1 4910 135 PAIN EXPOSURE ASSOCIATES WITH TELOMERE LENGTH EROSION IN VERY PRETERM INFANTS. VERY PRETERM (VPT) INFANTS (GESTATIONAL AGE < 32 WEEKS) REQUIRE LONG-LASTING HOSPITALIZATION IN THE NEONATAL INTENSIVE CARE UNIT (NICU), EVEN IN ABSENCE OF SEVERE MORBIDITIES. DURING NICU STAY, LIFE-SAVING INTERVENTIONS OCCUR AND INCLUDE INVASIVE AND PAINFUL SKIN-BREAKING PROCEDURES (NICU-RELATED STRESS), WHICH CONSTITUTE A MAJOR EARLY ADVERSE EXPERIENCE FOR VPT INFANTS. TELOMERES ARE REPEAT-SEQUENCE AT THE END OF CHROMOSOMES, WHICH SHORTEN WITH AGE AND ARE HIGHLY SUSCEPTIBLE TO LIFE ADVERSITIES: THE EXPOSURE TO EARLY ADVERSE EXPERIENCES IS ASSOCIATED WITH SHORTER TELOMERE LENGTH (TL). NONETHELESS, PREVIOUS RESEARCH DID NOT ASSESS LONGITUDINALLY THE ASSOCIATION BETWEEN NICU-RELATED STRESS AND TL IN VPT INFANTS. IN THE PRESENT STUDY, LEUKOCYTE TL WAS ASSESSED FROM CORD BLOOD AT BIRTH IN 46 VPT INFANTS AND IN A GROUP OF 31 FULL-TERM (FT) INFANTS, AS WELL AS AT NICU DISCHARGE IN VPTS ONLY. NICU-RELATED STRESS WAS MEASURED AS THE NUMBER OF SKIN-BREAKING PROCEDURES OCCURRING THROUGHOUT THE NICU STAY. A SIGNIFICANT DIFFERENCE EMERGED FOR TL BETWEEN VPT INFANTS AND FT COUNTERPARTS AT BIRTH. TL DECREASED FROM BIRTH TO DISCHARGE IN VPT INFANTS, ALTHOUGH THE CHANGE WAS NOT SIGNIFICANT IN THE GROUP AS A WHOLE. THE AMOUNT OF NICU-RELATED STRESS EMERGED AS THE PRIMARY PREDICTOR OF TL EROSION IN VPT INFANTS, EVEN CONTROLLING FOR NEONATAL AND CLINICAL CONFOUNDERS. FURTHERMORE, VPT INFANTS EXPOSED TO HIGH NICU-RELATED STRESS EXHIBITED A MARKED AND SIGNIFICANT DECREASE IN TL, WHEREAS VPT EXPOSED TO LOW NICU-RELATED STRESS EXHIBITED A NON-SIGNIFICANT INCREASE. THE PRESENT STUDY CONFIRMS PREVIOUS EVIDENCE OF LONGER TELOMERES IN VPT INFANTS AT BIRTH COMPARED TO FT CONTROLS. MOREOVER, NICU-RELATED STRESS EMERGED AS A KEY REGULATOR OF TL EROSION FROM BIRTH TO DISCHARGE IN VPT INFANTS. FUTURE RESEARCH IS WARRANTED TO FURTHER EXPLORE TL EROSION IN VPT INFANTS AND THE FACTORS ASSOCIATED WITH INDIVIDUAL DIFFERENCES IN NICU-RELATED STRESS SUSCEPTIBILITY AT THE EPIGENETIC LEVEL. 