Objective
The purpose of this study was to test whether treating periodontal disease (PD) in pregnancy will reduce the incidence of spontaneous preterm delivery (SPTD) at ≤35 weeks of gestation.
Study Design
A multicenter, randomized clinical trial was performed. Subjects with PD were randomized to scaling and root planing (active) or tooth polishing (control). The primary outcome was the occurrence of SPTD at <35 weeks of gestation.
Results
We screened 3563 subjects for PD; the prevalence of PD was 50%. Seven hundred fifty-seven subjects were assigned randomly; 378 subjects were assigned to the active group, and 379 subjects were assigned to the placebo group. Active treatment did not reduce the risk of SPTD at <35 weeks of gestation (relative risk, 1.19; 95% confidence interval [CI], 0.62–2.28) or composite neonatal morbidity (relative risk, 1.30; 95% CI, 0.83–2.04). There was a suggestion of an increase in the risk of indicated SPTD at <35 weeks of gestation in those subjects who received active treatment (relative risk, 3.01; 95% CI, 0.95–4.24).
Conclusion
Treating periodontal disease does not reduce the incidence of SPTD.
Preterm birth, which remains a major public health issue in the United States, accounts for substantial morbidity and death. Unfortunately, the incidence of preterm birth has been largely unchanged in recent years, hovering at 12%. Over the past decade, research has focused on associations between clinical and subclinical infections and preterm birth. This research has led to a greater understanding of potential mechanisms by which infection and the resultant inflammatory response can lead to preterm birth.
For Editors’ Commentary, see Table of Contents
See related editorial, page 101
Destructive periodontal disease (periodontitis) is common, with a reported prevalence of >30% in some populations. There is substantial observational evidence from a variety of populations that links maternal periodontal disease to preterm birth, possibly because of the maternal inflammatory response to periodontal disease. Given the prevalence, biologic plausibility, and epidemiologic association of periodontal disease with preterm birth, we believed that an intervention that was targeted at periodontal disease treatment was an attractive 1 to examine, in the hopes of reducing the risk of preterm birth. Thus, the purpose of this study was to assess, in a randomized controlled clinical trial, whether treatment of periodontal disease in pregnancy could reduce the incidence of spontaneous preterm birth.
Materials and Methods
We performed a multicenter, randomized, controlled clinical trial of treatment of periodontal disease to reduce the incidence of preterm birth. Subjects were recruited from 3 prenatal care clinics in the metropolitan Philadelphia area. Patients between 6 and 20 weeks gestation were eligible for screening and enrollment. Gestational age was determined before random assignment in all subjects. The project estimated due date was based on a combination of last menstrual period and ultrasound, with standard pregnancy dating algorithms. Subjects were ineligible for the following reasons: periodontal treatment during the pregnancy, antibiotic use within 2 weeks, use of antimicrobial mouthwash within 2 weeks, multiple gestation, and known mitral valve prolapse.
Eligible women were screened for periodontal disease by trained research nurses or dental hygienists. Unfortunately, there is no single universally accepted measure of periodontal disease. For subjects with ≤10 natural teeth, all teeth were examined. For subjects with >10 teeth, a maxillary and mandibular quadrant was selected randomly. The random quadrants were selected in 2 steps. First step, nurses calibrated to perform the periodontal screening and recording examined every tooth in the mouth to determine eligibility. As a second step, calibrated dental hygienists, examined teeth and used a randomization code to select the random quadrant that qualified for the study.
Six attachment readings per tooth on the distobuccal, direct buccal, mesiobuccal, distolingual, direct lingual, and mesiolingual sites were taken. Periodontal disease was defined as attachment loss ≥3 mm on ≥3 teeth. Subjects who met this requirement were eligible for random assignment. Moderate-severe periodontal disease was defined as attachment loss of ≥5 mm on ≥3 teeth.
Patients with periodontal disease who returned for the scheduled treatment visit (within 2 weeks of screening) were then consented, randomly assigned, and enrolled into the study. Subjects were randomly assigned to receive either scaling and planing (active) or superficial cleaning (control). Randomization was accomplished centrally at the University of Pennsylvania, although each clinical site had its own randomization scheme. A permuted block randomization procedure was used to formulate assignment lists to assure close to equal numbers of subjects in each treatment group. A uniform block size of 4 was used.
Once randomly assigned, each subject received an assigned treatment by the trained dental hygienists. The following treatments were used:
Active treatment arm: scaling and root planing
This study procedure involved removing stains, plaque, and calculus above and below the gum line of the tooth. The root surface was left smooth and clean, thus removing the biofilm from the subgingival pocket that has endotoxins. After topical xylocaine was used on the gingivae, the hygienist used the rotating cup to remove stains and plaque from the supergingival portion of the tooth. The ultrasonic scaler was first used to remove the large pieces of calculus on the tooth and in the pocket between the gum and the tooth. Gracey curettes were used to clean and smooth the root surface. An explorer (dental instrument that is flexible and has a sharp tip) was run over the tooth to assure that the tooth was smooth and that the calculus had been removed. A rotating cup was used to remove plaque from the supergingival portion of the tooth with the use of minimally abrasive polishing paste.
Control treatment arm: superficial tooth cleaning procedure
This study procedure involved the removal of superficial stain and plaque from the tooth. This procedure is completely different than scaling and root planing because this cleaning was superficial. The hygienist used the rotating cup to remove stains and plaque from the supergingival portion of the tooth using minimally abrasive polishing paste. No sharp instruments were used for the subgingival removal of calculus.
