Dynamic changes in postnatal growth predict adolescent mental health problems in survivors of extremely low birth weight (ELBW).

Although individuals born at extremely low birth weight (ELBW; ≤1000 g) are known to be at greater risk for mental health problems than individuals born at normal birth weight (NBW; ≥2500 g), contributions of postnatal growth to these relations have not been fully explored. We compared individual differences in the Ponderal Index [(PI; weight(kg)/height(m3)] and head circumference (HC) in predicting internalizing and externalizing behaviors in childhood and adolescence in a cohort of ELBW survivors (N = 137) prospectively followed since birth. Baseline models indicated that infants who were born thinner or with smaller HC showed greater PI or HC growth in the first 3 years. Latent difference score (LDS) models showed that compensatory HC growth in the first year (ΔHC = 20.72 cm), controlled for birth HC, predicted ADHD behaviors in adolescence in those born with smaller HC. LDS models also indicated that the PI increased within the first year (ΔPI = 1.568) but decreased overall between birth and age 3 years (net ΔPI = -4.597). Modeling further showed that larger increases in the PI in the first year and smaller net decreases over 3 years predicted more internalizing behaviors in adolescence. These findings suggest early growth patterns prioritizing weight over height may have negative effects on later mental health in ELBW survivors, consistent with developmental programming theories.

Mathematical performance in childhood and early adult outcomes after very preterm birth: an individual participant data meta-analysis.

AIM: To investigate the strength of the independent associations of mathematics performance in children born very preterm (<32wks' gestation or <1500g birthweight) with attending postsecondary education and their current employment status in young adulthood. METHOD: We harmonized data from six very preterm birth cohorts from five different countries and carried out one-stage individual participant data meta-analyses (n=954, 52% female) using mixed effects logistic regression models. Mathematics scores at 8 to 11 years of age were z-standardized using contemporary cohort-specific controls. Outcomes included any postsecondary education, and employment/education status in young adulthood. All models were adjusted for year of birth, gestational age, sex, maternal education, and IQ in childhood. RESULTS: Higher mathematics performance in childhood was independently associated with having attended any postsecondary education (odds ratio [OR] per SD increase in mathematics z-score: 1.36 [95% confidence interval {CI}: 1.03, 1.79]) but not with current employment/education status (OR 1.14 per SD increase [95% CI: 0.87, 1.48]). INTERPRETATION: Among populations born very preterm, childhood mathematics performance is important for adult educational attainment, but not for employment status.

DNA methylation profiles in adults born at extremely low birth weight.

Effects of stresses associated with extremely preterm birth may be biologically "recorded" in the genomes of individuals born preterm via changes in DNA methylation (DNAm) patterns. Genome-wide DNAm profiles were examined in buccal epithelial cells from 45 adults born at extremely low birth weight (ELBW; ≤1000 g) in the oldest known cohort of prospectively followed ELBW survivors (Mage = 32.35 years, 17 male), and 47 normal birth weight (NBW; ≥2500 g) control adults (Mage = 32.43 years, 20 male). Sex differences in DNAm profiles were found in both birth weight groups, but they were greatly enhanced in the ELBW group (77,895 loci) versus the NBW group (3,424 loci), suggesting synergistic effects of extreme prenatal adversity and sex on adult DNAm profiles. In men, DNAm profiles differed by birth weight group at 1,354 loci on 694 unique genes. Only two loci on two genes distinguished between ELBW and NBW women. Gene ontology (GO) and network analyses indicated that loci differentiating between ELBW and NBW men were abundant in genes within biological pathways related to neuronal development, synaptic transportation, metabolic regulation, and cellular regulation. Findings suggest increased sensitivity of males to long-term epigenetic effects of extremely preterm birth. Group differences are discussed in relation to particular gene functions.

Long-term stability of frontal electroencephalogram alpha power and asymmetry at rest in adults born at extremely low or normal birth weight: A 10-year longitudinal study.