2018 2 5214 40 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 3 3664 33 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 4 5958 56 TELOMERE LENGTH AND SALIVARY CORTISOL STRESS REACTIVITY IN VERY PRETERM INFANTS. DURING THE NEONATAL INTENSIVE CARE UNIT (NICU) STAY, VERY PRETERM (VPT) INFANTS ARE EXPOSED TO LIFE-SAVING YET PAIN-INDUCING SKIN-BREAKING PROCEDURES (I.E., NICU PAIN-RELATED STRESS) WHICH CONTRIBUTE TO THE PROGRAMMING OF HYPO-RESPONSIVE HPA AXIS DEVELOPMENT DURING THE FIRST MONTHS OF LIFE. UNFORTUNATELY, TO DATE THE MECHANISMS LINKING NICU PAIN-RELATED STRESS AND ALTERED HPA AXIS REGULATION ARE ONLY LIMITEDLY KNOWN. TELOMERE LENGTH (TL) REGULATION IS AN EPIGENETIC MECHANISM PREVIOUSLY SHOWN TO BE AFFECTED BY EARLY STRESS EXPOSURES AND CAPABLE OF ASSOCIATING WITH HPA AXIS REACTIVITY IN CHILDREN. IN VPT INFANTS, NICU PAIN-RELATED STRESS WAS FOUND TO ASSOCIATE WITH DECREASED TL FROM BIRTH TO DISCHARGE, BUT THERE IS NO EVIDENCE FOR THE ASSOCIATION BETWEEN TL AND HPA AXIS IN THESE INFANTS. IN THIS STUDY, WE PROSPECTIVELY EXAMINED THE RELATIONSHIP BETWEEN NICU PAIN-RELATED STRESS AND HPA AXIS REACTIVITY TO AN AGE-APPROPRIATE SOCIO-EMOTIONAL CONDITION (I.E., THE STILL-FACE PROCEDURE, SFP) IN HEALTHY VPT INFANTS AT 3-MONTH CORRECTED AGE. NICU PAIN-RELATED STRESS WAS COMPUTED AS THE RATIO BETWEEN THE NUMBER OF SKIN-BREAKING PROCEDURES AND LENGTH OF NICU STAY. A DIFFERENTIAL SCORE (I.E., ?TL) WAS OBTAINED SUBTRACTING TL AT BIRTH FROM TL AT DISCHARGE. A NORMALIZED (LOG10) CORTISOL REACTIVITY INDEX (CRI) WAS OBTAINED BY AVERAGING POST-STRESS (20 MIN AFTER SFP) SALIVARY CORTISOL SAMPLE ON BASELINE VALUE. A REGRESSION MODEL CONTROLLING FOR NEONATAL AND SOCIO-DEMOGRAPHIC CONFOUNDERS SHOWED THAT ?TL WAS THE ONLY SIGNIFICANT PREDICTOR OF CRI. ALTHOUGH PRELIMINARY, THESE FINDINGS CONTRIBUTE TO OUR KNOWLEDGE OF THE MECHANISMS LINKING EARLY EXPOSURES TO ADVERSITY AND LATER IN LIFE REGULATION OF THE HPA AXIS IN VPT INFANTS. 2019 5 4917 53 PAIN-RELATED STRESS DURING THE NEONATAL INTENSIVE CARE UNIT STAY AND SLC6A4 METHYLATION IN VERY PRETERM INFANTS. VERY PRETERM (VPT) INFANTS NEED LONG-LASTING HOSPITALIZATION IN THE NEONATAL INTENSIVE CARE UNIT (NICU) DURING WHICH THEY ARE DAILY EXPOSED TO PAIN-RELATED STRESS. ALTERATIONS OF DNA METHYLATION AT THE PROMOTER REGION OF THE SLC6A4 HAVE BEEN ASSOCIATED WITH EARLY ADVERSE EXPERIENCES IN INFANTS. THE MAIN AIM OF THE PRESENT WORK WAS TO INVESTIGATE THE ASSOCIATION BETWEEN LEVEL OF EXPOSURE TO PAIN-RELATED STRESS DURING HOSPITALIZATION AND CHANGES IN SLC6A4 DNA METHYLATION AT NICU DISCHARGE IN VPT INFANTS. IN ORDER TO EXCLUDE THE POTENTIAL EFFECT OF BIRTH STATUS (I.E., PRETERM VS. FULL-TERM BIRTH) ON SLC6A4 METHYLATION, WE PRELIMINARILY ASSESSED SLC6A4 EPIGENETIC DIFFERENCES BETWEEN VPT AND