MOTOR: Maternal Oral Therapy to Reduce Obstetric Risk

STUDY DESIGN:

The intervention is designed as a multi-center, randomized, controlled, clinical trial to
determine the effects of periodontal therapy on the rate of preterm birth. Study participants
will be assigned to one of two study arms. All pregnant women who present to the designated
Obstetrical (OB) clinics are potential subjects for this study. A total of 1800 patients will
be enrolled at 3 performance sites, enrolling about 600 subjects at each site at a rate of
about 171 subjects/year at each site, randomly assigning these subjects to one of 2 treatment
arms. Randomization will be performed using a computer-generated assignment scheme designed
and performed in a masked manner by the data coordinating center. Each performance site will
enroll about 300 subjects into each treatment group using the intent-to-treat principle,
obtaining follow-up on all subjects. In treatment Group 1 participants will be assigned to
standard localized periodontal therapy of scaling and root planning with subgingival
polishing between three and six months of gestation. Group 2 will receive the same local
periodontal therapy immediately following delivery.

MASKING:

The dental examiner will not be aware of the randomization treatment assignments of
participants until after a complete baseline periodontal examination has been conducted. The
study protocol allows the dental examiner to know the treatment assignment of participants
but this knowledge will not affect the assessment of the primary obstetric outcome of the
study. OB personnel or individuals collecting OB data will be masked as to dental treatments.
At delivery the second dental exam will be made without the examiner knowing the pregnancy
outcome.

PRIMARY/SECONDARY OUTCOME MEASURES:

The primary outcome is preterm delivery at less than 37 weeks gestational age, as determined
by ultrasound dating. Secondary outcomes include (1) preterm delivery less than 35 weeks, (2)
weight for gestational age, and (3) neonatal morbidity/mortality. It is our central
hypothesis that mothers with periodontitis that receive periodontal treatment during the
second trimester of pregnancy will experience a lower rate of preterm delivery at <37 weeks
and secondarily <35 weeks; that periodontal treatment of these pregnant mothers will result
in an increase in the weight for gestational age of deliveries occurring less than 37 weeks
gestational age and reduce neonatal morbidity and mortality. We will determine the effects of
periodontal therapy on the rate of preterm birth at GA<37 weeks as the principal outcome and
on mean birth weight among neonates with GA<35 weeks, as a secondary outcome adjusting for
race, gender and gestational age.

POTENTIAL CONFOUNDERS AND COVARIATES:

There are many potential risk factors that relate to preterm birth and growth restriction
that need to be considered in this investigation. There are also exposures, effect modifiers
and covariates that influence periodontal disease status and preterm birth. Data will be
collected on the major variables of interest to include race, age, smoking, previous preterm
delivery, first births, bacterial vaginosis, chorioamnionitis, sexually transmitted diseases
(STDs), antibiotic usage, socioeconomic status (SES) and substance abuse. In addition we will
measure fetal fibronectin and collect vaginal smears to examine for potential subclinical
vaginosis. Detailed information will be collected on these potential factors and used to
assure that randomization has effectively balanced risk between treatment arms and to permit
post-hoc assessments.

PLAN FOR MONITORING:

There will be an administrative Steering committee consisting of the Obstetric and
Periodontal Principal Investigator(PI) from each clinical site, the NIDCR co-investigators
and the Data and Statistical Coordinating Center (DSCC) investigators. The Steering committee
will meet twice the first year and once a year thereafter. Study coordinators will also
attend one of the two annual meetings. Data will be collected on dental, obstetric and
neonatal outcomes by the data & statistical coordinating center, monitoring weekly for
adverse events. The DSCC will be collating adverse events and safety data centrally to
provide safety assessment reports to the DSMB. The DSMB will monitor outcomes and adverse
events and assure maternal and infant safety and provide feedback to NIDCR every 6 months or
as needed.

ADVERSE EVENTS:

The dental examiner will conduct a comprehensive oral soft tissue (cancer screening) and
periodontal examination at baseline and at post partum. Following enrollment mothers will be
followed up by, OB surveillance through parturition, a post-delivery dental follow-up and
neonatal surveillance that includes chart review after discharge. All of these provide an
opportunity to detect and monitor adverse events. All reported and observed serious adverse
events will be documented on an adverse event case report form describing the onset,
duration, severity, assessment of causality and relationship to treatment intervention. This
will be followed until resolution. A member of the investigative team will review subject's
OB charts on a weekly basis to note any adverse events or treatment provided (outside of
routine). In addition all neonatal discharge summary findings will be collected to monitor
any adverse neonatal morbidity such as neonatal sepsis and necrotizing enterocolitis. Any
dental treatment will be noted in the subject's clinical record to be reviewed by the dental
examiner.

PLAN FOR DATA ANALYSIS:

The details of the analysis plan appear in the body of the protocol, and are summarized here.
The incidence of preterm birth as the principal outcome will be evaluated using a chi-square
test. Approximately 240 cases are expected at gestational age (GA)<35 weeks. Success of
randomization for possible confounders will be evaluated by logistic regression models.
Significance will be indicated by an alpha level of 0.05. Mean birth weight among preterm
babies will be analyzed for correlations and significant differences between study arms using
a non-parametric test (Kruskal-Wallis test) Parametric (regression) models will be used to
adjust for gestational age and other factors.]. Analyses will be conducted using the intent
to treat philosophy. Data will be collected on a series of potential risk factors,
covariates, confounders and effect modifiers that may influence the primary and secondary
outcomes or periodontal status. Any unbalanced distribution of risks or exposures will be
included in the regression model analysis. Adverse event data will be reported regularly.
Interim analyses for efficacy will be conducted after 600 and 1200 completed pregnancies.

Inclusion Criteria:

- Willing to be randomized and complete treatment protocols and provide informed consent

- Planning on prenatal care and delivery at the enrollment center

- Pregnant and able to complete periodontal treatment prior to 236 weeks gestation

- At least 16 years old at enrollment

- Minimum of 20 teeth present

- Three (3) or more periodontal sites with > 3mm clinical attachment loss

Exclusion Criteria:

- Multiple gestation

- Positive history of HIV infection, AIDS, autoimmune disease, or diabetes (gestational
diabetes is acceptable)

- Any medical contraindication to periodontal probing or periodontal treatment that
would require antibiotic prophylaxis, (e.g., congenital heart disease, use of Phen-
fen for weight loss without a clear