MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
SCHOOL OF DENTISTRY
CHAPEL HILL, NC 27599-7450
CENTER FOR ORAL AND SYSTEMIC
DISEASES
MOTOR : Maternal Oral Therapy
to Reduce Obstetric Risk
Clinical Protocol
A UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL MULTI-CENTER CLINICAL TRIAL PROTOCOL
THREE CLINICAL PERFORMANCE SITES :
UNIVERSITY OF ALABAMA1
UNIVERSITY OF TEXAS AT SAN ANTONIO2
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL3/DUKE UNIVERSITY MEDICAL CENTER4
DATA AND STATISTICS COORDINATING CENTER:
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL SCHOOL OF PUBLIC HEALTH5
PREPARED BY STEVEN OFFENBACHER, DDS, PHD3, JAMES D. BECK PHD3
AND THE MOTOR INVESTIGATORS
UNC: LLOYD CHAMBLESS5, DAVID COUPER PHD5, DAWN STEWART, PHD5, HEATHER L. JARED, RDH, MS3,4
DUKE: PHIL HEINE MD4, AMY P. MURTHA MD4
UAB: JOHN HAUTH MD1, MARJORIE JEFFCOAT DMD1
UTHSCSA: DAVID COCHRAN DDS, PHD2, DONALD DUDLEY MD2
OCTOBER 1, 2003
MOTOR: Clinical Protocol, October 1, 2003
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
MOTOR Investigators
DATE OF PROTOCOL:
PRINCIPAL
INVESTIGATOR:
CO-PRINCIPAL
INVESTIGATOR:
October 1, 2003
Steven Offenbacher, DDS, PhD, MMSc
Professor and Director
Center for Oral and Systemic Diseases and Department of Periodontology
University of North Carolina School of Dentistry
Chapel Hill, NC 27599-7450
Telephone: 919-962-7081
Fax: 919-966-3683
E-mail: Steve_Offenbacher@DENTISTRY.UNC.EDU
James D. Beck
Professor and Co-Director
Center for Oral and Systemic Diseases and Department of Periodontology
University of North Carolina School of Dentistry
Chapel Hill, NC 27599-7450
Telephone: 919-962-7081
Fax: 919-966-3683
E-mail: Steve_Offenbacher@DENTISTRY.UNC.EDU
THREE INVESTIGATIVE CENTERS
PERIODONTAL PI
OBSTETRIC PI
CONTACT PERSON
Steven Offenbacher, DDS, PhD, MMSc
Dr. R. Phillips Heine
Professor and Director
Director Maternal Fetal Medicine
Center for Oral and Systemic Diseases
Associate Professor
Department of Periodontology
DUMC
UNC School of Dentistry
P O Box 3967
Chapel Hill, NC 27599-7450
Durham, NC 27710
Telephone: 919-962-7081
Telephone: (919) 681-5220
Fax: 919-966-3683
Fax: (919) 681-7861
E-mail:Steve_offenbacher@dentistry.unc.edu Email: heine010@mc.duke.edu
Heather Jared, RDH, Ms
Dental Research Center
UNC Chapel Hill
(919) 962-7081
(919) 966-7537
Dr. Marjorie K. Jeffcoat*
Chairman, Dept. of Periodontology
School of Dentistry
University of Alabama at Birmingham
1919 7th Avenue, S.
Birmingham, AL 35294
jeffcoat@dental.upenn.edu
Eliz G. Bolton
UAB School of Dentistry
(205) 934-4506
fax-(205) 934-7901
Birmingham, AL 35294-7333
MOTOR: Clinical Protocol, October 1, 2003
Dr. John Hauth
UAB School of Medicine
OHB 458
Birmingham, AL 35294-7333
(205) 934-5611
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
Dr. David L. Cochran
UTHSCSA/Periodontics-7894
7703 Floyd Curl Dr.
San Antonio, TX 78284-3900
Cochran@uthscsa.edu
Dr. Donald Dudley
7703 Floyd Curl Dr.
Mail Code 7831
San Antonio, TX 78284-3900
dudleyd@uthscsa.edu
N.J. (Jodie) Harrison
UTHSCSA/Periodontics-7894
7703 Floyd Curl Dr.
San Antonio, TX 78289-3900
(210) 567-3601 fax-(210) 567-6299
Harrison@uthscsa.edu
* Dr. Jeffcoat has relocated to University of Pennsylvania where she is serving as Dean. She will remain study PI at UAB
maintaining a joint appointment, but will be replaced locally by Dr. Michael Reddy at UAB who will be the on-site periodontal
investigator.
DATA AND STATISTICS COORDINATING CENTER
Lloyd (Woody) E.. Chambless, PhD
wchambless@unc.edu
University of North Carolina
137 E. Franklin Street, Suite 400
Mail Station: 8030, Room 28
Chapel Hill, NC 27514
Phone: 919-962-3264 Fax: 919-962-3265
David Couper, PhD (Co-PI) david_couper@mail.cscc.unc.edu
University of North Carolina
137 E. Franklin Street, Suite 400
Mail Station: 8030, Room 12
Chapel Hill, NC 27514
Phone: 919-962-3229 Fax: 919-962-3265
Dawn Stewart, MS
dawn_stewart@unc.edu
University of North Carolina
137 E. Franklin Street, Suite 400
Mail Station: 8030, Room 34
Chapel Hill, NC 27514
Phone: 919-962-3029 Fax: 919-962-3265
MOTOR: Clinical Protocol, October 1, 2003
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
Abstract
STUDY OBJECTIVES:
The principal objective is to conduct a 5 year, multi-centered,
clinical trial enrolling mothers with periodontal disease prior to 236
weeks gestational age, randomizing to one of two treatment arms:
Group 1- Scaling and root planning with a subgingival polish, by 23 6
gestational age or Group 2- post-partum scaling and root planning
with a subgingival polish (delayed treatment control). The overall
goal of this clinical trial is to satisfy the following specific aims: 1) to
determine the effects of maternal periodontal treatments during the
second trimester on the rate of preterm birth at <37 weeks
gestational age (GA) 2) to determine the effects of maternal
periodontal treatments during the second trimester on mean birth
weight adjusting for gestational age among neonates GA<37 weeks
and on neonatal morbidity, and 3) to collect and archive biological
samples during the conduct of trial to enable future studies
regarding mechanism of infectious pathogenesis.
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 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. 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.
MOTOR: Clinical Protocol, October 1, 2003
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
SAMPLE SIZE:
The target sample size is to enroll 1800 pregnant moms (600 at
each performance site) who meet the inclusion criteria at study
entry and consent to participate in the study.
METHOD FOR SUBJECT
ASSIGNMENT:
All pregnant women who present to the designated OB clinics are
potential subjects for this study. Patients will be consented,
screened for eligibility and randomized to one of two study arms.
Randomization will be performed using a computer-generated
assignment scheme designed and performed in a masked manner
by the data coordinating center.
PRIMARY and 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, STDs, antibiotic usage, 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.
MOTOR: Clinical Protocol, October 1, 2003
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
PLAN FOR
MONITORING:
ADVERSE EVENTS:
PLAN FOR DATA
ANALYSIS:
There will be an administrative Steering committee consisting of the
Obstetric and Periodontal PI from each clinical site, the NIDCR coinvestigators 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.
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.
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 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
MOTOR: Clinical Protocol, October 1, 2003
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
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.
MOTOR: Clinical Protocol, October 1, 2003
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
SCHOOL OF DENTISTRY
CHAPEL HILL, NC 27599-7450
Table of Contents
1.0
INTRODUCTION ..................................................................................................................................... 11
2.0
BACKGROUND AND RATIONALE...................................................................................................... 11
2.1
Healthcare significance of research problem.............................................................................11
2.2
Infection, inflammation and preterm birth ...................................................................................12
2.3
Summary of previous findings of periodontal infection associated preterm birth ..........14
3.0
AIMS AND HYPOTHESES ..................................................................................................................... 15
4.0
STUDY DESIGN ....................................................................................................................................... 16
4.1
Overview ...............................................................................................................................................16
4.2
Human Subjects .................................................................................................................................17
4.3
Inclusion Criteria ...............................................................................................................................17
4.4
Exclusion Criteria..............................................................................................................................17
4.5
Informed Consent .............................................................................................................................18
4.6
Patient Incentives ...............................................................................................................................18
4.7
Study Flowchart and Schedule of Visits ......................................................................................18
4.8
Study Visit 1: OB screening visit, oral screening and enrollment ........................................19
4.9
Study Visit 2: Baseline periodontal and baseline OB/GYN exam and randomization .....20
4.9.1
4.9.2
4.9.3
4.9.1
OB/GYN Baseline Visit 2A ........................................................................................ 20
Dental Baseline Visit 2B ............................................................................................ 20
Patient Randomization .............................................................................................. 20
Patient Histories and Tracking ................................................................................. 21
4.10
Study Visit 3: Post-partum exam, obstetric and neonatal outcomes ................................................21
4.11
Study Visit 4: Group 2 treatment ....................................................................................................21
5.0
5.1
6.0
PERIODONTAL DISEASE MEASUREMENTS .................................................................................. 21
Clinical indices.......................................................................................................................................22
DENTAL EXAMINER CALIBRATION PROCEDURE ..................................................................... 23
6.1
Introduction ...........................................................................................................................................23
6.2
Summary ................................................................................................................................................23
7.0 PLAQUE, SERUM, PLASMA AND LEUKOCYTE BUFFY COAT SAMPLING ................................. 24
8.0
OBSTETRIC MEASURES AND SAMPLES ......................................................................................... 25
8.1
Fetal Fibronectin ...................................................................................................................................25
8.2
Vaginal Microbial Flora .......................................................................................................................25
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
8.3
Vaginal pH Determination ................................................................................................................26
8.4
Vaginal Gram Stain ............................................................................................................................26
8.5
Maternal Blood Samples ..................................................................................................................26
9.0
NEONATAL MEASURES ....................................................................................................................... 26
10.0
PARTICIPANT IDENTIFICATION ...................................................................................................... 27
11.0
TREATMENT PROCEDURES ............................................................................................................... 27
11.1
Periodontal Treatments ........................................................................................................................27
11.1.1
Investigational Materials .......................................................................................... 28
12.0
POST-PARTUM EXAMINATION AND BIOLOGICAL SAMPLE COLLECTION ......................... 28
13.0
POST-PARTUM SCALING AND ROOT PLANING (GROUP 2 ONLY) ........................................ 28
14.0
SAFETY EVALUATIONS........................................................................................................................ 28
14.1
Oral safety ............................................................................................................................................29
14.2
OB Safety..............................................................................................................................................29
14.3
Oral Rescue treatments ....................................................................................................................29
14.4
Neonatal Safety...................................................................................................................................29
15.0
OBSTETRIC & NEONATAL MONITORING, DATA CLOSURE AND ANALYSES .................... 29
16.0
EXAMINER CALIBRATIONS................................................................................................................. 30
17.0
CONDITIONS FOR DISCONTINUING SUBJECTS ........................................................................... 30
18.0
ADVERSE EXPERIENCE REPORTING .............................................................................................. 30
19.0
DATA ANALYSIS AND STATISTICS .................................................................................................. 31
19.1
Sample Size Determination .............................................................................................................31
19.2
Power for varying event rates in the two treatment groups and sample sizes .................32
19.3
Data analysis .......................................................................................................................................32
19.4
Analysis of endpoints .......................................................................................................................32
19.5
Interim Analyses for Efficacy & Safety .........................................................................................33
20.0 ETHICAL AND REGULATORY REQUIREMENTS FOR PROTOCOLS INVOLVING HUMAN
SUBJECTS ............................................................................................................................................................. 34