FULL-TERM (FT) INFANTS AT BIRTH. FIFTY-SIX VPT AND THIRTY-TWO FT INFANTS PARTICIPATED IN THE STUDY. THE LEVEL OF EXPOSURE TO PAIN-RELATED STRESS WAS QUANTIFIED ON THE BASIS OF THE AMOUNT OF SKIN-BREAKING PROCEDURES TO WHICH THEY WERE EXPOSED. VPT INFANTS WERE DIVIDED IN TWO SUB-GROUPS: LOW-PAIN EXPOSURE (LPE, N = 25) AND HIGH-PAIN EXPOSURE (HPE, N = 31). DNA METHYLATION WAS EVALUATED AT BIRTH FOR BOTH VPT AND FT INFANTS, ASSESSING 20 CPG SITES WITHIN THE SLC6A4 PROMOTER REGION. THE SAME CPG SITES WERE RE-EVALUATED FOR VARIATIONS IN DNA METHYLATION AT NICU DISCHARGE IN LPE AND HPE VPT INFANTS. NO DIFFERENCES IN SLC6A4 CPG SITES' METHYLATION EMERGED BETWEEN FT AND VPT INFANTS AT BIRTH. METHYLATION AT CPG SITES 5 AND 6 SIGNIFICANTLY INCREASED FROM BIRTH TO NICU DISCHARGE ONLY FOR HPE VPT INFANTS. FINDINGS SHOW THAT PRETERM BIRTH PER SE IS NOT ASSOCIATED WITH EPIGENETIC ALTERATIONS OF THE SLC6A4, WHEREAS HIGHER LEVELS OF PAIN-RELATED STRESS EXPOSURE DURING NICU STAY MIGHT ALTER THE TRANSCRIPTIONAL FUNCTIONALITY OF THE SEROTONIN TRANSPORTER GENE. 2015 6 5961 56 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 7 5216 30 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 8 2605 21 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 9 5197 27 PRENATAL GLUCOCORTICOIDS EXPOSURE AND FETAL ADRENAL DEVELOPMENTAL PROGRAMMING. CLINICALLY, WE APPLY SYNTHETIC GLUCOCORTICOIDS TO TREAT FETAL AND MATERNAL DISEASES, SUCH AS PREMATURE LABOR AND AUTOIMMUNE DISEASES. ALTHOUGH ITS CLINICAL EFFICACY IS POSITIVE, THE FETUS WILL BE EXPOSED TO EXOGENOUS SYNTHETIC GLUCOCORTICOIDS. PRENATAL ADVERSE ENVIRONMENTS (SUCH AS XENOBIOTICS EXPOSURE, MALNUTRITION, INFECTION, HYPOXIA AND STRESS) CAN CAUSE FETUSES OVEREXPOSURE TO EXCESSIVE ENDOGENOUS MATERNAL GLUCOCORTICOIDS. THE LEVEL OF GLUCOCORTICOIDS IS THE KEY TO FETAL TISSUE MATURATION AND POSTNATAL FATE. A LARGE NUMBER OF STUDIES HAVE FOUND THAT PRENATAL GLUCOCORTICOIDS EXPOSURE CAN LEAD TO FETAL ADRENAL DYSPLASIA AND DYSFUNCTION, CONTINUING AFTER BIRTH AND EVEN INTO ADULTHOOD. AS THE CORE ORGAN OF FETAL-ORIGINATED ADULT DISEASES, FETAL ADRENAL DYSPLASIA IS CLOSELY RELATED TO THE SUSCEPTIBILITY AND OCCURRENCE OF MULTIPLE CHRONIC DISEASES, AND THERE ARE ALSO OBVIOUS GENDER DIFFERENCES. HOWEVER, ITS INTRAUTERINE PROGRAMMING MECHANISMS HAVE NOT BEEN FULLY ELUCIDATED. THIS REVIEW SUMMARIZES RECENT ADVANCES IN PRENATAL GLUCOCORTICOIDS EXPOSURE AND FETAL ADRENAL DEVELOPMENTAL PROGRAMMING ALTERATIONS, WHICH IS OF GREAT SIGNIFICANCE FOR EXPLAINING ADRENAL DEVELOPMENTAL TOXICITY AND THE INTRAUTERINE ORIGIN OF FETAL-ORIGINATED ADULT DISEASES. 