Neonatal Cranial Ultrasound Findings among Infants Born Extremely Preterm: Associations with Neurodevelopmental Outcomes at 10 Years of Age.

OBJECTIVE: To examine the association between neonatal cranial ultrasound (CUS) abnormalities among infants born extremely preterm and neurodevelopmental outcomes at 10 years of age. STUDY DESIGN: In a multicenter birth cohort of infants born at <28 weeks of gestation, 889 of 1198 survivors were evaluated for neurologic, cognitive, and behavioral outcomes at 10 years of age. Sonographic markers of white matter damage (WMD) included echolucencies in the brain parenchyma and moderate to severe ventricular enlargement. Neonatal CUS findings were classified as intraventricular hemorrhage (IVH) without WMD, IVH with WMD, WMD without IVH, and neither IVH nor WMD. RESULTS: WMD without IVH was associated with an increased risk of cognitive impairment (OR 3.5, 95% CI 1.7, 7.4), cerebral palsy (OR 14.3, 95% CI 6.5, 31.5), and epilepsy (OR 6.9; 95% CI 2.9, 16.8). Similar associations were found for WMD accompanied by IVH. Isolated IVH was not significantly associated these outcomes. CONCLUSIONS: Among children born extremely preterm, CUS abnormalities, particularly those indicative of WMD, are predictive of neurodevelopmental impairments at 10 years of age. The strongest associations were found with cerebral palsy.

Socioeconomic status and early blood concentrations of inflammation-related and neurotrophic proteins among extremely preterm newborns.

The main objective of this study was to evaluate the relationship between mother's socioeconomic disadvantage and blood concentrations of inflammation-related proteins among extremely preterm newborns (<28 weeks gestation), a group at heightened risk of cognitive impairment when exposed to systemic inflammation. We measured the concentrations of 27 inflammatory and neurotrophic proteins in blood specimens collected a week apart during the first postnatal month from 857 extremely preterm newborns in the United States. We classified children according to 3 indicators/correlates of socioeconomic disadvantage, mother's eligibility for government-provided medical care insurance (Medicaid), mother's formal education level, and mother's IQ approximated with the Kaufman Brief Intelligence Test- 2. The risks of a top-quartile concentration of each protein on each of 5 days a week apart, on two occasions during the first two postnatal weeks, and during the next two weeks were modeled as functions of each indicator of socioeconomic disadvantage. The risks of top quartile concentrations of multiple (2-5) inflammation-related proteins on multiple days during the first two weeks were increased for each of the 3 indicators of socioeconomic disadvantage, while the risks of top quartile concentrations of selected neurotrophic proteins were reduced. Adjustment for socioeconomic disadvantage did not alter the relationships between protein concentrations and both low IQ and low working memory 10 years later. Among extremely preterm newborns, indicators of socioeconomic disadvantage are associated with modestly increased risk of systemic inflammation in postnatal blood during the first postnatal month and with a slightly reduced risk of a neurotrophic signal, but do not confound relationships between protein concentrations and outcomes.

Antecedents of epilepsy and seizures among children born at extremely low gestational age.

OBJECTIVE: To identify specific risk factors for epilepsy for individuals born extremely preterm. STUDY DESIGN: In a prospective cohort study, at 10-year follow-up, children were classified as having epilepsy or seizures not associated with epilepsy. We evaluated for association of perinatal factors using time-oriented, multinomial logistic regression models. RESULTS: Of the 888 children included in the study, 66 had epilepsy and 39 had seizures not associated with epilepsy. Epilepsy was associated with an indicator of low socioeconomic status, maternal gestational fever, early physiologic instability, postnatal exposure to hydrocortisone, cerebral white matter disease and severe bronchopulmonary dysplasia. Seizure without epilepsy was associated with indicators of placental infection and inflammation, and hypoxemia during the first 24 postnatal hours. CONCLUSIONS: In children born extremely preterm, epilepsy and seizures not associated with epilepsy have different risk profiles. Though both profiles included indicators of infection and inflammation, the profile of risk factors for epilepsy included multiple indicators of endogenous vulnerability.

