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

Children born premature and experiencing BPD are at increased risk for neurocognitive, behavioral, and social dysfunctions.

Abstract

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.

What’s Known on This Subject:

Among children born extremely preterm, those who experience bronchopulmonary dysplasia (BPD) are at increased risk of neurocognitive, executive, memory, and language difficulties. The majority of these studies have been done when higher cortical functions including executive function are not easily measured.

What This Study Adds:

Among children born extremely preterm, those who had BPD tend to exhibit neurocognitive, behavioral, and social dysfunctions that persist until the age of 10 years. These developmental dysfunctions are more pronounced in children who experience severe BPD.

Children who develop bronchopulmonary dysplasia (BPD) are at increased risk of brain injury^1–3 and abnormal brain development.^4,5 Furthermore, therapies for BPD, such as postnatal steroids, appear to reduce brain volume⁶ and adversely affect long-term development.⁷ Cerebral palsy and other developmental disorders, including intellectual disability, occur more frequently in very low birth weight children who had BPD^8–10 compared with very low birth weight children who did not develop BPD,^4,10–14 although the authors of some studies fail to find a difference between the 2 groups.^13,15 Children who experience BPD are also at increased risk of executive dysfunction^11,16–21 and memory difficulties.¹⁵

It is still unknown to what extent immaturity and oxygen dependency contribute to both BPD and neurodevelopmental impairments, nor do we know to what extent other factors associated with immaturity and/or BPD, such as blood gas derangements^22,23 or systemic inflammation,²⁴ lead to neurodevelopmental impairments. Most studies of neurodevelopment in children with a history of BPD are limited in 1 of 3 ways. First, in some studies, BPD is defined on the basis of chest radiographs or oxygen dependency at 28 days. In other studies, the researchers reported outcomes of children before the surfactant and antenatal steroid treatment era. Finally, in some studies, young age at follow-up precluded the assessment of executive functions, higher cortical processes, and academic achievement.^{4,10–14,25–31}

In this report, we compare cognitive, language, and executive functions as well as academic achievement, social skills, and quality of life scores at age 10 years in children born extremely preterm who developed BPD to those of children who did not develop BPD.

Methods

Participants

The Extremely Low Gestational Age Newborns (ELGAN) study is a multicenter, prospective, observational study of the risk of structural and functional neurologic disorders in extremely preterm infants.³² A total of 1506 infants born before the 28th week of gestation were enrolled during the years 2002–2004, and 1198 survived to 10 years; 966 children had data on inflammatory related proteins and were recruited for an age-appropriate neurocognitive assessment. Of these 966 children, 889 (92%) returned for follow-up; 882 had diagnosis of BPD at 36 weeks’ corrected gestational age. In this report, we compare the prevalence of low scores on assessments of cognition (Differential Ability Scales II [DAS II], n = 863), executive function (NEuroPSYchological Assessment II [NEPSY II], n = 834), academic achievement (Wechsler Individual Achievement Test-III [WIAT III], n = 854, and Oral and Written Language Scales [OWLS], n = 842) limitations, and quality of life (Pediatric Quality of Life Inventory [PedsQL], n = 848), as well as undesirably high scores on assessments of social functions (Social Responsiveness Scale [SRS], n = 842) among children with a diagnosis of BPD (Supplemental Table 1). Enrollment and consent procedures for this study were approved by the institutional review boards of all participating institutions. Demographic, pregnancy, and newborn variables have been reported elsewhere.³²

BPD

The physiologic definition of BPD was first published after the initiation of the ELGAN study.³³ Consequently, information about the results of a room air challenge were not available for most ELGAN study subjects. We modified Jobe’s³⁴ definition to allow us to base severity of BPD on data we collected at 36 weeks’ postmenstrual age (PMA) about oxygen supplemental and need for ventilation assistance. Our definitions are as follows: no to mild BPD (no oxygen), moderate (oxygen only), and severe (oxygen and ventilator assistance). Our definition of severe BPD differs from that of the Eunice Kennedy Shriver National Institute of Child Health and Human Development consensus definition of severe BPD in that it is only a subset of the Eunice Kennedy Shriver National Institute of Child Health and Human Development consensus definition of severe BPD.

