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Maternal periodontal disease in early pregnancy and risk for a small-for-gestational-age infant
American Journal of Obstetrics and Gynecology (2006) 194, 1316–22
www.ajog.org
Maternal periodontal disease in early pregnancy and risk for a small-for-gestational-age infant Kim A. Boggess, MD,a,b James D. Beck, PhD,b Amy P. Murtha, MD,c Kevin Moss,b Steven Offenbacher, DDS, PhDb Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicinea and Center for Oral and Systemic Diseases,b University of North Carolina, Chapel Hill, NC; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC c Received for publication June 29, 2005; revised November 29, 2005; accepted November 30, 2005
KEY WORDS Pregnancy Periodontal disease Small-for-gestationalage
Objective: The objective of the study was to determine whether periodontal disease is associated with delivery of a small-for-gestational-age infant. Study design: In a prospective study of oral health, periodontal disease was categorized as health, mild, or moderate/severe on the basis of clinical criteria. Small for gestational age was defined as birth weight less than the 10th percentile for gestational age. A risk ratio (95th percentile confidence interval) for a small-for-gestational-age infant among women with moderate or severe periodontal disease was calculated. Results: Sixty-seven of 1017 women (6.6%) delivered a small-for-gestational-age infant, and 143 (14.3%) had moderate or severe periodontal disease. The small-for-gestational-age rate was higher among women with moderate or severe periodontal disease, compared with those with health or mild disease (13.8% versus 3.2% versus 6.5%, P ! .001). Moderate or severe periodontal disease was associated with a small-for-gestational-age infant, a risk ratio of 2.3 (1.1 to 4.7), adjusted for age, smoking, drugs, marital and insurance status, and pre-eclampsia. Conclusion: Moderate or severe periodontal disease early in pregnancy is associated with delivery of a small-for-gestational-age infant. Understanding the mechanism of periodontal disease– associated adverse pregnancy outcomes could lead to interventions to improve fetal growth. Ó 2006 Mosby, Inc. All rights reserved.
Normal fetal growth is an important indicator of fetal well-being. Fetal growth restriction complicates 3% to 7% of all pregnancies, affecting almost 200,000 births annually. Fetal growth restriction contributes to
Supported by National Institutes of Health Grants K08 HD043284 and R01 DE12453 and the University of North Carolina General Clinical Research Center Grant RR00046. Reprints not available from the authors. 0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.11.059
one third of all cases of low birth weight in infants, resulting in significant economic and emotional burden.1 Infants who are small for gestational age (less than the 10th percentile for birth weight) have significantly higher neonatal mortality rates when compared with appropriate- and large-for-gestational-age infants.2 Although the mechanisms of intrauterine growth impairment are not fully elucidated, there are many maternal, placental, and fetal factors that function in concert to assure normal fetal growth.
Boggess et al Human data suggest a relationship between maternal infection and poor fetal growth. Congenital infection with cytomegalovirus, rubella, and Toxoplasma gondii is associated with growth-restricted and microcephalic infants.1 Pregnancies complicated by abnormal genital flora3,4, maternal urinary tract infection,5 or Ureaplasma urealyticum3 isolation from the placenta demonstrate increased rates of fetal growth restriction. Periodontal disease is a chronic oral infection commonly identified in pregnant women,6 which has recently been recognized as a risk factor for preterm birth, preeclampsia, and second-trimester miscarriage.7-10 Periodontal disease is characterized by an overgrowth of normal oral flora with a polymicrobial anaerobic and Gram-negative flora that results in local (gingival) and systemic inflammatory and immune responses.11,12 The causal mechanism of periodontal disease-associated adverse pregnancy outcomes is unknown, although maternal or fetal inflammatory responses to oral pathogens may be involved.13,14 The objectives of this study were to determine the relationship between maternal periodontal disease and delivery of a small-for-gestational-age (SGA) infant and to determine the role of maternal systemic inflammation in this relationship.
