Saving Lives at Birth: Primary Prevention of Periodontal Disease in Relation to Preterm Birth in Malawi (Prevention of Prematurity and Xylitol)
Phase: NA
Conditions: Preterm Birth, Periodontal Disease, Caries, Dental
Sponsor: Baylor College of Medicine

 
 
  
 
 
 
 
 
 
 
Prevention of Prematurity and Xylitol (PPaX) Trial 
 
ClinicalTrials.gov ID NCT02333227 
 
Last Update or Approval: 11/1/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals 
  
Protocol Number:    H-35933 
Status:                        Approved 
Initial Submit Date:  2/20/2015 
Approval Period:       11/1/2021 - 10/31/2026 
 
  
Section Aa:  Title & PI 
A1.  Main Title 
      PREVENTION OF PREMATURITY AND XYLITOL (PPAX) TRIAL 
 
 
A2.  Principal Investigator 
  
      Name:   
KJERSTI AAGAARD 
Phone:   
713-798-8467 
      Id:   
159224 
Fax:   
 
      Department:   OB-GYN: MATERNAL FETAL MEDICINE 
Email:    
aagaardt@bcm.tmc.edu 
      Center:   
 
Mail Stn:   BCM610 
 
 
A3.  Administrative Contact 
  
      Name: 
CYNTHIA DO SHOPE 
Phone:   
713-798-4192 
      Id:   
038910 
Fax:   
713-798-4216 
       
 
Email:    
cshope@bcm.tmc.edu 
       
 
Mail Stn:   BCM610 
 
 
A3a.  Financial Conflict of Interest 
Does any member of study personnel (Investigator (including investigator’s spouse and/or dependent children)) that are involved in 
the design, conduct, or reporting of the research have a Significant Financial Interest (SFI) that would reasonably appear to be 
affected by the research for which funding is sought and/or associated with an entity/business that would reasonably appear to be 
affected by the research? 
          No 
 
 
  
Section Ab:  General Information     
A4.  Co-Investigators 
  
      Name:   
JUDY LEVISON 
Phone:   
713-873-3537 
 
Id:   
131823 
Fax:   
 
 
Department:   OB-GYN: GYNECOLOGY 
Email:    
jlevison@bcm.tmc.edu 
 
Center:   
 
Mail Stn:   BCM610 
 
  
      Name:   
KATHLEEN ANTONY 
Phone:   
713-798-5505 
 
Id:   
163658 
Fax:   
713-798-6044 
 
Department:   OB-GYN: MATERNAL FETAL MEDICINE 
Email:    
antony@bcm.tmc.edu 
 
Center:   
 
Mail Stn:   BCM610 
 
  
      Name:   
GREGORY VALENTINE 
Phone:   
 
 
Id:   
230560 
Fax:   
 
 
Department:   OB-GYN: MATERNAL FETAL MEDICINE 
Email:    
230560@bcm.edu 
 
Center:   
 
Mail Stn:   BCM610 
 
 
A5.  Funding Source: 
      Organization:  THRASHER RESEARCH FUND 
 
 
A6a.  Institution(s) where work will be performed: 
      BCM: Baylor College of Medicine 
Baylor College of Medicine Children's Clinical Centers of Excellence Network 
 
 

A6b.  Research conducted outside of the United States: 
      
Country:  MALAWI 
Facility/Institution:  Baylor International Pediatrics AIDS Initiative (BIPAI) Malawi Center of Excellence 
Contact/Investigator:  Peter Kazembe 
Phone Number:   
 
If documentation of assurances has not been sent to the Office of Research, please explain: 
The process for IRB approval from Malawi has been granted and received and the approval has been attached in Section S. 
 
The qualifications of all the staff are included in the protocol itself and in the attached summary. The staff conducting research in 
Malawi is Dr. Peter Kazembe, BCM. In addition, the other people assisting will be the other faculty listed on the protocol. All other 
physicians, connections, and support staff within each country are described in the protocol and summary; many are Baylor 
College of Medicine faculty, and largely will not be conducting research as much as they will be assisting with country logistics. 
 
Although there is therapeutic intent, all subjects enrolled are in Malawi and thus Medicaid/Medicare does not apply. 
 
 
A7.  Research Category: 
       
 
 
A8. Therapeutic Intent 
Does this trial have therapeutic intent? 
      No 
 
 
  
A9. ClinicalTrials.gov Registration 
Does this protocol/trial require registration on ClinicalTrials.gov due to it: meeting the definition of an Applicable Clinical Trial, being 
required under the terms and conditions of an award, or being proposed to be published in ICMJE journals? 
      
No, this clinical is not a clinical trial, or does not meet the definition of an Applicable Clinical Trial, or does not need to be 
registered under the terms and conditions of an award, or is not a clinical trial with results intended to be reported in an journal 
belonging to the ICMJE. Registration is not required. 
 
