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Brain Development and Maternal Behavior in Relation to Cognitive and Language Outcomes in Preterm-Born Children

  • Jillian Vinall Miller
    Affiliations
    Department of Anesthesiology, Perioperative & Pain Medicine, University of Calgary, Calgary, Alberta, Canada

    Behaviour and the Developing Brain, Alberta Children’s Hospital Research Institute, Calgary, Alberta, Canada
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  • Vann Chau
    Affiliations
    Department of Paediatrics (Neurology), University of Toronto and the Hospital for Sick Children, Toronto, Ontario, Canada

    Neurosciences & Mental Health, SickKids Research Institute, Toronto, Ontario, Canada

    BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
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  • Anne Synnes
    Affiliations
    BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada

    Department of Pediatrics (Neonatology), University of British Columbia, Vancouver, British Columbia, Canada
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  • Author Footnotes
    1 SPM and REG contributed equally to this work as senior authors.
    Steven P. Miller
    Footnotes
    1 SPM and REG contributed equally to this work as senior authors.
    Affiliations
    Department of Paediatrics (Neurology), University of Toronto and the Hospital for Sick Children, Toronto, Ontario, Canada

    Neurosciences & Mental Health, SickKids Research Institute, Toronto, Ontario, Canada

    BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
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  • Author Footnotes
    1 SPM and REG contributed equally to this work as senior authors.
    Ruth E. Grunau
    Correspondence
    Address correspondence to Ruth E. Grunau, Ph.D.
    Footnotes
    1 SPM and REG contributed equally to this work as senior authors.
    Affiliations
    BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada

    Department of Pediatrics (Neonatology), University of British Columbia, Vancouver, British Columbia, Canada
    Search for articles by this author
  • Author Footnotes
    1 SPM and REG contributed equally to this work as senior authors.
Open AccessPublished:March 26, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.03.010

      Abstract

      Background

      Children born very preterm (≤32 weeks gestational age) show poorer cognitive and language development compared with their term-born peers. The importance of supportive maternal responses to the child’s cues for promoting neurodevelopment is well established. However, little is known about whether supportive maternal behavior can buffer the association of early brain dysmaturation with cognitive and language performance.

      Methods

      Infants born very preterm (N = 226) were recruited from the neonatal intensive care unit for a prospective, observational cohort study. Chart review (e.g., size at birth, postnatal infection) was conducted from birth to discharge. Magnetic resonance imaging, including diffusion tensor imaging, was acquired at approximately 32 weeks postmenstrual age and again at term-equivalent age. Fractional anisotropy, a quantitative measure of brain maturation, was obtained from 11 bilateral regions of interest in the cortical gray matter. At 3 years (n = 187), neurodevelopmental testing (Bayley Scales of Infant and Toddler Development-III) was administered, and parent-child interaction was filmed. Maternal behavior was scored using the Emotional Availability Scale-IV. A total of 146 infants with neonatal brain imaging and follow-up data were included for analysis. Generalized estimating equations were used to examine whether maternal support interacted with mean fractional anisotropy values to predict Cognitive and Language scores at 3 years, accounting for confounding neonatal and maternal factors.

      Results

      Higher maternal support significantly moderated cortical fractional anisotropy values at term-equivalent age to predict higher Cognitive (interaction term β = 2.01, p = .05) and Language (interaction term β = 1.85, p = .04) scores.

      Conclusions

      Findings suggest that supportive maternal behavior following early brain dysmaturation may provide an opportunity to promote optimal neurodevelopment in children born very preterm.

      Keywords

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      ). However, the extent that positive maternal-child interaction in early childhood is able to moderate FA within the cortical gray matter to improve neurodevelopmental outcomes in children born very preterm has not been examined. Therefore, we examined whether greater maternal supportive behavior at 3 years buffered the relationship between cortical gray matter in the neonatal period and cognitive and language outcomes in children born very preterm. We hypothesized that supportive and responsive maternal behavior would attenuate the association of early brain dysmaturation with poorer neurodevelopmental outcomes in children born very preterm, over and above neonatal illness (i.e., small for gestational age [SGA], postnatal infection), brain injury (i.e., white matter injury volume), and lower maternal education.

      Methods and Materials

      This study was approved by the University of British Columbia and Children’s and Women’s Hospital Clinical Research Ethics Board. Parent written informed consent was obtained.

      Participants

      Infants born very preterm [24–32 weeks GA (
      World Health Organization
      Preterm birth.
      )] admitted to a tertiary-level NICU were recruited to this prospective longitudinal cohort study between April 2006 and April 2013. GA was based on the last menstrual period or early ultrasound (<24 weeks); if the difference between the two methods was >7 days, the ultrasound date was used. Multiple births were included. Exclusions were congenital malformation or syndrome, antenatal TORCH (toxoplasma, other viral, rubella, congenital cytomegalovirus, herpes) infection, or ultrasound evidence of a parenchymal hemorrhagic infarction >2 cm, because the latter was strongly predictive of early mortality, and these babies were often too unstable for early-life MRI.

      Medical Chart Review

      A neonatal research nurse performed day-by-day medical and nursing chart review from birth to NICU discharge or term-equivalent age (TEA), whichever came first; we were not able to account for clinical events occurring after TEA. Data included GA, sex, SGA, retinopathy of prematurity, days of mechanical ventilation, presence of chronic lung disease, number of invasive procedures, morphine exposure, necrotizing enterocolitis, and infection. Infection was defined as either clinical sepsis or confirmed infections.

      Magnetic Resonance Imaging

      Infants were scanned without pharmacological sedation at median 32 weeks and again at median 40 weeks PMA in an MRI-compatible isolette (Lammers Medical Technology) with a specialized neonatal head coil (Advanced Imaging Research). A Siemens 1.5-T Avanto magnet and Vb 13A software were used to obtain the following sequences: three-dimensional coronal volumetric T1-weighted images, axial fast spin echo T2-weighted images, and diffusion tensor images (see Supplemental Methods). Total white matter injury volumes were manually segmented on the T1-weighted images using the three-dimensional Visualization Display software (http://bic.mni.mcgill.ca/ServicesSoftwareVisualization) as described previously (
      • Guo T.
      • Duerden E.G.
      • Adams E.
      • Chau V.
      • Branson H.M.
      • Chakravarty M.M.
      • et al.
      Quantitative assessment of white matter injury in preterm neonates: Association with outcomes.
      ).