Early Postnatal IGF-1 and IGFBP-1 Blood Levels in Extremely Preterm Infants: Relationships with Indicators of Placental Insufficiency and with Systemic Inflammation.

OBJECTIVE: To evaluate to what extent indicators of placenta insufficiency are associated with low concentrations of insulin-like growth factor 1 (IGF-1) and IGF-1-binding protein-1 (IGFBP-1) in neonatal blood, and to what extent the concentrations of these growth factors are associated with concentrations of proteins with inflammatory, neurotrophic, or angiogenic properties. STUDY DESIGN: Using multiplex immunoassays, we measured the concentrations of IGF-1 and IGFBP-1, as well as 25 other proteins in blood spots collected weekly from ≥ 880 infants born before the 28th week of gestation, and sought correlates of concentrations in the top and bottom quartiles for gestational age and day the specimen was collected. RESULTS: Medically indicated delivery and severe fetal growth restriction (sFGR) were associated with low concentrations of IGF-1 on the first postnatal day and with high concentrations of IGFBP-1 on almost all days. Elevated concentrations of IGF-1 and IGFBP-1 were accompanied by elevated concentrations of many other proteins with inflammatory, neurotrophic, or angiogenic properties. CONCLUSION: Disorders associated with impaired placenta implantation and sFGR appear to account for a relative paucity of IGF-1 on the first postnatal day. Elevated concentrations of IGF-1 and especially IGFBP-1 were associated with same-day elevated concentrations of inflammatory, neurotrophic, and angiogenic proteins.

Neurocognitive function of 10-year-old multiples born less than 28 weeks of gestational age.

INTRODUCTION: Few studies have examined the relationship between birth plurality and neurocognitive function among children born extremely preterm. STUDY DESIGN: We compared rates of Z-scores ≤-2 on 18 tests of neurocognitive function and academic achievement at age 10 years in 245 children arising from twin pregnancies, 55 from triplet pregnancies, and 6 from a septuplet pregnancy to that of 568 singletons, all of whom were born before the 28th week of gestation. RESULTS: In total, 874 children were evaluated at the age of 10 years. After adjusting for confounders, children of multifetal pregnancies performed significantly better on one of six subtests of executive function than their singleton peers. Performance was similar on all other assessments of intelligence, language, academic achievement, processing speed, visual perception, and fine motor skills. CONCLUSION: We found no evidence that children born of multifetal pregnancies had worse scores than their singleton peers on assessments of neurocognitive and academic function.

Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm.

We evaluated the relationship between blood levels of inflammatory and neurotrophic proteins during the first postnatal month in 692 children born before the 28th week of gestation and executive function limitations among those 10-year olds who had an IQ ≥ 70. The measures of dysfunction were Z-scores ≤ -1 on the Differential Ability Scales-II working memory (WM) assessment) (N = 164), the NEPSY-II (A Developmental NEuroPSYchological Assessment-II) Inhibition-Inhibition assessment) (N = 350), the NEPSY-II Inhibition-Switching assessment) (N = 345), as well as a Z-score ≤ -1 on all three assessments (identified as the executive dysfunction composite (N = 104). Increased risks of the executive dysfunction composite associated with high concentrations of inflammatory proteins (IL-8, TNF-α, and ICAM-1) were modulated by high concentrations of neurotrophic proteins. This pattern of modulation by neurotrophins of increased risk associated with inflammation was also seen for the working memory limitation, but only with high concentrations of IL-8 and TNF-α, and the switching limitation, but only with high concentrations of ICAM-1. We infer that among children born extremely preterm, risks of executive function limitations might be explained by perinatal systemic inflammation in the absence of adequate neurotrophic capability.

Antecedents of Obesity Among Children Born Extremely Preterm.