Ten-Year Follow-up Visit

Families willing to participate were scheduled for 1 visit, during which all of the measures reported here were administered in 3 to 4 hours, including breaks. The assessments were selected to provide the most comprehensive information about cognitive, academic function. While the child was tested, the parent or caregiver completed a general health questionnaire (medical diagnoses and receipts of medications), language, behavior, and quality of life. Questionnaires were also provided to the child’s school teacher to obtain teacher-reported behavioral status. Examiners who were unaware of the child’s medical history assessed neurodevelopment in several clinically important domains.

Cognitive, Language, Executive, and Academic Measures

General cognitive ability or IQ was assessed with the DAS II verbal and nonverbal reasoning scales.³⁵ Expressive and receptive language skills were evaluated with the OWLS, in which semantic, morphologic, syntactic, and pragmatic production and comprehension of elaborated sentences are assessed.³⁶ The WIAT III provides standard scores in word recognition and decoding, spelling, and numeric operations.³⁷ Attention and executive function were assessed with both the DAS II and the NEPSY II.^38,39

Gross Motor Function

Children’s motor function was assessed with Gross Motor Function Classification System (GMFCS). A child was classified as level III or higher if he or she needed mobility assistance (level III: walks using a hand-held mobility device; level IV: self-mobility with limitations, may use powered mobility; level V: transported in a manual wheelchair).⁴⁰

Communication Function Classification System

Children’s communication function was assessed with the Communication Function Classification System (CFCS).⁴¹ A child was classified as level 3 or higher if he or she needed assistance in communicating with partners (level III: communicates with familiar partners effectively but needs assistance with unfamiliar partners; level IV: inconsistently sends and receives messages with familiar partners; level V: seldom sends and receives messages).

Seizures or Epilepsy

Seizure identification was achieved via a screening questionnaire followed by an open-ended interview conducted by an epileptologist.⁴²

Autism Assessment

If the child screened positive for autism on the parent-completed Social Communication Questionnaire (SCQ), the parent was then asked to complete the Autism Diagnostic Interview, Revised (ADIR).⁴³ Children who met the modified ADIR criteria for autism spectrum disorder (ASD) were administered the Autism Diagnostic Observation Schedule 2 (ADOS2).⁴⁴ All children who met standardized criteria for ASD on both ADIR and ADOS2 were classified as having ASD.

SRS and Children’s Communication Checklist 2

Children were also assessed with the SRS,^44,45 the Dean Handedness Survey^46,47 and questionnaires for the Manual Ability Classification System,⁴⁸ the GMFCS,⁴⁰ the PedsQL,^49,50 the Children’s Communication Checklist 2 (CCC2),⁵¹ and the SCQ.⁵²

Data Analyses

We evaluated the null hypothesis that BPD is not associated with any cognitive, executive function, language, academic achievement, neurologic, social, or behavioral outcomes. We began by assessing correlates of BPD, including the maternal demographic and newborn characteristics at birth (Supplemental Table 2). Then we evaluated the overall distribution of each assessment at age 10 years, including the 25th, 50th, and 75th centile values (Fig 1). Because we did not evaluate a term comparison group, we relied on comparisons to historical normative samples that are described by the authors of the assessments we used.^35–38

FIGURE 1.

Distribution of scores. All subtest z scores are adjusted to population norms. Light gray is ventilation and oxygen, medium gray is oxygen only, dark gray is no BPD. AA, auditory attention; AS, animal sorting; AW, arrows; GEO, geometric puzzles; INI, inhibition inhibition; INN, inhibition naming; INS, inhibition switching; LC, listening comprehension; NO, numerical operations; NV, nonverbal reasoning; OE, oral expression; PwD, pseudoword decoding; RS, auditory response set; Sp, spelling; V, verbal; VP, visuomotor precision; WM, working memory; WR, word reading.

For assessment of neurocognitive and social function, we created logistic regression models of the risk of a score 1 or more SDs less than the normative mean of each assessment (that is, z scores ≤−1). These models, which included potential confounders (maternal education, mother’s eligibility for government-provided medical care insurance, delivery for preeclampsia or fetal indication, gestational age, and birth weight z score), allowed us to calculate odds ratios indicating the strength of the association between the severity of BPD and each outcome. Unadjusted forest plots are available in Supplemental Figs 6–9.