      Diffusion Tensor Imaging

      DTI is an MRI technique that enables the measurement of the diffusion of water in tissue. FA indicates the orientation of diffusion and provides the relative difference between the largest eigenvalue (λ1) reflective of the primary (axial) diffusion axis as compared with other directions (λ2 and λ3). Using Siemens DTI and DTI Evaluation modules (Vb 13A), the DTI scans were processed and DTI parameters were collected bilaterally in 11 manually placed cortical regions of interest on both scans (precentral gyrus, postcentral gyrus, secondary somatosensory cortex, superior frontal gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, anterior and posterior insula, anterior and posterior cingulate gyrus, and occipital gray matter), given their distinct maturational trajectories and functions and ability to be assessed with high reliability by an experienced neuroscientist (JVM) [a subset of these data was published in a paper examining the impact of neonatal factors on early brain development (
      • Vinall J.
      • Grunau R.E.
      • Brant R.
      • Chau V.
      • Poskitt K.J.
      • Synnes A.R.
      • Miller S.P.
      Slower postnatal growth is associated with delayed cerebral cortical maturation in preterm newborns.
      )]. Previous studies have demonstrated these regions’ associations with cognitive and language outcomes in children born preterm (
      • Ball G.
      • Pazderova L.
      • Chew A.
      • Tusor N.
      • Merchant N.
      • Arichi T.
      • et al.
      Thalamocortical connectivity predicts cognition in children born preterm.
      ,
      • Kersbergen K.J.
      • Leroy F.
      • Išgum I.
      • Groenendaal F.
      • de Vries L.S.
      • Claessens N.H.P.
      • et al.
      Relation between clinical risk factors, early cortical changes, and neurodevelopmental outcome in preterm infants.
      ). To avoid multiple comparisons relative to our sample size, mean bilateral FA values from the 11 cortical regions of interest were averaged for analysis. Our main hypothesis related to overall cortical maturation, and given that regional cortical FA differences decrease with increasing PMA (see Supplemental Methods), the 11 cortical regions were also averaged at each time point to examine mean cortical FA early in life (median 32 weeks PMA) and at TEA.

      Demographics

      Parent information was obtained by questionnaire. We used mothers’ level of education as an index of socioeconomic status (SES) for statistical analysis (
      • Benavente-Fernández I.
      • Synnes A.
      • Grunau R.E.
      • Chau V.
      • Ramraj C.
      • Glass T.
      • et al.
      Association of socioeconomic status and brain injury with neurodevelopmental outcomes of very preterm children.
      ), categorized as primary or secondary school, undergraduate degree, or postgraduate degree. Mother’s level of education is the most important SES indicator in relation to child development (
      • Böhm B.
      • Katz-Salamon M.
      • Smedler A.C.
      • Lagercrantz H.
      • Forssberg H.
      Karolinska Institute
      Developmental risks and protective factors for influencing cognitive outcome at 5 1/2 years of age in very-low-birthweight children.
      ,
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      • Ariet M.
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      • et al.
      Effects of birth weight and sociodemographic variables on mental development of neonatal intensive care unit survivors.
      ).

      Maternal Behavior

      Mothers participated in a 5-minute semistructured teaching session with their child at 18 months and 3 years, which were filmed and stored on DVDs. Three blinded coders (one primary, two reliability) trained by the developer of the Emotional Availability Scale-IV systematically rated maternal behavior using the Emotional Availability Scale-IV (see Supplemental Methods) (
      • Saunders H.
      • Kraus A.
      • Barone L.
      • Biringen Z.
      Emotional availability: Theory, research, and intervention.
      ,
      • Biringen Z.
      • Derscheid D.
      • Vliegen N.
      • Closson L.
      • Easterbrooks M.A.
      Emotional availability (EA): Theoretical background, empirical research using the EA Scales, and clinical applications.
      ). This scale captures four dimensions of maternal behavior: sensitivity (appropriate responses/authenticity of affect), structuring (provision of guidance), nonintrusiveness (no overstimulation/overprotection), and nonhostility (nonthreatening/nonfrightening). Scores range from 7 to 29, with higher scores denoting more positive emotional availability. Given the importance of maternal sensitivity for neurodevelopment (
      • Grunau R.E.
      • Whitfield M.F.
      • Petrie-Thomas J.
      • Synnes A.R.
      • Cepeda I.L.
      • Keidar A.
      • et al.
      Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants.
      ,
      • Tu M.T.
      • Grunau R.E.
      • Petrie-Thomas J.
      • Haley D.W.
      • Weinberg J.
      • Whitfield M.F.
      Maternal stress and behavior modulate relationships between neonatal stress, attention, and basal cortisol at 8 months in preterm infants.
      ,
      • Magill-Evans J.
      • Harrison M.J.
      Parent-child interactions and development of toddlers born preterm.
      ,
      • Vinall J.
      • Miller S.P.
      • Synnes A.R.
      • Grunau R.E.
      Parent behaviors moderate the relationship between neonatal pain and internalizing behaviors at 18 months corrected age in children born very prematurely.
      ) and high correlations with the other three dimensions (see Supplemental Methods), only maternal sensitivity was used for analysis. Given that maternal sensitivity did not differ between 18 months (mean = 20.01, SD = 4.11) and 3 years (mean = 21.01, SD = 3.91) (F1,141 = 3.75, p = .06), only maternal sensitivity at 3 years was used.

      Neurodevelopmental Assessment

      At 3 years, neurodevelopment was assessed by experienced physiotherapy or psychology staff using the Bayley Scales of Infant and Toddler Development-III (Bayley-III) (
      • Bayley N.
      Bayley Scales of Infant Development.
      ). Cognitive and Language composite scores were obtained (mean = 100, SD = 15). Higher composite scores indicate better neurodevelopmental functioning.