BACKGROUND: Childhood obesity is a pervasive public health problem with risk factors such as maternal prepregnancy BMI and rapid infant weight gain. Although catch-up weight gain promotes more favorable neurodevelopment among infants born preterm, it is not clear whether faster weight gain early in life, or other correlates of preterm birth, are associated with later obesity in this population. METHODS: We used prospective data from the multicenter, observational Extremely Low Gestational Age Newborn Study. Among 1506 eligible individuals in the initial cohort, 1198 were eligible for follow-up at 10 years of age. We examined BMI in 871 children (58% of the cohort; 74% of survivors) and analyzed relationships between antecedents and overweight or obesity at 10 years of age. A time-oriented approach to multinomial multivariable regression enabled us to calculate odds of overweight and obesity associated with pre- and postnatal antecedents. RESULTS: Prepregnancy maternal BMI ≥25 and top quartile infant weight gain in the first year were associated with increased risk of both overweight and obesity at 10 years of age. Single marital status was a risk factor for later child obesity and exposure to tobacco smoke was a risk factor for later child overweight. CONCLUSIONS: The risk profiles for overweight and obesity at 10 years of age among children born extremely preterm appear to be similar to the risk profiles of overweight and obesity among children born at term.

Risk factors for chronic lung disease and asthma differ among children born extremely preterm.

OBJECTIVES: To evaluate the hypothesis that chronic lung disease of prematurity (CLD) is a risk factor for asthma in children born extremely preterm, and the hypothesis that the risk factors for CLD are similar to those for asthma. METHODS: A retrospective analysis was performed using data collected prospectively from 882 children born before the 28th week of gestation between 2002 and 2004 who returned for follow-up at ages 12 and 24 months and 10 years. We created time-oriented logistic regression models to compare risk factors for CLD, defined as need for supplemental oxygen at 36 weeks postmenstrual age, and parent-reported asthma at 10 years of age. RESULTS: CLD diagnosed during neonatal admission was associated with bronchodilator use at 12 months and 24 months (P < 0.001), but not with an asthma diagnosis at 10 years (Odds Ratio 1.3; 95% confidence interval 0.98-1.8). While risk factors for CLD include lower gestational age (OR 2.7; 1.5-4.7) and fetal growth restriction (OR 2.3; 1.4-3.7), risk factors for asthma include mother's eligibility for public insurance (Medicaid) (OR 1.8; 1.1-2.8), and higher weight gain velocity during the first year (OR 1.5; 1.02-2.2) and between the 2nd and 10th year (OR 1.7; 1.2-2.4). CONCLUSIONS: Among children born extremely preterm, the diagnosis of CLD and its antecedents were associated with transient preschool wheezing, but not with asthma. Post-NICU factors, such as growth velocity and socioeconomic disadvantage, appear to have stronger associations with asthma than exposures during NICU admission.

Behavioural dysfunctions of 10-year-old children born extremely preterm associated with corticotropin-releasing hormone expression in the placenta.

AIM: To evaluate the relationship between corticotropin-releasing hormone (CRH) expression in the placenta and the risk of school-related dysfunctions at the age of 10 years among children born extremely preterm (EP). METHODS: Corticotropin-releasing hormone expression was measured in the placenta of 761 EP children, who had the following assessments at the age of 10 years: Differential Ability Scales, Oral and Written Language Scales, the Wechsler Individual Achievement Test-III, NEPSY-II and the Child Symptom Inventory-4. We evaluated whether lowest and highest quartiles of CRH mRNA were associated with undesirable scores on these assessments. With 272 evaluations, we would expect 14 to be significant at p < 0.05. RESULTS: Only 16 associations were statistically significant. On the other hand, seven of these were social limitations among girls whose placenta CRH mRNA was in the top quartile. Adjusting for delivery indication or restricting the sample to one delivery indication group resulted in few differences. CONCLUSION: Overall, placenta CRH mRNA concentrations in the top or bottom quartiles were not associated with increased risks of dysfunctions 10 years later. Girls whose placenta CRH expression was in the top quartile, however, were at increased risk of seven indicators/correlates of social limitations.

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation.

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2-5.3) and IL-6 (OR; 95% CI: 2.6; 1.03-6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2-6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3-5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1-3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1-4.2).

The risk of neurodevelopmental disorders at age 10 years associated with blood concentrations of interleukins 4 and 10 during the first postnatal month of children born extremely preterm.