Material and methods This study was a planned secondary analysis of data collected as part of the prospective, observational Oral Conditions and Pregnancy study, which was a study of the relationship between maternal periodontal disease and preterm birth risk. The sample size was determined by the primary analysis. The overall study population and methods, and findings for the primary outcome of preterm birth, have been previously published.6,15 The current analysis to determine the relationship between maternal periodontal disease and delivery of an SGA infant was not considered in estimating sample size or calculating power to detect differences in SGA rates among women with varying degrees of periodontal disease. Institutional Review Board approval was granted to conduct the study, and written informed consent was obtained from all study participants. Eligible healthy women with a singleton pregnancy were enrolled prior to 26 weeks’ gestation. Gestational age was assigned based on last menstrual period confirmed by a first- or second-trimester ultrasound. Demographic, health behavior, and medical history data were obtained by patient questionnaire at the first visit and were reviewed by a physician at the first prenatal visit. Information on events of the pregnancy, labor and delivery, and health of the neonate were collected from the medical record, laboratory and pathology data, and the infant’s medical record and entered into the Oral Conditions and Pregnancy Study database (Microsoft Access, 1997 SR2, Microsoft, Redmond, WA).
1317 An oral health examination was performed at the first or second prenatal visit, with detailed methodology previously reported.6 Five certified dental hygienists were trained by a standard examiner and calibrated at the start of the study and at 6-month intervals, using pocket depth and attachment loss measurements. All weighted kappa scores were greater than 85% and intraclass correlation coefficients were 0.9 or higher.6 Gingival pocket depths, degree of attachment loss, and gingival bleeding on probing at 6 sites per tooth for all teeth present, including third molars, were measured and recorded. Clinical periodontal status was categorized based on pocket depth and bleeding criteria. Periodontal health or the absence of periodontal disease was defined as absence of gingival pocket depths greater than 4 mm and no gingival pocket depths greater than 3 mm that also bled on probing. Mild periodontal disease was defined as 1 or more tooth sites with greater than 4-mm pocket depth or 1 or more tooth pockets greater than 3 mm that bled on probing, up to 15 tooth sites. Moderate/severe periodontal disease was defined as 15 or more tooth sites with pocket depths greater than 4 mm. Maternal serum was collected at the enrollment visit and stored 80(C for future measurement of maternal inflammatory and immune responses. For this analysis, maternal serum C-reactive protein levels were measured using a commercially available ultrasensitive enzymelinked immunosorbent assay (R & D Systems, Minneapolis, MN). The lower and upper limits of detection are 1.0 pg/mL and 50 pg/mL, respectively. The inter- and intra-assay variability of the assay is 3% and 15%, respectively. The maternal serum C-reactive protein levels were measured with no knowledge of oral health exam results or birth outcomes. Small-for-gestational age was defined as a birth weight less than the 10th percentile for gestational age based on population standards. To determine 10th percentiles for birth weight for the population, birth certificate data were obtained from the North Carolina Center for Health Statistics.16 All singleton live births for the years of the study period (1997 to 2001) were entered into a database to develop population standard birth weight curves. Birth certificates with missing data were excluded, resulting in 562,393 birth certificate records available. For gestational ages between 32 and 45 weeks, the 10th percentile for birth weight at each week was determined after adjusting for maternal race, parity, and infant gender. Below 32 weeks’ gestation, maternal race, parity, and baby gender did not have a significant impact on birth weight percentiles because of sample sizes, so an unadjusted 10th percentile for gestational age week was determined for births less than 32 weeks’ gestation (Figure 1). All analyses were performed using Statistical Analytical Systems 8.0 (SAS Institute, Cary, NC). Bivariate
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Boggess et al
Results
Figure 1 Rate of delivery of an SGA infant by maternal periodontal disease category (health versus mild versus moderate/ severe) and serum C-reactive protein quartile (Q1, less than the 25th percentile; Q2, 25th to 49th percentile or greater; Q3, 50th to 74th percentile or greater; Q4, 75th percentile or greater).
analysis was performed on a priori candidate risk factors to determine variables associated with the delivery of an SGA infant using Student t test or c2 test. All variables associated with delivery of an SGA infant (P ! .2) were then entered into a multivariable logistic regression model and then removed in a step-wise fashion if P ! .2 by the backward elimination procedure. Variables were also assessed for confounding by testing to see whether the point estimate for the relationship between delivery of an SGA infant and moderate/severe periodontal disease changed by more than 5% by inclusion of that variable in the model. After construction of the final model, the odds ratio was used to estimate the risk ratio (RR) for SGA using a macro application in SAS, which approximates the correction described by Zhang and Yu.17 All variables included in the final model were determined to be independent by assessing for collinearity by calculating the condition index for the model. A condition index greater than 30 reflects moderate to severe collinearity and would reduce confidence in the analysis.18 A separate analysis was conducted to examine the role of maternal inflammation in the relationship between moderate/severe periodontal disease and delivery of an SGA infant. To determine whether confounding was present, the final model excluding maternal serum C-reactive protein level greater than the 75th percentile was compared with a model including serum C-reactive protein level greater than the 75th percentile. Risk ratios (95th percentile confidence interval [CI]) for delivery of an SGA infant were calculated using multivariable logistic regression analysis and stratified by maternal serum C-reactive protein level less than the 75th percentile versus greater than the 75th percentile and the maternal periodontal disease category.