2019 10 3595 19 IMPLICATIONS OF MATERNAL CONDITIONS AND PREGNANCY COURSE ON OFFSPRING'S MEDICAL PROBLEMS IN ADULT LIFE. IN THE LAST DECADE, NUMEROUS EPIDEMIOLOGICAL, CLINICAL AND EXPERIMENTAL DATA SHOW THAT PERICONCEPTIONAL, PERINATAL AND POSTNATAL ENVIRONMENT DETERMINES THE OFFSPRING'S RISK FOR LATER-LIFE CHRONIC DISEASE. FOR THIS PHENOMENON, THE TERM "FETAL" OR "PERINATAL PROGRAMMING" IS USED. IN EXPOSED OFFSPRING ALREADY IN CHILDHOOD AND EARLY ADULTHOOD, METABOLIC AND CARDIOVASCULAR CHANGES CAN BE OBSERVED, LEADING TO OBESITY, DIABETES AND HYPERTENSION. NOWADAYS, THE MODE OF CONCEPTION (E.G., IN VITRO FERTILIZATION), MATERNAL METABOLIC CONDITIONS (E.G., UNDERNUTRITION, OVERNUTRITION, DIABETES) AND COMPLICATIONS DURING PREGNANCY (E.G., PREECLAMPSIA, INTRAUTERINE GROWTH RESTRICTION) ARE SUSPECTED TO BE NEGATIVE PREDICTORS FOR OFFSPRING'S LONG-TERM HEALTH. MECHANISMS RESPONSIBLE FOR THESE EFFECTS STILL REMAIN MAINLY UNCLEAR, BUT INCLUDE EPIGENETIC, TRANSCRIPTIONAL, ENDOPLASMIC RETICULUM STRESS, AND REACTIVE OXYGEN SPECIES. THIS REVIEW PRESENTS A PIECE OF THE PUZZLE WITH REGARDS TO PERICONCEPTIONAL AND EARLY PERINATAL CONDITIONS DETERMINING LATER-LIFE RISK FOR CHRONIC ADULT DISEASE. 2016 11 5178 23 PREGNANCY AS A FUNDAMENTAL DETERMINANT OF CHILD HEALTH: A REVIEW. PURPOSE OF REVIEW: MATERNAL CONDITIONS AND EXPOSURES DURING PREGNANCY INCLUDING OVER- AND UNDERNUTRITION ARE ASSOCIATED WITH POOR CHILDBIRTH OUTCOMES, GROWTH, DEVELOPMENT AND CHRONIC CHILDHOOD DISEASES. WE EXAMINED CONTEMPORARY PREGNANCY-RELATED DETERMINANTS OF CHILD HEALTH. RECENT FINDINGS: WHILE MATERNAL UNDERNUTRITION REMAINS A MAJOR CONTRIBUTOR TO LOW BIRTH WEIGHT, MATERNAL OBESITY AFFECTS FOETAL GROWTH, BIRTH WEIGHT, SURVIVAL AND IS ASSOCIATED WITH CHILDHOOD OBESITY, ASTHMA AND AUTISTIC SPECTRUM DISORDERS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC CHANGES, THE PRENATAL MICROBIOME AND MATERNAL IMMUNE ACTIVATION (MIA), A NEUROINFLAMMATORY PROCESS INDUCED BY DIET AND OTHER EXPOSURES CAUSE FOETAL PROGRAMMING RESULTING IN THESE CHRONIC CHILDHOOD DISEASES. MATERNAL DIET IS POTENTIALLY A MODIFIABLE RISK FACTOR FOR CONTROLLING LOW BIRTH WEIGHT, OBESITY AND CHRONIC DISEASE IN CHILDHOOD. FURTHER STUDIES ARE WARRANTED TO REFINE GUIDANCE ON DIETARY RESTRICTION AND PHYSICAL ACTIVITY DURING PREGNANCY AND DETERMINE HOW MIA AND PRENATAL MICROBIOTA CAN BE APPLIED TO CONTROL CHILDHOOD DISEASES ARISING FROM PROGRAMMING. 