 
  
Section B:  Exempt Request 
B.  Exempt From IRB Review 
      Not Applicable 
 
 
  
Section C:  Background Information 
      
The burden of perinatal morbidity and mortality related to preterm birth is astounding. In 2005, the WHO estimated that 9.6% or 
12.9 million births worldwide were born preterm at <37 weeks of gestation, and were accompanied by as a high as a 42% 
mortality rate (http://www.who.int/bulletin/volumes/88/1/08-062554). Despite regional advances and slight decreases in the U.S. 
preterm birth rate in the last two years, adverse birth outcomes related to the length of gestation (preterm birth and near-term 
birth) are recognized as one of the most significant disorders in maternal-child health at global scale. Worldwide, more than 20 
million infants are born each year with low birth weight, with more than 95% of these being delivered in developing nations (1, 2). 
Of the 4 million newborn deaths annually, nearly 1/3 (27%) are directly attributable to prematurity with another 36% secondary to 
opportunistic infections (sepsis, pneumonia, gastrointestinal) related to prematurity and low birth weight (1). 75% of the 4 million 
deaths occur within the first week of life, with the vast majority occurring in the first 48 hours (1, 2). In poor rural communities, 
infant mortality related to preterm and low birth rate birth exceeds that in urban communities, and is not solely attributed to limited 
access to secondary and tertiary care (1). Because the empiric recurrence risk of preterm birth approximates 40-50% (3), global 
primary prevention of preterm birth is essential (4). 
 
Identifiable causes of preterm birth are generally ascribed to one of three categories: 45-50% idiopathic, 30% in association with 
preterm premature rupture of the membranes, and 15-20% are iatrogenic or maternally indicated (5). However, multiple factors 
including modifiable behaviors (smoking), maternal periodontal disease, prior history of preterm birth, multiple gestations, 
race/ethnicity (African-American women have a higher risk than Caucasians), and foreshortened cervical length (where at <25 
weeks 2.0 cm is the 5th%, and 2.5 cm is the 10th%) have been postulated to influence the occurrence of preterm births (6-9). The 
combination of two or more factors can possibly synergistically or additively increase the risk for spontaneous preterm birth. For 
example, in addition to identifying polymorphisms rendering susceptibility of risk for the delivery of preterm and growth restricted 
births (10,11), we have previously demonstrated that maternal tobacco use in pregnancy meaningfully alters the placental 
epigenome and subsequent gene expression (12,13). Accurate determination of the relative and additive or synergistic 

contribution of underlying etiologies, such as periodontal disease and oral health with behavioral and socioeconomic factors are 
hampered by a fundamental lack of understanding of the process of parturition (5, 12-16). As such, the cause(s) of as great as 
80% of spontaneous preterm births remain classified as ¿unknown¿ (1-5). However, maternal oral health is emerging as a leading 
contributor to risk of spontaneous and infectious-related preterm birth on a global scale (7-9; 17-26). 
 
Pertaining to the soundness of the observations, 195 studies in the 16 years since Offenbacher¿s original observations (17) have 
been published (PubMed search, March, 2014) and the overwhelming majority demonstrate a link between poor maternal oral 
health and risk of preterm birth (example references 17-33). 
 
As noted, a relationship between maternal oral health and risk of preterm birth and low birth weight infants has long-been 
demonstrated (17, 18; 27-29) in both industrialized nations (17-19) and rural and developing regions (27-30). In initial data from 
two single-center clinical trials, periodontal treatment in gravidae with dental caries reduced the rate of preterm birth (31,32). 
However, more definitive analysis from three large, multicenter randomized controlled trials have failed to show a benefit to non-
surgical treatment for periodontitis (inflammation secondary to periodontal infection), specifically ¿scaling and root planing¿ (i.e., 
removal of dental plaque and calculus from the tooth enamel and root; 19, 20, 33). In sum, three observations persist: ¿ Peridontal 
disease in gravidae poses risk of preterm birth and delivery of a low birth weight infant globally; ¿ However, treating periodontal 
disease by scaling and root planing in gravidae who manifest such oral microbial inflammation poses no benefit to the prevention 
of preterm birth, but also no harm (i.e., it improved periodontal disease but did not decrease nor increase the risk of preterm 
delivery); ¿ It is unknown whether primary prevention of dental caries and periodontitis may show benefit (identified gap in our 
knowledge and justification for our proposed study). 
 
Periodontitis (defined as a destructive inflammation of the peridontium) has a prevalence of 30% or greater in women of child 
bearing age (8, 34). By definition, it involves microbial infiltration of the peridontium, which stimulates a chronic inflammatory 
response, recurrent bacteremia, and the production of cytokines and prostaglandins which trigger risk of preterm birth (17-34). It is 
the same production of prostaglandins (primarily PGE2 and reactive intermediates) which are felt to mediate the risk of preterm 
birth (2-9). 
 