The idea that individual differences in resting frontal EEG alpha activity have "trait-like" features that are associated with stress vulnerabilities presumes that these physiological patterns should be stable across time. We know, however, relatively little regarding the very long-term (i.e., ≥10 years) stability of resting frontal EEG alpha power and asymmetry in typically or atypically developing populations. Here, we examined the long-term stability of regional electroencephalogram (EEG) alpha (8-13 Hz) power and asymmetry at rest across a decade in the oldest known prospectively followed cohort of extremely low birth weight (ELBW; <1000 g) adult survivors and normal birth weight (NBW; >2500 g) controls. Regional EEG was collected at rest from the left and right frontal (F3, F4) and parietal (P3, P4) scalp sites using a stretchable cap during baseline eyes-open and eyes-closed conditions in young adulthood (ages 21-25 years) and again in adulthood (ages 30-35 years). We found moderate stability in regional EEG absolute alpha spectral power measures across all scalp sites for each birth weight group between the young adulthood and adulthood assessments. As well, we found the frontal alpha asymmetry measure was stable, albeit weakly, between the two assessment periods only in the NBW group. However, parietal alpha asymmetry was weak-to-moderately stable for each birth weight group across the 10-year period. Findings are discussed in terms of their implications for understanding associations between individual differences in frontal and parietal brain activity at rest and long-term stress vulnerability in typical and atypical development.

Brain, interrupted: alpha/delta EEG ratio in survivors of pre- and post-natal adversity.

RESULTS: Young adults born at extremely low birth weight (prenatal adversity; N = 64, Mage = 23.14 years, SDage = 1.26 years) had a lower alpha/delta ratio score compared to normal birth weight controls (N = 76, Mage = 23.60 years, SDage = 1.09 years), while youth exposed to child maltreatment (postnatal adversity; N = 39, Mage = 16.18 years, SDage = 1.15) had a higher alpha/delta ratio compared to controls (N = 23, Mage = 16.00 years, SDage = 1.50 years). CONCLUSIONS: Our results suggest that being exposed to pre- and post-natal adversity may have different long-term consequences on brain development. We speculate that these differences might be associated with some of the different functional outcomes known to characterize each type of adverse experience.

Grip strength is lower in adults born with extremely low birth weight compared to term-born controls.

BACKGROUND: Grip strength predicts long-term morbidity and mortality in adults. We compared grip strength in adults born with extremely low birth weight (ELBW; under 1 kg) and a normal birth weight control group (NBW) and describe change in grip strength over a 10-year period in a longitudinal cohort study of preterm birth. METHODS: Grip strength, body composition, and device-measured physical activity were assessed in 95 mature adults (MA) born ELBW (age 31.6 (1.6) mean (SD) years, 59 females) and 88 born NBW (age 31.9 (1.4) years, 52 females). Regression models were used to examine the effect of perinatal factors, body composition, physical activity, and physical self-efficacy on grip strength. RESULTS: Grip strength was lower in MA born ELBW compared to NBW (31.8 (10.0) vs. 39.8 (11.2) kg; p < 0.001). Birth weight group was associated with grip strength independent of sex, height, and lean mass index, but device-measured physical activity was not. The change in grip strength from mid-20s to MA was similar in ELBW and NBW participants. DISCUSSION: Grip strength in MA born ELBW is low and is similar to a reference group 25-30 years older, suggesting higher risk for cardiovascular and all-cause mortality. IMPACT: Adults born extremely preterm have reduced grip strength compared to control participants born at full term. Reduced grip strength is a predictor of frailty and increased cardiovascular disease risk. Change in grip strength from age in mid-20s to mid-30s is similar in those born preterm and full-term-born controls. Grip strength is related to lean mass and not to device-measured physical activity-and correlates of grip strength are similar in those born preterm and term-born controls. Grip strength is a simple measure that may provide information about the health of adults born preterm.

Cumulative risks predict epigenetic age in adult survivors of extremely low birth weight.

Long-term sequelae of extremely low birth weight (ELBW; ≤1000 g) may contribute to accelerated biological aging. This hypothesis was examined by analyzing a range of risk factors with a molecular age marker in adults born at ELBW or normal birth weight (NBW; ≥2500 g). DNAm age-the weighted average of DNA methylation at 353 cytosine-phosphate-guanine (CpG) sites from across the genome-was derived from a sample of 45 ELBW (Mage  = 32.35 years) and 47 NBW control (Mage  = 32.44 years) adults, using the Illumina 850k BeadChip Array. At two assessments undertaken 9 years apart (at 23 and 32 years), cumulative risks were summed from six domains with potential to affect physiological and psychological health: resting respiratory sinus arrhythmia, blood pressure, basal cortisol, grip strength, body mass index, and self-esteem. At age 32 years, cumulative risks were differentially associated with epigenetic age in ELBW survivors (interaction, p < 0.01). For each additional risk factor they possessed, ELBW survivors (B = 1.43) were biologically 2.16 years older than NBW adults (B = -0.73), by the fourth decade of life. Developmental change, epigenetic maintenance, and intervention targets are discussed.