20.1
Study Conduct ....................................................................................................................................34
20.2
Informed Consent ..............................................................................................................................34
20.3
Institutional Review Board or Ethical Review Committee .......................................................34
20.4
Protocol Amendments and Emergency Deviations ..................................................................34
20.5
Monitoring of the Study ....................................................................................................................35
20.6
Study Records ....................................................................................................................................35
20.7
Inspection of Records .......................................................................................................................35
21.0
INVESTIGATOR’S STATEMENT .......................................................................................................... 35
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
22.0
22.1
HUMAN SUBJECTS ................................................................................................................................ 37
Risks to the Subjects .......................................................................................................................37
22.1.1
22.1.2
22.1.3
22.2
Human Subjects Involvement and Characteristics: .............................................. 37
Sources of Materials : ............................................................................................ 38
Potential Risks: ........................................................................................................... 39
Adequacy of Protection against Risks .........................................................................................40
22.2.1 Recruitment and Informed Consent ............................................................................ 40
22.2.2 Protection against Risk ................................................................................................. 40
22.3
Potential Benefits of the Proposed Research to the Subjects and Others.........................41
22.4
Importance of the Knowledge to be Gained................................................................................41
22.5
Inclusion of Women ...........................................................................................................................42
22.6
Inclusion of Minorities ......................................................................................................................42
23.0
REFERENCES .......................................................................................................................................... 43
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
1.0
INTRODUCTION
Case control and prospective cohort studies support the concept that maternal periodontal
infections are associated with an increased risk of premature delivery and low birth weight
infants, adjusting for traditional obstetric risk factors. Human data also support the concept
that maternal periodontal infections are associated with an increased risk for fetal growth
restriction, pre-eclampsia, perinatal stress as well as increased fetal morbidity and
mortality. The long term goal of our research is to understand the mechanisms by which
maternal periodontal infections mediate these abnormal pregnancy outcomes and whether
treating periodontal disease in pregnant women improves pregnancy outcomes. This
protocol describes procedures and guidelines for conducting a clinical intervention trial
entitled MOTOR “Maternal Oral Therapy to Reduce Obstetric Risk” It is our central
hypothesis that mothers with periodontitis who receive periodontal treatment during the
second trimester of pregnancy will experience a lower rate of preterm birth at gestational
age less than 37 weeks. We also hypothesize that periodontal treatment of these pregnant
mothers will result in a higher mean birth weight of the premature infants of gestational age
less than 37 weeks. We have organized three clinical research centers with joint
periodontal and obstetric expertise at the University of Alabama (Jeffcoat/Hauth), the
University of Texas at San Antonio (Cochran/Dudley) and the University of North
Carolina/Duke (Offenbacher & Beck/ Heine & Murtha) that will collaborate to conduct a
multi-centered clinical trial utilizing a Central Coordinating Center at the UNC School of
Public Health (Chambless, Couper and Stewart). Our principal objective is to conduct a
multi-centered, clinical trial enrolling mothers with periodontal disease prior to 23 6 weeks
gestational age randomized to two treatment arms: Group 1) Scaling and root planning
plus oral prophylaxis (tooth polish), prior to 236 weeks gestational age or Group 2) Postpartum scaling and root planning plus oral prophylaxis (delayed treatment control).
2.0
2.1
BACKGROUND AND RATIONALE
Healthcare significance of research problem
Each year about half a million babies born in the United States, which is about one in ten
births, arrive too early and too small 1,2. Preterm birth that occurs at less than 37 weeks
gestation and associated low birth weight (LBW) of less than 2500 grams (about 5 1/2 lbs)
represent the major cause of neonatal mortality and, among survivors, a major contributor
to long-term disability 3. There are tremendous disparities in the prevalence of preterm
birth and attendant neonatal complications. For example, pregnant African American
women experience a rate of premature delivery approximately three-fold that of Whites or
Hispanics. Furthermore, the incidence of LBW has not changed significantly over the last
several decades. Despite advances in maternal prenatal care and increased public
awareness, the incidence of preterm birth has not changed significantly over the last 40
years. It has been suggested 4 that the inability of the healthcare system to decrease the
occurrence of these unfavorable pregnancy outcomes is likely due to fact that we have not
as yet identified all of the contributing causes of preterm birth and therefore fail to
appropriately target and manage relevant risk factors. Thus far, smoking and alcohol
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
consumption are generally accepted as two major modifiable risk factors 4,5. Other
potential risk factors appear to be less informative from a clinical management standpoint.
Some of these reported risk factors 6-8 include parity (that is, the number of previous births,
since the rate is higher among first births), short cervical length, short maternal stature, low
maternal weight, high physical and psychological stress, low socioeconomic status and
education, and poor maternal nutrition. These factors are not consistently confirmed by
epidemiological studies and prospective treatment studies targeting these risk factors have
not been encouraging 5,7,8.
Currently, the best single predictor of risk for preterm birth among pregnant women is
whether the mother has already experienced a preterm delivery – a clinical history finding
that increases the risk almost 3-fold 2. Thus the risk of preterm birth tends to remain with
the mother throughout multiple pregnancies, even with increased levels of prenatal
surveillance and preventive interventions. This finding and the coupled observation that
there is a familial tendency for preterm birth has lead to the suggestion that there may be
genetic components to risk 9. Whatever the genetic contribution, penetrance is far from
complete, as it is not uncommon for a multiparous mother to have both normal full-term
deliveries, as well as prematurities in her pregnancy history. Thus, intermittent, short-term
exposures during the pregnancy may also play an important role in determining the
outcome of a specific partus.
2.2
Infection, inflammation and preterm birth
One of the more important acute exposures that has been implicated in preterm birth is an
acute maternal genitourinary tract infection at some point during the pregnancy 2,10.
Bacterial vaginosis (BV) is a gram negative, predominantly anaerobic infection of the
vagina, usually diagnosed from clinical signs and symptoms. It is associated with a
decrease in the normal lactobacillus-dominated flora and an increase in anaerobes and
facultative species including Gardnerella vaginalis, Mobiluncus curtsii, Prevotella bivia and
Bacteroides ureolyticus. BV is a relatively common condition that occurs in about 10% of
all pregnancies. It may ascend from the vagina to the cervix and even result in
inflammation of the maternal-fetal membranes (chorioamnionitis). Extending beyond the
membranes, the organisms may appear in the amniotic fluid compartment that is shared
with the fetal lungs and/or may involve placental tissues and result in exposure to the fetal
hematogenously. Despite the observed epidemiological linkage of bacterial vaginosis (BV)
with preterm birth, the results from randomized clinical trials to determine the effects of
treating BV with systemic antibiotics on incident preterm birth are equivocal (see 10 for
review). Several potential explanations for the failure of clinical trials to show a beneficial
effect of treatment have been suggested 11,12, including problems associated with target
population selection, diagnostic criteria, as well as the efficacy of the intervention
strategies. Nonetheless, there are compelling molecular data linking maternal infection
and concomitant inflammation to preterm birth as well as neonatal complications. It
appears that inflammation of the uterus and membranes represents a common effector
mechanism that results in preterm birth, and that either clinical or subclinical infection
remains a logical and highly suspect candidate as a stimulus for increased inflammation.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
Thus, BV remains an important putative risk factor or lower genital tract marker of
subsequent preterm birth.
Early reports of an association between maternal periodontal disease and preterm birth 13
immediately raised the question as to whether these mothers with an oral anaerobic
infection might also have a greater prevalence of clinical or subclinical vaginosis. Early
results based upon either clinical definition of BV or microscopic determinations do not
seem to indicate that the association of periodontal disease with preterm birth is due to a
concomitant vaginosis or chorioamnionitis 13,14. Studies by Jeffcoat et al. 15 suggest that
incidence of BV by vaginal Gram stain scoring was not different between patients with
periodontitis as compared to patients without periodontitis (p=0.56) Although more studies
are needed to clarify these associations, the data thus far indicate that the effects of
periodontal disease on preterm birth appear to be independent of vaginal and reproductive
track infections. Thus, the effects of periodontal disease are an additional burden on the
maternal-fetal unit.
Acute infections involving distant organ systems, other than the genitourinary track, have
been clearly shown to be capable of ultimately targeting the fetal-placental unit. The
literature is replete with diverse examples of maternal primary distant infections that result
in an abnormal pregnancy outcome, including rubella (endocrine), shigellosis
(gastrointestinal), encephalitis (neurological) and pneumonia (pulmonary) 16. Most induce
maternal cytokinemia and resultant fever that threatens the pregnancy and some of these
infectious agents have been shown to target the placenta inducing local inflammation and
necrosis. Some infectious agents that are abortofacient, such as Rubella and
Campylobacter are capable of crossing the fetal placental barrier and result in direct
exposure into the fetal circulation. Thus, maternal systemic infections can elicit an
inflammatory response that results in inflammation of the maternal-fetal-placental unit
including the uterus, the chorioamniotic membranes, the placenta, the amniotic fluid, the
fetal lungs and the fetal circulation. These inflammatory stimuli induce hyperirritability of
the smooth muscle of the uterus enhancing contractility, cervical dilation and premature
labor. Inflammation of the chorioamniotic membranes results in thinning and premature
rupture. Infection and the resulting inflammatory response can also elicit damage to the
placenta. Placental damage can cause areas of focal hemorrhage and necrosis and that
results in poor fetal perfusion, fetal growth restriction and distress. Most of the obstetric
predisposing conditions that result in preterm birth and growth restriction are thought to be
orchestrated by a common biochemical effector pathway that has been initially described
by Romero 17. An elegant review of these effector mechanism concepts with special
application to periodontal disease has been recent provided by Curtis and colleagues in
(Williams reference 18 ).
Infectious exposure to the mother during pregnancy is currently believed to be a significant
factor that triggers in utero fetal stress that ultimately contributes to long-term growth and
development problems that begin with the neonate and extend throughout the lifetime of
the individual. The quality of the environment, as well as the duration of the gestation in
utero has been suggested to be a critical determinant of long-term well being of the
individual ranging from cognitive and learning skills to susceptibility to heart disease 1,19-21.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
Maternal infections during pregnancy and attendant inflammatory responses have been
linked to specific neonatal problems including periventricular leukomalacia (white matter
necrosis), respiratory distress (often leading to chronic lung disease of preterm birth) and
cerebral palsy 1,19-21 Furthermore, increasing evidence suggest that the molecular and
cellular inflammatory effector pathways that underlie the pathogenesis of preterm birth are
also involved in growth restriction and developmental problems ranging from respiratory
distress to cognitive and learning disabilities. For example, fetal neurological tissues are
especially susceptible to damage via cytokines, such as interferon gamma, that induce
apoptosis and impair synapse development of embryological neurons 22,23. Thus, the threat
of maternal infectious exposures during pregnancy does not appear to be solely limited to
effects on the duration of the pregnancy but also to perinatal growth and development.
