Prevention of Developmental Delay and Xylitol (PDDaX) Study

The goals of this study are to: evaluate and validate the low-cost, transportable, easily-administered Malawi Developmental Assessment Tool (MDAT) for neurodevelopmental assessment of children aged 4-8 years old in Malawi, as compared to the gold-standard yet more cumbersome and costly Kaufman Assessment Battery for Children-II (KABC-II) among (1) n=500 formerly preterm children and (2) n=500 formerly term children.

Additionally, we will evaluate the effects of gestational xylitol exposure compared to a lack of gestational xylitol exposure on neurodevelopmental outcomes of children aged 4-8 years old in Malawi through the following four neurodevelopmental tests: (3) KABC-II (cognitive outcomes), (4) EF Touch (executive functions), (5) Strengths and Difficulties Questionnaire (social-emotional outcomes), and (6) MDAT (motor and cognitive outcomes).

The researchers will leverage subjects who completed the parent Prevention of Prematurity and Xylitol Trial, which enrolled 10069 pregnant individuals in Malawi and demonstrated a significant 24% reduction in incidence of preterm birth and low birthweight offspring in gravidae who chewed xylitol-containing chewing gum compared to those who did not. By ensuring that these offspring did not have higher rates of neurodevelopmental impairment, the study will promote promising multi-center international and domestic trial evaluating the impact of xylitol-containing chewing gum use and optimal dosage during pregnancy.

Study Overview

• Status: Recruiting
• Conditions: Neurodevelopmental Disorders; Prematurity
• Intervention / Treatment: Dietary supplement: Maternal Use of Xylitol Chewing Gum During Pregnancy; Dietary supplement: No Maternal Xylitol Chewing Gum Use During Pregnancy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Greg Valentine, MD; Phone Number: (206) 543-3200; Email: gcvalent@uw.edu

Study Locations

• Malawi
  • Lilongwe, Malawi
    • Recruiting
    • Baylor College of Medicine Children's Foundation-Malawi
    • Contact: Phoebe Nyasulu; Email: pnyasulu@baylor-malawi.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 8 years (Child)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Xylitol-exposed formerly term children; n=250 formerly term children born during the PPaX trial who were born to gravidae in the interventional arm (received xylitol chewing gum but had access to a dentist and received prenatal counseling)	Dietary supplement: Maternal Use of Xylitol Chewing Gum During Pregnancy; There are no current interventions within this follow-up study. However, the mothers enrolled in the parent PPaX trial received xylitol-containing chewing gum (1 gram per stick of gum and instructed to chew 1-2 sticks of gum twice daily for a total dose of 2-4 grams/day of xylitol throughout pregnancy starting pre-conception or at <20 weeks gestation).
Active Comparator: Non xylitol-exposed formerly term children; n=250 formerly term children born during the PPaX trial who were born to gravidae in the active comparator arm (no xylitol chewing gum but had access to a dentist and received prenatal counseling)	Dietary supplement: No Maternal Xylitol Chewing Gum Use During Pregnancy; There are no current interventions within this follow-up study. Children born to mothers who received access to a dentist and prenatal education (oral health, prevention of preterm birth) are in the active comparator group
Experimental: Xylitol-exposed formerly preterm children; n=250 formerly preterm children born during the PPaX trial who were born to gravidae in the interventional arm (received xylitol chewing gum but had access to a dentist and received prenatal counseling)	Dietary supplement: Maternal Use of Xylitol Chewing Gum During Pregnancy; There are no current interventions within this follow-up study. However, the mothers enrolled in the parent PPaX trial received xylitol-containing chewing gum (1 gram per stick of gum and instructed to chew 1-2 sticks of gum twice daily for a total dose of 2-4 grams/day of xylitol throughout pregnancy starting pre-conception or at <20 weeks gestation).
Active Comparator: Non xylitol-exposed formerly preterm children; n=250 formerly preterm children born during the PPaX trial who were born to gravidae in the active comparator arm (no xylitol chewing gum but had access to a dentist and received prenatal counseling)	Dietary supplement: No Maternal Xylitol Chewing Gum Use During Pregnancy; There are no current interventions within this follow-up study. Children born to mothers who received access to a dentist and prenatal education (oral health, prevention of preterm birth) are in the active comparator group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Validation of the MDAT in Former Preterm Children	compared to the KABC-II	1 month (1-2 clinic visits)
Validation of the MDAT in Former Term Children	compared to the KABC-II	1 month (1-2 clinic visits)
KABC-II mental processing index	In n=500 former term and n=500 former preterm children aged 4-8 years old with half of each being gestationally xylitol exposed vs not exposed	1 month (1-2 clinic visits)
EF Touch composite score	In n=500 former term and n=500 former preterm children aged 4-8 years old with half of each being gestationally xylitol exposed vs not exposed	1 month (1-2 clinic visits)
SDQ composite	In n=500 former term and n=500 former preterm children aged 4-8 years old with half of each being gestationally xylitol exposed vs not exposed	1 month (1-2 clinic visits)
MDAT composite neurodevelopmental outcome	In n=500 former term and n=500 former preterm children aged 4-8 years old with half of each being gestationally xylitol exposed vs not exposed	1 month (1-2 clinic visits)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of cognitive delay per specific KABC-II subdomain	sequential processing (working memory), simultaneous processing (visual processing), planning ability (fluid reasoning), and learning ability (long-term memory and retrieval)	1 month (1-2 clinic visits)
Incidence of executive function delay per specific EF Touch subdomains	processing speed ("Bubbles"), visual spatial working memory ability ("Farmer"), working memory ("Pick the Picture" and "Houses"), inhibitory motor control ("Pig", "Silly Sounds Game", and "Arrows"), and Flexible thinking ("Something's the Same")	1 month (1-2 clinic visits)
Incidence of social-emotional delay per specific SDQ subdomains	Emotional symptoms, conduct problems, hyperactivity/inattention, peer relationship problems, and prosocial behavior	1 month (1-2 clinic visits)
Incidence of neurodevelopmental delay as per MDAT subdomains	Gross motor, fine motor, social, and language	1 month (1-2 clinic visits)

Collaborators and Investigators

• Sponsor: University of Washington
• Investigators: Principal Investigator: Greg Valentine, MD, University of Washington

Publications and helpful links

General Publications

• Valentine GC, Collett B, Wallie S, Mhango J, Engmann C, Sullivan E, Seferovic M, Willoughby M, Shayo B, Walson JL, Milgrom P, Aagaard K, Juul SE. The Prevention of Developmental Delay and Xylitol (PDDaX) trial: study protocol of a nested cohort follow-up from the PPaX (Prevention of Prematurity and Xylitol) trial examining neurodevelopmental outcomes among offspring at 4-8 years of age in Malawi. Trials. 2025 Nov 14;26(1):506. doi: 10.1186/s13063-025-09204-y.

Study record dates

Study Major Dates

• Study Start (Actual): April 4, 2023
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: April 27, 2022
• First Submitted That Met QC Criteria: April 29, 2022
• First Posted (Actual): May 4, 2022

Study Record Updates

• Last Update Posted (Actual): August 19, 2026
• Last Update Submitted That Met QC Criteria: August 15, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Pregnancy; Oral Health; Prematurity; Xylitol
• Additional Relevant MeSH Terms: Urogenital Diseases; Mental Disorders; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Premature Birth; Neurodevelopmental Disorders
• Other Study ID Numbers: STUDY00015305

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No