A Phase 2/3 interventional study of Xylitol Chewing gum and Sorbitol chewing gum in Preterm Birth, Low Birthweight Neonate and Periodontitis, sponsored by University of Washington. Recruiting at 1 site in Malawi. Open to female participants. Per ClinicalTrials.gov, last updated 2026-09-10.
Sponsored by University of Washington · Phase 2/3, Interventional, and Prevention
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.
The hypothesis is that xylitol-containing chewing gum use compared to control (flavored gum base) during pregnancy, starting before 20 weeks' gestation, will lead to reduced risk of adverse pregnancy outcomes, namely preterm birth, as well as improved metrics of periodontal disease and improve neurodevelopmental outcomes of offspring at 2 years corrected gestational age, with most beneficial effect seen in those with 6.4 grams/day xylitol dose.
The study will utilize an individually randomized, placebo-controlled, double-blinded, phase II/III clinical trial with a 1:1:1 allocation ratio between xylitol-containing chewing gum (6.4 grams of xylitol/day), xylitol-containing chewing gum (2.1 grams of xylitol/day), and placebo (flavored gum base, sorbitol, 0 grams of xylitol/day).
Intervention (1st arm): Epic dental chewing gum (xylitol-containing chewing gum containing 1.06 grams xylitol/pellet). Participants will chew 6 Epic xylitol-containing chewing gum pellets each day (2 pellets three times daily in pre-made blister packs). Each participant will be instructed to chew 2 pieces of gum three times daily for 5 minutes each time starting at study entry (\<20 weeks' gestation) and continuing until delivery.
Intervention (2nd arm): Epic dental chewing gum (xylitol-containing chewing gum containing 1.06 grams xylitol/pellet). Participants will chew 2 Epic xylitol-containing chewing gum pellets and 4 placebo gum pellets per day, representing 2 pellets three times daily in pre-made blister packs. Each participant will be instructed to chew 2 pieces of gum three times daily for 5 minutes each time starting at study entry (\<20 weeks' gestation) and continuing until delivery.
Control: Flavored gum base (sorbitol) without xylitol, instructing the participants to chew 2 pieces of gum three times daily for 5 minutes each time, the same as the intervention, starting at study entry (\<20 weeks' gestation) and continuing until delivery. These pellets will be non-xylitol placebo pellets of gum that otherwise taste and look the same as the intervention.
All gum will be pre-packaged into blister packs with the proper mix of Epic xylitol-containing chewing gum and/or placebo pellets to ensure the proper daily dose is administered per group the participant is randomized.
All patients who meet inclusion criteria will be approached without regard to race, ethnicity, parents' country of origin, or religious preferences.
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This study's planned enrollment of 6,000 is above the median of 84 across 1,666 interventional studies indexed under Premature Birth.
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All patients who meet inclusion criteria will be approached without regard to sex, race, ethnicity, parents' country of origin, or religious preferences.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Sorbitol flavored chewing gum (0 grams of xylitol/day)
Other: Sorbitol chewing gum
Xylitol flavored chewing gum (2 grams of xylitol/day). The participants will receive 4 pellets of sorbitol (placebo) gum per day as well as 2 pellets of xylitol (intervention) gum per day in pre-packaged blister packs to ensure double-blinded study design.
Drug: Xylitol Chewing gum · Other: Sorbitol chewing gum
Xylitol flavored chewing gum (6 grams of xylitol/day)
Drug: Xylitol Chewing gum
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.
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.
Preterm Birth
\<37 weeks gestation
Time frame: delivery
Low birthweight offspring
\<2500 gram birthweight of offspring
Time frame: at delivery
Neonatal mortality
Death of neonate between birth-28 days after birth
Time frame: first 28 days after delivery
Infant Mortality
Death of neonate between birth and 1 year after birth
Time frame: 1 year after birth
Neurodevelopmental Outcomes at 12 months
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.
Time frame: 1 year after birth
Periodontitis
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).
Time frame: at 28-30 weeks of pregnancy at 6-8 weeks postpartum (in the enrolled pregnant individuals)
Gingivitis
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.
Time frame: at 28-30 weeks of pregnancy at 6-8 weeks postpartum (in the enrolled pregnant individuals)
Plan to share: Yes — De-identified data collected as part of the XaPPP trial will be preserved and shared as per NIH policy. Identifiers will not be shared to protect participant confidentiality. Biospecimens will not be shared unless data from the biospecimens has already been analyzed, which will be shared without identifiers.
Supporting information: Study protocol, Clinical study report
Time frame: The information will be available 1 year after the completion of the last participant's data is entered and the database is finalized.
Access criteria: cientific data will be findable and identifiable via DASH or through directly contacting the PI (Valentine) or associated XaPPP trial investigators. If other NIH-sponsored data archives are available and preferred by Access will be limited to registered users who submit proposed specific questions or analysis plans and sign a data use agreement. "Supervised" indicates that individual requests are reviewed to protect the intellectual property rights of the project investigative team by restricting external development of manuscripts using the study data that substantially overlap with those that are already in development by study investigators. We will form a publications committee, with investigator representatives from the Study Team at the University of Washington (Seattle, Washington, USA), Baylor College of Medicine Children's Foundation-Malawi (Lilongwe, Malawi), and Baylor College of Medicine (Houston, Texas, USA) to establish manuscript development and publication guidelines.
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