Growth impairment that occurs during gestation can result in a neonate that is small for
gestational age (SGA, typically defined as a birth weight that is below the 10th percentile of
weight for that gestational age). Thus, current evidence suggests that maternal stressors
result in both a maternal and a fetal inflammatory response that impairs fetal growth and
development as well as expediting parturition by weakening and rupturing membranes and
inducing labor. The relative stability or slight increase in the incidence of these neonatal
conditions in the population over the last several decades suggests that current strategies
to identify and manage maternal infection and inflammation during pregnancy remain to be
optimized.
2.3
Summary of previous findings of periodontal infection associated preterm
birth
The role of maternal periodontitis as a potential maternal-fetal stressor that has detrimental
effects on the pregnancy outcome is a relatively new field of investigation. Early work with
pregnant rodent models demonstrated that low-grade challenges with oral organisms
during pregnancy resulted in impaired fetal growth. This was demonstrated using a chronic
subcutaneous infection model with Porphyromonas gingivalis and also in a model of
experimental periodontitis. In both models the infectious challenge was associated with an
inflammatory challenge to the fetus, as measured by amniotic fluid PGE 2 and TNF and
attendant growth restriction 24. Since there are no animal models of preterm birth, these
data provided important proof-of-concept experiments that raised the possibility that
distant, low grade oral infections might also trigger inflammation of the human maternalfetal unit in a manner analogous to that seen with reproductive tract infections. The first
reported human case-control study suggested that mothers with premature (<37 weeks
gestational age), low birth weight babies (under 2500g) had more severe periodontal
disease than mothers with full term deliveries and that periodontitis appeared to confer
considerable risk independent of other traditional obstetric risk factors ( 12). However, this
investigation was a relatively small study of 124 cases and this design does not permit the
establishment of temporality of exposure (periodontal disease) as it relates to the outcome
(preterm birth). Nonetheless, the potential magnitude of the effect of periodontal disease
was surprisingly large (adjusted odds ratio 6.7, p=0.003) and provided impetus for further
study prompting the conduct of prospective studies to appropriately measure attributable
risk and cross-sectional studies to confirm this association.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
Importantly, a separate NIDCR-funded, prospective study of 1313 mothers conducted at
the University of Alabama by, Hauth, Jeffcoat and colleagues has, in parallel, confirmed
that maternal periodontitis is an independent risk factor for preterm birth 15. These
investigators report that with increasing severity of periodontal disease as an exposure
there is an increased risk for preterm birth with odds ratios in the range of 4-7 for severe
periodontitis, adjusting for age, race, smoking and parity. Thus, maternal periodontitis as a
potential risk factor for preterm birth appears to be gaining considerable supportive
evidence, although other case-control studies on low risk populations in Europe have not
seen a relationship 25. Furthermore, two small independent studies have reported that
providing periodontal treatments to pregnant women with periodontal disease may reduce
the risk of preterm birth 26,27. In an observational study Mitchell-Lewis 26 suggested that
mothers in a dental school environment receiving care experienced a lower rate of
prematurity than a community-based control group. However, an intervention trial by Lopez
27 provides a more direct test of the association. In this study, 390 mothers were randomly
assigned to one of two groups - periodontal treatment prior to 22 weeks vs delayed,
antepartum treatment. The observed rate of preterm birth (<37 weeks) was 10.2% in the
untreated and 1.8% in the periodontal treatment group (p<0.001). This suggestion is
supported by recent pilot data generated by our colleagues at the University of Alabama.
In a paper entitled “Periodontal Disease and Preterm Birth: Results of a Pilot Intervention
Study” (J Periodontology 2003;74:1214-1218, Jeffcoat MK, Hauth JC, Geurs NC, Reddy
MS, Cliver SP, Hodgkins PM and Goldenberg RL) the rate of prematurity at <35 weeks
was 6.3% in the reference group and 0.8% in the scaling and root planning group. The
effects of periodontal treatment were strong, but in this pilot of 366 mothers assigned to 3
treatment arms, the findings did not achieve statistical significance comparing scaling and
root planning to the prophylaxis group. In total, these preliminary findings are encouraging
and build a strong rationale for conducting a prospective cohort study to provide a more
robust measure of attributable risk as well as a multi-center, randomized controlled clinical
trial to test the hypothesis that treating periodontal disease reduces risk of preterm birth.
3.0
AIMS AND HYPOTHESES
The objective of this study is to conduct a multi-center, randomized, delayed treatmentcontrolled clinical trial to determine the effects of periodontal therapy on the rate of preterm
birth at gestational age (GA) <37 weeks as the principal outcome and GA<35 weeks,
mean birth weight among neonates with GA< 37 weeks, adjusting for race, baby’s gender,
and gestational age, and neonatal morbidity/mortality, as secondary outcomes.
The specific aims of this intervention study are:
Specific Aim 1: to determine the effects of periodontal therapy consisting of scaling
and root planing (S&RP) and oral hygiene instructions among pregnant women with
periodontal disease on the rate of preterm delivery at GA<37weeks, as compared to
a delayed treatment group. 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.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
Specific Aim 2: to determine the effects of periodontal therapy consisting of S&RP
and oral hygiene instructions among pregnant women with periodontal disease on
the rate of preterm delivery at GA<35weeks, mean birth weight of premature
neonates at GA <37 weeks and neonatal morbidity/mortality as compared to a
delayed treatment group. It is hypothesized that periodontal treatment will result in
a lower rate of preterm delivery, an increase in the mean birth weight of the
premature infants adjusting for race, baby gender and gestational age, and
decreased neonatal morbidity/mortality
Specific Aim 3: To collect and archive biological samples during the conduct of the
clinical trial to enable future studies regarding mechanisms of infectious
pathogenesis of prematurity and growth restriction, including assessments of
maternal and fetal inflammatory and immune responses and studies of intrauterine
fetal exposure to oral and vaginal pathogens of maternal origin
4.0
4.1
STUDY DESIGN
Overview
This study involves the coordinated efforts of both a dental team and an obstetric team at
each of the three field centers. All patients presenting for routine obstetric care early in
pregnancy will potentially be eligible to be enrolled. Patients will be screened for potential
inclusion or exclusion by medical and obstetric history. Once a patient has been
determined to potentially meet the inclusion/exclusion criteria she will be approached for
informed consent. Once informed consent has been obtained, further eligibility will be
determined by a periodontal screening exam to identify those with periodontal disease,
and an obstetric screening exam with ultrasound to enable study personnel to confirm
eligibility. Eligible patients will then be enrolled and randomized to one of the two treatment
arms Group 1) a periodontal treatment arm providing care by 23 6 weeks gestation or
Group 2) a post-partum periodontal treatment that is delayed until the mother leaves the
hospital. At baseline all mothers will receive an oral cancer screening, full-mouth
measurements of periodontal disease status and samples of dental plaque will be
collected. This baseline visit will be performed by dental staff, generally within or adjacent
to the OB clinic using a dental chair. At a baseline prenatal OB visit samples will be
collected for this study during the vaginal exam (microbial samples to test for vaginosis)
and blood tests (additional serum and plasma tubes). A detailed OB history will be
collected. Group 1 mothers will have periodontal care by 23 6 weeks gestational age
consisting of scaling and root planing, using local anesthesia as needed, with oral
prophylaxis and oral care instructions. These procedures will usually be completed in one
to two dental treatment visits, however up to four visits may be provided. Mothers assigned
to Group two will have no dental visits until after delivery. All mothers and babies will be
followed from enrollment through delivery and discharge to determine outcomes and to
monitor for adverse events (periodontal, obstetric and neonatal). At delivery, birth weight
and gestational age will be determined for primary and secondary outcome analyses. At
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
post-partum, there will be a repeat oral examination and plaque sampling performed prior
to discharge. Neonatal status will also be monitored through discharge. After delivery
Group 2 mothers will be scheduled for their periodontal treatment post-partum. During the
course of this study, all mothers will receive routine obstetric care through their obstetric
clinic, independent and unobstructed by this study protocol. Thus, in terms of obstetric and
neonatal management of care, this study serves only to superimpose an additional dental
treatment procedure upon routine obstetric care. In addition, the periodontal care is nonexperimental and within the current standards of care for the management of periodontal
disease among pregnant women.
4.2
Human Subjects
A total of 1800 subjects assigned to one of two treatment arms will be selected based on
the following inclusion and exclusion criteria. Eligibility will be determined by a medical
history, periodontal screening examination and an obstetric screening that includes an
ultrasound for gestational age determination and to rule out the potential presence of
multiple gestation and other obstetric exclusions.
4.3
Inclusion Criteria






4.4
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 23 6 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, 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 echocardiogram, mitral valve prolapse)
Rampant decay, symptomatic teeth or any other dental finding such as periodontal
abscess or endodontic fistula that would preclude enrollment.
Chronic use of medications that cause gingival enlargement such as phenytoin,
cyclosporin -A, or calcium channel antagonists
Chronic use of steroids
Concomitant use of orthodontic appliances (braces)
Any obstetric finding that precludes enrollment in the study
Participation in another randomized controlled trial or not agreeing to refrain from
participation in another randomized controlled trial during the current pregnancy.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
4.5
Informed Consent
This process involves a HIPPA certification of a waiver for chart screening and clinic
surveillance to identify potential study subjects. Patients will be approached in the OB/GYN
clinic by study personnel for obtaining informed consent for screening. Patients will usually
be first approached by obstetric personnel to ascertain eligibility and patient interest
followed by explanation of the study and obtaining informed consent for screening. Once
consent has been obtained there will be both an oral and obstetric screening to determine
study eligibility. If the patient is eligible and willing to participate informed consent for
participation in the entire study will be obtained. Two of the sites plan to have one consent
form that covers screening and study enrollment. In compliance with federal guidelines, all
informed consent processes and HIPPA regulations will be applied in accordance with the
requirements of the local IRB Committee for the use of Humans Subjects for Research
Purposes at each of the individual clinical performance sites.
4.6
Patient Incentives
Participants will receive periodontal therapy at no cost and a monetary sum of
approximately $5.00 in cash at each study visit to facilitate transportation to and from the
clinic.