      Analyses

      Statistical analyses were performed using IBM SPSS Statistics version 25. Normality plots were examined for all variables considered, and no violations were detected. For descriptive purposes, a median split of maternal sensitivity was performed (lower sensitivity = total scores 10–20.5; higher sensitivity = total scores 21–29), and two-tailed t tests and χ2 tests were conducted to test the differences between children and their mothers with higher and lower maternal sensitivity. Two-tailed t tests and χ2 tests were also conducted to compare the data between those included and excluded for analysis. Maternal sensitivity was treated as a continuous variable for the linear models. Generalized estimating equations were used to account for twin pairings and examine whether the interactions between maternal sensitivity at 3 years and mean FA values both early in life and at TEA were associated with Bayley-III Cognitive and Language outcomes at 3 years in children born very preterm. SGA, postnatal infection, and white matter injury volumes were included as markers of neonatal illness and brain injury given their robust associations with neurodevelopmental outcomes (
      • Guo T.
      • Duerden E.G.
      • Adams E.
      • Chau V.
      • Branson H.M.
      • Chakravarty M.M.
      • et al.
      Quantitative assessment of white matter injury in preterm neonates: Association with outcomes.
      ,
      • Sacchi C.
      • Marino C.
      • Nosarti C.
      • Vieno A.
      • Visentin S.
      • Simonelli A.
      Association of intrauterine growth restriction and small for gestational age status with childhood cognitive outcomes: A systematic review and meta-analysis.
      ,
      • Stoll B.J.
      • Hansen N.I.
      • Adams-Chapman I.
      • Fanaroff A.A.
      • Hintz S.R.
      • Vohr B.
      • et al.
      Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection.
      ). PMA at scan was included to account for normative brain maturation. Further, we included mothers’ marital status and level of education as SES indicators. Models with significant interactions were repeated to account for additional neonatal confounding and maternal factors: 1) number of invasive procedures, days of mechanical ventilation, and morphine exposure and 2) necrotizing enterocolitis, retinopathy of prematurity, and maternal ethnicity.

      Results

      Cohort Characteristics

      Of the 226 survivors, 83% (187 children; 90 [48.1%] female) returned for follow-up at 3 years (Figure 1). Of those that returned (cohort characteristics in Table S1), 146 had complete data pertaining to this study (i.e., limited number that had both quality neonatal imaging data and parent-child interaction follow-up data at 3 years). There were no significant differences in GA (t232 = 1.26, p = .21), sex (χ21,193 = 0.98, p = .32), size at birth (χ21,232 = 1.65, p = .20), rates of postnatal infection (χ21,192 = 3.46, p = .06), or white matter injury volumes (t181 = 0.22, p = .41) between those with complete versus incomplete data. Further, the 146 children included in this study did not significantly differ in Cognitive (t163 = −1.29, p = .20) or Language (t144 = −1.44, p = .15) scores compared with children who returned for follow-up but with incomplete data. The 146 children included in this study were born at a median of 27.7 weeks (interquartile range: 26.0–30.0) gestation. They were scanned initially at median 32.2 (interquartile range: 30.6–33.7) weeks PMA and, when possible, again at TEA (median 40.1 [interquartile range: 38.6–42.3]). At 3 years, Cognitive and Language scores were significantly higher in children of mothers with greater sensitivity as compared with children of mothers with lower sensitivity at 3 years (Table 1).
      Figure thumbnail gr1
      Figure 1Participant flowchart. DTI, diffusion tensor imaging; GA, gestational age; PMA, postmenstrual age.
      Table 1Characteristics of the Cohort
      CharacteristicsnLower Maternal Sensitivity (Total Score 10–20.5), n = 69Higher Maternal Sensitivity (Total Score 21–29), n = 77p Value
      Neonatal Characteristics
       Gestational age at birth, weeks14628.0 (26.4–29.7)27.7 (25.6–30.2).91
       Sex, male, n (%)14637 (53.6%)40 (51.9%).78
       Twin births, n (%)1465 (7.2%)22 (28.6%)<.001
       Small for gestational age, n (%)14611 (15.9%)12 (15.6%).98
       Infection, n (%)14638 (55.1%)36 (46.8%).26
       Necrotizing enterocolitis, n (%)14616 (23.2%)14 (18.2%).38
       Retinopathy of prematurity, n (%)122.26
      None35 (59.3%)36 (57.1%)
      Without laser treatment16 (27.1%)22 (34.9%)
      With laser treatment8 (13.6%)5 (7.9%)
       Mechanical ventilation, days1455.0 (2.0–21.5)5.5 (2.0–36.5).65
       Chronic lung disease, n (%)14517 (24.6%)22 (28.6%).55
       Invasive procedures14595.0 (58.5–141.5)96.0 (59.8–181.3).65
       Morphine, mg/kg1450.1 (0.0–2.2)0.1 (0.0–3.9).25
       Postmenstrual age at scan 1, weeks14631.9 (30.3–33.4)32.3 (30.9–33.9).09
       Postmenstrual age at scan 2, weeks
      Three of the 146 infants did not complete a second scan. Of the 143 with two scans, one was of poor quality and white matter injury volume could not be calculated.
      14340.1 (38.0–41.8)40.1 (38.7–42.6).56
       White matter injury at scan 1, volume1460.0 (0.0–28.8)0.0 (0.0–11.2).56
       White matter injury at scan 2, volume
      Three of the 146 infants did not complete a second scan. Of the 143 with two scans, one was of poor quality and white matter injury volume could not be calculated.
      1420.0 (0.0–39.3)0.0 (0.0–0.0).36
      Child Characteristics at 3 Years
       Bayley-III Cognitive composite146100.0 (90.0–105.0)105.0 (100.0–115.0).001
       Bayley-III Language composite128106.0 (94.8–112.0)112.0 (103.0–120.3).01
      Maternal Characteristics at 3 Years
       Age, years14537.0 (32.0–41.4)34.7 (31.9–38.9).26
       Marital status, n (%)145.49
      Single5 (7.2%)1 (1.3%)
      Married52 (75.4%)64 (84.2%)
      Common Law9 (13.0%)10 (13.2%)
      Separated3 (4.3%)0 (0.0%)
      Divorced0 (0.0%)1 (1.3%)
       Ethnicity, n (%)145<.001
      East Asian19 (28.0%)9 (11.7%)
      First Nations4 (5.9%)1 (1.3%)
      Hispanic1 (1.5%)4 (5.2%)
      Mixed2 (2.9%)7 (9.0%)
      South Asian9 (13.0%)1 (1.3%)
      White33 (48.5%)54 (70.1%)
       Occupation, n (%)
      Two mothers with lower maternal sensitivity and 4 mothers with higher maternal sensitivity indicated that they were receiving social assistance.
      146.40
      Unemployed/student2 (2.9%)1 (1.2%)
      Stay-at-home mother11 (15.9%)11 (14.2%)
      Maternity leave1 (1.4%)3 (3.9%)
      Employment55 (79.7%)63 (81.8%)
       Education, n (%)146.03
      Primary or secondary school10 (14.5%)10 (13.0%)
      Undergraduate degree54 (78.3%)47 (61.0%)
      Postgraduate degree5 (7.2%)20 (26.0%)
       Number of children in the home1442 (1.0–2.0)2 (1.0–2.8).07
      Values are reported as n (%) or median (interquartile range).
      a Three of the 146 infants did not complete a second scan. Of the 143 with two scans, one was of poor quality and white matter injury volume could not be calculated.
      b Two mothers with lower maternal sensitivity and 4 mothers with higher maternal sensitivity indicated that they were receiving social assistance.