In the last year, we and others have made breakthroughs towards understanding the link between maternal oral health and risk of 
preterm birth (35-45). A recent cross-sectional study of 195 patients (35) demonstrated Gram-positive and Gram-negative 
intracellular bacteria harbored in the basal plate (which comprises the tissue layer directly at and below the maternal-fetal 
interface). These were observed in nearly 1/3 of placental specimens, with a high prevalence among preterm deliveries <28 
weeks gestation but regardless of clinical or pathologic evidence of chorioamnionitis (35). Although current paradigms suggest 
that the majority of intrauterine infections which are associated with preterm birth originate in the lower genital tract and ascend 
into an otherwise ¿sterile¿ intrauterine environment (36), we have most recently demonstrated that the majority of taxa detected in 
the placenta with DNA-based technology are not found in the urogenital tract, but rather represent commensal species common to 
the oral cavity (37-42). Some of these oral microbes, such as Fusobacterium nucleatum (a Gram-negative oral anaerobe) may 
facilitate hematogenous transmission during placentation as a result of their ability to bind vascular endothelium and alter 
permeability, thereby functioning as an ¿enabler¿ for other common commensals, such as Escherichia coli (37; 42-45). The 
results of our study (37) indicate that the placenta harbors a low-abundance but metabolically rich microbiome. The placental 
microbiome is largely comprised of non-pathogenic commensal microbiota from the Firmicutes, Tenericutes, Proteobacteria, 
Bacteroidetes, and Fusobacteria phyla. In aggregate, the placental microbiome profiles were most akin (Bray-Curtis (B-C) 
dissimilarity <0.3) to the non-pregnant human oral microbiome. 16S-based OTU analyses revealed a strong and significant 
correlation of the placental microbiome with with risk of preterm birth <37 weeks (p=0.001;These latter findings further highlight 
the likely underlying biologic and molecular mechanisms linking maternal oral health to preterm birth which serves as additional 
rationale to our clinical trial as proposed herein. 
 
So if we know that there is biologic evidence linking maternal oral health to preterm birth, but treating active periodontal disease 
does not reduce these morbidities, is it possible that primarily preventing periodontitis (or lessening its severity) might prevent 
preterm birth? If so, what are the least expensive, practical, and efficacious preventative measures? Globally, many strategies 
related to prevention of dental caries have focused on reduction of dietary simple sugars. One class of substitutes is the polyols 
(i.e., sugar alcohols), the most common and efficacious of which include xylitols used in chewing gum such as Spry and ¿sugar 
free¿ gummy snacks. What makes the polyols attractive candidates for the prevention of oral disease (notably in a rural 
population) is based on these well-grounded observations (references 46-52): ¿ In rural communities, where running water, lack of 
toothpaste and toothbrushes, and inadequate dental care are realities of everyday life, distribution of polyol gum or gummy 
candies is an attractive alternative; Although research gaps exist on optimal dosing, meta-analyses and multiple prospective and 
randomized controlled trials demonstrate that xylitol containing chewing gum prevent periodontitis (level I evidence); ¿ While the 
mechanism of action by which the polyols reduce dental caries is uncertain, it is clear that they are efficacious. Hypothesized 
mechanisms include increasing salivary flow by masticiation, enhancing alkaline pH to minimize demineralization/promote 
remineralization of tooth enamel, and altering the oral microbiome via diminishing abundance of virulent species Streptococcus 
mutans; ¿ Xylitol chewing gum has been demonstrated by other investigators to (1) prevent otitis media (double blind, randomized 
controlled trial, and (2) maternal consumption prevents dental decay in children at 2 and 5 years of age, even when the children 
did not chew the gum (level I evidence). 
 
References: 1. United Nations Population Fund (UNFPA) 2009. Focus on 5: Women¿s Health and the MDGs. 2. Iams JD, et al. 
Interventions to reduce the morbidity and mortality of preterm birth. Lancet 2008; 371: 164-175. 3. Sather, M., Fajon, A. V., 
Zaentz, R., and Rubens, C. E. (2010) Global report on preterm birth and stillbirth (5 of 7): advocacy barriers and opportunities. 
BMC Pregnancy Childbirth 10 Suppl 1, S5.(2012) Practice bulletin no. 127: management of preterm labor. Obstet Gynecol 119, 
1308 4. Ganu RS, Ma J, Aagaard KM. (2012) The role of microbial communities in parturition: Is there evidence of association 

