The purpose of this study is to understand if chewing xylitol-gum initiated before 20 weeks of pregnancy and continued until delivery affects the bacteria that are found in the oral and vaginal cavities, signs of inflammation within the gingiva of the oral cavity, the health of the tissues in the mouth (clinical parameters of periodontal disease) and placentae, and the bacteria in the mouth and gut of newborns among pregnant individuals in Malawi. In addition, we will evaluate the impact of xylitol-containing chewing gum use during pregnancy on the offsprings neurodevelopment at approximately 6- and 18-months corrected age.
After consenting to the study, pregnant participants who have a singleton gestation and are \<20 weeks' gestation will be randomised into either the intervention arm ( 6.36grams of daily xylitol; Epic dental gum, 1.06 grams Xylitol per piece of gum; chew two pieces for 5 minutes after meals, thrice a day) or the placebo control arm (Sorbitol Gum base; Epic sorbitol-containing gum, 0 grams/day of xylitol; chew two pieces for 5 minutes after meals, thrice a day) by randomly picking from a group of opaque, sealed envelopes containing group allocation. The participants will also undergo a dental assessment and sampling, and vaginal sampling at enrolment, 28- 30 weeks of pregnancy, at birth - 48 hours and 4-6 weeks after birth. In addition, placental and breastmilk specimens will be obtained at the time of delivery, and stored in a biobank for future analyses. The investigators will also obtain oral and meconium (and stool at 4-6 weeks) samples of their newborns at birth and 4-6 weeks after birth. Furthermore, at 6- and 18-months corrected age, the infants will undergo neurodevelopmental assessments using the the Hammersmith Infant Neurologic Exam (HINE), Developmental Assessment of Young Children 2nd Edition (DAY-C), and Malawi Development Assessment Tool (MDAT). The assessments will be done by two community health workers trained in these methods and will be compared to assessments by a paediatric neurologist.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
80
Two pieces of xylitol gum after meals, thrice a day.
Two pieces of sorbitol gum after meals, thrice a day.
Area 25 Health Center
Lilongwe, Malawi
Periodontal disease at 28-30 weeks of pregnancy
The investigators will create scaled periodontal disease score comprising of sum of scores for gingival bleeding (+1 if bleeding was present, per tooth), gingival pockets (+1 for pockets of 4-5 mm and +2 for 6 mm or deeper, per tooth), and loss of attachment (+1 for 4-5 mm loss, +2 for 6-8 mm, +3 for 9-11 mm, and +4 for 12 mm or more, per tooth with values recorded for index teeth) divided by the number of teeth present will be created for every dental visit. A score of \>0 will indicate presence of periodontal disease. The investigators will compare periodontal disease status at 28-30 weeks of pregnancy to that at enrolment.
Time frame: Enrolment and 28-30 weeks of pregnancy.
Periodontal disease at 6 weeks postpartum
The investigators will create scaled periodontal disease score comprising of sum of scores for gingival bleeding (+1 if bleeding was present, per tooth), gingival pockets (+1 for pockets of 4-5 mm and +2 for 6 mm or deeper, per tooth), and loss of attachment (+1 for 4-5 mm loss, +2 for 6-8 mm, +3 for 9-11 mm, and +4 for 12 mm or more, per tooth with values recorded for index teeth) divided by the number of teeth present will be created for every dental visit. A score of \>0 will indicate presence of periodontal disease. The investigators will compare periodontal disease status at 6 weeks postpartum to that at enrolment.
Time frame: Enrolment and 6 weeks postpartum
Alterations in the maternal oral microbiome communities
Using 16S rRNA sequencing to assess strain level changes in sub gingival plaque composition within and between those exposed to xylitol and placebo gum using exact amplicon sequence variants.
Time frame: Enrolment and at 28-30 weeks, delivery and 4-6 weeks after
Alterations in the maternal vaginal microbiome communities
Using 16S rRNA sequencing to assess strain level changes in the vaginal microbiome at the vaginal introitus and posterior fornix. The investigators will compare compositional differences between sites in relationship to treatment
Time frame: Enrolment and at 28-30 weeks, delivery and 4-6 weeks after
Inflammatory mediator changes in the maternal gingival crevicular fluid compared to changes in the placenta.
The investigators will assess changes in local oral inflammation associated with xylitol exposure or not by evaluating the gingival crevicular fluid using a 10-plex pro inflammatory cytokine panel.
Time frame: Enrolment and at 28-30 weeks, and at delivery
Alterations within the infants' oral microbiome communities
The investigators will us 16S rRNA sequencing to assess strain level changes within the oral swabs of the infants born during the MAX trial and assess changes in the composition within and between those exposed to xylitol and placebo gum.
Time frame: 4-6 weeks
Alterations within the infants' gut microbiome communities
The investigators will use 16S rRNA sequencing to assess strain level changes in the stool/meconium samples from the infants' gut microbiome and assess compositional changes within and between those exposed to xylitol and placebo gum.
Time frame: 4-6 weeks
To determine the impact of chewing xylitol-containing gum (6.4 grams/day) vs placebo gum in pregnancy on neurodevelopmental outcomes of offspring at 6 and 18 months
We will use the MDAT z-score as a primary outcome. Secondary outcomes include DAYC-2 raw score and HINE optimality scores and asymmetries. Relevant descriptive statistics, and non-parametric tests will be used in analysis.
Time frame: At 6- and 18- months of corrected age.
To determine whether the addition of the DAYC-2 and HINE to the MDAT at 6 months of age improves the predictive validity for any NDD (1 SD below normative score on any MDAT domain), identified on the MDAT, DAYC-2 and/or HINE at 18 months corrected age.
We will utilise logistic regression to establish a predictive model for addition of the DAYC-2 and HINE to MDAT for NDD at 18 months corrected age.
Time frame: 6- and 18-months of corrected age
(Exploratory) To assess the intra-class correlation between an intensively trained Community Health Workers (CHW) in administering the MDAT, DAYC-2, and HINE as compared to a gold-standard examiner (Malawi-based Pediatric Neurologist).
We will use standard measures including Cronbach's alpha coefficient to compare all assessments between CHW and the gold standard examiner and generate a Bland-Altman plot. We will use the results of this exploratory aim to inform a power calculation for a planned future large investigation to determine how many assessments are needed by two examiners to assess the reliability of CHW exams.
Time frame: 6- and 18-months corrected age.
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