A cluster randomized trial of xylitol chewing gum for prevention of preterm birth: The PPaX trial

Gregory C Valentine; Kathleen M Antony; Haleh Sangi-Haghpeykar; Alexis C Wood; Rose Chirwa; Saukani Petro; Mary Dumba; Deborah Nanthuru; Cynthia Shope; Jesse Mlotha-Namarika; Jeffrey Wilkinson; Joshua Aagaard; Ellen J Aagaard; Maxim D Seferovic; Judy Levison; Peter Kazembe; Kjersti M Aagaard

doi:10.1016/j.medj.2024.10.016

A cluster randomized trial of xylitol chewing gum for prevention of preterm birth: The PPaX trial

Med. 2024 Nov 12:S2666-6340(24)00414-8. doi: 10.1016/j.medj.2024.10.016. Online ahead of print.

Authors

Gregory C Valentine¹, Kathleen M Antony², Haleh Sangi-Haghpeykar³, Alexis C Wood⁴, Rose Chirwa⁵, Saukani Petro⁵, Mary Dumba⁵, Deborah Nanthuru⁵, Cynthia Shope³, Jesse Mlotha-Namarika⁶, Jeffrey Wilkinson⁷, Joshua Aagaard⁸, Ellen J Aagaard⁹, Maxim D Seferovic³, Judy Levison¹⁰, Peter Kazembe¹¹, Kjersti M Aagaard¹²

Affiliations

¹ Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Baylor Foundation Malawi, Lilongwe, Malawi; Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address: gcvalent@uw.edu.
² Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Baylor Foundation Malawi, Lilongwe, Malawi; Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Wisconsin-Madison, 202 South Park Street, Madison, WI 53715, USA.
³ Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
⁴ Department of Pediatrics and the USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
⁵ Baylor Foundation Malawi, Lilongwe, Malawi.
⁶ Dental Department, Kamuzu Central Hospital, Lilongwe, Malawi.
⁷ Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Kamuzu Central Hospital, Lilongwe, Malawi.
⁸ St. Olaf College, Northfield, MN, USA.
⁹ Baylor University, Waco, TX, USA.
¹⁰ Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Baylor Foundation Malawi, Lilongwe, Malawi.
¹¹ It is with the deepest appreciation and profound sadness that we award posthumous authorship to Dr. Peter Kazembe for his invaluable role in the concept, execution, and conduct of the PPaX trial. Dr. Kazembe was, quite simply, one of the world's finest clinician scientists, and his passionate advocacy for women's and children's health in Malawi remains unparalleled.
¹² Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Department of Pediatrics and the USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA; Baylor Foundation Malawi, Lilongwe, Malawi; Department of Obstetrics and Gynecology, Kamuzu Central Hospital, Lilongwe, Malawi; St. Olaf College, Northfield, MN, USA; HCA Healthcare and HCA Healthcare Research Institute and HCA Healthcare Texas Maternal Fetal Medicine, Nashville, TN, Houston, TX, USA; Division of Fetal Medicine and Surgery, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Cambridge, MA, USA. Electronic address: kjersti.aagaard@hcahealthcare.com.

PMID: 39541971
DOI: 10.1016/j.medj.2024.10.016

Abstract

Background: Maternal periodontal disease is associated with preterm and low-birthweight deliveries, but randomized trials of likely efficacious treatments (e.g., dental scaling and root planing) during pregnancy have not reduced these adverse outcomes. As an alternative, we hypothesized that periconception initiation of xylitol chewing gum would reduce the occurrence of preterm or low-birthweight deliveries among a historical high-prevalence population in Malawi.

Methods: We conducted an open-label, parallel-enrollment, matched-pair, cluster-randomized, controlled clinical trial across eight health centers (sites) in and around Lilongwe, Malawi. Sites were paired by anticipated delivery volume and randomized to prenatal and oral health education alone (active control) or with twice-daily xylitol chewing gum (intervention) throughout the periconception and antenatal periods. For the primary prevention of preterm (<37 weeks) and low-birthweight (<2,500 g) deliveries (co-primary outcomes), comparison by allocation group was performed using generalized linear mixed models for each outcome as a fixed factor and the site(s) as a random factor.

Findings: 10,069 participants were enrolled (n = 4,549 at intervention sites, n = 5,520 at active control sites), with >95% available for analyses. Initiation of xylitol chewing gum resulted in significant reductions in the co-primary outcomes: preterm birth (12.6% [549/4,349] vs. 16.5% [878/5,321]; relative risk [RR] 0.76, 95% confidence interval [CI] 0.57-0.99) and <2,500-g neonates (8.9% [385/4,305] vs. 12.9% [679/5,260]; RR 0.70, 95% CI 0.49-0.99). Xylitol chewing gum use also led to fewer neonatal demises (0.2% [8/4,305] vs. 0.4% [22/5,260]; RR 0.41, 95% CI 0.19-0.89).

Conclusions: Periconception initiation and ongoing use of xylitol chewing gum significantly reduced the occurrence of preterm and low-birthweight deliveries in Malawi.

Funding: E.W. Al Thrasher Foundation (to K.A.) and USAID Saving Lives at Birth Grand Challenges Grant AID-OAA-G-11-00062 (to K.A.). Additional financial and in-kind support was graciously provided by Texas Children's Hospital and Baylor Foundation Malawi.

Keywords: Translation to population health; low birthweight; oral health; periodontal disease; prebiotics; pregnancy; preterm birth; prevention of preterm birth; xylitol.