Caries, Dental, Periodontal Disease, Preterm Birth
Conditions
Brief summary
The hypothesis of the investigators' project 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.
Detailed description
Significance and Impact: Adverse birth outcomes related to the length of gestation (preterm birth) are recognized as one of the most significant disorders in maternal-child health at a global scale. In the developed world, the preterm birth rate approximates 7%. In Malawi, the investigators have recently demonstrated that this rate more than triples to approximate 26.1%. Of the 4 million newborn deaths annually, nearly 1/3 (27%) are directly attributable to prematurity with another 36% secondary to related opportunistic infections (sepsis, pneumonia, gastrointestinal). 75% of the 4 million deaths occur within the first week of life, with the vast majority occurring in the first 48 hours. For those that do survive, there are persistent and lifelong risks due to stunted growth, chronic infection, retinopathy of prematurity, and bronchopulmonary dysplasia. The link between maternal oral health (periodontal disease in particular) and risk of preterm birth has been demonstrated across all populations (rural and urban, in both industrialized and developing regions) studied to date. However, in multiple randomized controlled trials treatment of active periodontal disease with scaling and planning during pregnancy has failed to demonstrate a significant benefit in preventing preterm birth. Why would maternal oral health impact preterm birth? In rodents, subcutaneous inoculations with periodontal pathogens cause dose-dependent decreases in pup weights, and elicit inflammatory responses that can trigger preterm birth when present in amniotic fluid. Periodontitis (defined as a destructive inflammation of the periodontium) has a prevalence of 30% or greater in women of child bearing age. By definition, it involves microbial infiltration of the periodontium, which stimulates a chronic inflammatory response, recurrent bacteremia, and the production of cytokines and prostaglandins which trigger risk of preterm birth. It is the same production of prostaglandins which are felt to mediate the risk of preterm birth. So if the investigators know that there is biologic evidence that periodontitis is related to preterm birth, but treating active periodontitis does not reduce these morbidities, is it possible that preventing periodontitis might prevent preterm birth and low birth weight? If so, what are the least expensive efficacious preventative measures? The investigators' 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.
Interventions
DIETARY_SUPPLEMENTXylitol gum
This is a cluster randomized trial, whereby 4 sites will receive the intervention of xylitol gum in the prepregnancy and early pregnancy interval.
Sponsors
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 64 Years
Healthy volunteers
Yes
Inclusion criteria
1. Enrollment at \<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 (preconception); and 4. Cognitively aware enough to participate in the study 5. \>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. \>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. \<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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Preterm Birth | Conception to date of delivery, <37 weeks gestation | This is a co-primary outcome: Measure rate of preterm birth \<37 weeks gestation, as defined by best obstetrical estimate based upon last menstrual period correlated with fundal height at entry to prenatal care or ultrasound, when available; all sites have access to referral for ultrasound. |
| Number of Infants <2500 Grams | Date of delivery to 1 week postnatal | This is a co-primary outcome: Measured weight at delivery to determine the rate of \<2500 gram infants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Infants With Adverse Neonatal Composite Morbidity and Mortality | Date of delivery to 28 days postnatal | Additive or singular composite neonatal morbidity up to 28 days of age. Composite neonatal morbidity and mortality outcomes are defined as: neonatal death, miscarriage \<28 weeks, stillbirth (fresh or macerated), neonatal sepsis, neonatal respiratory distress, neonatal seizures, feeding problems, fever, hypothermia, Apgar score \<7 at 5 minutes after birth, referral to other hospital or neonatal intensive care unit (NICU) |
| Number of Participants With Periodontal Disease | During pregnancy, up to 2 dental visits performed during pregnancy (approximately 37-40 weeks if term) to evaluate dental outcomes | We will measure the prevalence of periodontal disease among gravidae. We will use standardized World Health Organization (WHO) oral health forms and disease scoring. |
| Number of Participants With Dental Caries | During pregnancy, up to 2 dental visits performed during pregnancy (approximately 37-40 weeks if term) to evaluate dental outcomes | We will measure the prevalence of dental caries among gravidae. We will use standardized World Health Organization (WHO) oral health forms and disease scoring. |
Countries
United States
Participant flow
Recruitment details
Recruitment through outpatient prenatal clinics
Pre-assignment details
All patients who were eligible and consented for the study were enrolled and designated into either a control or intervention group based on this cluster-randomized design and the site of enrollment where the participant initially presented.
Participants by arm
| Arm | Count |
|---|---|
| Control Cluster of sites not receiving xylitol gum. This is a cluster randomized trial, whereby 4 sites will not receive the intervention of xylitol gum in the prepregnancy and early pregnancy interval. | 5,520 |
| Xylitol Cluster of sites receiving xylitol gum.
