Prevention of Developmental Delay and Xylitol (PDDaX) Study

Our primary objective is to assess the neurodevelopmental outcomes of 1000 randomly selected children delivered to gravid participants enrolled in the Prevention of Prematurity and Xylitol (PPaX) trial who are now 4-8 years of age. We will formally evaluate any differences in neurodevelopmental outcomes related to xylitol exposure or lack thereof by assessing the child's (a) cognition, (b) executive function, (c) social-emotional development, (d) gross motor skills, (e) fine motor skills, and (f) language. Examiners will assess these neurodevelopmental outcomes using the Kaufman Assessment Battery for Children-2nd Edition (KABC-II), the EF Touch, the Strengths and Difficulties Questionnaire (SDQ), the Malawi Developmental Assessment Tool (MDAT), the Anchor Items in Measuring Early Childhood Development (AIM-ECD), and the International Development and Early Learning Assessment (IDELA). Of note, the primary outcome of the PDDaX trial will be the overall cognitive score as determined by the mental processing index. We hypothesize that children born to mothers who used xylitol chewing gum during pregnancy have improved neurodevelopmental outcomes at 4-8 years of age compared to children born to mothers without xylitol use during pregnancy and stratified based on whether born premature or term at birth.

The N = 1000 children in the PDDaX follow-up study will be stratified into n = 500 former preterm (< 37 weeks' gestation and < 2500-g birthweight) and n = 500 former term (≥ 37 weeks' gestation and ≥ 2500-g birthweight) children with half in each group (n = 250) having xylitol exposure and the other half without gestational xylitol exposure (n = 250). Thus, there will be four strata of n = 250 making up the total of N = 1000 enrolled. This stratification based on gestational age at birth is necessary given that being born preterm is associated with adverse neurodevelopmental outcomes. Stratification helps to control for such confounding bias and will assess whether the effect of xylitol exposure on developmental outcomes differs in these two populations. Additionally, if the mother from the original PPaX trial is still alive and with the child, the mother will be invited to join the PDDaX trial for anthropometric assessments and an oral health assessment.

Participants that meet the inclusion criteria of the PDDaX study will be randomly selected from the PPaX database using a computer-generated algorithm. As this is a follow-up study to the parent PPaX trial, randomization of participants to exposure to the intervention (xylitol-containing chewing gum, or not) will be based upon the cluster randomized design of the PPaX trial and what treatment group the mother of the participant was assigned.

To be eligible for the PDDaX trial, children must have been born to formerly gravid participants enrolled in and completing the parent PPaX trial and be between 4 and 8 years of age. Additionally, participants in the PDDaX trial must be willing to undergo the neurodevelopmental assessments, travel to BCMCF for the neurodevelopmental assessments, undergo dental evaluations, and have their hearing and vision assessed. All children must have a parent or legal guardian consent to their participation in the PDDaX trial. Those who meet these inclusion criteria will be approached without regard to sex, race, ethnicity, parent's country of origin, or religious preferences. A child will be excluded from participating in the PDDaX trial if they were not born during the PPaX trial, the parents do not provide consent for enrollment, or the child is unwilling to participate in the neurodevelopmental, hearing, vision, and dental assessments.

Inclusion criteria

• Child born during the PPaX trial
• Enrollment age between 4-8 years old
• Parental or legal guardian consent obtained
• Willing to undergo 3 neurodevelopmental tests
• Willing to travel to BCMF for neurodevelopmental assessment
• Assent by the pediatric subject for participation in the study

Exclusion criteria

• Parent or legal guardian cognitively unable to provide consent
• Child unwilling to provide assent to participate in the study