We took precautions to blind the investigators to treatment assignment. The only exception to this was the hygienists who performed either the tooth polishing (control arm) or scaling and root planing (treatment arm), who by necessity were unblinded. The members of the investigative team who assessed our primary and secondary end points were blinded to treatment assignment.
We ensured that procedures for screening and treatment were standardized and monitored. Before the study started, a study investigator (M.J.) conducted training sessions that included demonstrations and 1-on-1 tutorials for each research nurse/dental hygienist. During the study, University of Pennsylvania dentists made weekly visits to each of the recruitment sites and randomly performed periodontal screens on 10% of the patients who were being screened for study eligibility by the hygienists/nurses.
Outcome: determination of preterm births
After active or control treatment was received, patients were observed and received prenatal care by their primary obstetricians, who were also blinded to study treatment allocation; this care was entirely at the subjects’ and providers’ discretion. The primary study outcome for this clinical trial was the occurrence of spontaneous preterm birth at <35 weeks of gestation. A “spontaneous” preterm birth is 1 that occurs because of either idiopathic preterm labor or from preterm premature rupture of the amniotic membranes, according to standard diagnostic criteria. The clinical outcomes were determined by a review of the patient’s inpatient delivery medical record. There were a number of secondary outcomes that also were of interest for this study, including subtypes of preterm birth (spontaneous, indicated), delivery at <37 weeks of gestation, delivery at <32 weeks of gestation, gestational age at delivery, and birthweight. We also considered major neonatal adverse outcomes (respiratory distress syndrome, chronic lung disease, necrotizing enterocolitis, grade III/IV IVH, sepsis, death) and, for analytic purposes, combined these into “composite neonatal morbidity/death.”
A priori sample size calculations assumed a type I error of 5%, a power of 80%, and a prevalence of preterm delivery at <35 weeks of gestation of 7%. In addition, a decrease in preterm delivery of 50% for preterm birth at <35 weeks of gestation was considered clinically relevant. Given these assumptions, we estimated that 636 patients would be needed per treatment group. In addition, our sample size was inflated by 5% for interim analysis and an additional 5% to account for potential loss to follow-up evaluation. Therefore, the goal was to recruit 700 subjects per treatment group, for a total of 1400 subjects for the randomized trial. Because of temporal restraints that were mandated by the mechanism of funding, enrollment stopped after 3 years of recruitment, which was well before we reached our target sample size. This report presents the results from 757 participants: 378 women who were assigned randomly to active treatment, and 379 women who were assigned to control treatment. This was approximately 54% of the planned recruitment.
Comparisons between those women who were assigned randomly to active treatment vs control treatment were performed with standard bivariate statistics. Dichotomous outcomes were compared with Fisher’s exact test or χ 2 test, where appropriate. Relative risks and 95% confidence intervals (CIs) also were reported. Continuous outcomes were compared with unpaired t tests, as appropriate. The intent-to-treat principle was used for the primary analysis.
Results
A total of 5085 pregnant women were assessed for eligibility, of which 3563 women were screened for periodontal diseases ( Figure ). Among those screened, the prevalence of periodontal disease was 50% (1765/3563 women); 1126 women were eligible for random assignment. Of these, 370 subjects did not return for the randomization visit, which left 756 subjects who were ultimately assigned randomly: 376 women to scaling and root planing and 380 women to control treatment. The mean gestational age at screening was 13.1 weeks, and the mean gestational age at treatment was 16.5 weeks.
Characteristics at randomization were similar between those in the active and control groups ( Table 1 ). The only exception was that a greater proportion of those women who were assigned randomly to active treatment were of high school education or lower. Approximately one half of the subjects were enrolled from the Hospital of the University of Pennsylvania, with similar enrollment numbers from the other 2 sites (Pennsylvania Hospital and Albert Einstein Medical Center). Importantly, the groups were balanced with respect to gestational age, periodontal disease severity, and history of a preterm delivery.
| Variable | Treatment | P value | |
|---|---|---|---|
| Active (n = 376) | Control (n = 380) | ||
| Average age, y a | 24.1 ± 5.2 | 24.4 ± 5.7 | .41 |
| Race b | .41 | ||
| White | 3.2 (12) | 1.9 (7) | |
| Black | 87.5 (329) | 87.3 (331) | |
| Other | 9.3 (35) | 10.8 (41) | |
| Hispanic | 8.2 (31) | 9.2 (35) | .63 |
| Education b | .04 | ||
| High school or lower | 71.5 (269) | 64.7 (246) | |
| Some college or college degree | 28.5 (107) | 35.3 (134) | |
| Marital status b | .88 | ||
| Married | 11.7 (44) | 12.4 (47) | |
| Single, never married | 85.6 (322) | 84.5 (321) | |
| Other | 2.7 (10) | 3.2 (12) | |
| Site b | 1.00 | ||
| Hospital of the University of PA | 55.9 (210) | 56.1 (213) | |
| Pennsylvania Hospital | 22.3 (84) | 22.1 (84) | |
| Einstein Hospital | 21.8 (82) | 21.8 (83) | |
| Screening assessment of severity of preterm delivery b | .90 | ||
| Mild periodontal disease | 45.2 (168) | 44.7 (169) | |
| Moderate/severe periodontal disease | 54.8 (204) | 55.3 (209) | |
| History of preterm delivery b | .62 | ||
| Previous preterm delivery | 11.7 (44) | 12.9 (49) | |
| No previous preterm delivery | 88.3 (332) | 87.1 (331) | |
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