4.7
Study Flowchart and Schedule of Visits
This section describes the patient flow through the clinical protocol that consists of four or
more study visits. These four visits include 1) a dental and obstetric screening, 2) an OB
and dental baseline 3) periodontal treatment visits (1-2 typically, but up to four) and 4) a
post-partum visit. A patient typically schedules an appointment for the baseline and
treatment visits. These visits are depicted in the following flow chart and described below.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
MOTOR Flowchart and Schedule of Visits
OBClinic
ClinicRecruitment
Recruitmentand
andInformed
InformedConsent
Consent
OB
ScreeningExams
Exams
Screening
Periodontal
Periodontal
OB
OB
Eligible Patients
BaselineExams
Exams
Baseline
Treatment
OB
Baseline
Periodontal
Periodontal
Obstetric
Obstetric
Randomization
Randomization
Group 1Treatment
Prior to 236
PeriodontalTreatment
Treatment
Periodontal
Prior
to
2366
Prior to 23
Delivery,Post-partum
Post-partumexam
exam
Delivery,
&
Neonatal
Monitoring
& Neonatal Monitoring
4.8
Surveillance Period
Group 2Delayed Treatment
Delivery,Post-partum
Post-partumexam
exam
Delivery,
&
Neonatal
Monitoring
& Neonatal Monitoring
PeriodontalTreatment
Treatment
Periodontal
Post-partum
Post-partum
Study Visit 1: OB screening visit, oral screening and enrollment
A total of 1800 subjects will be randomized into the study, 600 in each of 3 centers from an
estimated total patient pool of about 29,000 subjects. We conservatively assume that only
32% will meet the medical and dental criteria, and that only 50% will agree to participate.
Using these estimates, to enroll 1800 subjects we would need to screen approximately
11,250 patients over 42 months. If one center has difficulty recruiting, we should still have
an ample pool of patients to recruit from other centers to meet our goal after 42 months of
enrollment. All pregnant women who present to the OB clinics for a prenatal care visit who
meet the medical inclusion and exclusion criteria in time to be randomized and treated by
236 weeks gestation will be asked to participate by the physician. The study will be
explained by the OB nurse and study hygienist and with the physician; informed consent
for oral screening and OB screening will be obtained. Once consent has been obtained,
the patient will be screened for periodontal status in a dental chair located within the OB
clinic, and if eligible an OB screening (ultrasound) will be conducted to assure OB
eligibility. If both dental and medical eligibility criteria are met according to the
inclusion/exclusion criteria listed above, informed consent for the full study will be obtained
and an accession number is assigned to that study subject. Patients will be scheduled for
Study Visit 2 that will actually involve two appointments – one OB/GYN (Visit 2A) baseline
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
and one dental baseline (Visit 2B). Under most clinical situations the dental screening is
conducted first followed by OB screening. If the patient is eligible then the OB baseline
samples are completed at the end of the OB screening. Thus, Visit 2A occurs immediately
after ultrasound eligibility is confirmed and the vaginal and blood samples needed for this
study are collected during that OB examination visit. The patient is then scheduled for the
dental baseline visit and randomization occurs at the end of that dental baseline visit.
Patients will not be randomized until both dental and OB baselines are completed, but they
can occur in either order, depending on the availability of the ultrasound data. Patients will
be scheduled for both the Dental and OB visits usually during the same day, but no more
than 14 days apart.
4.9
Study Visit 2: Baseline periodontal and baseline OB/GYN exam and
randomization
4.9.1 OB/GYN Baseline Visit 2A
During the OB visit a speculum exam will be performed to collect vaginal and cervical
samples for microbiological determinations, inflammatory mediator measurements and
fetal fibronectin quantification. Antepartum maternal blood for cotinine assessments, as
well as vaginal and cervical samples (for fetal fibronectin and bacterial vaginosis testing) is
also collected at this first OB baseline visit.
4.9.2 Dental Baseline Visit 2B
Dental Baseline Visit 2B: Full mouth periodontal exam, as described above, will be
performed on all subjects within the dental unit. A licensed dental hygienist or dentist, not
involved in the periodontal treatment, will perform an exam of the oral cavity. The same
examining hygienist will also perform the postpartum examination at Study Visit 3. Oral
procedures include a cancer screening, a periodontal exam, and the collection of plaque
samples. These microbiological samples will be collected and stored for future studies.
Four plaque samples will be collected, selecting the deepest site in each quadrant and
stored separately for future analyses. After oral examination, patients will be randomized to
one of the two treatment groups.
4.9.3 Patient Randomization
Randomization: The DSCC will develop and implement an automated randomization
system and will also provide a telephone contact at the DSCC in case the automated
system fails. In order to ensure at an early stage in the study an approximately equal
distribution of subjects across the treatment groups a permuted block randomization
scheme will be used, stratifying subjects by clinical center. The Steering Committee, as
described in the Manual of Procedures, may decide to add other stratifying factors. To
minimize the possibility and effect of an investigator being able to predict some treatment
assignments, a random mixture of block sizes will be used within each center’s strata. The
20
MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
DSCC will provide the Steering Committee with weekly reports on the number of subjects
recruited and randomized. Once randomized to treatment groups, then intent-to-treat
methods will be followed. Patients assigned to treatment Group 1 will have treatments
previously described begun at this appointment, Group 2 patients will have treatments
performed postpartum. If needed additional dental treatments will be scheduled to
complete the scaling and root planing.
4.9.1 Patient Histories and Tracking
Patient Histories and Tracking: Each study subject will complete a demographic form.
This form collects the subject's address, employment status, education level, current
medications, alcohol/tobacco exposures, and psychosocial exposures. For each subject
enrolled, the study personnel will complete a medical history form. This form collects the
subject's address, insurance provider, past obstetrical and gynecologic history, present
obstetrical history, and general medical history. After enrollment, the subject is tracked
and followed throughout the pregnancy, ensuring the collection of necessary data and
biological samples. Each subject is listed on an active list of study patients and on a data
completion checklist sheet. These forms give details of which data or biological sample
has been collected and which still are needed. This sheet is updated after each contact
with the subject. During the subject's pregnancy, obstetric surveillance will be followed,
assuring the collection of all necessary data.
4.10
Study Visit 3: Post-partum exam, obstetric and neonatal outcomes
After the subject delivers the baby, oral and perinatal clinical data and biological samples
will be collected while she is still in the hospital. Samples collected in labor and delivery
include maternal blood, placental biopsies, and fetal cord blood that are collected,
processed and shipped to UNC for processing. At the post-partum visit additional oral
plaque samples will be collected bedside. Bedside exams will be performed to collect
periodontal clinical data. Additional maternal interviews are conducted and neonatal data
are collected until the baby is discharged. The study personnel will conduct a postpartum
interview that includes questions about exposures prior to and during the current
pregnancy, support provided by family members during the current pregnancy and contact
information for future use. Mothers who were randomized to Group 2 will be scheduled for
their periodontal treatment (Study Visit 4).
4.11
Study Visit 4: Group 2 treatment
This visit is to provide the treatment that Group 2 patients did not receive during Study Visit
2. This visit completes the patient treatment protocol and patients are advised of their
dental needs and treatment options.
5.0
PERIODONTAL DISEASE MEASUREMENTS
Periodontal disease will be measured at baseline and at postpartum. Periodontal disease
status will be expressed based upon clinical signs, as described below. Plaque will also be
21
MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
collected for future analyses to assess microbial burden, as determined by quantification of
plaque composition by DNA macroarray (checkerboard). All of these measures are to
determine the efficacy of periodontal therapy and provide baseline disease level
characterization to use as a control variable in secondary analyses. Specifically these
measures will be used to determine 1) whether baseline periodontal status relates to
periodontal therapeutic response and pregnancy outcome 2) whether certain oral
organisms that are suspected as fetal pathogens (specifically Campylobacter rectus and
Porphyromonas gingivalis) are eliminated or persist following therapy. None of these
measures are end-points of therapy but will be considered as they specifically relate to the
outcome as potential effect modifiers of preterm birth and growth restriction.
5.1
Clinical indices
Clinical periodontal parameters will be collected for all teeth. Clinical parameters that
include probing will be measured using a manual University of North Carolina (UNC-12)
periodontal probe at six sites per tooth (i.e. mesiobuccal, direct buccal, distobuccal,
mesiolingual, direct lingual, and distolingual) on all teeth including third molars. The
clinical parameters to be recorded include the following:
 Soft Tissue Examination: A visual intraoral soft tissue cancer screening will be
performed.
 Plaque scores (Silness and Loe H, 1967) for three buccal and the mid-lingual
surfaces of each tooth will be assigned using a 0 to 3 scale. Absence of plaque or
stain = 0, deposits covering less than one-third of crown surface = 1, less than twothirds = 2, more than two-thirds = 3.
 Gingival index score (Loe and Silness, 1963 ) using a 0 to 3 scale where normal =
0, mild inflammation = 1, moderate = 2 with bleeding on probing, and severe
inflammation = 3 with tendency to spontaneous bleeding.
 Probing Pocket Depth (PD) will be measured from the free gingival margin to the
base of the pocket, and will be recorded in whole millimeters. When taking probe
readings, the probe will be positioned parallel to the long axis of the tooth and
inserted to the base of the sulcus at the line angle. The probe will be walked in
each of the six sextants (mesiofacial, midfacial, distofacial, mesiolingual, midlingual
and distolingual) and the deepest reading will be recorded for each tooth sextant.
For the interproximal sextants, the probe will be angled slightly in order to insert into
the col space as close to the mid-interproximal area as possible. If a PD reading
falls between two-mm readings, the rule shall be to round up to the nearest mm.
 Bleeding upon Probing (BOP) will be recorded as presence or absence during
probing measures
 CEJ Measure will be measured from the cementoenamel junction (CEJ) to the
gingival margin and will be recorded in whole mm. If a reading falls between twomm readings, the rule shall be to round up and record the higher of the two
readings. If the gingival margin occurs coronal to the CEJ, the CEJ measure will be
recorded as a positive value. If the gingival margin occurs apical to the CEJ, the
CEJ measure will be recorded as a negative value. CEJ measurements will be
taken at the same site as the recorded deepest sulcus depth at each site.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK

Clinical attachment level (CAL) will be calculated as PD minus CEJ and shall
reflect the linear distance from the CEJ to the base of the pocket. CAL shall not be
recorded on case report forms, but rather will be calculated during the computer
analysis of data.
6.0
6.1
DENTAL EXAMINER CALIBRATION PROCEDURE
Introduction
Periodontal determination of plaque (PI), gingival inflammation (GI), gingival bleeding
(BOP), pocket probing depths (PD) and clinical attachment levels (CAL) are customarily
used in clinical studies to measure the disease status of periodontitis and to measure
effects of periodontal therapy. The measurement of these periodontal parameters poses
several limitations and technique-sensitive sources of variability. Probe penetration and
depth may vary with the degree of inflammation, probing force, angulation, position and
instrument tip diameter. Other confounding factors include patient discomfort, accuracy of
probe markings, anatomical differences in tooth crown and roots, and technique variability
within and between examiners. Thus, all of these measurements are important response
variables for inclusion in periodontal clinical trials.
Studies evaluating the efficacy of therapeutic interventions for periodontal disease require
stringent control of measurement error. In studies involving more than one examiner, use
of these assessment parameters must be based on acceptable levels of inter-examiner
variability. The levels of intra- and inter-examiner reliability should be determined for each
examiner and center involved in a clinical trial by the performance of a calibration session.
A training exercise with a standard examiner (SE) will help to standardize to a common
measurement technique and to a common definition of measurement parameters. An
interactive calibration session will enable the investigators to quantify the measurement
variability among and between examiners and enable the optimization of the measurement
process. Prior to the start of any clinical trial investigating a periodontal therapeutic, a
calibration session will be conducted according to the guidelines set forth in this document.