Visual configural processing in adults born at extremely low birth weight.

Being born at extremely low birth weight (ELBW; ≤1,000 g) is associated with enduring visual impairments. We tested for long-term, higher order visual processing problems in the oldest known prospectively followed cohort of ELBW survivors. Configural processing (spacing among features of an object) was examined in 62 adults born at ELBW (Mage  = 31.9 years) and 82 adults born at normal birth weight (NBW; ≥2,500 g: Mage  = 32.5 years). Pairs of human faces, monkey faces, or houses were presented in a delayed match-to-sample task, where non-matching stimuli differed only in the spacing of their features. Discrimination accuracy for each stimulus type was compared between birth weight groups, adjusting for neurosensory impairment, visual acuity, binocular fusion ability, IQ, and sex. Both groups were better able to discriminate human faces than monkey faces (p < .001). However, the ELBW group discriminated between human faces (p < .001), between monkey faces (p < .001), and to some degree, between houses (p < .06), more poorly than NBW control participants, suggesting a general deficit in perceptual processing. Human face discrimination was related to performance IQ (PIQ) across groups, but especially among ELBW survivors. Coding (a PIQ subtest) also predicted human face discrimination in ELBW survivors, consistent with previously reported links between visuo-perceptive difficulties and regional slowing of cortical activity in individuals born preterm. Correlations with Coding suggested ELBW survivors may have used a feature-matching approach to processing human faces. Future studies could examine brain-based anatomical and functional evidence for altered face processing, as well as the social and memory consequences of face-processing deficits in ELBW survivors.

Developmental programming of shyness: A longitudinal, prospective study across four decades.

Although shyness is a ubiquitous phenomenon with early developmental origins, little research has examined the influence of prenatal exposures on the developmental trajectory of shyness. Here, we examined trajectories of shyness from childhood to adulthood in three groups (N = 254), with varying degrees of prenatal adversity as indicated by the number of stressful exposures: extremely low birth weight (ELBW; <1000 g) survivors prenatally exposed to exogenous corticosteroids (ELBW+S, n = 56); ELBW survivors not prenatally exposed to exogenous corticosteroids (ELBW+NS, n = 56); and normal birth weight (NBW, n = 142) controls. Multilevel modeling revealed that the ELBW+S individuals exhibited the highest levels of childhood shyness, which remained stable into adulthood. The ELBW+NS and NBW controls had comparably low levels of childhood shyness; however, the ELBW+NS individuals experienced patterns of increasing shyness, while NBW controls displayed decreases in shyness into adulthood. We speculate that individuals exposed to multiple prenatal stressors (i.e., ELBW+S) may be developmentally programmed to be more sensitive to detecting social threat, with one manifestation being early developing, stable shyness, while increasing shyness among ELBW+NS individuals may reflect a later developing shyness influenced by postnatal context. We discuss the implications of these findings for understanding the developmental origins and developmental course of human shyness from childhood through adulthood.

Shyness and sociability among extremely low birth weight survivors in the third and fourth decades of life: Associations with relationship status.

OBJECTIVE: We examined differences between the oldest known longitudinally followed cohort of extremely low birth weight survivors (ELBW; < 1,000 grams) and normal birth weight (NBW; > 2,500 grams) control participants on shyness and sociability, as well as conflicted shyness in adulthood across nearly a decade from their 20s to 30s. METHOD: 100 ELBW survivors and 88 NBW control participants self-reported on shyness and sociability using the Cheek and Buss (1981; Cheek, 1983) shyness and sociability scale. Participants also self-reported on their relationship status. A composite measure of conflicted shyness was also computed (i.e., the product of shyness and sociability). RESULTS: We found that, in their 30s, ELBW survivors reported higher shyness, but similar levels of sociability and conflicted shyness compared to controls. However, the ELBW group exhibited a greater decrease in conflicted shyness than NBW controls from their 20s to their 30s. Greater decreases in conflicted shyness in both groups were associated with being male, as well as with changes in relationship status such as finding a partner or getting married. CONCLUSIONS: Relatively higher shyness among ELBW survivors in adulthood suggests that stressful pre- and early postnatal environments may have lasting effects on personality development. However, later social influences such as relationship status may attenuate some types of shyness in adulthood.

