Presented at the National Academy for State Health Policy's 20th Annual State Health Policy Conference in Denver, Colorado. Author: Gary Armitage

1. Effect of Periodontal Infections on Fetal Development & Pregnancy Outcomes National Academy for State Health Policy Denver, Colorado October 15, 2007 Gary C. Armitage, DDS, MS Professor of Periodontology, UCSF

2. Special Supplement Scientific American (October 2006)  “ Growing evidence suggests that poor oral hygiene during pregnancy can adversely affect the health of newborns.” For reprints: Call Crest Oral-B North American Customer Service at 800-543-2577.

3. Two Major Questions 1. Does the presence of periodontal (or oral) infections increase the risk of experiencing adverse pregnancy outcomes? [Risk factor question] 2. Does the treatment of periodontal (or oral) infections decrease the risk of experiencing adverse pregnancy outcomes? [Intervention question]

4. Systemic Diseases Caused by Oral Infections (1916) • Ophthalmic Disturbances (infectious conjunctivitis, suppurating keratitis, scleritis, cyclitis, iritis, retinitis, optic neuritis, glaucoma) • Aural Disturbances (otitis media, otlagia) • Diseases of the Alimentary Canal (septic gastritis, septic enteritis, colitis, appendicitis, proctitis, gastric and duodenal ulcers) • Diseases of the Blood (pernicious anemia, septic anemia) • Infectious Diseases of the Heart (pericarditis, myo- carditis, endocarditis) • Affections of the Nervous System (neuritis, trifacial neuralgia, chorea, mental depression and melancholia) • Diseases of the Joints (acute arthritis, gouty arthritis)

7. 28 y.o. WF Common Gingival Changes During Pregnancy:  Pyogenic Granuloma (“Pregnancy Tumor”)  Pregnancy Gingivitis Second Trimester 30 y.o. WF Second Trimester In addition to the pyogenic granuloma in this patient there is marked gingival inflam- mation around most teeth (arrows).    

8. Initiation & Progression of Periodontal Disease (The Health  Gingivitis  Periodontitis Paradigm) • Shallow gingival sulcus • Apical termination of JE at CEJ • Shallow periodontal pocket • Apical termination of JE at CEJ • Inflamed connective tissue • Deepened periodontal pocket • Loss of CT attachment & bone JE on root surface • Inflamed connective tissue

9. Clinical Appearance of Healthy & Diseased Periodontal Tissues No signs of inflammation No gingival recession Shallow probing depths Normal architecture (shape) Signs of inflammation Gingival recession Deep probing depths (pockets) Abnormal architecture

10. Purulent Exudate (Pus) is Often Seen in Cases of Chronic Periodontitis Redness & Swelling  Purulent Exudate (Pus)  Purulent exudate is a sign of inflammation. 55 y.o. WF

11. Bleeding on probing (BOP) is sign of periodontal inflammation. D C  BOP occurs because the epithelial lining of the pocket wall is thin & often ulcerated (arrow). a D = Dentin C = Cementum a = artifact x16 

12. Alveolar Bone (Offenbacher S. Scientific American 2006 (October);Special Supplement, pp. 24-29.) Tooth Enamel (Crown) Root of Tooth Dental Biofilm (Dental Plaque and Calculus) Periodontal Pocket (with ulcerated wall) 

13. BREAKING THROUGH: When oral bacteria in the mother’s blood breaches the placenta and reaches the fetus, it triggers an immune and inflammatory response, stressing the unborn child. Infections may account for up to 50% of premature births. “ What Every Woman Needs to Know” Steven Offenbacher Scientific American (Special Supplement: October, 2006) Campylobacter rectus Bergeyella sp. clone AF14 (AK152) 

14. A higher percentage of fetal cord blood samples from preterm infants (20.0%) are positive for IgM against C. rectus than those obtained from term infants (6.3%) [P < 0002]. S OM CM 0.1 µm (Borinski & Holt. Infect Immun 1990;58:2770-2776.) (Sára & Sleytr. J Bacteriol 2000;182:859-868.) 100 nm S-Layer of C. rectus Production of IgM by the fetus clearly shows that certain oral bacteria cross the placenta and gain access to the immune system of the baby. (Madianos et al. Ann Periodontol 2001;6:175-182.)