Xylitol gum: This is a cluster randomized trial, whereby 4 sites will receive the intervention of xylitol gum in the prepregnancy and early pregnancy interval. | 4,549 |
| Total | 10,069 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Enrolled prepregnant without neonatal outcome data available | 20 | 5 |
| Overall Study | Lost to Follow-up | 137 | 106 |
| Overall Study | Pregnancy Interrupted | 42 | 89 |
Baseline characteristics
| Characteristic | Control | Xylitol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5520 Participants | 4549 Participants | 10069 Participants |
| Race/Ethnicity, Customized African, black | 5520 Participants | 4549 Participants | 10069 Participants |
| Region of Enrollment Malawi | 5520 participants | 4549 participants | 10069 participants |
| Sex: Female, Male Female | 5520 Participants | 4549 Participants | 10069 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 5,520 | 0 / 4,549 |
| other Total, other adverse events | 0 / 5,520 | 0 / 4,549 |
| serious Total, serious adverse events | 2 / 5,520 | 0 / 4,549 |
Outcome results
Primary
Number of Infants <2500 Grams
This is a co-primary outcome: Measured weight at delivery to determine the rate of \<2500 gram infants.
Time frame: Date of delivery to 1 week postnatal
Population: There were 5260 of the 5520 subjects in the control group after removing 42 with an interrupted pregnancy, 20 prepregnant without information on neonatal outcomes, 137 lost to follow up, and 61 with only neonatal gestational age information.~There were 4305 of 4349 consented for enrollment in the xylitol intervention group, after removing 89 with an interrupted pregnancy, 5 prepregnant without neonatal outcomes data, 106 lost to follow up and 45 with only neonatal gestational age data.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Number of Infants <2500 Grams | 679 Participants |
| Xylitol | Number of Infants <2500 Grams | 385 Participants |
Comparison: Co-primary outcomesp-value: <0.05Mixed Models Analysis
Primary
Rate of Preterm Birth
This is a co-primary outcome: Measure rate of preterm birth \<37 weeks gestation, as defined by best obstetrical estimate based upon last menstrual period correlated with fundal height at entry to prenatal care or ultrasound, when available; all sites have access to referral for ultrasound.
Time frame: Conception to date of delivery, <37 weeks gestation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Rate of Preterm Birth | 878 Participants |
| Xylitol | Rate of Preterm Birth | 549 Participants |
p-value: <0.05Mixed Models Analysis
Secondary
Number of Infants With Adverse Neonatal Composite Morbidity and Mortality
Additive or singular composite neonatal morbidity up to 28 days of age. Composite neonatal morbidity and mortality outcomes are defined as: neonatal death, miscarriage \<28 weeks, stillbirth (fresh or macerated), neonatal sepsis, neonatal respiratory distress, neonatal seizures, feeding problems, fever, hypothermia, Apgar score \<7 at 5 minutes after birth, referral to other hospital or neonatal intensive care unit (NICU)
Time frame: Date of delivery to 28 days postnatal
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Number of Infants With Adverse Neonatal Composite Morbidity and Mortality | 238 Participants |
| Xylitol | Number of Infants With Adverse Neonatal Composite Morbidity and Mortality | 133 Participants |
p-value: <0.05Mixed Models Analysis
Secondary
Number of Participants With Dental Caries
We will measure the prevalence of dental caries among gravidae. We will use standardized World Health Organization (WHO) oral health forms and disease scoring.
Time frame: During pregnancy, up to 2 dental visits performed during pregnancy (approximately 37-40 weeks if term) to evaluate dental outcomes
Population: There were 461 subjects in the control group who completed at least 2 dental visits. There were 490 subjects in the intervention, xylitol group who completed at least 2 dental visits.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Number of Participants With Dental Caries | 123 Participants |
| Xylitol | Number of Participants With Dental Caries | 135 Participants |
p-value: <0.05Mixed Models Analysis
Secondary
Number of Participants With Periodontal Disease
We will measure the prevalence of periodontal disease among gravidae. We will use standardized World Health Organization (WHO) oral health forms and disease scoring.
Time frame: During pregnancy, up to 2 dental visits performed during pregnancy (approximately 37-40 weeks if term) to evaluate dental outcomes
Population: There were 461 subjects in the control group who completed at least 2 dental visits. There were 490 subjects in the intervention, xylitol group who completed at least 2 dental visits.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Control | Number of Participants With Periodontal Disease | 117 Participants |
| Xylitol | Number of Participants With Periodontal Disease | 102 Participants |
p-value: <0.05Mixed Models Analysis