Results

Sample Characteristics

Of the 863 children who had an assessment of IQ at or near age 10 years, 9% (n = 78) had severe BPD (at 36 weeks’ PMA required ventilation assistance as well as supplemental oxygen), 43% (n = 372) had moderate BPD (required supplemental oxygen, but not ventilation assistance), and 48% (n = 413) did not have BPD. A higher prevalence of BPD was also associated with younger maternal age at the time of delivery and absence of college degree. Children delivered for maternal or fetal indications had a higher prevalence of BPD and severe BPD than children delivered for spontaneous indications. Overall, the lower the gestational age, birth weight, and birth weight z score, the higher the prevalence of BPD and severe BPD (Supplemental Table 2).

Distribution of Cognitive, Executive, and Academic Achievement Scores

The central line in the box of the box-and-whisker plots indicates the median (50th centile), whereas the top of the box indicates the 75th centile and the bottom of the box indicates the 25th centile. Children with severe BPD consistently have the lowest scores on cognitive function (DAS II), language and academic achievement (OWLS, WIAT III), and executive function (NEPSY II) (Fig 1).

Cognitive, Language, and Academic Achievement Assessments

Eight percent to 10% of children who did not have BPD had intellectual disability as measured by DAS II component scores >2 SDs less than the expected mean (ie, z scores ≤−2). In contrast, 19% to 22% of children who had moderate BPD had such low scores, and 30% to 32% of children who had severe BPD had such low scores. This gradient of the lowest prevalence of a z score ≤−2 among those who did not have BPD and the highest prevalence among infants who had severe BPD applied to language functioning using the OWLS and academic achievement in reading, mathematics, and spelling using the WIAT III, and the opposite gradient was observed for z scores >1 for DAS II, OWLS, and WIAT III components (Supplemental Table 3).

Executive Function and Other Neurocognitive Functions

This gradient of z scores along the path from no BPD to severe BPD also applied to DAS II working memory and the following components of the NEPSY II: auditory attention, auditory response set, inhibition inhibition, inhibition switching, animal sorting, inhibition naming, arrows, and visuo-motor function. This BPD gradient was also present for less severely low scores (ie, z scores >−2, ≤−1) on the NEPSY II geometric puzzles assessment. The gradient observed between severe BPD and no or mild BPD occurred for z scores >1 (Supplemental Table 4).

After adjustment for potential confounding factors (gestational age category, low birth weight z score category, delivery for maternal or fetal indications, and maternal fever with 48 hours of delivery), odds ratios and 95% confidence intervals of z scores ≤−1 on each DAS II and NEPSY II neurocognitive assessment, these elevations were attenuated, but by and large they remained statistically significant for severe BPD, whereas for moderate BPD the following were no longer statistically significant: OWLS listening comprehension and oral expression, DAS II working memory, and NEPSY II auditory response set, inhibition inhibition, animal sorting, and arrows (Fig 2; unadjusted odds ratios can be found in Supplemental Fig 6).

FIGURE 2.

Forest plots of adjusted odds ratios and 95% confidence intervals of a z score ≤−1 on each DAS II and NEPSY II neurocognitive assessment at age 10 associated with severe (left panel) and moderate (right panel) BPD. Odds ratios were adjusted for gestational age (23–24 and 25–26 weeks), birth weight z score (<−2 and ≥−2, <−1), delivery for maternal or fetal indications, and maternal fever within 48 hours of delivery.

When children who had an IQ of <70 were eliminated from this sample, after adjustment for potential confounding factors, the risks of low scores on verbal and nonverbal reasoning, the DAS II working memory, auditory response set, and inhibition inhibition; OWLS oral expression; and WIAT III word reading components were no longer statistically significant among children with severe BPD. In contrast, children with moderate BPD were at increased risk of low scores on NEPSY II inhibition switching and WIAT III numerical operations components (Fig 3; unadjusted odds ratios can be found in Supplemental Fig 7).

FIGURE 3.