      Cortical FA Early in Life, Maternal Sensitivity, and Bayley-III Cognitive and Language Scores

      The interaction between mean cortical FA values at approximately 32 weeks PMA and maternal sensitivity was not associated with Bayley-III Cognitive (β = −1.09, p = .23) or Language (β = −0.68, p = .50) scores at 3 years after accounting for SGA (p < .05), postnatal infection (p < .05), age at scan (p > .05), white matter injury volumes (p < .01), and mother’s marital status (p > .05) and education (p < .05). See Tables 2 and 3 for full results.
      Table 2Relationship Between Mean Cortical FA Early in Life, Maternal Sensitivity, and Cognition
      PredictorsBayley-III Cognitive Composite Scores at 3 Years, n = 146 (27 Twins Included)
      β95% CIp
      Small for Gestational Age0.220.06 to 0.39.008
      Postnatal Infection−0.15−0.30 to −0.004.04
      Postmenstrual Age at Scan0.07−0.13 to 0.28.48
      White Matter Injury Volume−0.33−0.44 to −0.21<.001
      Early-Life Cortical FA0.65−0.35 to 1.64.20
      Marital Status0.003−0.15 to 0.15.97
      Mother’s Level of Education0.03−0.10 to 0.16.66
      Maternal Sensitivity1.15−0.22 to 2.52.10
      Maternal Sensitivity × FA−1.09−2.88 to 0.70.23
      FA, fractional anisotropy.
      Table 3Relationship Between Mean Cortical FA Early in Life, Maternal Sensitivity, and Language
      PredictorsBayley-III Language Composite Scores at 3 Years, n = 128 (25 Twins Included)
      β95% CIp
      Small for Gestational Age0.18−0.01 to 0.38.07
      Postnatal Infection−0.23−0.38 to −0.08.003
      Postmenstrual Age at Scan0.12−0.10 to 0.33.29
      White Matter Injury Volume−0.22−0.37 to −0.07.004
      Early-Life Cortical FA0.50−0.64 to 1.63.39
      Marital Status−0.01−0.17 to 0.15.94
      Mother’s Level of Education0.160.04 to 0.29.01
      Maternal Sensitivity0.77−0.75 to 2.29.32
      Maternal Sensitivity × FA−0.68−2.65 to 1.29.50
      FA, fractional anisotropy.

      Cortical FA at Term, Maternal Sensitivity, and Bayley-III Cognitive Scores

      Infants were between 33.4 and 48.1 weeks PMA at their second scan (27 [18.9%] <38 weeks and 115 [80.4%] >38 weeks). Infants were scanned prior to TEA if they were discharged early or were scanned after 42 weeks PMA if they were unable to return for a TEA scan. Despite variability in PMA, there is less variability in FA on the TEA scan (see Supplemental Methods). The interaction between mean cortical FA values at TEA and maternal sensitivity was associated with Bayley-III Cognitive scores at 3 years (β = 2.01, p = .05) after accounting for size at birth (β = 0.24, p = .003), postnatal infection (β = −0.19, p = .01), age at scan (β = 0.19, p = .04), white matter injury volumes (β = −0.13, p = .11), and mother’s marital status (β = 0.12, p = .15) and education (β = 0.11, p = .15) (Table 4). To assist with the interpretation of this interaction, post hoc analyses were conducted (Figure 2). The lowest Cognitive scores were among children with higher FA at TEA and lower maternal sensitivity at 3 years (i.e., mean Bayley-III Cognitive score = 103). The highest Cognitive scores were among children that had higher FA at TEA and mothers with greater sensitivity at 3 years (i.e., mean Bayley-III Cognitive score = 109).
      Table 4Relationship Between Mean Cortical FA at TEA, Maternal Sensitivity, and Cognition
      PredictorsBayley-III Cognitive Composite Scores at 3 Years, n = 127 (22 Twins Included)
      β95% CIp
      Small for Gestational Age0.240.08 to 0.40.003
      Postnatal Infection−0.19−0.34 to −0.05.01
      Postmenstrual Age at Scan0.190.01 to 0.37.04
      White Matter Injury Volume−0.13−0.30 to 0.03.11
      TEA Cortical FA−1.08−2.27 to 0.11.07
      Marital Status0.12−0.04 to 0.28.15
      Mother’s Level of Education0.11−0.04 to 0.27.15
      Maternal Sensitivity−1.33−2.97 to 0.31.11
      Maternal Sensitivity × FA2.010.002 to 4.02.05
      FA, fractional anisotropy; TEA, term-equivalent age.
      Figure thumbnail gr2
      Figure 2Maternal sensitivity, cortical brain development, and Bayley-III cognitive outcomes. Lower (25th percentile = 0.15) or higher (75th percentile = 0.18) fractional anisotropy (FA) values at term-equivalent age and lower (25th percentile = 18) or higher (75th percentile = 23.5) concurrent maternal sensitivity compared with Bayley-III Cognitive composite scores at 3 years.