15. Lines of Evidence Suggesting Periodontal Disease as a Risk Factor for Preterm Birth & Low Birthweight Natal Tooth; Navajo Baby Girl; 1-day old • Some epidemiologic studies • Detection of fetal cord blood IgM against C. rectus and P. intermedia .* • Many plausible mechanisms by which periodontal bacteria and inflammatory mediators (PGE 2 ) might trigger preterm birth. • Preliminary intervention data suggest that periodontal treatment lowers risk.** *Madianos et al. Ann Periodontol 2001;6:175-182. **López et al. J Periodontol 2002;73:911-924. **Jeffcoat et al. J Periodontol 2003;74:1214-1218.

16. Mothers who gave birth to preterm low birthweight infants had statistically significant increased amounts of mean clinical attachment loss (CAL) – OCAP Study Results. (Offenbacher et al. J Periodontol 1996;67:1103-1113.) Primi = primiparous (no previous birth); NBW = Normal Birth Weight OR = 7.5 (CI, 1.95 – 28.8) N = 93 cases and 31 controls

17. Periodontal infection and preterm birth. Results of a prospective study. (Jeffcoat et al. J Am Dent Assoc 2001;132:875-880) Adjusted odds ratios for preterm births in patients with generalized periodontitis. The odds ratios have been adjusted for smoking, parity, race, and maternal age. 4.45 5.28 7.07 Number in each group not specified. < 37 weeks (OR = 4.45;C, I2.16-9.18) < 35 weeks (OR = 5.28; CI, 2.05-13.60) < 32 weeks (OR = 7.07; CI, 1.70-27.40) N = 167 (estimated) Periodontitis Case = Women with ≥ 90 sites with ≥ 3 mm of attachment loss.

18. Higher risk of preterm birth and low birth weight in women with periodontal disease. (López et al. J Dent Res 2002;81:58-63.) Adjusted Risk Ratios and P Values for Risk Factors Associated with Preterm Birth/Low Birth Weight (PLBW) and with Preterm Birth (PTB) Risk Ratio Risk Ratio for PLBW for PTB (95% CI) P Value (95% CI) P Value Previous PLBW 4.8 (1.6-14.0) 0.0004 7.5 (2.2-24.8) 0.001 < 6 Prenatal visits 4.7 (1.9-11.1) < 0.0001 7.5 (2.6-20.6) 0.0001 Periodontitis 3.5 (1.5-7.9) 0.003 2.9 (1.0-8.1) 0.045 Low maternal weight gain 2.6 (1.1-6.5) 0.030 ––– –––

19. Rate of delivery of a small-for-gestational-age (SGA) infant by maternal periodontal disease category (health vs. mild vs. moderate/severe) and serum C-reactive protein quartiles. Q1 Q2 Q3 Q4 CRP Quartiles Periodontal Health Mild Periodontitis Moderate-Severe Periodontitis SGA (%) 20 15 10 5 0 (Boggess et al. Am J Obstet Gynecol 2006;194:1316-1322.) North Carolina Population (University of North Carolina & Duke Medical Center) [N = 1,017 women of whom 67 (6.6%) delivered an SGA infant] (n = 145) (n = 588) (n = 284) 13.8% 6.5% 3.2% (P < 0.001)

20. (Offenbacher at al. Obstet Gynecol 2006;107:29-36.) Maternal age (P < 0.001) African American (P < 0.001) Not married (P < 0.005) Food stamp eligible (P < 0.05) No medical insurance (P < 0.05) Previous preterm delivery (P < 0.001) Chorioamnionitis (P < 0.001) [However, n = only 10/13] Moderate-Severe Periodontal Disease (P < 0.001) Progression of Periodontal Disease (P < 0.001)