with preterm birth and perinatal morbidity and mortality? Am J Perintal. PMID 23161352. (2007) In Preterm Birth: Causes, 
Consequences, and Prevention (Behrman, R. E., and Butler, A. S., eds), Washington (DC) 5. Pararas, M. V., Skevaki, C. L., and 
Kafetzis, D. A. (2006) Preterm birth due to maternal infection: Causative pathogens and modes of prevention. Eur J Clin Microbiol 
Infect Dis 25, 562-569 6. Shub, A., Swain, J. R., and Newnham, J. P. (2006) Periodontal disease and adverse pregnancy 
outcomes. J Matern Fetal Neona 19, 521-528 7. Goldenberg, R. L., Culhane, J. F., Iams, J. D., and Romero, R. (2008) 
Epidemiology and causes of preterm birth. Lancet 371, 75-84 8. Aagaard-Tillery KM, Porter TF, Lane RH, Varner MW, 
Lacoursiere DY. (2008) In utero tobacco exposure is associated with modified effects of maternal factors on fetal growth. Am J 
Obstet Gynecol. 198(1):66 e1-6. 9. Aagaard-Tillery KM, Spong CY, Thom E, Sibai B, Wendel G, Jr., Wenstrom K, Samuels P, 
Simhan H, Sorokin Y, Miodovnik M, Meis P, O'Sullivan MJ, Conway D, Wapner RJ. (2010) Pharmacogenomics of maternal 
tobacco use: metabolic gene polymorphisms and risk of adverse pregnancy outcomes. Obstet Gynecol. 115(3):568-77. 10. Suter 
M, Abramovici A, Aagaard-Tillery KM. (2010) Genetic and epigenetic influences associated with intrauterine growth restriction due 
to in utero tobacco exposure. Pediatr Endocrinol Rev. 8(2):94-102. 11. Suter M, Abramovici A, Showalter L, Hu M, Shope CD, 
Varner M, Aagaard-Tillery KM. (2010) In utero tobacco exposure epigenetically modifies placental CYP1A1 expression. 
Metabolism. 59(10):1481-90. 12. Harris RA, Ben-Shachar S, Facchinetti R, Saade G, Van den Veyver IB and Aagaard-Tillery KM. 
(2011) Genome-wide array-based copy number profiling in placentas from unexplained stillbirth. Prenat Diagn. Jul 5. doi: 
10.1002/pd.2817. [Epub ahead of print] 13. Sbrana E, Suter MA, Abramovici A, Aagaard-Tillery KM. (2011) Maternal tobacco use 
is associated with increased markers of oxidative stress in the placenta. Am J Obstet Gynecol PMID 21803321. 14. Aagaard-
Tillery KM, Silver RM. (2006) Immunology of Normal Pregnancy. Sem Fetal Neo Med 11: 279-95. 15. Offenbacher S, Katz V, 
Fertik G, Collins J, Boyd D, Maynor G, McKaig R, Beck J. Periodontal infection as a possible risk factor for preterm low birth 
weight. J Periodontol. 1996; 67(10 Suppl):1103-13. 16. Offenbacher S, Beck JD, Jared HL, et al. Effects of periodontal therapy on 
rate of preterm delivery: A randomized controlled trial. Obstet Gynecol 2009; 114: 551-9. 17. Michalowicz BS, Hodges JS, 
DiAngelis AJ, et al. Treatment of periodontal disease and the risk of preterm birth. N Engl J Med 2006; 355: 1885-94. 18. Macones 
GA, Parry S, Nelson DB, et al. Treatment of localized periodontal disease in pregnancy does not reduce the occurrence of 
preterm birth: results from the Periodontal Infections and Prematurity Study (PIPS). Am J Obstet Gynecol. 2010 
Feb;202(2):147.e1-8. 19. Beck, S., Wojdyla, D., Say, L., Betran, A. P., Merialdi, M., Requejo, J. H., Rubens, C., Menon, R., and 
Van Look, P. F. (2010) The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull 
World Health Organ 88, 31-38 20. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J 
Med 2000; 342: 1500-1507. 21. Romero R, Schaudinn C, Kusanovic JP, et al. Detection of a microbial biofilm in intraamniotic 
infection. Am J Obstet Gynecol 2008; 198: 135.e1-5. 22. Fardini Y, Chung P, Dumm R, Joshi N, Han YW. Transmission of diverse 
oral bacteria to murine placenta: Evidence for the oral microbiome as a potential source of intrauterine infection. Infect Immun 
2010; 78: 1789-96. 23. Han YW, Shen T, Chung P, Buhimshi IA, Buhimshi CS. Uncultivated bacteria as etiologic agents of intra-
amniotic inflammation leading to preterm birth. J Clin Microbiol 2009; 47: 38-47. 24. Fardini Y, Wang X, Temoin S, et al. 
Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity. Mol Microbiol 2011; 
82: 1468-1480. 25. Goepfort AR, et al. Peridontal disease and upper gential tract inflammation in early spontaneous preterm birth. 
Obstet Gynecol 2004; 104: 777-783. 26. Davenport EX, et al. Maternal periodontal disease and preterm low birth weight. J Dent 
Res 2002; 81: 313-318. 27. Alhaj AA, et al. Epidemiology of preterm birth in Omdurman maternity hospital, Sudan. J Mat Fet Med 
2010; 23: 131-134. 28. Khader Y, et al. Maternal periodontal status and preterm low birth weight delivery. Arch Gynecol Obstet 
2009; 279: 165-169. 29. Jeffcoat MK, et al. Periodontal disease and preterm birth: Results of a pilot intervention study. J 
Peridontal 2003; 74: 1214-1218. 30. Lopez NJ, et al. Periodontal therapy may reduce preterm low birth weight with periodontal 
disease (RCT). J Peridontolol 2002; 73: 911-924. 31. Newnham JP, et al. Treatment of periodontal disease during pregnancy: A 
randomized controlled trial. Obstet Gynecol 2009; 114: 1239-1248. 32. Silk H, et al. Oral health in pregnancy. Am Fam Physician 
2008; 77: 1139-1144. 33. Stout MJ et al. Identification of intracellular bacteria in the basal plate of the human placenta in term and 
preterm gestations. Am J Obstet Gynecol. 208, 226.e1 (2013). 34. Romero R et al. Detection of a microbial biofilm in intraamniotic 
infection. Am J Obstet Gynecol. 198, 135.e1 (2008). 35. Aagaard KM et al. The placenta harbors a unique microbiome. Science 
TM, in press (2014). 36. Aagaard KM, et al. Metagenomic based approach to a comprehensive characterization of the vaginal 
microbiome signature in pregnancy. PLoS One 7:e36466 (2012). 37. The Human Microbiome Consortium. (2012) Structure, 
function and diversity of the human microbiome in an adult reference population. (Roles for Aagaard KM: Data Analysis Working 
Group; Body Site Expert; Wr 
 
 
  