6.2
Summary
The purpose of an examiner calibration session is to quantify intra- and inter-examiner
reliability of measuring periodontal soft and hard tissue parameters. Chairside and bedside
calibrations will be conducted. Examiner dental chairside calibrations take place at the
University of North Carolina School of Dentistry, GO Health Center. Dental calibrations at
bedside are conducted at the Caviness General Clinical Research Center at the University
of North Carolina School of Medicine and UNC Hospitals. A sample of persons with
evidence of adult periodontitis are recruited to serve as calibration subjects. Each
examiner will assess PI, GI, BOP and PD and CAL using the manual University of North
Carolina (UNC) probe. Prior to arrival in Chapel Hill, examiners will review the study
manual. The training session will begin with a review seminar. The standard examiner
(SE) will go over the criteria being used for each aspect of the examination and will answer
questions. The structure of the calibration session will be described. The seminar will also
23
MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
include a review of the clinical procedure manual, use of the specific indices,
instrumentation, case scenario slides, and demonstration models. A review of the use of
the direct data entry system (DDES) will also be conducted. During the calibration
session, data will be entered directly into the computer to allow for a comparison of data
calls. Thus, examiners will have an opportunity to become familiar with the data entry
program during the calibration. In addition, laboratory procedures for the collection,
shipping, and handling of biological specimens will be addressed. One practice calibration
subject will be examined by each examiner with the SE observing and providing direct and
immediate feedback on examiner technique. Examiners will practice taking a plaque
sample using the standard protocol described in the manual. After the practice calibration
subject has been examined, an opportunity is provided for discussion of the practice
session. Immediately following completion of data collection, scores will be printed and
compared for agreement within one millimeter. All disagreement calls will be discussed
and the call repeated on the subject in the presence of the SE. For PD and CEJ,
disagreement will be defined as a difference of more than 1 millimeter. At this point,
adjustments to the examiners' technique will be made. By the end of the second clinical
training day, we usually find that the SE and examiners are in close agreement.
Acceptable reliability for PD and CEJ measures are inter-rater/inter-examiner reliability
scores of at least .60 or above and intra-rater or intra-examiner reliability scores of at least
.75 or above. In our experience, most examiners exceed these minimum scores.
Examiners will return to their respective field center and will examine 5-10 “trial patients”.
They will then ship the examination data and biological specimens to study investigators at
the UNC School of Dentistry, Chapel Hill, where the data will be evaluated. When the
investigators are satisfied that the examiners can consistently follow the protocol, the
examiners will be given written permission to begin examinations in the field. Centralized
training sessions will be repeated annually.
7.0 PLAQUE, SERUM, PLASMA AND LEUKOCYTE BUFFY COAT SAMPLING
Four plaque samples will be collected during the periodontal exam visit. Plaque will be
sampled from the deepest probed site in each quadrant. The site is isolated with a cotton
roll and gross supragingival plaque or debris is removed. Samples are taken by placing a
sterile curette (preferably with a long straight shank) at the base of each sulcus, adapting the
cutting edge to the surface of the tooth and using a single upward exploratory stroke. Each
plaque sample will be stored separately at -40 or lower in a labeled vial containing TE and
sodium hydroxide will be added after collection and the sample vortexed by hand. Samples
are then shipped to UNC School of Dentistry to be stored for future microbiological analysis.
Blood will be collected for future analysis for serum, plasma and leukocyte buffy coat. Two 57ml vacutainer tubes of peripheral blood obtained by venipuncture of the antecubital area
will be collected for the purposes of this study. Usually this is done during a routine obstetric
blood draw and does not require an additional venipuncture. If needed, however it can be
collected during the dental baseline visit. All blood samples will be processed, labeled and
stored in –80 freezers until processed. Details appear in Manual of Procedures
24
MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
8.0
OBSTETRIC MEASURES AND SAMPLES
An extensive medical history, OB history, medications history, and OB progress notes
summary and discharge data set are collected. It is recognized that BV, STD and
chorioamnionitis are major clinical and subclinical risk factors that must be considered as
potential confounders. Thus, in addition to clinical signs and symptoms and treatment
indications, clinical samples will be collected for the post-hoc assessment of subclinical
disease. During the first OB visit a smear for gram stain will be taken and read for Nugent
scoring for bacterial vaginosis will be taken. Furthermore accurate gestational age
determination is critical to the outcome measure and will be obtained by ultrasound,
obtained as early as possible, but no later than 24 weeks gestational age.
Among the current best clinical indicators of preterm birth risk include cervical length and
fetal fibronectin, especially among those with previous preterm deliveries. Thus, fetal
fibronectin will be obtained by sampling the vaginal fluids in the region of the posterior
fornix and quantifying of fetal fibronectin by ELISA methods. Dacron vaginal swabs for
fibronectin will be collected on all mothers. Because costs prohibit performing transvaginal
ultrasounds on all study subjects, this information will not be collected.
8.1
Fetal Fibronectin
Fetal fibronectin samples must be collected prior to any other vaginal sample,
manipulation of the cervix or vaginal tract. During a sterile speculum examination a
Dacron swab will be lightly rotated around the external cervical os for approximately 15
seconds and then across the posterior vaginal fornix for an additional 15 seconds to
absorb cervicovaginal secretions. Subsequent attempts to saturate the swab may
invalidate the test. Only a Dacron swab should be used for the sample collection, cotton
swabs are not acceptable. While collecting the sample care should be used to avoid
obvious mucus aggregates and the swabs should be lightly rotated to prevent collection of
unnecessary cellular materials. Once the swab has been saturated immerse the Dacron
tip in the buffer. The shaft will be aligned with the top of the tube and broken at the score.
The shaft will then be aligned with the hole inside the tube cap and the pushed down lightly
while securing the cap. It is important to align the shaft to prevent leakage. The sample
will be stored for future analysis.
8.2
Vaginal Microbial Flora
Vaginal samples for microbial analysis will be collected from the posterior vaginal fornix
and the cervical os. These samples will be obtained after the fetal fibronectin samples and
before the vaginal pH measurement. Sterile paper points should be attached to ring
forceps and inserted into the vaginal tract at the posterior vaginal fornix. The paperpoints
should be gently rotated across the posterior vaginal fornix for approximately 15 seconds.
Remove the ring forcep insert the paperpoints into a microtube containing TE. A second
set of sterile paperpoints should be attached to the ring forceps and inserted into the
vagina at the cervical os. Once inserted the paperpoints should be gently rotated across
25
MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
the cervical os for approximately 15 seconds. Remove the ring forcep and insert the
paperpoints into a separate microtube containing TE. Once the samples have been
collected, sodium hydroxide should be added to both tubes, the lids secured and the tubes
vortexed. The samples will then be stored for future analysis.
8.3
Vaginal pH Determination
Vaginal pH samples will be collected after the vaginal microbial sampling. Using a dry
Dacron swab with a plastic shaft, take a vaginal secretion specimen from the upper third of
the vaginal sidewalls. Touch the swab to the reagent block on the ColorpHast indicator
strip. The pH must be read after the color has stopped changing but, before the paper
dries completely. Record the vaginal pH as indicated in the MOP. Only ColorpHast strips,
stored away from light, should be used to obtain vaginal pH. If the color falls between two
values on the chart, round up. Do not interpolate between two values.
8.4
Vaginal Gram Stain
A Gram stain from the vaginal sidewalls will be collected after the vaginal pH. Either
using a dry Dacron swab or the swab from the vaginal pH, take a vaginal secretion from
the upper third of the vaginal sidewalls. the swab should be gently rolled across the entire
glass slide, from end to end, avoiding blobbing and in a thin layer. The slide should be
fixed by allowing to air. A barcode with the patient identification code will be fixed to the
slide. The slide will then be stored for future analysis.
8.5
Maternal Blood Samples
Maternal blood samples for the study will be drawn at the baseline OB appointment.
These are performed only once, prepartum, to provide a serum tube and a CPT tube for
buffy coat and plasma. Details appear in the Manual of Procedures.
9.0
NEONATAL MEASURES
The principle and secondary outcomes for this study require the collection of gestational
age as determined by ultrasound and confirmed at birth by Dubowitz and delivery birth
weight. APGARS at one minute and at five minutes will also be determined. We also will
employ a composite neonatal outcome. This composite outcome is consistent with a
composite neonatal outcome used by the Maternal and Fetal Network and is contains the
following conditions:
 Fetal demise subsequent to randomization
 Infant death prior to discharge from hospital to home or a chronic care
facility
 Respiratory Distress Syndrome (RDS)
 Documented neonatal sepsis
 Significant intraventricular hemorrhage (IVH grades 3-4)
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK

Necrotizing enterocolitis (NEC stages 2-3)
Neonatal histories will be monitored by baby discharge summaries and daily surveillance
of the neonatal intensive care unit (NICU). The primary flag is admission to neonatal
intensive care. This will be followed on a daily basis for any infant entering the NICU, and
the event will be reported within 48 hour to the data coordinating center and forwarded to
the DSMB every 3 months. Critical issues that will be addressed by abstraction of the
neonatal discharge summary are the need for O2, any chronic lung disease of preterm
birth, sepsis, GBS infection, neonatal periventricular leukomalacia from ultrasounds on
very low birth weight infants and any events of necrotizing enterocolitis. As stated before,
these are important safety measures.
10.0
PARTICIPANT IDENTIFICATION
At screening, participants will be assigned a unique sequential 6-digit identification
registration number and accompanying digits or letters that comply with a bar
coding scheme to identify study, location, participant visits and samples acquired.
This unique identifier will be used for patient randomization assignment to treatment
group, to assure confidentiality, as well as patient and sample blinding.
11.0
TREATMENT PROCEDURES
Periodontal treatment procedures will be performed according to the randomization
assignment. The study site will institute a patient and specimen tracking system that
will accomplish the aims of the study but not interfere with the procedures of the OB
clinic or impede medical care. There are no OB treatment implications for this study,
as prenatal care will be provided as indicated by the primary OB physician and staff
without regard to the conduct of this study. All OB prenatal procedures will be in
accord with the standard of care and there are no OB treatments that would make
any patient ineligible or censured. Furthermore, the OB physicians and staff will not
know the periodontal treatment group assignment of the mother. All periodontal
treatments are consistent with the current standard of care for periodontal treatment
of pregnant women.
11.1
Periodontal Treatments
Scaling and root planing will be performed using anesthesia, if indicated. This will
be performed one quadrant at a time and finishing all four quadrants to completion
in 1 to 4 visits. All scaling and root planing procedures must be completed prior to
236 weeks gestational age. Hand instruments and ultrasonic devices may be used.
Patients are also give an oral prophylaxis with a rubber cup and prophy paste and
provided with oral care instructions and materials as described in the Manual of
Procedures.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
11.1.1
Investigational Materials
All subjects will receive a new manual toothbrush. Toothbrushes will be provided
for distribution to all subjects. Subjects will be instructed to brush as they would
normally. Appropriate quantities toothpaste will be provided for distribution to all
subjects in both groups. Sufficient product shall be provided for the subject and all
family members in the household.