Exposure to caring parenting and adult mental health in extremely low birthweight survivors.

AIM: Individuals born at extremely low birthweight (ELBW; <1000 g) are exposed to early adversities that increase the risk of mental health problems in later life. Caring parenting has been shown to offset the negative effects of early adversity in general population samples. However, the long-term impact of caring parenting on the mental health of preterm survivors in adulthood is not known. METHODS: Using data from the world's oldest longitudinally followed cohort of ELBW survivors (n = 179) and matched normal birthweight (NBW) control participants (n = 145), we examined if caring parenting moderated the link between preterm birth and mental health at 30-35 years of age. Participants reported on the parenting they received from their mothers using the parental bonding instrument. Self-esteem and internalising problems (i.e. depression, anxiety) were self-reported at 30-35 years of age using the Coopersmith Self-Esteem Inventory and Young Adult Self-Report questionnaire, respectively. RESULTS: A statistically significant interaction was found between birthweight status and caring maternal parenting on self-esteem and internalising psychopathology in adulthood. Stratified analyses demonstrated that caring parenting was associated with better self-esteem (P < 0.001) and lower levels of internalising symptoms (P = 0.001), but in NBW participants only. CONCLUSIONS: While the receipt of caring maternal parenting promoted mental health in adults born at NBW, it did not have the same protective effect on ELBW survivors. More research is needed to elucidate the aspects of parenting and the family environment that promote the long-term mental health of preterm survivors.

Exposure to antenatal corticosteroids and reduced respiratory sinus arrhythmia in adult survivors of extremely low birth weight.

Purpose/aim: Antenatal corticosteroid (ACS) therapy has dramatically increased survival rates among extremely low birth weight (ELBW) infants. However, the long-term effects of ACS on autonomic nervous system function have not been explored. Using the world's oldest longitudinally followed cohort of ELBW infants we compared respiratory sinus arrhythmia (RSA) among ELBW survivors whose mothers received ACS (ELBW-S), those who did not (ELBW-NS) and normal birth weight (NBW) controls in their 20 and 30 s. Methods: Resting electrocardiogram (ECG) was recorded from ELBW-S (n = 28), ELBW-NS (n = 36), and matched NBW controls (n = 79) at 22-26 and 29-36 years. Resting RSA was compared across groups via analyses of covariance (ANCOVA), adjusting for sex, medication use, postnatal steroid exposure and the presence of chronic health conditions. RSA was also compared across assessments for each group. Results: At 29-36 years, resting RSA in ELBW-S was significantly lower than in NBW controls. RSA in the ELBW-NS group was intermediate between ELBW-S and NBW groups. Although the ELBW-S group also showed nominally reduced RSA compared to NBW controls at the 22-26-year visit, this difference was not statistically significant. Conclusions: ELBW survivors exposed to ACS had lower RSA than NBW controls during their 30 s, suggestive of a decline in parasympathetic input to heart. ELBW survivors who received ACS may be particularly vulnerable to cardiovascular problems in later life.

Impact of extremely low-birth-weight status on risk and resilience for depression and anxiety in adulthood.