21. Kaplan-Meier curves for pregnancy-gestational age outcomes among 891 mothers when both antepartum and postpartum periodontal exam data were available. Delivery outcomes for mothers with no progression of periodontal disease (n = 658) or with progress- ion (n = 233). Progression was defined as ≥ 4 sites with ≥ 2 mm increase in probing depths (PD), with the postpartum PD ≥ 4 mm.   (Offenbacher at al. Progressive periodontal disease and risk of very preterm delivery. Obstet Gynecol 2006;107:29-36.)

22. Definition of Preeclampsia A complication of pregnancy characterized by hypertension, edema, and/or proteinuria; when convulsions and coma are associated it is called eclampsia . Riché et al. Periodontal disease increases the risk of preterm delivery among preecalamptic women. Ann Periodontol 2002;7:95-101. Boggess et al. Maternal periodontal disease is associated with an increased risk of preeclampsia. Obstet Gynecol 2003;101:227-231.

23. General linear model of the effect of changes in periodontal status during pregnancy on the adjusted rates of preterm delivery in preeclamptic and non-preeclamptic mothers. From: Riché et al. Ann Periodontol 2002;7:95-101 . Estimates of prevalence rates were adjusted for maternal race, age, marital status, food stamp usage, insurance, previous preterm deliv- ery, and chorioamnion- itis. *P = 0.26 (NS) † P = 0.0006 

24. A Predictable Event – Edematous tissue will shrink after the teeth are cleaned. Gingivitis (Pretreatment) • Redness • Swelling (edema) • Bleeding on probing Health (Post-treatment) • Absence of inflammation • Improved architecture • Better tissue tone 23 y.o. WF Baseline 3 Months post-treatment

25. Periodontal therapy may reduce the risk of preterm low birth weight in women with periodontal disease: A randomized controlled study. – I. (López et al. J Periodontol 2002;73:911-924.) • Purpose was to determine if periodontal therapy in pregnant women with periodontal disease reduces the risk of preterm low birth weight (PLBW). • 400 pregnant women were enrolled, with 200 assigned to a periodontal Treatment Group and 200 were used controls. • Treatment consisted of oral hygiene instructions, SRP, and once daily rinsing with 0.12% chlorhexidine; completed before 28 weeks of gestation. The Control Group was not treated until after delivery. • 163 women in the Treatment Group and 188 in the Control Group completed the study.

26. Periodontal therapy may reduce the risk of preterm low birth weight in women with periodontal disease: A randomized controlled study. – II. (López et al. J Periodontol 2002;73:911-924.) Incidence of Preterm Births (PTB), Low Birth Weight (LBW), Both (PLBW) Treatment Group Control Group (n = 163) (n = 188) N% N % P Value Intention-to-treat analysis PTB 21.10 12 6.38 0.017 LBW 10.55 7 3.72 0.083 PLBW 31.63 19 10.11 0.001 Protocol analysis PTB 21.22 12 6.38 0.001 LBW 10.61 7 3.72 0.11 PLBW 31.84 19 10.11 0.003 Odds Ratio = 5.49 (C.I. 1.65 to 18.22); P = 0.001 PLBW = Preterm/Low Birth Weight

27. – Large Intervention Studies – “Does Periodontal Therapy Reduce the Risk of Adverse Pregnancy Outcomes?” Obstetrics & Periodontal Therapy Study Enrollment = 823 4 Centers University of Minnesota (2 sites) University of Mississippi Columbia University Brian Michalowicz (PI) Enrollment Target = 1,800 3 Centers University of North Carolina University of Alabama University of Texas (San Antonio) Steven Offenbacher & James Beck (PIs) COMPLETED

28. Treatment of Periodontal Disease and the Risk of Preterm Birth (Michalowicz et al. N Engl J Med 2006;355:1885-1984. “ Treatment of periodontitis in pregnant women improves periodontal disease and is safe but does not significantly alter rates of preterm birth, low birth weight, or fetal growth restriction.”

