Prevention of Developmental Delay and Xylitol (PDDaX) Study

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
Prevention of Developmental Delay and Xylitol (PDDaX) Study

Conditions
-----------------
Prematurity, Neurodevelopmental Disorders

Intervention / Treatment
-----------------
* Dietary Supplement: Maternal Use of Xylitol Chewing Gum During Pregnancy
* Dietary Supplement: No Maternal Xylitol Chewing Gum Use During Pregnancy


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 4 Years
Maximum Age: 8 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: We will enroll 1000 children aged 4-8 years of age. n=500 will be former term children and additional n=500 will be former preterm children. Half in each group (n=250) will be gestationally xylitol-exposed, and the other half (n=250) will not be xylitol-exposed.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Xylitol-exposed formerly term children<br>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<br>* 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).<br>|
| Active Comparator: Non xylitol-exposed formerly term children<br>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<br>* 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<br>|
| Experimental: Xylitol-exposed formerly preterm children<br>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<br>* 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).<br>|
| Active Comparator: Non xylitol-exposed formerly preterm children<br>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<br>* 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<br>|

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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pregnancy, Xylitol, Oral Health, Prematurity