      Cortical FA at Term, Maternal Sensitivity, and Bayley-III Language Scores

      The interaction between mean cortical FA values at TEA and maternal sensitivity (β = 1.85, p = .04) was associated with Bayley-III Language scores at 3 years after accounting for size at birth (β = 0.16, p = .09), postnatal infection (β = −0.29, p < .001), age at scan (β = −0.04, p = .66), white matter injury volumes (β = −0.08, p = .62), and mother’s marital status (β = 0.04, p = .64) and education (β = 0.23, p = .004) (Table 5). Again, the lowest Language scores were among children with higher FA at TEA and lower maternal sensitivity at 3 years (i.e., mean Bayley-III Language score = 110) (Figure 3). The highest Language scores were among children with higher FA at TEA and mothers with greater sensitivity at 3 years (i.e., mean Bayley-III Language score = 116).
      Table 5Relationship Between Mean Cortical FA at TEA, Maternal Sensitivity, and Language
      PredictorsBayley-III Language Composite Scores at 3 Years, n = 111 (20 Twins Included)
      β95% CIp
      Small for Gestational Age0.16−0.03 to 0.35.09
      Postnatal Infection−0.29−0.45 to −0.13<.001
      Postmenstrual Age at Scan−0.04−0.23 to 0.15.66
      White Matter Injury Volume−0.08−0.42 to 0.25.62
      TEA Cortical FA−0.89−1.95 to 0.16.10
      Marital Status0.04−0.13 to 0.21.64
      Mother’s Level of Education0.230.08 to 0.39.004
      Maternal Sensitivity−1.28−2.70 to 0.15.08
      Maternal Sensitivity × FA1.850.09 to 3.61.04
      FA, fractional anisotropy; TEA, term-equivalent age.
      Figure thumbnail gr3
      Figure 3Maternal sensitivity, cortical brain development, and Bayley-III Language outcomes. Lower (25th percentile = 0.15) or higher (75th percentile = 0.18) fractional anisotropy (FA) values at term-equivalent age and lower (25th percentile = 18) or higher (75th percentile = 23.5) concurrent maternal sensitivity compared with Bayley-III Language composite scores at 3 years.

      Additional Neonatal and Maternal Confounding Factors

      The interactions between maternal sensitivity, mean cortical FA at TEA, and Bayley-III Cognitive and Language scores remained at p ≤ .05 after adjustment for additional neonatal and maternal factors, even when these factors were not themselves significant predictors (Table 6, Table 7, Table 8, Table 9).
      Table 6Relationship Between Mean Cortical FA at TEA, Maternal Sensitivity, and Cognition, Accounting for Invasive Procedures
      PredictorsBayley-III Cognitive Composite Scores at 3 Years, n = 113 (20 Twins Included)
      β95% CIp
      Small for Gestational Age0.280.12 to 0.44<.001
      Postnatal Infection−0.04−0.25 to 0.17.71
      Number of Invasive Procedures0.001−0.27 to 0.27.99
      Days of Mechanical Ventilation−0.16−0.42 to 0.10.23
      Morphine Exposure−0.04−0.14 to 0.07.49
      Postmenstrual Age at Scan0.16−0.01 to 0.32.06
      White Matter Injury Volume−0.06−0.18 to 0.06.32
      TEA Cortical FA−1.05−2.20 to 0.11.08
      Marital Status0.01−0.12 to 0.15.83
      Mother’s Level of Education0.07−0.08 to 0.21.34
      Maternal Sensitivity−1.24−2.79 to 0.31.12
      Maternal Sensitivity × FA1.90−0.001 to 3.82.05
      FA, fractional anisotropy; TEA, term-equivalent age.
      Table 7Relationship Between Mean Cortical FA at TEA, Maternal Sensitivity, and Language, Accounting for Invasive Procedures
      PredictorsBayley-III Language Composite Scores at 3 Years, n = 98 (18 Twins Included)
      β95% CIp
      Small for Gestational Age0.200.01 to 0.39.04
      Postnatal Infection−0.05−0.22 to 0.13.61
      Number of Invasive Procedures−0.18−0.47 to 0.11.22
      Days of Mechanical Ventilation−0.19−0.48 to 0.11.22
      Morphine Exposure0.03−0.08 to 0.15.54
      Postmenstrual Age at Scan−0.12−0.26 to 0.03.11
      White Matter Injury Volume0.13−0.12 to 0.37.32
      TEA Cortical FA−0.81−1.81 to 0.20.12
      Marital Status−0.03−0.16 to 0.10.64
      Mother’s Level of Education0.13−0.01 to 0.27.07
      Maternal Sensitivity−1.11−2.42 to 0.20.10
      Maternal Sensitivity × FA1.640.03 to 3.25.05
      FA, fractional anisotropy; TEA, term-equivalent age.
      Table 8Relationship Between Mean Cortical FA at TEA, Maternal Sensitivity, and Cognition, Accounting for Additional Neonatal Factors and Ethnicity
      PredictorsBayley-III Cognitive Composite Scores at 3 Years, n = 106 (15 Twins Included)
      β95% CIp
      Small for Gestational Age0.240.06 to 0.41.01
      Postnatal Infection−0.21−0.46 to 0.03.09
      Necrotizing Enterocolitis−0.12−0.32 to 0.08.25
      Retinopathy of Prematurity0.02−0.23 to 0.27.88
      Postmenstrual Age at Scan0.20−0.02 to 0.41.07
      White Matter Injury Volume−0.13−0.31 to 0.05.16
      TEA Cortical FA−1.27−2.63 to 0.09.07
      Marital Status0.12−0.05 to 0.28.17
      Mother’s Level of Education0.12−0.06 to 0.32.19
      Maternal Ethnicity−0.01−0.23 to 0.20.90
      Maternal Sensitivity−1.55−3.43 to 0.34.11
      Maternal Sensitivity × FA2.31−0.02 to 4.64.05
      FA, fractional anisotropy; TEA, term-equivalent age.
      Table 9Relationship Between Mean Cortical FA at TEA, Maternal Sensitivity, and Language, Accounting for Additional Neonatal Factors and Ethnicity
      PredictorsBayley-III Language Composite Scores at 3 Years, n = 91 (13 Twins Included)
      β95% CIp
      Small for Gestational Age0.17−0.03 to 0.37.09
      Postnatal Infection−0.28−0.50 to −0.06.01
      Necrotizing Enterocolitis−0.04−0.24 to 0.16.70
      Retinopathy of Prematurity−0.14−0.38 to 0.10.25
      Postmenstrual Age at Scan−0.05−0.27 to 0.17.67
      White Matter Injury Volume−0.09−0.42 to 0.23.57
      TEA Cortical FA−1.08−2.19 to 0.03.06
      Marital Status0.001−0.18 to 0.18.99
      Mother’s Level of Education0.230.06 to 0.40.01
      Maternal Ethnicity0.21−0.06 to 0.47.13
      Maternal Sensitivity−1.60−3.13 to −0.07.04
      Maternal Sensitivity × FA2.210.34 to 4.08.02
      FA, fractional anisotropy; TEA, term-equivalent age.