29. Kaplan-Meier curves for cumulative incidence of pregnancies ending before 37 weeks. (Michalowicz et al. N Engl J Med 2006;355:1885-1894 ) 5 spontaneous abortions or stillbirths in treatment group versus 14 in the control group (P = 0.08)

30. “ We have hypothesized that once the inflam- matory cascade is activated during pregnancy, interventions targeting this pathway may be ineffective in reducing the rate of preterm birth ( Arch Pediatr Adolesc Med 2005;159:89-90.). Treatment during pregnancy may be too late; it is possible that treatment either before preg- nancy (in nulliparous women) or in the period between pregnancies (for multiparous women, especially those with a history of preterm birth) may yield more promising results.” Goldenberg RL, Culhane JF. N Engl J Med 2006;355:1925-1927.

31. 69% 66.9% 69.6% 45.9% NO TREATMENT PERIODONTAL TREATMENT BASELINE (CONTROL) CONTROL (After Delivery) BASELINE (EXPERIMENTAL) EXPERIMENTAL (After Delivery) (Data from: Michalowicz et al. N Engl J Med 2006;355:1885-1894. ) [University of Minnesota, University of Kentucky, University of Mississippi, Columbia University] N = 410 N = 413

32. 81.7% 10.4% 68% 10% BASELINE BASELINE 7 MONTHS 6 MONTHS Apatzidou & Kinane. J Clin Periodontol 2004;31:132-140. Badersten et al. J Clin Perio- dontol 1981;8:57-72. UNIVERSITY OF LUND (SWEDEN) UNIVERSITY OF GLASGOW (SCOTLAND) N = 15 N = 20

33. 68% 69.6% 45.9% 10% BASELINE BASELINE 6 MONTHS ~ 6 MONTHS Apatzidou & Kinane. J Clin Periodontol 2004;31:132-140. Michalowicz et al. N Engl J Med 2006;355:1885-1894. RESULTS OF PERIODONTAL TREATMENT IN OPT STUDY [Change in % sites with Bleeding on Probing versus Baseline] TYPICAL (EXPECTED) RESULTS OF SCALING & ROOT PLANING N = 20 N = 413

34. Additional (Speculative) Conclusions that can be made from the OPT Results 1. Although the periodontal treatment that was provided was the standard of care (i.e., OHI, SRP, monthly evaluation + additional scaling “as needed”), it was insufficient to control the periodontal disease . The post- treatment presence of a high % of sites with BOP means that the patients were still infected. 2. Treatment may have been too late . 3. More frequent treatment may be needed .

35. _ THE UNIVERSITY OF WESTERN AUSTRALIA (PERTH) FACULTY OF Medicine, Dentistry and Health Sciences King Edward Memorial Hospital UNIVERSITY OF PENNSYLVANIA HEALTH SYSTEM Enrollment Goal = 1,080 Periodontal Treatment = OHI + SRP + 0.12% Chlorhexidine rinse [540 treated during 1st or 2nd trimesters; 540 treated after delivery] Principal Investigator = John P. Newnham, MD Enrollment Goal = 1,800 Periodontal Treatment = OHI + SRP [900 treated during 2nd trimester; 900 treated after delivery] Principal Investigators = James Beck, PhD & Steve Offenbacher, DDS, PhD University of North Carolina University of Alabama University of Texas (San Antonio) Enrollment Goal = > 1,000 (Phase III study) Periodontal Treatment = SRP versus “Superficial Cleaning” Principal Investigator = George A. Macones, MD “ Prevention of Pre-term Birth by Treatment of Periodontal Disease” “ Periodontal Infection and Prematurity Study” SRP = Scaling & Root Planing; OHI = Oral Hygiene Instructions

36. Yellow-eyed Penguin (Megadyptes antipodes) Otago Peninsula (Dunedin, New Zealand South Island)