Preterm Birth, Low Birthweight Neonate, Periodontitis, Gingivitis, Developmental Delay
Conditions
Keywords
xylitol, preterm birth, prematurity, pregnancy, periodontitis, periodontal disease, chewing gum
Brief summary
The ground-breaking Prevention of Prematurity and Xylitol (PPaX) cluster randomized controlled clinical trial was conducted in Lilongwe, Malawi and enrolled approximately 10,069 pregnant individuals seeking to evaluate the impact of xylitol-containing chewing gum compared to no chewing gum on reducing the occurrence of maternal periodontal disease, preterm birth, and low birthweight offspring. The premise of this study centers upon the numerous publications supporting a strong association between maternal periodontal disease and preterm birth. Given that xylitol-containing chewing gum is considered a prebiotic and known to reduce cariogenic and periodontopathic bacteria, the study evaluated and discovered a statistically significant reduction in maternal periodontal disease, preterm birth, and low birthweight offspring among pregnant individuals who chewed xylitol-containing chewing gum. While PPaX demonstrated the efficacy of xylitol to reduce preterm birth (PTB), the study had important limitations: (a) PPaX was an unblinded cluster-randomized study with only 8 clusters, 4 with xylitol-containing chewing gum and 4 without any gum (not placebo-controlled); (b) PPaX used a suboptimal dose of 2 grams of xylitol daily which may have reduced the effectiveness of the intervention given that recent literature suggests 5-10 grams/day more effectively improve oral health; and (c) PPaX did not evaluate infant mortality nor early neurodevelopmental outcomes. Notably, reducing fetal exposure to periodontal disease (PD) as well as PTB may improve neurodevelopmental outcomes for offspring as both prematurity and fetal exposure to inflammation are well-documented risk factors for neurodevelopmental delay (NDD) and infant mortality. The investigators will conduct a double-blind, placebo-controlled, individually randomized clinical trial with 3 arms among Malawian pregnant individuals (n=6000) at \<20 weeks of pregnancy with the co-primary outcomes being the incidence of PTB and low birthweight offspring. The 3 study arms (n=2000 each) will be (a) an optimized dose of xylitol-containing chewing gum (6.4 grams/day), (b) the PPaX trial xylitol dose (2.1 grams/day), or (c) flavored sorbitol gum base (placebo control). This trial overcomes the PPaX trial's limitations and will definitively answer whether xylitol prevents PTB in Malawi. The investigators will additionally collect biospecimens from a random sampling of the participants for biobanking for later analysis of inflammatory and microbiome alterations that may occur with xylitol exposure compared with placebo. The investigators hypothesize that pregnant individuals who chew xylitol-containing chewing gum will have a significant reduction in periodontal disease metrics at 28-30 weeks' gestation (e.g. bleeding on probing) as well as offspring with improved neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development 4th edition and reduced risk of adverse pregnancy outcomes including preterm birth.
Interventions
Xylitol chewing gum (1 gram per pellet of gum). This is a dietary supplement, but clinicaltrials.gov requires us to identify it as a "drug" due to IND requirements.
OTHERSorbitol chewing gum
Sorbitol (non-xylitol) chewing gum. This is a dietary supplement, but clinicaltrials.gov requires us to identify it as a "drug" due to IND requirements.
Sponsors
University of Washington
Baylor College of Medicine
Baylor College of Medicine Children's Foundation Malawi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Intervention model description
Three-arm, Double-blind, placebo-controlled, individually randomized clinical trial
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
Inclusion criteria
* Able to provide informed consent. For those under 18 years of age, an approval will additionally be sought from the parent or guardian * Less than 20 weeks' gestation (by best obstetric estimate) * At least 20 natural teeth * Planning to deliver at one of the health facilities within the XaPPP trial * Receiving antenatal obstetric care at one of the 8 health districts * Willing to chew two pieces of gum thrice daily for 5 minutes after the morning, day and evening meals throughout pregnancy * Willing to attend all study visits * Willing to provide biospecimens (oral, vaginal, placental, breast milk) * Willing to undergo at least two dental exams including oral microbiota sampling at study enrolment \<20 weeks of pregnancy, 28-30 weeks of pregnancy, and 6-8 weeks after giving birth * Willing to have their child undergo follow up through at least 12 months after birth including neurodevelopmental examination(s) * Speaks Chichewa or English All patients who meet inclusion criteria will be approached without regard to sex, race, ethnicity, parents' country of origin, or religious preferences.
Exclusion criteria
* Those who upon screening and enrolment but dislike the taste of the gum and state they will not chew the gum throughout pregnancy * Gravidae with known or suspected non-viable pregnancy (including life threatening congenital anomalies such as cardiac, neurological or others) * Pregnant individual has a life-threatening diagnosis such as cancer requiring treatment during pregnancy * Pregnant women with a known or suspected morbidly adherent placenta (such as placenta accrete, increta and percreta) * Known allergy to xylitol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Preterm Birth | delivery | \<37 weeks gestation |
| Low birthweight offspring | at delivery | \<2500 gram birthweight of offspring |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neonatal mortality | first 28 days after delivery | Death of neonate between birth-28 days after birth |
| Infant Mortality | 1 year after birth | Death of neonate between birth and 1 year after birth |
| Neurodevelopmental Outcomes at 12 months | 1 year after birth | Bayley Scales of Infant and Toddler Development. Standardized score range from 0-200 with 100 being the median and 15 points being 1 standard deviation. Higher scores represent better outcomes. Domains of cognitive, motor, and language will be assessed. |
| Periodontitis | at 28-30 weeks of pregnancy at 6-8 weeks postpartum (in the enrolled pregnant individuals) | Periodontitis will be defined as (a) interdental clinical attachment level (CAL) detectable at ≥ 2 non-adjacent teeth, or (b) buccal or oral CAL ≥ 3 mm with pocketing ≥ 2 teeth but the observed CAL cannot be ascribed to non-periodontitis-related causes.116 The sites with periodontitis should have CAL ≥ 1 mm and probing depth ≥ 4 mm, along with the presence of bleeding on probing (BOP). |
| Gingivitis | at 28-30 weeks of pregnancy at 6-8 weeks postpartum (in the enrolled pregnant individuals) | Gingivitis will be defined as having ≥50% of the sites with bleeding on probing (BOP) in a full-mouth examination. By selecting ≥50% with BOP, we are seeking to capture significant differences in gingival inflammation consistent with our previous trials. |
Contacts
CONTACTGreg Valentine, MD MED FAAP
PRINCIPAL_INVESTIGATORGreg Valentine
University of Washington
Outcome results
None listed