BACKGROUND: Preterm birth is associated with an increased risk of depression and anxiety, but it is not known if this is due to greater exposure to risk, or if perinatal adversity amplifies the impact of traditional risk factors. This study sought to determine if exposure to perinatal adversity modifies associations between traditional risk and resilience factors and depression and anxiety in adulthood. METHODS: A sample of 142 extremely low-birth-weight (ELBW < 1,000 g) survivors and 133 sociodemographically matched normal birth weight (NBW) control participants was followed longitudinally to 22-26 years of age. Separate postnatal risk and resilience scales were created using eight risk and seven resilience factors, respectively. Depression and anxiety were assessed using the internalizing scale of the Young Adult Self-Report (YASR). This scale was also dichotomized at the 90th percentile to define clinically significant psychopathology. RESULTS: While the average number of risk exposures did not differ between groups, ELBW survivors were more susceptible to risk than NBW control participants. For the ELBW group, each additional risk factor resulted in a 2-point increase in internalizing scores, and two and a half times the odds of clinically significant internalizing symptoms (OR = 2.47, 95% CI = 1.63, 3.76). The protective effect of resiliency factors was also blunted among ELBW survivors. CONCLUSIONS: Extremely low-birth-weight survivors may be more sensitive to traditional risk factors for psychopathology and less protected by resiliency factors. Intervention strategies aimed at preventing or reducing exposure to traditional childhood risk factors for psychopathology may reduce the burden of mental illness in adult survivors of prematurity.

Trajectories of psychopathology in extremely low birth weight survivors from early adolescence to adulthood: a 20-year longitudinal study.

BACKGROUND: Individuals born extremely preterm are exposed to significant perinatal stresses that are associated with an increased risk of psychopathology. However, a paucity of longitudinal studies has prevented the empirical examination of long-term, dynamic effects of perinatal adversity on mental health. Here, internalizing and externalizing problems from adolescence through adulthood were compared in individuals born at extremely low birth weight (ELBW; <1,000 g) and normal birth weight (NBW; >2,500 g). METHODS: Internalizing and externalizing data were collected over 20 years in three waves, during adolescence, young adulthood, and adulthood. Growth models were used to compare longitudinal trajectories in a geographically based sample of 151 ELBW survivors and 137 NBW control participants born between 1977 and 1982 matched for age, sex, and socioeconomic status at age 8. RESULTS: After adjusting for sex, socioeconomic and immigrant status, and family functioning, ELBW survivors failed to show the normative, age-related decline in internalizing problems over time relative to their NBW peers (ß = .21; p < .01). Both groups exhibited small declines in externalizing problems over the same period. Self-esteem (but not physical health, IQ, or maternal mood) partially mediated the association between ELBW status and internalizing problems. CONCLUSIONS: Extremely low birth weight survivors experienced a blunting of the expected improvement in depression and anxiety from adolescence to adulthood. These findings suggest that altered physiological regulatory systems supporting emotional and cognitive processing may contribute to the maintenance of internalizing problems in this population.

Early developmental influences on self-esteem trajectories from adolescence through adulthood: Impact of birth weight and motor skills.

While the trajectory of self-esteem from adolescence to adulthood varies from person to person, little research has examined how differences in early developmental processes might affect these pathways. This study examined how early motor skill development interacted with preterm birth status to predict self-esteem from adolescence through the early 30s. We addressed this using the oldest known, prospectively followed cohort of extremely low birth weight (<1000 g) survivors (N = 179) and normal birth weight controls (N = 145) in the world, born between 1977 and 1982. Motor skills were measured using a performance-based assessment at age 8 and a retrospective self-report, and self-esteem was reported during three follow-up periods (age 12-16, age 22-26, and age 29-36). We found that birth weight status moderated the association between early motor skills and self-esteem. Stable over three decades, the self-esteem of normal birth weight participants was sensitive to early motor skills such that those with poorer motor functioning manifested lower self-esteem, while those with better motor skills manifested higher self-esteem. Conversely, differences in motor skill development did not affect the self-esteem from adolescence to adulthood in individuals born at extremely low birth weight. Early motor skill development may exert differential effects on self-esteem, depending on whether one is born at term or prematurely.

How do childhood intelligence and early psychosocial adversity influence income attainment among adult extremely low birth weight survivors? A test of the cognitive reserve hypothesis.

Perinatal and later postnatal adversities have been shown to adversely affect socioeconomic trajectories, while enhanced early cognitive abilities improve them. However, little is known about the combined influence of these exposures on social mobility. In this study, we examined if childhood IQ moderated the association between four different types of postnatal adversity (childhood socioeconomic disadvantage, childhood sexual abuse, lifetime psychiatric disorder, and trait neuroticism) and annual earnings at 30-35 years of age in a sample of 88 extremely low birth weight survivors. Our results suggested that higher childhood IQ was associated with greater personal income at age 30-35. Extremely low birth weight survivors who did not face psychological adversities and who had higher childhood IQ reported higher income in adulthood. However, those who faced psychological adversity and had higher childhood IQ generally reported lower income in adulthood. Our findings suggest that cognitive reserve may not protect preterm survivors against the complex web of risk factors affecting their later socioeconomic attainment.