2022 12 4612 38 NEONATAL PAIN AND COMT VAL158MET GENOTYPE IN RELATION TO SEROTONIN TRANSPORTER (SLC6A4) PROMOTER METHYLATION IN VERY PRETERM CHILDREN AT SCHOOL AGE. CHILDREN BORN VERY PRETERM ARE EXPOSED TO REPEATED NEONATAL PROCEDURES THAT INDUCE PAIN AND STRESS DURING HOSPITALIZATION IN THE NEONATAL INTENSIVE CARE UNIT (NICU). THE COMT VAL158MET GENOTYPE IS INVOLVED WITH PAIN SENSITIVITY, AND EARLY LIFE STRESS IS IMPLICATED IN ALTERED EXPRESSION OF METHYLATION OF THE SEROTONIN TRANSPORTER. WE EXAMINED: (1) WHETHER METHYLATION OF THE SEROTONIN TRANSPORTER GENE (SLC6A4) PROMOTER DIFFERS BETWEEN VERY PRETERM CHILDREN AND FULL-TERM CONTROLS AT SCHOOL AGE, (2) RELATIONSHIPS WITH CHILD BEHAVIOR PROBLEMS, AND (3) WHETHER THE EXTENT OF NEONATAL PAIN EXPOSURE INTERACTS WITH THE COMT VAL158MET GENOTYPE TO PREDICT SLC6A4 METHYLATION AT 7 YEARS IN THE VERY PRETERM CHILDREN. WE EXAMINED THE ASSOCIATIONS BETWEEN THE COMT GENOTYPES, NEONATAL PAIN EXPOSURE (ADJUSTED FOR NEONATAL CLINICAL CONFOUNDERS), SLC6A4 METHYLATION AND BEHAVIOR PROBLEMS. VERY PRETERM CHILDREN HAD SIGNIFICANTLY HIGHER METHYLATION AT 7/10 CPG SITES IN THE SLC6A4 PROMOTER COMPARED TO FULL-TERM CONTROLS AT 7 YEARS. NEONATAL PAIN (ADJUSTED FOR CLINICAL CONFOUNDERS) WAS SIGNIFICANTLY ASSOCIATED WITH TOTAL CHILD BEHAVIOR PROBLEMS ON THE CHILD BEHAVIOR CHECKLIST (CBCL) QUESTIONNAIRE (ADJUSTED FOR CONCURRENT STRESSORS AND 5HTTLPR GENOTYPE) (P = 0.035). CBCL TOTAL PROBLEMS WAS SIGNIFICANTLY ASSOCIATED WITH GREATER SLC6A4 METHYLATION IN VERY PRETERM CHILDREN (P = 0.01). NEONATAL PAIN (ADJUSTED FOR CLINICAL CONFOUNDERS) AND COMT MET/MET GENOTYPE WERE ASSOCIATED WITH SLC6A4 PROMOTER METHYLATION IN VERY PRETERM CHILDREN AT 7 YEARS (P = 0.001). THESE FINDINGS PROVIDE EVIDENCE THAT BOTH GENETIC PREDISPOSITION AND EARLY ENVIRONMENT NEED TO BE CONSIDERED IN UNDERSTANDING SUSCEPTIBILITY FOR DEVELOPING BEHAVIORAL PROBLEMS IN THIS VULNERABLE POPULATION. 