLIGHT TWO PROMISING PROPHYLACTIC STRATEGIES, OXYTOCIN ADMINISTRATION AND PROBIOTIC USE, THAT HAVE THE POTENTIAL TO ATTENUATE THE EPIGENETIC CONSEQUENCES OF EARLY ADVERSITY. OVERALL, WE ADVANCE UNDERSTANDING OF THE CAUSAL RELATIONSHIP BETWEEN TRAUMA AND ADOLESCENT CHRONIC PAIN BY HIGHLIGHTING EPIGENETIC MECHANISMS THAT UNDERLIE THIS TRANSMISSION OF RISK, ULTIMATELY INFORMING HOW TO PREVENT THIS RISING EPIDEMIC. 2023