BACKGROUND: Interleukin (IL)-4 and IL-10 are viewed mainly as anti-inflammatory cytokines. Yet, high concentrations have also been associated with inflammation-related diseases in newborns. METHODS: We measured the concentrations of IL-4 and IL-10, as well as IL-8 and ICAM-1 in blood specimens collected on postnatal day 21 (N = 555), day 28 (N = 521), and both days 21 and 28 (N = 449) from children born extremely preterm (EP) (<28 weeks gestation) who at age 10 years had a DAS-II IQ Z-score > -2 (which approximates a score of >70) and the following assessments, CCC-2, and CSI-4, DAS-II, NEPSY-II, OWLS-II, SCQ, and WIAT-III. Selected children also were assessed with the ADI-R and the ADOS-2. We modeled the risk of low scores or dysfunctions associated with top quartile concentrations of IL-4 and IL-10 on each day and on both days. RESULTS: The risks of low scores on the Animal Sorting and Arrows components of the NEPSY-II, both components of the OWLS-II, and the PseudoWord and Spelling components of the WIAT-III were heightened among children who had top quartile concentrations of IL-4 on postnatal days 21 and 28. Children who had high concentrations of IL-10 on days 21 and 28, individually and collectively, were at increased risk of low scores on the WIAT-III Spelling component. High concentrations of IL-4 on day 28 were associated with autism spectrum disorder (ASD). High concentrations of IL-10 on day 28 were also associated with a doubling of ASD risk, but this did not achieve statistical significance. Top quartile concentrations of IL-4 and IL10 on both days were not associated with increased risk of social, language, or behavioral dysfunctions. CONCLUSION: Among children born EP, those who had top quartile concentrations of IL-4 and/or IL-10 on postnatal days 21 and/or 28 were more likely than their peers to have low scores on components of the NEPSY-II, OWLS-II, and WIAT-III assessments, as well as identification as having an ASD. What is known: What is not known: What this study adds.

Cognitive Development and Quality of Life Associated With BPD in 10-Year-Olds Born Preterm.

OBJECTIVES: To compare neurocognitive, language, executive function, academic achievement, neurologic and behavioral outcomes, and quality of life at age 10 years in children born extremely preterm who developed bronchopulmonary dysplasia (BPD) to children who did not develop BPD. METHODS: The Extremely Low Gestational Age Newborns study population included 863 children born extremely preterm whose BPD status before discharge was known had an IQ (Differential Ability Scales II [DAS II]) assessment at 10 years. We evaluated the association of BPD with any cognitive (DAS II), executive function (NEuroPSYchological Assessment II), academic achievement (Wechsler Individual Achievement Test-III and Oral and Written Language Scales [OWLS]) as well as social dysfunctions (Social Responsiveness Scale). We used logistic regression models, adjusting for potential confounding factors, to assess the strength of association between the severity of BPD and each outcomes. RESULTS: Three hundred and seventy-two (43%) children were oxygen-dependent at 36 weeks postconception age, whereas an additional 78 (9%) were also oxygen- and ventilator-dependent. IQ scores 2 or more SDs below the expected mean (ie, z scores ≤-2) occurred twice as commonly among children who had BPD as among those who did not. Children with severe BPD consistently had the lowest scores on DAS II, OWLS, Wechsler Individual Achievement Test-III, NEuroPSYchological Assessment II, and Social Responsiveness Scale assessments. CONCLUSIONS: Among 10-year-old children born extremely preterm, those who had BPD were at increased risk of cognitive, language, and executive dysfunctions; academic achievement limitations; social skill deficits; and low scores on assessments of health-related quality of life.

Accuracy of the Bayley-II mental development index at 2 years as a predictor of cognitive impairment at school age among children born extremely preterm.

OBJECTIVE: To describe the accuracy of the Bayley Scales of Infant Development-Second Edition (BSID-II) Mental Development Index (MDI) at 2 years of age for prediction of cognitive function at school age of children born extremely preterm. DESIGN: Study participants were enrolled in the Extremely Low Gestational Age Newborn Study between 2002 and 2004. Two-thirds of surviving children (n = 795) were assessed at 2 years with the BSID-II and at 10 years with an intelligence quotient (IQ) test. We computed test characteristics for a low MDI (<70), including predictive value positive. RESULTS: Almost two-thirds of children with a low MDI had a normal IQ (≥ 70) at 10 years. Concordance between MDI and IQ was highest among children with major motor and/or sensory impairment, and when MDI was adjusted for gestational age. CONCLUSION: Most children born extremely preterm with low BSID-II MDI at 2 years have normal intelligence at school age.