2014 13 4797 23 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 14 4998 22 PERINATAL ORIGINS OF ADULT DISEASE. EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES HAVE SHOWN THAT THE PERI-CONCEPTION PERIOD, PREGNANCY, AND INFANCY ARE WINDOWS OF PARTICULAR SENSIBILITY TO ENVIRONMENTAL CLUES WHICH INFLUENCE LIFELONG TRAJECTORIES ACROSS HEALTH AND DISEASE. NUTRITION, STRESS, AND TOXINS INDUCE EPIGENETIC MARKS THAT CONTROL LONG-TERM GENE EXPRESSION PATTERNS AND CAN BE TRANSMITTED TRANSGENERATIONALLY. CHRONIC DISEASES OF ADULTHOOD SUCH AS HYPERTENSION, DIABETES, AND OBESITY THUS HAVE EARLY, DEVELOPMENTAL ORIGINS IN THE PERINATAL PERIOD. THE EARLY EPIGENOME, IN INTERACTION WITH OTHER ACTORS SUCH AS THE MICROBIOME, ADD POWERFUL LAYERS OF DIVERSITY TO THE BIOLOGICAL PREDISPOSITION GENERATED BY THE GENOME. SUCH "PROGRAMMING" IS A NORMAL, ADAPTIVE COMPONENT OF DEVELOPMENT, INCLUDING IN NORMAL PREGNANCIES AND BIRTHS. HOWEVER, PERINATAL DISEASE, EITHER MATERNAL (SUCH AS PRE-ECLAMPSIA, GES-TATIONAL DIABETES, OR INFLAMMATORY DISEASE) OR FETAL, AND NEONATAL DISEASES (SUCH AS INTRAUTERINE GROWTH RESTRICTION AND PRETERM BIRTH) ARE MAJOR CONDITIONS OF ALTERED PROGRAMMING, TRANSLATED INTO AN INCREASED RISK FOR CHRONIC DISEASE IN THESE PATIENTS WHEN THEY REACH ADULTHOOD. EARLY PREVENTION, OPTIMAL PERINATAL NUTRITION, AND SPECIFIC FOLLOW-UP MEASURES ARE KEY FACTORS IN THE EARLY PRESERVATION OF LONG-TERM HEALTH. 2018 15 4847 30 OPIOID DEPENDENCE AND PREGNANCY: MINIMIZING STRESS ON THE FETAL BRAIN. INCREASE IN THE NUMBER OF OPIOID-DEPENDENT PREGNANT WOMEN DELIVERING BABIES AT RISK FOR NEONATAL ABSTINENCE SYNDROME PROMPTED A US GOVERNMENT ACCOUNTABILITY OFFICE REPORT DOCUMENTING DEFICITS IN RESEARCH AND PROVIDER KNOWLEDGE ABOUT CARE OF THE MATERNAL/FETAL UNIT AND THE NEONATE. THERE ARE 3 GENERAL SOURCES OF DEPENDENCE: UNTREATED OPIOID USE DISORDER, PAIN MANAGEMENT, AND MEDICATION-ASSISTED TREATMENT WITH METHADONE OR BUPRENORPHINE. A SURVEY OF METHADONE PATIENTS' EXPERIENCES WHEN TELLING A PHYSICIAN OF THEIR PREGNANCY AND OPIOID DEPENDENCE DEMONSTRATED PHYSICIAN CONFUSION ABOUT PROPER CARE, FREQUENT NEGATIVE INTERACTIONS WITH THE MOTHER, AND FAILURES TO PROVIDE APPROPRIATE REFERRAL. PATIENTS IN PAIN MANAGEMENT WERE DISCHARGED WITHOUT REFERRAL WHEN THE PHYSICIAN WAS TOLD OF THE PREGNANCY. METHADONE AND BUPRENORPHINE WERE FREQUENTLY SEEN NEGATIVELY BECAUSE THEY "CAUSED" NEONATAL ABSTINENCE SYNDROME. MOST MOTHERS SURVEYED HAD TO FIND OPIOID TREATMENT ON THEIR OWN. HOW DEPENDENCE IS MANAGED MEDICALLY IS A CRITICAL DETERMINANT OF THE LEVEL OF STRESS ON BOTH MOTHER AND FETUS, AND THEREFORE ANOTHER DETERMINANT OF NEONATAL HEALTH. THE EFFECTS OF BOTH OPIOID WITHDRAWAL STRESS AND MATERNAL EMOTIONAL STRESS ON NEONATAL AND DEVELOPMENTAL OUTCOMES