Forest plots of adjusted odds ratios and 95% confidence intervals of a z score ≤−1 on each DAS II and NEPSY II neurocognitive assessment at age 10 associated with severe (left panel) and moderate (right panel) BPD for children with a DAS II IQ ≥70. Odds ratios were adjusted for gestational age (23–24 and 25–26 weeks), birth weight z score (<−2 and ≥−2, <−1), delivery for maternal or fetal indications, and maternal fever within 48 hours of delivery.

Neurologic and Behavioral Outcomes

The typical BPD gradient was seen for ADOS2-based diagnoses of ASD (13%, 9%, 4%), motor impairments (ie, higher classification on the Manual Ability Classification System and the GMFCS), communication impairment (highest classification on the CFCS for children), and lower quality of life (ie, higher scores on the PedsQL inventory, including physical, social, school, and psychosocial functioning). Lower quality of emotional function was similarly associated with both severe and moderate BPD (30%–31% vs 24%). Children who had severe BPD had higher prevalence than others of a seizure, epilepsy, receipt of medication for seizures, and left handedness (Supplemental Table 5).

For children who had severe BPD, these elevations were somewhat less prominent after adjustment for potential confounding factors, but the elevated odds of a high T-score on the total score, as well as the social cognition, social communication, and social motivation components, remained statistically significant (Fig 4; unadjusted odds ratios can be found in Supplemental Fig 8). The risk of a “positive” SCQ assessment also remained significantly elevated. After adjustments, children with moderate BPD were also at significantly increased risk of low scores on the speech, coherence, and initiation components (Fig 5; unadjusted odds ratios can be found in Supplemental Fig 9).

FIGURE 4.

Forest plots of adjusted odds ratios and 95% confidence intervals of a T-score ≥60 on SRS subtests, of screening positive on SCQ, and of documented characteristics of ASD based on the ADOS2 at age 10 associated with severe (left panel) and moderate (right panel) BPD. Odds ratios were adjusted for gestational age (23–24 and 25–26 weeks), birth weight z score (<−2 and ≥−2, <−1), delivery for maternal or fetal indications, and maternal fever within 48 hours of delivery.

FIGURE 5.

Forest plots of adjusted odds ratios and 95% confidence intervals of a z score ≤−1 on the CCC2 subtests at age 10 associated with severe (left panel) and moderate (right panel) BPD. Odds ratios were adjusted for gestational age (23–24 and 25–26 weeks), birth weight z score (<−2 and ≥−2, <−1), delivery for maternal or fetal indications, and maternal fever within 48 hours of delivery.

Discussion

In this cohort of 10-year-old children born before 28 weeks of gestation, those who had BPD were at increased risk of neurocognitive, behavioral, and social dysfunctions. Children with severe BPD were more likely than other children to have low scores on cognitive, language, academic achievement, executive, emotional, social, and physical functioning. Their parents rated them as experiencing a lower quality of life. The multitude of dysfunctions we found at 10 years in children with BPD, even after adjusting for potential confounders, were most prominent in children who experienced severe BPD.

Lower cognitive function and academic achievement have been found repeatedly among children who had BPD than among their peers.^4,10–14 Similar to our study, the majority of the studies of school-aged children found that children with BPD have higher rates of executive function limitations compared with their peers.^16–20 The main difference between our study and other studies is the modification of classification of BPD by Jobe.³⁴ We stratified our BPD into moderate with supplemental oxygenation and severe with ventilatory support and supplemental oxygen, whereas in other studies, researchers combined all categories of BPD into with and without BPD.

Possible Explanations for Our Findings

Prematurity may be the main reason for the development of BPD. Other contributions might come from an increase in reactive oxygen species.^53,54

Infection

Children who experience sepsis^55,56 and those who acquire other nosocomial infections⁵⁷ are at risk for BPD. Infections in the perinatal period are associated with white matter abnormalities and later motor and cognitive impairments.^58–61

Systemic Inflammation

Assisted ventilation appears to increase the probability of systemic inflammation,⁶² which in turn is associated with increased risk of BPD.²² Lung inflammation contributes to the pathogenesis of BPD and may be accompanied by systemic responses. Systemic inflammation appears to put newborns at increased risk of multiple indicators of brain injury.^63–69

Growth Restriction

BPD risk is heightened among infants born small for gestational age,^70,71 who are also at increased risk of delayed development.⁷² The complexity of the situation is suggested by the observation that newborn lambs who are growth restricted are at increased risk of ventilation-induced brain damage.⁷³

Intermittent Hypoxia

Children whose pulse oximeter oxygen saturation was in the range of 85% to 89% were not at increased risk of disability.⁷⁴ Thus, it is unlikely that low oxygen saturation contributes to what we found.