Section D:  Purpose and Objectives 
      
Our overarching hypothesis is that comprehensive primary preterm birth prevention, inclusive of maternal oral health with xylitol 
chewing gum (the intervention), will reduce the rate of periodontal disease and caries, preterm birth prevalence, and neonatal 
mortality. We propose two aims to test our hypothesis: ¿ Aim 1 (primary outcome). Our primary aim will be to determine the 
impact of xylitol gum on the (1) rate of preterm birth <37 and <34 weeks gestation, (2) rate of <2000 gram infants, (3) rate of 
survival of <2000 gram infants to 30 days, and (4) composite neonatal morbidity of <2000 gram infants at 30 days of age. ¿ Aim 2 
(secondary outcome). Xylitol chewing gum has been demonstrated by other investigators to prevent otitis media (double blind, 
randomized controlled trial (RCT), and maternal consumption prevents dental decay in children up to 5 years of age, even when 
the children did not chew the gum (RCT). In Malawi, where running water and inadequate dental care are realities of everyday life, 
we will determine whether use of xylitol gum will decrease the prevalence of (1) periodontal disease, and (2) caries among 
gravidae. 
 
 
  
Section E:  Protocol Risks/Subjects 
E1.  Risk Category 

      Category 1: Research not involving greater than minimum risk. 
 
 
E2.  Subjects 
Gender: 
      Female 
 
 
Age: 
      Adult (18-64 yrs) 
 
 
Ethnicity: 
      All Ethnicities 
 
 
Primary Language: 
      Chichewe 
 
 
Groups to be recruited will include: 
      Both patients and healthy, non-patient, normals 
 
 
Which if any of the following vulnerable populations will be recruited as subjects? 
      Pregnant women, Women of child bearing potential 
 
 
Vulnerable populations require special protections.  How will you obtain informed consent, protect subject confidentiality, and prevent 
undue coercion? 
      Please see Section J. 
 
 
E3.  Pregnant woman/fetus 
Will pregnant women and/or fetuses (as described in 45 CFR 46 Subpart B) be enrolled in the research? 
      Yes 
 
 
E4.  Neonates 
Will neonates of uncertain viability or nonviable neonates (as described in 45 CFR 46 Subpart B) be enrolled in the research? 
      No 
 
 
E5.  Children 
Will children be enrolled in the research? 
      No 
 
 
  
Section F:  Design/Procedure 
F1.  Design 
Select one category that most adequately describes your research: 
      z.r) Randomized, Efficacy Study -- Surgical Techniques/Interventions 
 
 
Discuss the research design including but not limited to such issues as: probability of group assignment, potential for subject to be 
randomized to placebo group, use of control subjects, etc. 
      
This is a cluster randomized trial. We assessed 12 cluster sites for potential eligibility and excluded 4 sites (around Malawi) 
because they could not provide reliable delivery data. Of the 8 cluster sites chosen, 4 will be randomly allocated to oral health 
education and xylitol gum and 4 will be allocated to oral health education and no xylitol gum. The randomization will occur as 
follows: 1. The first site will be randomized, then computer matched by number of deliveries to the non-intervention site. 2. This 
process will be repeated in sequence until all 8 sites (4 matched sets) are allocated. 
 
 
Inclusion Criteria: 
      
The following represent our a priori decided upon inclusion criteria: (1) Enrollment at less than or equal to 20 weeks gestation by 
best obstetrical estimate; or (2) Enrollment post partum with an anticipated next pregnancy within 18 months; or (3) Enrollment 
preconception with an anticipated pregnancy within 18 months; and (4) Cognitively aware enough to participate in the study; (5) 
Greater than or equal to 18 years of age (in Malawi, constitutes a legal adult and capacity to consent for study); (6) Willing to 
participate in the study; (7) Willing to undergo at least two periodontal exams; (8) Willing to chew 1 piece of xylitol gum for 10 
minutes after the morning and evening meal (intervention sites); (9) Anticipating to remain within the region for 18 months. 
 
 
Exclusion Criteria: 
      (1) Greater than 20 weeks gestation by best obstetrical estimate; (2) Post partum and not anticipating another pregnancy within 18 
months; (3) Preconception and not anticipating another pregnancy within 18 months; (4) Not cognitively aware enough to 

participate in the study; (5) Not willing to undergo at least two periodontal exams; (6) Less than 18 years of age; (7) Not willing to 
chew 1 piece of xylitol gum for 10 minutes after the morning and evening meal (intervention sites); (8) Anticipating a move outside 
of the region within 18 months. 
 
 
F2.  Procedure 
      
1. Subjects will be recruited by study personnel for potential enrollment during their prenatal visits 2. If enrolled, subjects will be: A) 
giving medical history/information; B) undergoing a minimum of 2 periodontal exams; (Visit 1 and 2) C) participating in antenatal 
care; D) chewing xylitol gum (at intervention cluster sites) twice a day following meals; E) undergo delivery (Visit 3) Participants 
will also be asked to consent to collection of data and potential use of xylitol gum. As previously described, since this product is 
commercially available over the counter and for the indication of the prevention of dental disease, no IND is necessitated. 
 
