Xylitol and the Prevention of Periodontal disease and Preterm Birth (XaPPP) Trial

Preterm birth (PTB) is the leading cause of under-5-year-old mortality and neurodevelopmental impairment worldwide and affects between 5-29% of pregnancies. Periodontal disease (PD), including either gingivitis or periodontitis, is a risk factor for PTB. Unfortunately, PTB and PD disproportionately occur in many low- and middle-income countries where access to physicians and dentists is limited. Using a novel inexpensive and non- invasive treatment approach, we recently completed a cluster-randomized trial in Malawi entitled the Prevention of Prematurity and Xylitol (PPaX) Trial in which we demonstrated that use of xylitol-containing chewing gum significantly reduced clinical metrics of maternal periodontal disease (p=0.03) and the occurrence of PTB (xylitol 12.6% vs control 16.5%, aRR 0.76, 95% CI 0.59-0.99). Xylitol is a naturally occurring sugar alcohol found in several chewing gum products and is a prebiotic, known to prevent the growth of periodontopathic bacteria and dampen the pro-inflammatory cascade. As infection and inflammation are risk factors for PTB, xylitol may be a novel, inexpensive innovation that improves maternal and offspring outcomes. While the results of the PPaX trial are promising, we propose to conduct a double-blinded, 3-arm, placebo- controlled trial to address the PPaX trial’s limitations and prove the results are reproducible. PPaX trial limitations included: (a) lack of blinding, (b) lack of placebo control, (c) lack of optimized xylitol dosing based on recent evidence that 5-10 grams of xylitol/day is best for oral health benefit, (d) and lack of individual randomization (PPaX was cluster randomized with only 8 clusters). These limitations inflate the risk of spurious findings. The proposed individually randomized trial will enroll n=6000 Malawian pregnant individuals at <20 weeks’ gestation. 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). The Specific Aims of the research are to determine whether optimized-dose xylitol vs placebo or PPaX-trial-dose xylitol vs placebo impacts: (1) the incidence of PTB or low birthweight offspring (co-primary outcomes), (2) clinical metrics of PD, and (3) adverse offspring outcomes including neonatal mortality, infant mortality and 12-month neurodevelopmental outcomes. We anticipate xylitol-containing chewing gum will prevent PTB and low birthweight offspring and improve overall maternal and offspring outcomes, with most benefit seen with the optimized xylitol daily dose. The findings from this work will definitively prove and confirm whether xylitol has such preventive benefit in a Malawian population, confirm an optimal daily dose, lead to definitive action in Malawi and lay the foundation for a future multi-country, multi-institution clinical trial confirming generalizable benefit worldwide. This trial has the potential to lead to a momentous breakthrough in medicine that could ultimately prevent death and/or disability for millions worldwide. Project Number: 3R01HD119029-01S1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Gregory Valentine | Institution: UNIVERSITY OF WASHINGTON, SEATTLE, WA | Award Amount: $243,610 | Activity Code: R01 | Study Section: Reproductive, Perinatal and Pediatric Health Study Section[RPPH] View on NIH RePORTER: https://reporter.nih.gov/project-details/3R01HD11902901S1