ARE REVIEWED. CURRENTLY, THERE HAVE BEEN EFFORTS TO CRIMINALIZE MATERNAL OPIOID DEPENDENCE AND TO ENCOURAGE OR COERCE PREGNANT WOMEN TO UNDERGO WITHDRAWAL. THIS PRACTICE POSES BOTH ACUTE RISKS OF FETAL HYPOXIA AND LONG-TERM RISKS OF ADVERSE EPIGENETIC PROGRAMMING RELATED TO CATECHOLAMINE AND CORTICOSTEROID SURGES DURING WITHDRAWAL. CONTEMPORARY STUDIES OF THE EFFECTS OF WITHDRAWAL STRESS ON THE DEVELOPING FETAL BRAIN ARE URGENTLY NEEDED TO ELUCIDATE AND QUANTIFY THE RISKS OF SUCH PRACTICES. AT BIRTH, INCONSISTENCIES IN THE HOSPITAL MANAGEMENT OF NEONATES AT RISK FOR NEONATAL ABSTINENCE SYNDROME HAVE BEEN OBSERVED. NEGLECT OF THE CRITICAL ROLE OF MATERNAL COMFORTING IN NEONATAL ABSTINENCE SYNDROME MANAGEMENT IS AN IATROGENIC AND PREVENTABLE CAUSE OF POOR OUTCOMES AND LONG HOSPITALIZATIONS. ROOMING-IN ALLOWS FOR CONTINUOUS CARE OF THE BABY AND MATERNAL/NEONATAL ATTACHMENT, OFTEN UNWITTINGLY DISRUPTED BY THE NEONATAL INTENSIVE CARE UNIT ENVIRONMENT. RECOMMENDATIONS ARE MADE FOR FURTHER RESEARCH INTO PHYSICIAN/PATIENT INTERACTIONS AND INTO OPTIMAL DOSING OF METHADONE AND BUPRENORPHINE TO MINIMIZE MATERNAL/FETAL WITHDRAWAL. 2017 16 4065 26 MATERNAL AND GESTATIONAL INFLUENCES ON CHILDHOOD BLOOD PRESSURE. EXPOSURES THAT CONTRIBUTE TO A SUB-OPTIMAL INTRAUTERINE ENVIRONMENT CAN HAVE AN EFFECT ON THE DEVELOPING FETUS. IMPAIRED FETAL GROWTH THAT RESULTS IN LOW BIRTH WEIGHT IS AN ESTABLISHED RISK FACTOR FOR CARDIO-METABOLIC DISORDERS LATER IN LIFE. RECENT EPIDEMIOLOGIC AND PROSPECTIVE COHORT STUDIES THAT INCLUDE THE MATERNAL AND GESTATIONAL PERIOD HAVE IDENTIFIED MATERNAL AND GESTATIONAL CONDITIONS THAT CONFER INCREASED RISK FOR SUBSEQUENT CARDIO-METABOLIC DISORDERS IN THE ABSENCE OF LOW BIRTH WEIGHT. MATERNAL PRE-CONCEPTION HEALTH STATUS, INCLUDING CHRONIC OBESITY AND TYPE 2 DIABETES, INCREASE RISK FOR CHILDHOOD OBESITY AND OBESITY-RELATED HIGHER BLOOD PRESSURE (BP) IN CHILD OFFSPRING. MATERNAL GESTATIONAL EXPOSURES, INCLUDING GESTATIONAL DIABETES, GESTATIONAL HYPERTENSION, AND PREECLAMPSIA, ARE ASSOCIATED WITH HIGHER BP IN OFFSPRING. OTHER MATERNAL EXPOSURES SUCH AS CIGARETTE SMOKE AND AIR POLLUTION ALSO INCREASE RISK FOR HIGHER BP IN CHILD OFFSPRING. RECENT, BUT LIMITED, DATA INDICATE THAT ASSISTED REPRODUCTIVE TECHNOLOGIES CAN BE ASSOCIATED WITH HYPERTENSION IN CHILDHOOD, DESPITE OTHERWISE NORMAL GESTATION AND HEALTHY NEWBORN. GESTATIONAL EXPOSURES ASSOCIATED WITH HIGHER BP IN CHILDHOOD CAN BE