Plans for study oversight are as follows: 1. Post-approval, this study will be monitored by the PI and co-PI at BCM in Houston by 
ensuring that data entry is up to date on a weekly basis. The PI and co-PI will also take regular trips to Malawi to ensure that all 
study related material is collected and stored according to plan and in compliance with confidentiality requirements. 2. Complaints 
about the study will be handled by local investigators in Malawi under the guidance of the PI and co-PI at Baylor. 3. Non-
compliance on the part of study staff will be address by the PI and co-PI. Study staff will be re-educated on study procedures and 
confidentiality requirements if indicated, and disciplinary action will be taken if appropriate. 4. Unanticipated Problems Involving 
Risk to Subjects or Others will be handled by local investigators with immediate notification of BCM PIs and co-PIs. Specifically, if 
there are unanticipated risks or adverse events, then a significant adverse event report will be filed with the Baylor Institutional 
Review Board and it will also be reported to the Malawi Ministry of Health for evaluation. 
 
 
  
Section G:  Sample Size/Data Analysis 
G1.  Sample Size 
How many subjects (or specimens, or charts) will be used in this study? 
      Local: 10360              Worldwide: 10360 
 
 
Please indicate why you chose the sample size proposed: 
      
Successful engagement in meaningful global research, and notably a randomized trial, necessitates tremendous up-front leg work 
and demonstration of feasibility. We have invested three years in preparation for the proposed PPaX trial and are confident in 
having now parsed down the necessary components suggesting that we can execute the proposed trial on budget and on time, 
that we should execute the proposed study testing xylitol gum as an intervention, and that it will take a cluster randomization 
design enrolling a total sample size of 9360 subjects at 8 proposed sites to demonstrate effect size. 
 
We have estimated that a total sample size of 9360 subjects will be sufficient to demonstrate a 33% reduction in the primary 
outcomes of (1) preterm birth <37 and <34 weeks, and (2) associated neonatal morbidity and mortality based upon our prior work 
in Malawi. In our study design (where the health center serves as the unit of randomization), we have accounted for a 30% loss to 
follow up and calculated our per site enrollment to necessitate 1170 subjects at each of 8 sites. 
 
 
G2.  Data Analysis 
Provide a description of your plan for data analysis. State the types of comparisons you plan (e.g. comparison of means, comparison 
of proportions, regressions, analysis of variance). Which is the PRIMARY comparison/analysis? How will the analyses proposed 
relate to the primary purposes of your study? 
      
Intercluster (between cluster) analysis will include univariate and multivariate analyses analyzing the number of clusters, average 
cluster size, range of cluster size, rate of preterm birth, rate of neonatal complications, rate of periodontal disease, rate of maternal 
comorbidities, range and variance of each measure; analysis by intention to treat and by multivariate measures with GEE. 
Intracluster (per subject, by cluster) analysis will include univariate and multivariate analyses analyzing the number of subjects, 
average gestational age, rate of preterm birth, rate of neonatal complications, rate of periodontal disease, rate of maternal 
comorbidities, range and variance of each measure; analysis by intention to treat and by multivariate measures with GEE. 
 
 
  
Section H:  Potential Risks/Discomforts 
H1.  Potential Risks/Discomforts 
Describe and assess any potential risks/discomforts; (physical, psychological, social, legal, or other) and assess the likelihood and 
seriousness of such risks: 
      
The potential risks to participants in this study are minor and include the physical risks associated with some of the sample and 
data collection, risk of psychological distress, and risks to privacy. a.Physical Risks: Intervention: there are no known significant 
risks to chewing gum b.Psychological Risks: There is no recognized potential risk of psychological distress to the study 
participants as a result of reflecting on their diagnosis and health history. c.Privacy Risks: There is a small, potential risk of loss of 
confidentiality. Stringent methods described below will be employed to protect against this risk such that this risk is unlikely. 
 
 
H2.  Data and safety monitoring plan 

     Do the study activities impart greater than minimal risk to subjects? 
          No 
 
 
H3.  Coordination of information among sites for multi-site research 
Is the BCM Principal Investigator acting as the SPONSOR-INVESTIGATOR for this multi-site research? 
          Yes 
 
 
Is BCM the COORDINATING CENTER for this multi-site research? 
          Yes 
 
 
If the answer to EITHER of the questions above is "Yes", please complete the following questions: 
       
 
 
If this is a multicenter study and the BCM PI is an INVESTIGATOR with responsibilities of SPONSOR or if BCM is the 
COORDINATING CENTER, describe the management of information among the sites related to participant protections. Your 
description should include reporting of unanticipated problems, protocol modifications, IRB and/or institutional approvals, and interim 
results among the sites. 
      
We will follow rigorous procedures to ensure the accuracy, quality, and confidentiality of study data. These procedures include 
staff training and retraining, close supervision, a Manual of Procedures, and quality control reviews. 
 
Dr. Alan Harris is a PhD trained bioinformatician with a background in anthropology. He has worked in Dr. Aagaard¿s laboratory 
since 2008, and designed and implemented the on-line database utilized in the seed grant. He will continue to execute the 
database and assure quality data with inset custom QA QC measures. He will additionally coordinate the database entry and 
personnel, and complete the biostatistical analyses on rolling data. 
 