Antecedents of Screening Positive for Attention Deficit Hyperactivity Disorder in Ten-Year-Old Children Born Extremely Preterm.

BACKGROUND: The incidence of attention deficit hyperactivity disorder is higher among children born very preterm than among children who are mature at birth. METHODS: We studied 583 ten-year-old children who were born before 28 weeks of gestation whose IQ was above 84 and had a parent-completed Child Symptom Inventory-4, which allowed classification of the child as having or not having symptoms of attention deficit hyperactivity disorder. For 422 children, we also had a teacher report, and for 583 children, we also had a parent report of whether or not a physician made an attention deficit hyperactivity disorder diagnosis. RESULTS: The risk profile of screening positive for attention deficit hyperactivity disorder based on a parent's report differed from the risk profile based on the teacher's report, whereas the risk profile according to a physician and according to any two observers closely resembled the parent-reported profile. Among the statistically significant risk factors were young maternal age (parent, physician, and two observers), maternal obesity (parent, physician, and two observers), maternal smoking (parent, physician, and two observers), magnesium given at delivery for seizure prophylaxis (parent and two observers), recovery of Mycoplasma sp. from the placenta (teacher and two observers), low gestational age (parent and two observers), low birth weight (teacher and physician), singleton (parent, physician, and two observers), male (parent, teacher, physician, and two observers), mechanical ventilation on postnatal day seven (physician), receipt of a sedative (parent and two observers), retinopathy of prematurity (parent), necrotizing enterocolitis (physician), antibiotic receipt (physician and two observers), and ventriculomegaly on brain scan (parent and two observers). CONCLUSIONS: The multiplicity of risk factors identified can be subsumed as components of four broad themes: low socioeconomic state, immaturity or vulnerability, inflammation, and epigenetic phenomena.

Circulating biomarkers in extremely preterm infants associated with ultrasound indicators of brain damage.

AIM: To assess to what extent the blood concentrations of proteins with neurotrophic and angiogenic properties measured during the first postnatal month convey information about the risk of sonographically-identified brain damage among very preterm newborns. METHODS: Study participants were 1219 children who had a cranial ultrasound scan during their stay in the intensive care nursery and blood specimens collected on 2 separate days at least a week apart during the first postnatal month. Concentrations of selected proteins in blood spots were measured with electrochemiluminescence or with a multiplex immunobead assay and the risks of cranial ultrasound images associated with top-quartile concentrations were assessed. RESULTS: High concentrations of multiple inflammation-related proteins during the first 2 postnatal weeks were associated with increased risk of ventriculomegaly, while high concentrations of just 3 inflammation-related proteins were associated with increased risk of an echolucent/hypoechoic lesion (IL-6, IL-8, ICAM-1), especially on day 7. Concomitant high concentrations of IL6R and bFGF appeared to modulate the increased risks of ventriculomegaly and an echolucent lesion associated with inflammation. More commonly high concentrations of putative protectors/repair-enhancers did not appear to diminish these increased risks. CONCLUSION: Our findings provide support for the hypothesis that endogenous proteins are capable of either protecting the brain against damage and/or enhancing repair of damage.

Neonatal systemic inflammation and the risk of low scores on measures of reading and mathematics achievement at age 10 years among children born extremely preterm.