Trajectories of self-esteem in extremely low birth weight survivors through adulthood.

Although the developmental course of self-esteem has been examined in general population samples, there is a lack of research examining the trajectory of self-esteem in populations who experience unique developmental challenges. We compared the trajectory of self-esteem in extremely low birth weight (ELBW; <1000 grams) survivors and normal birth weight (NBW) controls from mid-adolescence through their early 30s. Self-esteem was reported during three follow-up periods (age 12-16, age 22-26, age 30-35). Adjusting for sex, chronic health problems, socioeconomic status, and social support, no difference was noted in self-esteem in the two groups in adolescence, but birth weight status predicted rate of change of self-esteem from adolescence to adulthood. The NBW controls showed the expected, normative increases in self-esteem from mid-adolescence to young adulthood, while ELBW individuals displayed stable, low levels of self-esteem into young adulthood. Our findings highlight that ELBW survivors may not experience the normative trajectory of self-esteem into young adulthood.

Extremely low birth weight babies grown up: Gene-environment interaction predicts internalizing problems in the third and fourth decades of life.

Extremely low birth weight (ELBW; <1000 g) infants have been exposed to stressful intrauterine and early postnatal environments. Even greater early adversity has been experienced by ELBW survivors who were also born small for gestational age (SGA; <10th percentile for GA) compared to those born appropriate for GA (AGA). ELBW survivors, particularly those born SGA, face increased risk for internalizing problems compared to normal BW (NBW; ≥2500 g) controls. Internalizing problems are related to allelic variations in the promoter region of the serotonin transporter linked polymorphic region gene (5-HTTLPR). We followed the oldest longitudinal cohort of ELBW survivors to adulthood. Participants provided buccal cells and reported on internalizing problems, using the Young Adult Self-Report when they were in their mid-20s (ELBW/SGA, N = 28; ELBW/AGA, N = 60; NBW, N = 81) and mid-30s (ELBW/SGA, N = 27; ELBW/AGA, N = 58; NBW, N = 76). The findings indicate that ELBW/SGAs carrying the 5-HTTLPR short allele reported increased internalizing problems, particularly depression, during the third and fourth decades of life. This is the first known report on gene-environment interactions predicting psychopathology among ELBW survivors. Our findings elucidate putative neurobiological pathways that underlie risk for psychopathology.

Adults born preterm: a review of general health and system-specific outcomes.

In this review of 126 publications, we report that an overwhelming majority of adults born at preterm gestations remain healthy and well. However, a small, but a significant fraction of them remain at higher risk for neurological, personality and behavioural abnormalities, cardio-pulmonary functional limitations, systemic hypertension and metabolic syndrome compared to their term-born counterparts. The magnitude of increased risk differed across organ systems and varied across reports. The risks were proportional to the degree of prematurity at birth and seemed to occur more frequently among preterm infants born in the final two decades of the 20th century and later. These findings have considerable public health and clinical practice relevance. CONCLUSION: Preterm birth needs to be considered a chronic condition, with a slight increase in the risk for long-term morbidities among adults born preterm. Therefore, obtaining a history of gestational age and weight at birth should be a routine part of care for patients of all age groups.

Sensitivity to facial expressions among extremely low birth weight survivors in their 30s.

The current study investigated the impact of birth weight on the ability to recognize facial expressions in adulthood among the longest known prospectively followed cohort of extremely low birth weight survivors (ELBW; <1,000 g). We measured perceptual threshold to detect subtle facial expressions and confusion among different emotion categories in order to disentangle visual perceptual ability from emotional processing. ELBW adults (N = 64, Mage = 31.9 years) were more likely than normal birth weight (NBW) controls (N = 82, Mage = 32.5 years) to see fear in angry faces. This finding was not a result of increased perceptual efficiency in processing fearful expressions in the ELBW adults, since the two groups did not differ on their threshold to detect emotion in low intensity facial expressions. These findings suggest that a processing bias toward fear may reflect long-term developmental effects from being born at ELBW that may portend socioemotional problems that characterize ELBW survivors.