      Discussion

      In a prospective longitudinal cohort study of very preterm–born children, we examined whether maternal sensitivity at 3 years buffers the relationship between cortical gray matter dysmaturation early in life and at TEA and cognitive and language abilities at 3 years after accounting for neonatal illness, brain injury, and maternal education. Consistent with previous reports, being born SGA and the presence of postnatal infections and/or brain injuries were associated with lower neurodevelopmental outcome scores (
      • Guo T.
      • Duerden E.G.
      • Adams E.
      • Chau V.
      • Branson H.M.
      • Chakravarty M.M.
      • et al.
      Quantitative assessment of white matter injury in preterm neonates: Association with outcomes.
      ,
      • Sacchi C.
      • Marino C.
      • Nosarti C.
      • Vieno A.
      • Visentin S.
      • Simonelli A.
      Association of intrauterine growth restriction and small for gestational age status with childhood cognitive outcomes: A systematic review and meta-analysis.
      ,
      • Padilla N.
      • Falcón C.
      • Sanz-Cortés M.
      • Figueras F.
      • Bargallo N.
      • Crispi F.
      • et al.
      Differential effects of intrauterine growth restriction on brain structure and development in preterm infants: A magnetic resonance imaging study.
      ,
      • Schneider J.
      • Miller S.P.
      Preterm brain Injury: White matter injury.
      ,
      • Rand K.M.
      • Austin N.C.
      • Inder T.E.
      • Bora S.
      • Woodward L.J.
      Neonatal infection and later neurodevelopmental risk in the very preterm infant.
      ,
      • Alshaikh B.
      • Yusuf K.
      • Sauve R.
      Neurodevelopmental outcomes of very low birth weight infants with neonatal sepsis: Systematic review and meta-analysis.
      ). In addition, we confirmed the well-established findings that children of mothers with a lower level of education showed, on average, lower language scores (
      • Hart B.
      • Risley T.R.
      Meaningful Differences in the Everyday Experience of Young American Children.
      ). Greater maternal sensitivity was associated with better cognitive and language outcomes in children with less mature cortical gray matter at TEA. This builds on the recent observations of Vanes et al. (
      • Vanes L.D.
      • Hadaya L.
      • Kanel D.
      • Falconer S.
      • Ball G.
      • Batalle D.
      • et al.
      Associations between neonatal brain structure, the home environment, and childhood outcomes following very preterm birth.
      ) by obtaining objective measures of maternal sensitivity to provide new evidence for additional mitigatory effects of maternal behavior. Together, this work provides support for postdischarge interventions targeting maternal sensitivity, which may lead to improved neurodevelopment for children born very preterm.
      In this study, maternal sensitivity buffered DTI measures of cortical dysmaturation at TEA but not early in life. Previously, using an animal model of prematurity, it was found that disruptions to MRI-defined cortical microstructure occur by disturbing neuronal arborization (
      • Dean J.M.
      • McClendon E.
      • Hansen K.
      • Azimi-Zonooz A.
      • Chen K.
      • Riddle A.
      • et al.
      Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization.
      ). Prior to 36 weeks PMA, the linearity of water movement can still be readily measured within the cerebral cortex owing to the presence of radial glial cells and the relative immaturity of neurons and synapses (
      • McKinstry R.C.
      • Mathur A.
      • Miller J.H.
      • Ozcan A.
      • Snyder A.Z.
      • Schefft G.L.
      • et al.
      Radial organization of developing preterm human cerebral cortex revealed by non-invasive water diffusion anisotropy MRI.
      ,
      • Deipolyi A.R.
      • Mukherjee P.
      • Gill K.
      • Henry R.G.
      • Partridge S.C.
      • Veeraraghavan S.
      • et al.
      Comparing microstructural and macrostructural development of the cerebral cortex in premature newborns: Diffusion tensor imaging versus cortical gyration.
      ,
      • Schneider J.
      • Kober T.
      • Bickle Graz M.
      • Meuli R.
      • Hüppi P.S.
      • Hagmann P.
      • Truttmann A.C.
      Evolution of T1 relaxation, ADC, and fractional anisotropy during early brain maturation: A serial imaging study on preterm infants.
      ). The immaturity of the cerebral cortex at 32 weeks PMA, which is the approximate age of our first scan in infants, may explain why we were not able to fully capture the disruption to the dendritic arborization associated with cognitive and language outcomes at 3 years to show maternal moderation of outcomes. Indeed, using the fetal ovine cortex, Dean et al. (
      • Dean J.M.
      • McClendon E.
      • Hansen K.
      • Azimi-Zonooz A.
      • Chen K.
      • Riddle A.
      • et al.
      Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization.
      ) demonstrated progressive developmental decrease in cortical FA, which became disrupted 4 weeks after preterm ischemia during the late gestational period as a direct result of the reduced elaboration of basal dendritic arbors of pyramidal neurons.
      As hypothesized, we found that children with the lowest cognitive and language outcomes had greater cortical dysmaturation (higher FA values on the term MRI scan) and lower maternal sensitivity at 3 years. Children with the highest cognitive and language outcomes also had higher FA values at term and greater maternal sensitivity at 3 years. Cortical FA in the preterm brain demonstrates a biphasic pattern with cortical maturation. Prior to 38 weeks PMA, FA typically demonstrates a steep decrease, consistent with the disappearance of radial glial fibers and neuronal/glial proliferation, dendritic arborization, and synapse formation (
      • McKinstry R.C.
      • Mathur A.
      • Miller J.H.
      • Ozcan A.
      • Snyder A.Z.
      • Schefft G.L.
      • et al.
      Radial organization of developing preterm human cerebral cortex revealed by non-invasive water diffusion anisotropy MRI.
      ,
      • Marín-Padilla M.
      Ontogenesis of the pyramidal cell of the mammalian neocortex and developmental cytoarchitectonics: A unifying theory.
      ,
      • Mrzljak L.
      • Uylings H.B.
      • Kostovic I.
      • Van Eden C.G.
      Prenatal development of neurons in the human prefrontal cortex: I. A qualitative Golgi study.
      ,
      • Rakic P.
      Developmental and evolutionary adaptations of cortical radial glia.
      ). However, following 38 weeks PMA, FA increases in cortical gray matter with increasing cellular and organelle density (
      • Batalle D.
      • O’Muircheartaigh J.
      • Makropoulos A.
      • Kelly C.J.
      • Dimitrova R.
      • Hughes E.J.
      • et al.
      Different patterns of cortical maturation before and after 38 weeks gestational age demonstrated by diffusion MRI in vivo.
      ,
      • Ouyang M.
      • Jeon T.
      • Sotiras A.
      • Peng Q.
      • Mishra V.
      • Halovanic C.
      • et al.
      Differential cortical microstructural maturation in the preterm human brain with diffusion kurtosis and tensor imaging.
      ). Therefore, dependent on their PMA, relatively higher values of FA at their term scan could demonstrate cortical dysmaturation or greater cortical maturation. Maternal sensitivity may moderate cortical dysmaturation, given that higher cognitive and language outcome scores were observed among the children whose mothers demonstrated greater maternal sensitivity at 3 years.
      Other studies have also reported a positive association between sensitive maternal interactions and improved cognitive outcomes. Previously, it was reported that mothers’ interactions with a combined group of preterm and full-term children predicted 17% of the variance in child cognitive scores and 22% of the variance in receptive communication skills at 18 months after accounting for prematurity, sex, child behavior, paternal behavior, and family SES (
      • Magill-Evans J.
      • Harrison M.J.
      Parent-child interactions and development of toddlers born preterm.
      ). Moreover, positive mother-infant relationships predicted approximately a 5-point increase in IQ in adults born very preterm after accounting for confounding factors such as SES (
      • Breeman L.D.
      • Jaekel J.
      • Baumann N.
      • Bartmann P.
      • Wolke D.
      Neonatal predictors of cognitive ability in adults born very preterm: A prospective cohort study.
      ). However, interacting with infants born very preterm poses different challenges for mothers compared with full-term mother-infant dyads. Infants born preterm are less responsive, vocalize less, and avert their gaze more, and generally the interaction is less positive (
      • Miles M.S.
      • Holditch-Davis D.
      Parenting the prematurely born child: Pathways of influence.
      ,
      • Field T.M.
      Effects of early separation, interactive deficits, and experimental manipulations on infant-mother face-to-face interaction.
      ,
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      ,
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      ,
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      ,
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      Smiling and fussing in seven-month-old preterm and full-term black infants in the still-face situation.
      ). Even 3 years after their birth, mothers rated their preterm-born child as being less confident, relaxed, quiet, calm, generous, and satisfied than their term-born siblings (