 
When research is conducted in collaboration with outside entities or organizations, the PI must obtain the necessary approvals from 
those entities. The BCM IRB may request documentation that such approvals have been obtained. Please list and describe the 
planned sites for this multi-site research for which the BCM PI is either Sponsor-Investigator and/or Coordinating Center. Sites that 
do not meet the requirements for inclusion in section A6a of the protocol summary and BCM informed consent documents should be 
listed here. 
      Letters of support from Malwai, stating that the Ministry of Health supports the project, are attached. The IRB Approval Letter from 
the Ministry of Health is also attached. 
 
 
  
Section I:  Potential Benefits 
Describe potential benefit(s) to be gained by the individual subject as a result of participating in the planned work. 
      Potential benefits may include a reduction in preterm birth and an improvement in oral health. 
 
 
Describe potential benefit(s) to society of the planned work. 
      If comprehensive oral healthcare and chewing xylitol gum indeed reduces the risk of preterm birth, society would benefit from this 
knowledge. 
 
 
Do anticipated benefits outweigh potential risks? Discuss the risk-to-benefit ratio. 
      The benefits to the participants and to society outweigh the minimal risks of this project. 
 
 
  
Section J:  Consent Procedures 
J1.  Waiver of Consent 
Will any portion of this research require a waiver of consent and authorization? 
      No 
 
 
  
J1a.  Waiver of requirement for written documentation of Consent 
Will this research require a waiver of the requirement for written documentation of informed consent? 
      No 
 
 
J2.  Consent Procedures 
Who will recruit subjects for this study? 
      PI 
PI's staff 
 
 

Describe how research population will be identified, recruitment procedures, any waiting period between informing the prospective 
participant and obtaining consent, steps taken to minimize the possibility of coercion or undue influence and consent procedures in 
detail. 
      
The research population will be drawn from eight clinical sites, all in the greater Lilongwe region of Malawi (a 54 km urban-rural 
region surrounding Lilongwe). Through BIPAI, TCH and BCM have had a continual presence in this region since 2007 and we 
have been partnered in this region for obstetrical care since 2011. 
 
Women will be recruited in one of two settings: when they present for prenatal care/ at the time of antenatal booking at less than 
20 weeks, or postpartum (on the postpartum ward) or preconception with a desire to have another pregnancy in less than 18 
months. Women will be approached by trained and experienced community health workers. 
 
 
Are foreign language consent forms required for this protocol? 
      Yes 
 
 
Which of the following ways will you document informed consent in languages other than English? 
      A full-length informed consent document 
 
 
J3.  Privacy and Intrusiveness 
Will the research involve observation or intrusion in situations where the subjects would normally have an expectation of privacy? 
      No 
 
 
J4.  Children 
Will children be enrolled in the research? 
      No 
 
 
J5.  Neonates 
Will non-viable neonates or neonates of uncertain viability be involved in research? 
      No 
 
 
J6.  Consent Capacity - Adults who lack capacity 
Will Adult subjects who lack the capacity to give informed consent be enrolled in the research? 
      No 
 
 
J7.  Prisoners 
Will Prisoners be enrolled in the research? 
      No 
 
 
  
Section K:  Research Related Health Information and Confidentiality 
Will research data include identifiable subject information? 
      Yes 
 
 
Information from health records such as diagnoses, progress notes, medications, lab or radiology findings, etc. 
      Yes 
 
 
Specific information concerning alcohol abuse: 
      No 
 
 
Specific information concerning drug abuse: 
      No 
 
 
Specific information concerning sickle cell anemia: 
      No 
 
 
Specific information concerning HIV: 
      Yes 
 
 
Specific information concerning psychiatry notes: 
      No 
 
 
Demographic information (name, D.O.B., age, gender, race, etc.): 
      Yes 
 
 

Full Social Security #: 
      No 
 
 
Partial Social Security # (Last four digits): 
      No 
 
 
Billing or financial records: 
      No 
 
 
Photographs, videotapes, and/or audiotapes of you: 
      No 
 
 
Identifiable biospecimens 
      No 
 
 
Other: 
      No 
 
 
At what institution will the physical research data be kept? 
      The physical data is maintained at one of two locations. It is either held securely at the BIPAI Baylor Center of Excellence in 
Lilongwe, Malawi or in the laboratory of Dr. Aagaard at Baylor College of Medicine, Houston Texas (at study completion). 
 
 
How will such physical research data be secured? 
      
As described in our protocol, data will be under secure storage and locked in the secured records room at the BIPAI Baylor COE 
or in the laboratory of Dr. Aagaard. The enrollment logs are kept separate from the data to reduce risk of identifying information 
being with deidentified (subject codes). 
 
 
At what institution will the electronic research data be kept? 
      Baylor College of Medicine. Data is uploaded in a completely deidentified manner on a secure server and maintained at Baylor 
College of Medicine. 
 
 
Such electronic research data will be secured via BCM IT Services- provided secured network storage of electronic research data 
(Non-Portable devices only): 
      Yes 
 
 
Such electronic research data will be secured via Other: 
      No 
 
 
Will there be anyone besides the PI, the study staff, the IRB and the sponsor, who will have access to identifiable research data? 
      No 
 
 
Please describe the methods of transmission of any research data (including PHI, sensitive, and non-sensitive data) to sponsors 
and/or collaborators. 
      If sent to collaborators, it is only sent with SSL encryption. 
 