Pain and/or Neuroapoptotic Analgesic or Sedatives

Pain-related stress in the very preterm newborn has been associated with altered brain structure and function.⁷⁵ These findings have encouraged efforts to minimize pain, including that associated with prolonged assisted ventilation.⁷⁶ Among children born very premature, those exposed to sedatives and/or opioid drugs for >7 days performed as well on neurodevelopmental assessments at age 5 as their 1457 peers who were not so exposed.⁷⁷ In light of “limited evidence of benefit and potential for harm,”⁷⁸ the use of opioids for agitation resulting from mechanical ventilation remains controversial.⁷⁹

Diminished Human Contact

Lagercrantz⁸⁰ has suggested that “more skin-to-skin care for several hours per day and talking and singing to the infant a lot may help” diminish the occurrence of ASD among children on the ventilator. If this hypothesis is correct, some of the social dysfunctions we identified might be easily preventable.

The Multihit Hypothesis and Causal Pathways

The high risk of dysfunctions among children who had BPD, especially severe BPD, is in keeping with the hypothesis that multiple risk factors together and/or in sequence might be especially damaging to the developing brain.^81–84 Extreme prematurity and/or vulnerability and fetal growth restriction are among the earliest risk factors, whereas systemic inflammation might be the most obvious of the subsequent risk factors.^83,85 Part of the process might reflect secondary exacerbation of damage,^86,87 although the sequence of events in some situations likely begins with sensitization.⁸⁸

Beyond Low IQ

Elimination of children who had a median IQ of <70 from the sample did not change our findings appreciably, suggesting that the functions we assessed are not due to low IQ.^89–91 Even though children with severe BPD were more likely to have low scores on cognitive, language, academic achievement, executive emotional, social and physical functioning, and diminished quality of life, approximately one-half of our cohort had scores in the normal range for academic achievement (Supplemental Table 3).

For our current study, we wanted to see to what extent BPD predicted later dysfunctions regardless of the contributions of antecedents. We recognize that systemic inflammation and other correlates of ventilation and BPD might have contributed to what we found.^24,63,92

Strengths and Limitations

Our study has several strengths. First, in contrast to a majority of the existing studies, our sample size is large, making it unlikely that we have missed important associations because of lack of statistical power or that we claimed associations that might reflect stability of small numbers. Second, we selected infants on the basis of gestational age, not birth weight, to minimize confounding due to factors related to growth restriction.⁹³ Third, we collected our data prospectively. Fourth, attrition at neurocognitive assessment was modest. Fifth, the individuals who evaluated study participants at 10 years of age were not aware of their medical histories. The weaknesses of our study are those of all observational studies. We are unable to distinguish between causation and association as explanations for what we found.

Conclusions

Ten years after they were born extremely preterm in this cohort, those who had BPD were at increased risk of cognitive, language, and executive dysfunctions, as well as low scores on assessments of academic achievement, social skills, and quality of life. These limitations were especially prominent among those who were ventilator-dependent at 36 weeks’ PMA. Almost half of children who had severe BPD had scores in the normal range for academic achievement.

Glossary

ADIR

Autism Diagnostic Interview, Revised

ADOS2

Autism Diagnostic Observation Schedule 2

ASD

autism spectrum disorder

BPD

bronchopulmonary dysplasia

CCC2

Children’s Communication Checklist 2

CFCS

Communication Function Classification System

DAS II

Differential Ability Scales II

ELGAN

Extremely Low Gestational Age Newborns

GMFCS

Gross Motor Function Classification System

NEPSY II

NEuroPSYchological Assessment II

OWLS

Oral and Written Language Scales

PedsQL

Pediatric Quality of Life Inventory

PMA

postmenstrual age

SCQ

Social Communication Questionnaire

SRS

Social Responsiveness Scale

WIAT III

Wechsler Individual Achievement Test-III