      • Bidder R.T.
      • Crowe E.A.
      • Gray O.P.
      Mothers’ attitudes to preterm infants.
      ). Furthermore, children with poorer cognitive or language function may present more of a challenge for maternal engagement. Despite these differences in child behavior, mothers of children born preterm have been found to be equally as sensitive and responsive toward their children as mothers of children born full term (
      • Bilgin A.
      • Wolke D.
      Maternal sensitivity in parenting preterm children: A meta-analysis.
      ). However, children born very preterm are more sensitive to environmental context, including their interactions with their parents, than their term-born peers (
      • Tu M.T.
      • Grunau R.E.
      • Petrie-Thomas J.
      • Haley D.W.
      • Weinberg J.
      • Whitfield M.F.
      Maternal stress and behavior modulate relationships between neonatal stress, attention, and basal cortisol at 8 months in preterm infants.
      ,
      • Vinall J.
      • Miller S.P.
      • Synnes A.R.
      • Grunau R.E.
      Parent behaviors moderate the relationship between neonatal pain and internalizing behaviors at 18 months corrected age in children born very prematurely.
      ,
      • Crnic K.A.
      • Greenberg M.T.
      Transactional relationships between perceived family style, risk status, and mother-child interactions in two-year-olds.
      ,
      • Brummelte S.
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      Cortisol levels in former preterm children at school age are predicted by neonatal procedural pain-related stress.
      ).
      In this study, mothers in the higher sensitivity group had more education. Recently, we showed that the association of brain injury with poorer cognition was attenuated in children born to mothers with higher education (
      • Benavente-Fernández I.
      • Synnes A.
      • Grunau R.E.
      • Chau V.
      • Ramraj C.
      • Glass T.
      • et al.
      Association of socioeconomic status and brain injury with neurodevelopmental outcomes of very preterm children.
      ). Mothers with greater social advantage may themselves have more social support, thereby providing more opportunities for sensitive interactions with their children (
      • Zelkowitz P.
      • Papageorgiou A.
      • Bardin C.
      • Wang T.
      Persistent maternal anxiety affects the interaction between mothers and their very low birthweight children at 24 months [published correction appears in Early Hum Dev 2009; 85:337].
      ). Moreover, mothers of children with greater brain maturation and cognitive and language outcomes may be less stressed and thus better able to engage and sensitively interact with their children. Although we did not find differences in maternal sensitivity between 18 months and 3 years, future research would benefit from assessing maternal sensitivity at multiple time points from birth to further examine critical windows when sensitive maternal interaction can best moderate brain and neurodevelopmental trajectories. In support of this study, parenting behaviors assessed in the NICU have been related to later parenting interaction quality (
      • Gerstein E.D.
      • Poehlmann-Tynan J.
      • Clark R.
      Mother-child interactions in the NICU: Relevance and implications for later parenting.
      ). This suggests that maternal sensitivity may modulate long-term outcomes in infants born very preterm. These data also highlight the importance of assessing maternal involvement both in the NICU and on follow-up and providing intervention for mothers showing difficulties.
      Given the important role of parent-child interaction for promoting positive outcomes (
      • Miles M.S.
      • Holditch-Davis D.
      Parenting the prematurely born child: Pathways of influence.
      ), many parent-based interventions have been developed with the goals of improving parent-infant attachment, reducing parent stress, and improving parent efficacy in supporting their infant in the NICU and after discharge. Two randomized controlled trials of parent-based interventions have demonstrated increased brain maturation in infants belonging to the intervention group relative to standard care. Infants of mothers in a combined NICU and home-based intervention (Mother-Infant Transaction Program) had greater white matter maturation at term and better communicative and symbolic behavior at 6 months than infants of mothers randomized to standard care (
      • Milgrom J.
      • Newnham C.
      • Martin P.R.
      • Anderson P.J.
      • Doyle L.W.
      • Hunt R.W.
      • et al.
      Early communication in preterm infants following intervention in the NICU.
      ,
      • Milgrom J.
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      • Anderson P.J.
      • Doyle L.W.
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      • Lee K.
      • et al.
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      ). Similarly, infants of mothers enrolled in a NICU-based intervention (Family Nurture Intervention) that promotes emotional connection had increased regional independence of frontopolar electrocortical activity at TEA and higher Bayley-III Cognitive and Language scores at 18 months relative to children whose mothers were randomized to standard care (
      • Welch M.G.
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      • Ludwig R.J.
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      • Barone J.L.
      • Myers M.M.
      Family nurture intervention in preterm infants increases early development of cortical activity and independence of regional power trajectories.
      ,
      • Welch M.G.
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      • Austin J.
      • Hane A.A.
      • Stark R.I.
      • Hofer M.A.
      • et al.
      Family Nurture Intervention in the Neonatal Intensive Care Unit improves social-relatedness, attention, and neurodevelopment of preterm infants at 18 months in a randomized controlled trial.
      ). Therefore, parent-based early interventions in the NICU resulted in improved cortical maturation and cognitive and language outcomes for children born very preterm. However, a recent meta-analysis of early developmental interventions for preterm infants revealed that once these children reached school age, a substantial benefit was no longer evident (
      • Spittle A.
      • Orton J.
      • Anderson P.J.
      • Boyd R.
      • Doyle L.W.
      Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants.
      ). There is increasing evidence that the needs of the individual family need to be assessed and addressed. Stage-specific, individualized, and targeted approaches may be more beneficial to child outcomes (
      The NICHD Early Child Care Research Network, editor
      Child Care and Child Development: Results from the NICHD Study of Early Child Care and Youth Development.
      ).
      Our cognitive and language outcomes were quite high, likely because the Bayley-III yields higher scores than previous versions of this scale (
      • Johnson S.
      • Moore T.
      • Marlow N.
      Using the Bayley-III to assess neurodevelopmental delay: Which cut-off should be used?.
      ,
      • Vohr B.R.
      • Stephens B.E.
      • Higgins R.D.
      • Bann C.M.
      • Hintz S.R.
      • Das A.
      • et al.
      Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes.
      ,
      • Aylward G.P.
      Continuing issues with the Bayley-III: Where to go from here.
      ). It is also important to note that the majority of mothers in this sample were university educated. Therefore, our results likely underestimate the role of mother involvement for very preterm children with more social disadvantage.
      There were several limitations to our study. Medical and nursing chart review was conducted from birth to NICU discharge or TEA, whichever came first; therefore, clinical events past term age were not considered. We were also unable to compare our findings with a full-term control group with birth MRI and follow-up data. Further, by averaging FA values from bilateral regions of interest to avoid multiple comparisons, we were not able to detect possibly important lateralized or regional interactions between FA, maternal sensitivity, and outcomes. Results by Vanes et al. (
      • Vanes L.D.
      • Hadaya L.
      • Kanel D.
      • Falconer S.
      • Ball G.
      • Batalle D.
      • et al.
      Associations between neonatal brain structure, the home environment, and childhood outcomes following very preterm birth.
      ) were also not lateralized.
      Future research should include whole-brain assessments of cortical microstructural development with more sophisticated diffusion models not available at the time this cohort was studied (
      • Ouyang M.
      • Jeon T.
      • Sotiras A.
      • Peng Q.
      • Mishra V.
      • Halovanic C.
      • et al.
      Differential cortical microstructural maturation in the preterm human brain with diffusion kurtosis and tensor imaging.
      ,
      • Eaton-Rosen Z.
      • Melbourne A.
      • Orasanu E.
      • Cardoso M.J.
      • Modat M.
      • Bainbridge A.
      • et al.
      Longitudinal measurement of the developing grey matter in preterm subjects using multi-modal MRI.
      ). Advances in MRI acquisition and analysis that allow for automatic segmentation and quantification of cortical FA in early life may refine our ability to detect relationships between FA, maternal sensitivity, and neurodevelopmental outcomes.

