723 - Association of Etiology of Prematurity with Early Neurodevelopmental Outcomes in Children Born Very Preterm

Publication Number: 2705.723

Sophie Piedboeuf, CHU de Québec - Université Laval, Québec City, PQ, Canada; Etienne Pronovost, CHU de Québec-Université Laval, Quebec City, PQ, Canada; David Simonyan, CHU de Québec, Québec, PQ, Canada; Audrey Hébert, CHU de Quebec, Quebec city, PQ, Canada; Mireille Guillot, CHU de Québec - Université Laval, Quebec, PQ, Canada

Background: Although survival among very preterm infants has improved, rates of neurodevelopmental impairment remain high. Optimizing outcomes requires a shift towards individualized neonatal care informed by antenatal and postnatal determinants. However, the role of antenatal factors and placental pathology in shaping neurodevelopment is not well understood.

Objective: To determine the relationship between the etiology of preterm birth and neurodevelopmental outcomes at 18-22 months' corrected age in children born very preterm.

Design/Methods: This is a secondary analysis of the MOBYDIck randomized controlled trial (NCT02371460), conducted in infants born < 29 weeks' gestation across 16 Canadian neonatal intensive care units, whose mothers were randomized to receive omega-3 supplementation or placebo during lactation. Infants were classified into two previously characterized endotypes: 1) inflammation/infection (preterm labor, cervical insufficiency, placental abruption, chorioamnionitis, or spontaneous rupture of membranes) and 2) dysfunctional placentation (gestational hypertension, pre-eclampsia/eclampsia, or small for gestational age). Primary outcomes were Bayley-III cognitive, language, and motor scores at 18-22 months' corrected age. Secondary outcomes included components of neurodevelopmental impairment. Mean differences (MD) were estimated using GEE with multivariate linear regression models adjusted for (1) perinatal and (2) both perinatal and postnatal variables. All analyses were adjusted for clustering due to multiple births, study site, and treatment group.

Results: Among the 363 children included in this analysis (192 males, 53%; mean gestational age 26.7 weeks, SD 1.5), 301 (83%) were categorized in the infection/inflammation endotype and 62 (17%) in the dysfunctional placentation endotype. Compared to infants in the inflammation/infection endotype, those in the dysfunctional placentation endotype had lower cognitive (MD -5.5 [95% CI -9.9 to -1.1], P=0.02) and language scores (MD -5.3 [95% CI -9.8 to -0.7], P=0.02) in models accounting for perinatal variables. These differences were attenuated after adjustment for postnatal variables. No significant differences were observed in the motor score or secondary outcomes.

Conclusion(s): The etiology of prematurity is associated with early neurodevelopment, with dysfunctional placentation linked to lower cognitive and language scores. These findings highlight the potential of placental and antenatal factors as markers to identify high-risk infants and guide tailored surveillance and early interventions. Validation in larger cohorts is warranted.

Table 1. Maternal and Infant's Characteristics
a) According to criteria from Bell et al.

b) At least 1 episode of clinical or laboratory proven sepsis after 3 days of life that required intravenous antibiotic treatment of at least 5 days from birth to 40 weeks postmenstrual age.

c) Worst grade from birth based on criteria from Papile et al.

d) Based on Jensen's definition

e) Based on article from Schmidt et al., presence of morbidities including severe bronchopulmonary dysplasia (Grade 2 or 3), severe retinopathy of prematurity (Retinopathy grade 4 or higher, or requiring treatment) and severe brain injury (intraventricular hemorrhage grade 3 or 4, or periventricular leukomalacia).


Table 2. Primary Neurodevelopmental Outcomes at 18-22 Months' Corrected Age
a) Model 1: GEE linear regression model adjusted for clustering due to multiple births, study site and treatment allocation group with additional adjustment for the following perinatal covariates included as fixed effects: maternal education, sex and gestational age. Statistical significance was determined by using the Wald chi-square test.

b) Model 2: Model 1 with additional adjustment for early postnatal covariates summarized as a neonatal morbidity count.


Table 3. Secondary Neurodevelopmental Outcomes at 18-22 Months' Corrected Age
a) GEE log-binomial model adjusted for clustering due to multiple births

b) Considered present if any Bayley-III score <85, presence of cerebral palsy (CP) defined as Gross Motor Function Classification System (GMFCS) ≥1, sensorineural/mixed hearing loss or auditory neuropathy or unilateral or bilateral visual impairment.

c) Considered present if any Bayley-III score <70, severe CP defined as GMFCS ≥3, bilateral visual impairment or hearing loss requiring amplification.