RELATED TO FAMILIAL LIFESTYLE FACTORS, GENETICS, OR EPIGENETIC MODIFICATION OF FETAL DEOXYRIBONUCLEIC ACID (DNA). THESE FACTORS, OR COMBINATION OF FACTORS, AS WELL AS OTHER ADVERSE INTRAUTERINE CONDITIONS, COULD INDUCE FETAL PROGRAMING LEADING TO HEALTH CONSEQUENCES IN LATER LIFE. CURRENT AND DEVELOPING RESEARCH WILL PROVIDE ADDITIONAL INSIGHTS ON GESTATIONAL EXPOSURES AND FETAL ADJUSTMENTS THAT INCREASE RISK FOR HIGHER BP LEVELS IN CHILDHOOD. 2020 17 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 18 1755 27 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 19 5200 27 PRENATAL MATERNAL STRESS PREDICTS METHYLATION OF GENES REGULATING THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL SYSTEM IN MOTHERS AND NEWBORNS IN THE DEMOCRATIC REPUBLIC OF CONGO. EXPOSURE TO STRESS EARLY IN LIFE PERMANENTLY SHAPES ACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL (HPA) AXIS AND THE BRAIN. PRENATALLY, GLUCOCORTICOIDS PASS THROUGH THE PLACENTA TO THE FETUS WITH POSTNATAL IMPACTS ON BRAIN DEVELOPMENT, BIRTH WEIGHT (BW), AND HPA AXIS FUNCTIONING. LITTLE IS KNOWN ABOUT THE BIOLOGICAL MECHANISMS BY WHICH PRENATAL STRESS AFFECTS POSTNATAL FUNCTIONING. THIS STUDY ADDRESSES THIS GAP BY EXAMINING THE EFFECT OF CHRONIC STRESS AND TRAUMATIC WAR-RELATED STRESS ON EPIGENETIC CHANGES IN FOUR KEY GENES REGULATING THE HPA AXIS IN NEONATAL CORD BLOOD, PLACENTA, AND MATERNAL BLOOD: CRH, CRHBP, NR3C1, AND FKBP5. PARTICIPANTS WERE 24 MOTHER-NEWBORN DYADS IN THE CONFLICT-RIDDEN REGION OF THE EASTERN DEMOCRATIC REPUBLIC OF CONGO. BW DATA WERE COLLECTED AT DELIVERY AND MATERNAL INTERVIEWS WERE CONDUCTED TO ASSESS CULTURALLY RELEVANT CHRONIC AND WAR-RELATED STRESSORS. CHRONIC STRESS AND WAR TRAUMA HAD WIDESPREAD EFFECTS ON HPA AXIS GENE METHYLATION, WITH SIGNIFICANT EFFECTS OBSERVED AT TRANSCRIPTION FACTOR BINDING (TFB) SITES IN ALL TARGET GENES TESTED. SOME CHANGES IN METHYLATION WERE UNIQUE TO CHRONIC OR WAR STRESS, WHEREAS OTHERS WERE OBSERVED ACROSS BOTH STRESSOR TYPES. MOREOVER, STRESS EXPOSURES IMPACTED MATERNAL AND FETAL TISSUES DIFFERENTLY, SUPPORTING THEORETICAL MODELS THAT STRESS IMPACTS VARY ACCORDING TO LIFE PHASE. METHYLATION IN SEVERAL NR3C1 AND CRH CPG SITES, ALL LOCATED AT TFB SITES, WAS ASSOCIATED WITH BW. THESE FINDINGS SUGGEST THAT PRENATAL STRESS EXPOSURE IMPACTS DEVELOPMENT VIA EPIGENETIC CHANGES IN HPA AXIS GENES. 2016 20 4078 24 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