      Conclusions

      Maternal sensitivity is an important determinant of cognitive and language development in children born very preterm at 3 years of age. Promoting greater maternal sensitivity may offer an opportunity to optimize neurodevelopmental outcomes in these children, particularly among mothers with less education. Infants who are born SGA or have postnatal infections or brain injuries may benefit from early and targeted interventions. The results from this study support continued development and facilitation of parent-directed interventions to improve parent sensitivity to help children born very preterm reach their full potential.

      Acknowledgments and Disclosures

      This study was supported by the Canadian Institutes of Health Research (CIHR) (Operating Grant Nos. MOP-79262 [to SPM] and MOP-86489 [to REG]). SPM is supported by the Bloorview Children’s Hospital Chair in Pediatric Neuroscience. REG holds a senior scientist salary award from the British Columbia Children’s Hospital Research Institute. JVM received a CIHR Frederick Banting and Charles Best Doctoral Award and is supported by the Alberta Children’s Hospital Foundation.
      All authors had full access to the full data in the study and accept responsibility to submit for publication. JVM conducted the formal analysis, assisted with the investigation and visualization, wrote the original draft, and contributed to writing, reviewing, and editing. VC assisted with data curation, investigation, writing, reviewing, and editing. AS assisted with the investigation, resources, writing, reviewing, and editing. SPM and REG contributed to conceptualization, funding acquisition, methodology, supervision, writing, reviewing, and editing. All authors had access to and verified the underlying data. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
      We thank the children and their parents for their participation in this study. We also thank the Neonatal Follow-Up Program staff at the British Columbia Women’s Hospital and Cecil Chau, Mary Beckingham, Janet Rigney, Dr. Ken Poskitt, and Dr. Jessie Guo for their invaluable contributions.
      The authors report no biomedical financial interests or potential conflicts of interest.

      Supplementary Material

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      Linked Article

      • Sensitive Parenting: A Key Moderator of Neonatal Cortical Dysmaturation and Neurodevelopmental Outcomes in Children Born Very Preterm
        Biological PsychiatryVol. 92Issue 8
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          Childhood exposure to harsh and controlling parenting behavior is associated with a host of adverse developmental outcomes, including cognitive delay, executive dysfunction, socioemotional problems, and poorer quality peer relationships (1). Parents of infants born very preterm (VPT) (<32 weeks’ gestation) are at increased risk of early disruptions to the parent–child relationship (2). In addition to the stress and trauma of having their VPT infant admitted to the neonatal intensive care unit (NICU), parents face prolonged separation from their infant, are unable to take on the primary caregiving role, and witness their medically fragile infant undergo intensive, life-saving procedures (2).
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