BACKGROUND: Difficulties with reading and math occur more commonly among children born extremely preterm than among children born at term. Reasons for this are unclear. METHODS: We measured the concentrations of 27 inflammatory-related and neurotrophic/angiogenic proteins (angio-neurotrophic proteins) in multiple blood specimens collected a week apart during the first postnatal month from 660 children born before the 28th week of gestation who at age 10 years had an IQ ≥ 70 and a Wechsler Individual Achievement Test 3rd edition (WIAT-III) assessment. We identified four groups of children, those who had a Z-score ≤ -1 on the Word Reading assessment only, on the Numerical Operations assessment only, on both of these assessments, and on neither, which served as the referent group. We then modeled the risk of each learning limitation associated with a top quartile concentration of each protein, and with high and lower concentrations of multiple proteins. RESULTS: The protein profile of low reading scores was confined to the third and fourth postnatal weeks when increased risks were associated with high concentrations of IL-8 and ICAM-1 in the presence of low concentrations of angio-neurotrophic proteins. The profile of low math scores was very similar, except it did not include ICAM-1. In contrast, the profile of low scores on both assessments was present in each of the first four postnatal weeks. The increased risks associated with high concentrations of TNF-α in the first two weeks and of IL-8 and ICAM-1 in the next two weeks were modulated down by high concentrations of angio-neurotrophic proteins. CONCLUSIONS: High concentrations of angio-neurotrophic proteins appear to reduce/moderate the risk of each learning limitation associated with systemic inflammation. The three categories of limitations have protein profiles with some similarities, and yet some differences, too.

Antenatal and neonatal antecedents of learning limitations in 10-year old children born extremely preterm.

BACKGROUND: Children born extremely preterm are at increased risk of learning limitations. AIM: To identify the antecedents of learning limitations of children born extremely preterm. STUDY DESIGN: Prospective observational study from birth to age 10 years. Variables entered into the multinomial logistic regression analyses were ordered temporally, with the earliest occurring predictors/covariates of each learning limitation risk entered first and not displaced by later occurring covariates. SUBJECTS: 874 children who were born before the 28th week of gestation. OUTCOME MEASURES: A reading limitation was defined as a score one or more standard deviations below the expected mean on the WIAT-III Word Reading and a mathematics limitation was defined as a similarly low score on the Numerical Operations component. RESULTS: 56 children had a "reading ONLY" limitation, 132 children had a "math ONLY" limitation and 89 children had "reading AND math" limitations. All risk profiles included an indicator of socioeconomic disadvantage (e.g., mother's "racial" identity and eligibility for government-provided health care insurance), an indicator of newborn's immaturity/vulnerability (e.g., high illness severity score, receipt of hydrocortisone, and/or ventilator-dependence at 36 weeks post-menstruation), and all but the math only limitation included an indicator of fetal growth restriction and inflammation (i.e., pregnancy urinary tract infection or late ventilator-dependence). CONCLUSIONS: The themes of socioeconomic disadvantage and immaturity/vulnerability characterize all three risk profiles, while the themes of fetal growth restriction and inflammation are characteristic of a reading limitation only, and the reading and math limitations entity.

Hand Preference and Cognitive, Motor, and Behavioral Functioning in 10-Year-Old Extremely Preterm Children.

The association of hand preference (left, mixed, and right) with cognitive, academic, motor, and behavioral function was evaluated in 864 extremely preterm children at 10 years of age. Left-handed and right-handed children performed similarly but mixed-handed children had greater odds of functional deficits across domains than right-handed children.

Antenatal and Neonatal Antecedents of Executive Dysfunctions in Extremely Preterm Children.

To find out why children born extremely preterm are at heightened risk of executive dysfunctions, the authors assessed 716 children who were 10 years old born extremely preterm whose IQ was ≥ 70. A working memory dysfunction (n = 169), an inhibition dysfunction (n = 360), a switching dysfunction (355), and all 3 (executive dysfunction; n = 107) were defined on the basis of Z-scores ≤ -1 on the Differential Ability Scales-II Working Memory composite, and/or on the NEPSY-II Inhibition-Inhibition and Inhibition-Switching subtests. All risk profiles include an indicator of socioeconomic disadvantage. The risk profile of each of the 3 individual dysfunctions includes an indicator of the newborn's immaturity, and the risk profiles of the inhibition dysfunction and switching dysfunction also include an indicator of inflammation. Only the switching dysfunction was associated with fetal growth restriction. The risk factors for executive dysfunction can be subsumed under the 4 themes of socioeconomic disadvantage, immaturity/vulnerability, inflammation, and fetal growth restriction.