12.0
POST-PARTUM EXAMINATION AND BIOLOGICAL SAMPLE COLLECTION
After the subject delivers the baby, oral and perinatal clinical data and biological
samples will be collected while she is still in the hospital. Samples collected in labor
and delivery include maternal blood, placental biopsies, and fetal cord blood that
are collected, processed and shipped to UNC for processing. At the post-partum
visit additional samples will be collected bedside and include oral plaque samples.
Bedside exams will be performed to collect periodontal clinical data. Additional
maternal interviews are conducted and neonatal data are collected until the baby is
discharged. The study personnel will conduct a postpartum interview that includes
questions about exposures prior to and during the current pregnancy, support
provided by family members during the current pregnancy and contact information
for future use. Mothers who were randomized to Group 2 will be scheduled for their
periodontal treatment (Study Visit 4).
13.0
POST-PARTUM SCALING AND ROOT PLANING (GROUP 2 ONLY)




14.0
A scaling and root planing appointment will be conducted approximately 4
weeks after delivery.
The dental health care provider will perform an oral soft tissue screening for
adverse events and will evaluate periodontal inflammatory status through
visual examination.
The study dental health care provider will perform conventional scaling and
root planing periodontal therapy incorporating clinical judgment for the use of
local anesthesia. Hand instrumentation will be supplemented with ultrasonic
scaling per standards of care. If more than 1 visit is required for the
periodontal treatment, additional appointments will be scheduled as needed.
Full mouth prophy polishing will follow the scaling and root planing.
The dental health care provider will monitor for safety and adverse events.
SAFETY EVALUATIONS
Patient demographics, medical history, vital signs, medications and infections will be
reviewed from the OB patient record. At every study visit, patient vital signs will be
assessed including pulse, respiration, and blood pressure.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
14.1
Oral safety
At each dental study visit an assessment of the subjects' extra- and intra-oral structures
will be conducted. Each examination will include a survey of the face, lymph nodes, lips,
buccal mucosa, floor of the mouth, tongue, hard and soft palates, gingiva, edentulous
ridges and teeth. Findings will be recorded as normal or abnormal. In particular, oral soft
tissues will be evaluated as part of safety monitoring and documentation will be given to
the participant for referral purpose. The attending dentist will be available to all patients for
urgent dental care.
14.2
OB Safety
Data will be collected and recorded at each visit regarding adverse events reported by
subjects. OB charts will be monitored weekly by the research RN and adverse events
documented. Any patient who fails to make a scheduled appointment will be contacted by
phone within one week. Additional details of OB surveillance appear in the Manual of
Procedures.
14.3
Oral Rescue treatments
The attending dentist will see any patient with oral complaints for evaluation and
management. Appropriate urgent care treatments will be offered to all patients with
dental emergencies.
14.4
Neonatal Safety
As described previously, neonatal intensive care unit admissions will be monitored
daily and findings from neonatal discharge summaries reviewed.
15.0
OBSTETRIC & NEONATAL MONITORING, DATA CLOSURE AND ANALYSES
Patient enrollment will end at approximately 48 months. If the last mothers are
enrolled at 48 months then the last mothers should deliver at approximately 54
months, providing 6 months from the last delivery to check, clean and close the
database. A postpartum maternal database will have been constructed to collect
interview data and data abstracted from the subject's chart (written and electronic)
at the completion of the pregnancy. These data include delivery information for the
current pregnancy, updated maternal medical history, changes to previous and
current pregnancy history and documents any obstetric or neonatal complications
that were diagnosed perinatally. For any subject whose placenta is sent to
pathology for diagnosis, a pathology report will be generated.
A neonatal database will have been created to collect information on each infant
beginning at delivery. This database will collect gestational age (based upon
ultrasound), birth weight, infant length, and head circumference for all infants. For
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
infants needing intensive care attention additional information will be collected.
These data include morbidity and mortality outcomes that will be used to create: a
composite perinatal outcome assessment score including at least one of the
following: fetal demise subsequent to randomization, infant death prior to discharge,
type 1 respiratory distress syndrome (includes Hyaline membrane disease and
respiratory insufficiency of prematurity) and documented neonatal sepsis, Grade 3-4
IVH (intraventricular hemorrhage) and Stage 2-3 NEC. For infants admitted to the
intensive care unit, information will be collected until the infant is discharged from
the hospital. Spontaneous abortions, neonatal deaths, neonatal admissions to the
ICU, respiratory distress, NEC, sepsis and GBS will be recorded to assess the
potential effects of periodontal therapy on these events. These parameters will be
considered in the context of gestational age and obstetric complications. These data
will be reported to the DSMB for evaluation.
16.0
EXAMINER CALIBRATIONS
All clinical examiners will be calibrated and certified prior to commencement of the
study for training of study procedures and for documentation of acceptable intraand inter-examiner measurement reliability. Both chair side and bedside calibration
will be performed. Calibration for cervical length determinations will be conducted
via a training session and certification process. These calibration procedures are
described in the Manual of Procedures.
17.0
CONDITIONS FOR DISCONTINUING SUBJECTS
Subjects in this clinical study may be discontinued for the following reasons: 1) death and
2) withdrawal of consent.
18.0
SERIOUS ADVERSE EVENT REPORTING
A serious adverse event is “any untoward medical occurrence that results in death, is
life threatening, requires or prolongs hospitalization, causes persistent or significant
disability or incapacity, results in congenital anomalies or birth defects or, in the opinion
of the investigators, represents other significant hazards or potentially serious harm to
research participants or others (From Section 3.1 of “Guidelines for Developing a
Manual of Operations (MOP)”, National Institute of Dental and Craniofacial Research,
drafted 15 November 2002.)
All serious adverse events will be recorded although a distinction will be drawn between
reactions normally experienced in conjunction with conventional periodontal therapy and
experiences not usually encountered. Details of monitoring schedule appear in Chapter 10
of the Manual of Procedures and include a two week follow-up after periodontal therapy
that increases to weekly during the last trimester.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
Unanticipated adverse events will be evaluated by weekly OB patient chart reviews by the
OB research nurse. The onset, duration, treatment, and outcome of all such unanticipated
adverse experiences must be recorded on the appropriate case report forms.
In the event of a serious adverse experience the site’s principal investigator will contact the
DSCC within 5 days. The DSCC will report to the DSMB and NIDCR according to the
guidelines established by those groups. Sites are responsible for their own IRB reporting.
Any adverse experience that is determined to be reportable to the Regulatory Authorities
should be promptly reported to the Institutional Review Board (IRB).
19.0
19.1
DATA ANALYSIS AND STATISTICS
Sample Size Determination
The sample size for the study was determined using Specific Aim 2. At the time the grant
was awarded, the current Specific Aim 2 was Specific Aim 1. At the first DSMB meeting
the Board members expressed concern that the assumptions used were optimistic and
recommended that Specific Aims 1 and 2 be interchanged, with the sample size left
unchanged. This section describes how the sample size was determined using the original
Specific Aim 1 (now Specific Aim 2). The next section discusses the power for the current
Specific Aim 1 for the chosen sample size
Specific Aim 2 involves comparing the proportions of neonates having gestational age
(GA) <35 weeks across the two treatment groups. Power calculations were performed
using a test of equality of the two proportions, assuming a total sample size of 1800 split
equally across the two groups. All statistical tests are assumed to use  = 0.05. Power
calculations were done using nQuery Advisor 4.0.
In the UAB pilot trial that has been recently published (J of Periodontology 2003; 74:12141218) the rate of GA<35 weeks presenting in the untreated group was 6.4%.and the rate
among women treated using scaling and root planning was 0.8%, an 87% reduction. We
base our sample size on a rate of 6% in group 2 (delayed periodontal therapy) versus 2%
in group 1 (periodontal therapy during pregnancy). These rates are somewhat more
conservative than those observed in the UAB pilot trial and include an allowance for
women to receive a treatment other than the one to which they were assigned. On top of
these rates we assume a loss to follow-up rate of 3% in each group. This 3% rate is
conservative as the rate in the pilot trial was 0.5% (2 out of 368). In addition we are adding
the 3% loss to follow-up rate to each group under an intent-to-treat assumption, with the
further assumption that all individuals lost had a preterm birth. (If there is differential loss
to follow-up, analyses will be conducted with and without the latter assumption and both
results would be reported. Adding this 3% yields rates of GA<35 week of 9% versus 5%.
In this situation a sample size of 900 per treatment group will give power of 91% to detect
such a difference between the two treatment groups. The table below shows the effect on
the power of deviations from our assumptions about rates in the two groups and of
recruiting fewer subjects.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
19.2
Effect size detectable with study sample size
We determined the effect size detectable with 90% power for the same sample size and
statistical and loss to follow-up assumptions as the previous section. Without periodontal
treatment during pregnancy, the rate of GA<37 weeks is likely to be about 20%. If it is
20%, then we will have 90% power to detect a 6.3 percentage point treatment effect (that
is, a GA<37 rate of 13.7% in the women treated during pregnancy. If the GA<37 rate in
the delayed treatment group is just 16% we will have 90% power to detect a 5.8
percentage point difference.
The second part of Specific aim 2 involves comparing birth weights across treatment
groups among neonates with GA <37 weeks. In the UAB pilot study the rates of GA <37
weeks were 13.7% and 4.0% for treatment groups 1, and 2, respectively. We assumed a
standard deviation of 0.55kg for birth weight among neonates with GA <37 weeks. This
estimate was obtained using data from the Tasmanian Infant Health Survey. Under these
assumptions and using a two-sample t-test with 900 subjects per group, we have 90%
power to detect a difference of 0.34kg between the mean weights in the two treatment
groups. If the standard deviation of birth weights within each group is 0.6kg rather than
0.55kg the difference detectable with 90% power increases to 0.37kg. If the proportions
with GA<37 weeks are 10% and 5% and the standard deviation of birth weights is 0.55kg
then we have 90% power to detect a difference of 0.33kg. Truncation at GA <37 weeks is
likely to result in skewed distributions of birth weight within each treatment group. Thus
our primary analysis for this aim will use a non-parametric test rather than a t-test. This
will reduce the power somewhat from the estimates given here.
19.3
Data analysis
The Data and Statistical Coordinating Center will have primary responsibility for performing
data analysis for the writing groups developing core manuscripts and presentations. It will
also be responsible for preparing detailed data reports at regular intervals for the Steering
Committee. The CSCC has been producing analyses for writing groups, DSMBs, Steering
Committees, and policy boards of collaborative studies for more than 30 years (including
the LRC, SOLVD, ARIC, ACAS, STILE, DAIS, and COMBINE studies). We are
experienced in producing statistically sound tables and graphs that are easily understood
by non-statisticians. For details of the analyses to be conducted, see the Analysis of
Endpoints sub-section later in this section.