 
  
Will you obtain a Certificate of Confidentiality for this study? 
      No 
 
 
Please further discuss any potential confidentiality issues related to this study. 
      There are no further potential confidentiality issues. 
 
 
  
Section L:  Cost/Payment 
Delineate clinical procedures from research procedures. Will subject's insurance (or subject) be responsible for research related 
costs? If so state for which items subject's insurance (or subject) will be responsible (surgery, device, drugs, etc). If appropriate, 
discuss the availability of financial counseling. 
      Subjects will not be charged to participate. There are no ensuant costs to the research. Costs of the xylitol gum are covered by the 
Thrasher Research Fund and will not be incurred to the subjects. 
 
 
If subjects will be paid (money, gift certificates, coupons, etc.) to participate in this research project, please note the total dollar 
amount (or dollar value amount) and distribution plan (one payment, pro-rated payment, paid upon completion, etc) of the payment. 
 
Dollar Amount: 
      0 
 
 

Distribution Plan: 
      Subjects will not be paid to participate in this research project. 
 
 
  
Section M:  Genetics 
How would you classify your genetic study? 
       
 
 
Discuss the potential for psychological, social, and/or physical harm subsequent to participation in this research. Please discuss, 
considering the following areas: risks to privacy, confidentiality, insurability, employability, immigration status, paternity status, 
educational opportunities, or social stigma. 
       
 
 
Will subjects be offered any type of genetic education or counseling, and if so, who will provide the education or counseling and 
under what conditions will it be provided? If there is the possibility that a family's pedigree will be presented or published, please 
describe how you will protect family member's confidentiality? 
       
 
 
  
Section N:  Sample Collection 
None 
 
  
Section O:  Drug Studies 
Does the research involve the use of ANY drug* or biologic? (*A drug is defined as any substance that is used to elicit a 
pharmacologic or physiologic response whether it is for treatment or diagnostic purposes) 
      No 
 
 
Does the research involve the use of ANY gene transfer agent for human gene transfer research? 
      No 
 
 
O1.  Current Drugs 
  
Is this study placebo-controlled? 
      No 
 
 
Will the research involve a radioactive drug? 
      No 
 
 
  
Section P:  Device Studies 
     Does this research study involve the use of ANY device? 
          No 
 
 
  
Section Q:  Consent Form(s) 
PPaX Trial (Prevention of Prematurity and Xylitol) ENGLISH CONSENT 
 
  
Section R:  Advertisements 
None 
 
 
 
 

 
CONSENT FORM 
PPaX Trial (Prevention of Prematurity and Xylitol) ENGLISH CONSENT
Institutional Review Board for Baylor College of Medicine and Affiliated Hospitals
HIPAA Compliant
H-35933-  PREVENTION OF PREMATURITY AND XYLITOL (PPAX) TRIAL
Concise and Focused Presentation
You are invited to take part in a research study. Please read this information and feel free to ask any 
questions before you agree to take part in the study. You have the option not to participate in this study. 
Whether you participate or not, the care you and your baby receive will not change.
This is a study that is looking at the causes of preterm birth, which is when a baby is born too early. In 
Malawi, the preterm birth rate is high; it happens in more than 1 of 4 births. When a baby is born too 
early, it has a higher risk of dying. If it does survive, such babies have problems that can persist the rest 
of their life, like problems with their lungs (breathing) or problems with their intestines. One thing that 
increases the risk of a woman delivering a baby too early is having periodontal disease, which is 
inflammation and disease of the teeth and tooth-gums in the mouth. Some examples of mouth diseases 
include cavities or teeth-gum inflammation. It is thought that diseases in the mouth may cause preterm 
birth. 
In this study, some pregnancy care clinics will be giving a chewing gum with another version of a sugar, 
called xylitol. If you participate in this study, whether or not you receive the chewing gum depends on 
which community health center in Lilongwe that you receive your care at. We don't know if it will be 
helpful or not to receive the chewing gum for lowering your chance that your baby is born too soo. 
Therefore, half the health center sites will hand out the gum to enrolled women and half the health center 
sites will not. If you do not receive the xylitol chewing gum at your site, please do not be worried that we 
are not giving you something that is known to be helpful in preventing preterm birth. Instead, please 
understand that the reason we are doing this study is to learn if or if not the xylitol chewing gum will be 
helpful.
There are no concerning health risks if you choose to participate in this trial. Chewing xylitol gum is not 
dangerous. There are also no known benefits to participating in this trial, since we encourage all 
pregnant women to receive good oral health care in pregnancy.
Background
You are invited to take part in a research study. Please read this information and feel free to ask any 
questions before you agree to take part in the study.
This is a study that is looking at the causes of preterm birth, which is when a baby is born too early. In 
Malawi, the preterm birth rate is high; it happens in more than 1 of 4 births. When a baby is born too 
early, it has a higher risk of dying. If it does survive, such babies have problems that can persist the rest 
of their life, like problems with their lungs (breathing) or problems with their intestines. 
One thing that increases the risk of a woman delivering a baby too early is having periodontal disease, 
which is disease in the mouth. Some examples of mouth diseases include cavities or infections. It is 
thought that diseases in the mouth may cause preterm birth.
This research study is funded by Thrasher Research Foundation
Approved  from November 01, 2021  to October 31, 2026        Chair Initials: J. K.
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Last Amendment:
4/8/2019