19.4
Analysis of endpoints
Specific Aim 1: The primary endpoint will be evaluated in an intent-to-treat analysis using a
test of equality of two proportions. If the number of subjects in each cell is sufficient a chisquared test will be used, else Fisher's exact test will be used. Success of the
randomization and even distribution of possible confounders will be evaluated. If there
appears to be an unequal distribution of important confounders then as a secondary
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
analysis a logistic regression model will be used to adjust for these factors. Potential
confounders that will be considered are discussed below.
The first part and third parts of Specific Aim 2 (comparisons of rates of GA<35 weeks and
of neonatal morbidity/mortality, respectively) will be analyzed in the same way as Specific
Aim 1. The second part of Specific Aim 2 is to determine whether birth weight among
those infants with GA<37 weeks differs by treatment group. The truncation of gestational
age at 37 weeks is likely to yield a skewed distribution of birth weights within each
treatment group. Thus we propose using a non-parametric test (Kruskal-Wallis test) as the
primary analysis for this specific aim. Secondary analyses will use parametric models. In
order to adjust for covariates in secondary analyses we will investigate transforming the
birth weight to improve the normality of residuals in a linear model. The first such model
will include an adjustment only for gestational age.
Analyses will be conducted using the intent-to-treat philosophy. The length of gestation is
relatively short and information on the primary outcomes of interest should be obtainable
from maternity clinics, so even if subjects drop out of the study the number with missing
outcome information should be negligible. More problematic are pregnancies that do not
end in a live birth (such as miscarriages). These will be reported to the DSMB as adverse
events but also need to be considered in the analyses of the primary outcomes. For the
primary outcome we intend to regard such events as having GA<37 weeks. For Specific
Aim 2 assessing birth weight, all deliveries whether live or stillbirths will be used for
analyses.
Analyses for specific aims will also include investigation of possible effect modification by
race/ethnicity. We do not have evidence to suggest such effect modification and the study
is not powered to test for it. However, regardless of whether there is significant effect
modification by race/ethnicity, we will also report results within each race/ethnic group.
19.5
Interim Analyses for Efficacy & Safety
There are three potential reasons for ending a trial early: 1) harmful effects of the
treatment being used may be discovered, 2) efficacy of the treatment may be proved, or 3)
there may be no remaining hope for a reasonable evaluation of the proposed hypothesis.
The DSCC will report regularly to the DSMB on adverse events, irrespective of whether
there is any reason to suspect they may be harmful effects of the treatments.
We propose conducting two interim analyses for efficacy, with these analyses being
conducted after 600 and 1200 completed pregnancies. The primary outcome is length of
gestation and the maximum length of gestation is known and relatively short. Thus it is
feasible to specify doing the interim analyses after specified numbers of completed
pregnancies rather than at specified times. We propose using O’Brien-Fleming type
boundaries 38 as the decision criteria at the interim analyses for efficacy. To allow for extra
interim analyses to be requested by the DSMB or variation in the exact timing of the
analyses, we will use the Lan-DeMets alpha-spending function modification of the O’BrienFleming boundaries 39. In addition, conditional power as proposed by Halperin 40, will be
33
MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
used in the decision to stop the trial if the difference between treatments is small. This
method computes the conditional probability of rejecting the null hypothesis given a
specific alternative and the data already collected at the time of the analysis. If this
probability is too small, one may choose to discontinue the trial. Computationally, we will
use a generalization of the method of Lan and Wittes 41.
20.0 ETHICAL AND REGULATORY REQUIREMENTS FOR PROTOCOLS INVOLVING
HUMAN SUBJECTS
20.1
Study Conduct
The investigator agrees that the study will be conducted according to the principles of
Good Clinical Practices (GCP) and the Declaration of Helsinki. The investigator will
conduct all aspects of this study in accordance with all national, state, and local laws of the
pertinent regulatory authorities.
The principal investigator must sign the Investigator’s Statement (see section 11.0) and
provide a copy of a current Curriculum Vita for each study team member
20.2
Informed Consent
The study's informed consent document must be provided to the respective institutional
Investigational Review Boards for final approval. Before recruitment and enrollment, each
prospective patient candidate will be given a full explanation of the study, and allowed to
read the approved informed consent form. Once the investigator is assured that an
individual understands the implications of participating in the study, the subject will be
asked to give consent to participate in the study by signing the informed consent form.
The investigator will provide a copy of the signed informed consent form to the subject.
20.3
Institutional Review Board or Ethical Review Committee
Before initiation of the study, the investigator must obtain approval of the research protocol
and informed consent form from an IRB complying with the provisions specified in 21 CFR
Part 56 or applicable pertinent governmental regulations. The investigator must assure
IRB compliance with the applicable regulations.
The investigator is responsible for obtaining continued review of the clinical research at
intervals not exceeding one year or otherwise specified by the IRB.
20.4
Protocol Amendments and Emergency Deviations
Changes to the research covered by this protocol must be implemented by formal protocol
amendment. Amendments to the protocol may be initiated at the request of the
investigator. In either case, a formal amendment cannot be initiated until it has been
signed by the investigator and approved by the IRB.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
20.5
Monitoring of the Study
This will be performed by the coordinating center, as described in the Manual of
Procedures.
20.6
Study Records
All study records will be stored centrally at each clinical performance site maintaining
patient confidentially. Primary medical source documents will be abstracted to create a
separate obstetrical dataset that will augment the questionnaire information.
A
standardized data instrument will be used to collect medical and dental data on all
subjects.
20.7
Inspection of Records
This will be performed by the coordinating center, as described in Manual of Procedures.
21.0
INVESTIGATOR’S STATEMENT
I agree to conduct the trial as outlined in the protocol in accordance with the NIDCR's
guidelines and all applicable government regulations including proposed Part 54:
Obligations of Clinical Investigators of Regulated Articles.
These guidelines and
regulations include, but are not limited to:
*
Permission to allow the NIDCR or other regulatory agencies to inspect study facilities
and pertinent records at reasonable times and in a reasonable manner that ensures
patient confidentiality
*
Submission of the proposed clinical investigation including the protocol and the
consent form to a duly constituted IRB for approval and acquisition of written approval
for each prior to the use of the test article.
*
Use of written informed consent that is obtained prior to administration of test articles
containing all the elements of consent as specified in 21 CFR 50.25 of the federal
regulations and that has been previously approved by the NIDCR and the IRB.
*
Submission of any proposed change in or deviation from the protocol to the IRB using
a signed formal amendment document prepared by the NIDCR. Any proposed
changes or deviations from the protocol require that the informed consent also
reflects such changes or deviations and that the revised informed consent be
approved by the IRB.
*
Documentation and explanation of individual protocol deviations on the appropriate
CRF page or in letters to the NIDCR.
35
MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
*
Submission of reports of serious adverse events as outlined in the protocol to the IRB
and NIDCR within 10 working days.
*
Submission of timely progress reports to the IRB and NIDCR at appropriate intervals
on a schedule determined by the IRB.
*
Record keeping; federal regulations (21 CFR 31 2.62) require an investigator to
prepare and maintain adequate and accurate case histories designed to record all
observations and other data (such as test article accountability) pertinent to the
investigation on each individual enrolled in the study. The investigator must maintain
these records for a period of at least two years following completion of the study
report.
I agree that all information provided to me by the NIDCR including pre-clinical data,
protocols, CRFS and verbal and written information will be kept strictly confidential and
confined to the clinical personnel involved in conducting the trial. It is recognized that this
information may be related in confidence to the IRB. I also understand that no reports or
information about the trial or its progress will be provided to anyone not involved in the trial
other than the NIDCR, or in confidence to the IRB or the NIDCR or other legally constituted
authority.
______________________________
Principal Investigator (Signature)
___________________
Date
______________________________
Principal Investigator (Print)
______________________________
____________________
______________________________
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
22.0
HUMAN SUBJECTS
The following details regarding the use of Human subjects applies to all three performance
sites.
22.1
Risks to the Subjects
22.1.1 Human Subjects Involvement and Characteristics:
All pregnant women presenting for prenatal care between 16 0 and 236 weeks gestational
age will be invited to enroll in the periodontal treatment study, but is limited to women the
age of 16 and over (age of legal consent). All patients will be seen by their primary care
OB nurses and physicians who will manage their comprehensive obstetric care in a routine
manner using protocols recommended by the American College of Obstetricians and
Gynecologists. This study does not in any manner, influence, or modify the obstetric,
perinatal or neonatal care received by the subjects. The experimental trial is to determine
whether providing periodontal care during pregnancy decreases the overall incidence of
pregnancy complications. Thus, the intervention component is periodontal care, but we are
collecting data by observing the obstetric outcomes. The dental component will be
provided by licensed dental professionals and all treatments are in accordance with ADA
(American Dental Association) and AAP (American Association of Periodontology)
guidelines for examining and treating periodontal conditions in pregnant women. None of
the periodontal examination or treatment procedures are experimental as they reflect the
procedures and standard of care that might be delivered in the private dental sector in the
second trimester of pregnancy. After obtaining informed consent pregnant mothers will
have a short oral screening exam that consists of periodontal probing measures, checking
for the presence of gum disease. If disease is present, mothers will be asked to consent to
participate in the full MOTOR study (Maternal Oral Therapy to Reduce Obstetric Risk).
Subjects must be willing to be randomized to one of two treatment arms. The two
treatments are procedurally identical in nature, but one group (Group 1) receives
periodontal treatment early in the second trimester and the other group (Group 2) receives
care post-partum. The timing of the therapy for Group 1 is in accordance with standard
ADA guidelines which recommend that the periodontal care should be delayed until the
second trimester to be beyond the organogenesis embryonic stage and to be prior to the
third trimester to minimize both maternal and fetal stress. The diagnostics performed are
routine manual examinations with periodontal probes and will not necessitate radiographs.
The care provided may include local anesthesia, the use of hand and ultrasonic
instruments, but are not generally regarded as invasive or surgical procedures. At postpartum a repeat oral examination is performed in the hospital, prior to discharge. Mothers
will be inconvenienced by the additional dental examinations, the oral interviews and
dental treatments, but will gain improved oral health. We recognize that certain mothers
will also receive systemic antibiotics to manage OB/Gyn. Conditions, such as bacterial
vaginosis (BV) or STDs and that these may impact our periodontal status or effects of
therapy. We will monitor these treatments only and will not have any impact on the clinical
decisions regarding the clinical management of those conditions. It is expected that the
effect of systemic antibiotic usage should be randomized across treatment groups, but we
will be able to correct for any unbalanced treatments post-hoc. Also, any research findings
that are generated as part of this study, such as the independent reading of vaginal
37
MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
smears for the determination of subclinical BV, will not be conducted as CLIA laboratory
analyses, therefore these results will not be used for the clinical management of the
patients and the data will be separate from the patient’s clinical chart.
As this is a study on pregnancy outcomes in women with periodontal disease, all members
of the study population will be women who are pregnant. Members of minority racial
groups will be encouraged to participate so that our study population mirrors the minority
composition of the three communities.
All women will have the study explained to them orally. Women agreeing to participate in
the study protocol will sign a consent form agreeing to participate and will be given a copy
of the consent. The protocol will be submitted to the Institutional Review Board for the
protection of human subjects at each of the respective institutions for review and approval.
In addition the UNC Go Health Center will be calibrating examiners for MOTOR. This
training is administratively under a separate clinical protocol that involves the use of
patients who participate in the oral examination for initial certification of examiners and
periodic recalibration. These subjects who are examined in both dental units and hospital
settings are covered under a separate Human subjects IRB protocol and informed
consent. Finally, there is also a truncated “study screening only” informed consent that is
used to check these mothers for the presence or absence of periodontal disease for
eligibility purposes. This also includes an oral cancer screening done only for the benefit of
the subject. For the purposes of this application and human subjects discussion, these
latter two protocols and informed consent are not discussed, as they are covered under
existing approved protocols.
22.1.2
Sources of Materials :
Human specimens will include maternal plaque, maternal blood for DNA, vaginal fluid
samples and maternal serum. At the time of delivery placental biopsies will be collected
and fetal cord blood will be processed for serum. Maternal blood will be drawn for obstetric
purposes for clinical reasons and an additional aliquot collected during the same blood
draw will be utilized for research purposes. During the routine speculum examination at the
prenatal visit additional swabs of the vaginal fornix will be performed for research
purposes. Maternal plaque will be sampled from the teeth during the oral examination and
stored for research purposes. Placental biopsies are routinely taken for histology for all
preterm deliveries. Additional biopsy fragments will be collected for research purposes.
Fetal cord blood is normally discarded, but will be collected for research purposes in this
investigation. Clinical and history data will be collected by oral examination, patient
interview and medical chart abstraction. These will involve the creation of secondary
computerized source documents for the study which will be maintained separate from the
patients’ medical records and identified only by study participant ID number. All biological
samples are also identified by the patient ID number only.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
22.1.3 Potential Risks:
This is a non-invasive protocol. Periodontal examinations are performed post-partum in
accordance with the ADA and American Academy of Periodontology recommendations for
the clinical examination and management of periodontal patients. There may be some
minor discomfort during the periodontal examination, but it is minimal and is identical to the
types of diagnostic procedures carried out during a routine dental examination. Blood will
be collected from mothers during their routine blood draw and will not require an additional
phlebotomy. Cord blood samples are collected from the placenta postpartum and provide
no risk to mother or newborn.
Periodontal therapy is performed during the second trimester to minimize the obstetric risk
in accordance with the ADA and American Academy of Periodontology recommendations
for the clinical management of periodontal conditions during pregnancy. There is some
clinical risk associated with scaling and root planning (e.g. discomfort) venipuncture (e.g.
bruising), and the collection of vaginal samples (e.g. discomfort), but procedures are within
the normal risks associated with these dental and obstetric procedures.
Group 2 subjects will be identified for post-partum periodontal therapy. These individuals
will have delayed treatment of their periodontal condition. It is important to note that
patients who would have any acute severe or symptomatic dental problems that should be
addressed prior to delivery are specifically excluded from this study. That places the level
of oral disease within that which would be considered elective and would typically be
deferred until after delivery. If there should be an acute episode in either treatment group
the patient will be seen and receive urgent care by the study dentists.
Scaling and root planing with or without the use of local anesthesia as performed during
the second trimester of pregnancy is the current standard of care to treat periodontal
disease in pregnant women. The risks include mild discomfort during or after the
procedure. Excessive bleeding, sensitivity or post-operative discomfort is not anticipated.
There is a transient and acute mild bacteremia induced by scaling and root planning, but
this has not been perceived to represent significant risk. It is important to note that the
UAB pilot included this treatment arm and there were no adverse events reported for the
almost 200 subjects who had this procedure. Other clinical trials either in the literature or
underway (Moms 2B) are not experiencing any AEs. However, the data are far from
complete regarding this important issue of maternal and fetal safety. Therefore, it will be an
important contribution of this study to provide evidence regarding the safety of periodontal
treatment during pregnancy as it is possible that treatment may result in a transient
bacteremia that may influence the pregnancy outcome or the health of the neonate. For
this reason we have a surveillance plan in place that will be coordinated through the DSCC
and reported to the DSMB formed for this study that will perform oversight for the
expressed purposes of protecting human subjects. The group 2 subjects will have delayed
treatment. It is estimated that the treatment delay will be approximately 20 weeks. This
time frame is well within what would be acceptable delay especially among women were
not seeking dental care. These women are seeking obstetric care, not periodontal care.
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
Within our own university-based periodontal clinics, a 6 month waiting list is not unusual for
initial admission for screening examinations. Thus, a short delay is not normally perceived
to place the patient at risk for significant periodontal destruction, since this is a chronic,
slow-progressing condition. If however, the clinician perceives that the periodontal
condition is sufficiently problematic, that is either symptomatic or placing the periodontal
tissues at significant risk during the pregnancy, then the subject is not eligible for the study
and will be referred for care.
22.2
Adequacy of Protection against Risks
22.2.1 Recruitment and Informed Consent
Pregnant women arriving for their first prenatal visit will be approached by their physician
in the OB clinic and informed of the study. If they express interest, then the study
personnel (research nurse or dental hygienist) will describe the study to them. If the
potential subject remains interested, then informed consent for a screening exam will be
requested and the subject will be provided a copy of the signed consent form. If the
results of the screening exam indicate that the subject meets the periodontal inclusion
criteria as well as the other inclusion and exclusion criteria, the subject will be told that they
meet the criteria for the study, an accession number is generated, and an appointment is
made for the initial dental visit. At the first dental visit, detailed informed consent is
provided by the dental personnel and the subject is asked to sign the study consent form.
Informed consent will be maintained in the patient’s chart and a copy stored in the study
coordinator’s office.
All confidentiality and anonymity will be maintained by using an ID system that provides
patient data and links to biological samples but is not linked to patient identifiers.
22.2.2 Protection against Risk
The study biological sampling protocols do not confer significant additional clinical risk.
The subjects may withdraw from the study at any time and may also elect to have their
biological samples discarded at any time. Our bar-coding system that catalogues sample
location greatly facilitates the logging out of the study subject’s samples, retrieval from
storage and permanent destruction of biologicals. This function will be managed by the
DSCC and the UNC laboratory.
Safety is a critical concern and there are extensive safeguards in the study design that
have been discussed in Section C and detailed in the clinical manual in Appendix C. It is
noteworthy that Drs Jeffcoat and Hauth have already enrolled almost 400 subjects in this
treatment protocol and have had no adverse events and no significant problems with
patient tolerance of the periodontal treatments or antibiotic usage.
Mothers will have safety obstetric monitoring and antepartum evaluation to determine the
effects of periodontal therapy on the gestational age and weight of the newborn, as an
adjunctive therapy to the routine obstetric standard of care. The Coordinating Center will
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
provide reports to the NIDCR-appointed Data Safety Monitoring Board (DSMB) that will
periodically assess the progress and safety outcomes to assure that periodontal therapy is
not placing any mothers or neonates at unacceptable risk. These assessments will include
neonatal health problems including NEC (necrotizing enterocolitis), GBS (Group B
Streptococcal infection) and respiratory distress as an indicator of perinatal safety.
22.3
Potential Benefits of the Proposed Research to the Subjects and Others
We anticipate that periodontal treatment will significantly reduce the rate of preterm birth at
less than 37 and 35 weeks gestation and increase the mean fetal weight for those less
than 37 weeks gestational age. The UAB intervention trial has experienced a significant
87% reduction in preterm births at less than 35 weeks gestational age with no adverse
events, enrolling and treated 366 subjects of which 2/3 had scaling and root planing. This
clinical trial should provide practical new information to guide the proper management of
this common clinical problem and may eventually result in a dramatic change in the
standard of care to reduce the incidence and severity of abnormal pregnancy outcomes.
Mothers will benefit from having an oral examination that includes an oral cancer screening
and periodontal assessments. There are minimal risks; only possibility of slight discomfort
during the oral examination and treatments and this risk of discomfort is minimal compared
to the social, economic and emotional trauma that is a consequence of preterm delivery. It
has been our experience that women are anxious to contribute to any study that may lead
to improving our identification of potential causes of pregnancy complications. At the end
of the study, all patients are seen by a staff dentist for treatment recommendations and
appropriate referral for care. Thus, mothers will have an improvement in oral health as a
consequence of participation and possibly have beneficial impact on the pregnancy.
Mothers will also receive the benefits of oral care to reduce periodontal disease and they
will receive reimbursement for visits that include parking and other transportation
expenses. Additional study participation incentives may include free oral hygiene
instructions and oral care aids such as toothpaste and toothbrushes.
22.4
Importance of the Knowledge to be Gained
Despite improvements in prenatal care and in our ability to improve the survival and the
health of preterm infants, there has been no decrease in the overall rate of preterm
delivery in the US in the last 4 decades. The causes of this problem have not been
adequately identified to enable successful interventions. Periodontal disease represents a
preventable and treatable condition, which if demonstrated to be the cause of disparities
among those at highest risk- including the underserved minority populations, then these
data may have a significant impact on reducing the number of preterm deliveries among
this group. Each gram of neonatal birth weight under 2500g costs 75$ in NICU costs. Our
data in OCAP indicate that infants born between 28-32 weeks gestational age are on
average 400g smaller among mothers with periodontal disease as compared to gestational
age matched infants from mothers without periodontal disease. This translates into
approximately $30,000 of NICU costs and higher rates of long-term disability. Thus, the
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MOTOR: MATERNAL ORAL THERAPY TO REDUCE OBSTETRIC RISK
identification of a modifiable risk factor among these API pregnant women would have the
potential to have tremendous health and quality of life benefits.
22.5
Inclusion of Women
All subjects in this study are women. The earliest age of eligibility has been lowered from
18 to 16, which is in response to study section recommendations and consistent with local
laws regarding age of consent. It is important to note that these populations of younger
individuals who are at high risk for preterm delivery also have a much higher prevalence of
periodontal disease that predicted, based upon national studies of periodontal health
among adolescents and young adults, such as the NHANES study. It is our hypothesis that
this disparity may account for the increased risk for prematurity. It is also important to point
out that this periodontal disease in these individuals is not due to a clinical diagnosis of
juvenile periodontitis, as it does not follow the clinical presentation of this rather uncommon
condition. We propose to enroll women for 42 months beginning November 1, 2003 and
ending May 1, 2007.
22.6
Inclusion of Minorities
Our performance sites have been selected to provide representation for Whites, African
Americans, Hispanic/Latino and Others who are seeking prenatal care. No special efforts
are planned for outreach to enrich these populations within the clinical centers as the
proposed enrollment distribution of the clinics meets our need for racial and ethnic
diversity. The MOTOR study is being conducted within tertiary care facilities that are
normally enriched for high risk patients via the community referral system. Thus, mothers
with previous preterm deliveries and African Americans tend to be over-represented
relative to their proportion within the community at large. Since this sample represents a
high risk target group, the applicability of the findings may not be strictly generalizable to
all pregnant women. However, as with all intervention trials designed to test efficacy, the
study is targeted to those with the highest risk to provide the largest possible therapeutic
margin of benefit. We propose to enroll women for 42 months beginning November 1,
2003 and ending May 1, 2007.
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23.0
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