One thousand one hundred seventeen women enrolled at an average of 14 weeks’ gestation had complete data available and comprise the study cohort for this analysis. Maternal demographic characteristics, candidate risk factor and obstetric data, and clinical periodontal disease status are shown in Table I. The incidence of the delivery of an SGA infant was 6.6% (67 of 1017) and was more frequent among preterm, compared with term, deliveries (11% versus 5.6%, P ! .01). Two hundred eighty-four of 1017 (28.0%) had periodontal health, 588 (57.8%) had mild periodontal disease, and 145 (14.3%) had moderate/severe periodontal disease. Women with an SGA infant were also more likely to have moderate/severe periodontal disease than women without an SGA infant (29.9% versus 13.2%, P ! .001). The SGA rate was higher among women with moderate/severe periodontal disease, compared with those with health or mild disease (13.8% versus 6.5% versus 3.2%, P ! .001). The final model and adjusted RRs (95th percentile) for delivery of an SGA infant are shown in Table II. The condition index for the final model was 14.3. The mean serum C-reactive protein level for the cohort was 16.1 G 25.1 pg/mL, and the median (interquartile range) was 4.8 (1.0 to 15.8) pg/mL. Women who delivered an SGA infant had a significantly higher mean serum C-reactive protein level and were more likely to have serum C-reactive protein in the upper quartile than women without an SGA infant (22.9 pg/mL G 29.8 versus 15.8 pg/mL G 24.8, P = .05 and 34.6% versus 24.7%, P = .11, respectively). Women with moderate/severe periodontal disease had a significantly higher mean serum C-reactive protein level and were also more likely to have serum C-reactive protein in the upper quartile than those with periodontal health or mild disease (29.3 pg/mL G 32.4 versus 9.5 pg/mL G 17.7 versus 16.1 pg/mL G 24.9, P ! .0001 and 41.2% versus 15.2% versus 26%, P ! .0001, respectively). The rate of delivery of an SGA infant stratified by maternal periodontal disease and serum C-reactive protein quartile is shown in Figure 2. Among women with serum C-reactive protein level in the upper quartile, those with moderate/severe periodontal disease had a significantly higher rate of delivery of an SGA infant, compared with those with health and mild periodontal disease (19.6% versus 3.2% versus 6.8%, P ! .02). Risk ratios (95th percentile) for delivery of an SGA infant, stratified by maternal C-reactive protein category and periodontal disease category, are shown in Table III. Addition of maternal serum C-reactive protein level in the final model changed the point estimate for moderate/severe periodontal disease to predict the delivery of an SGA infant by 15%. The adjusted RR (95th percentile CI) for an SGA infant among women with
Boggess et al Table I
1319
Demographic, candidate risk factor and obstetric data, and periodontal disease status of cohort
Gestational age at study enrollment, wk (mean G SD) Maternal age, y (mean G SD) Maternal weight, kg (mean G SD) Unmarried Uninsured Use of public assistance Smoking Alcohol use Illicit substance usey Sexually transmitted diseasez during pregnancy Bacterial vaginosis during pregnancyx Previous delivery less than 37 wk Delivery less than 37 wk Preeclampsia Periodontal disease at enrollment Health Mild Moderate/severe
Non-SGA infant (n = 950)
SGA infant (n = 67)
14.9 G 4.9
15.9 G 4.7
28.4 73.4 445 483 159 145 158 36 133
24.9 70.6 50 51 24 16 12 6 13
(6.6) (19.9) (46.8) (50.8) (16.7) (15.2) (16.2) (3.8) (14.1)
(5.9) (17.6) (74.6) (76.1) (35.8) (23.9) (17.9) (8.9) (19.4)
P value* .74 !.001 .22 !.001 !.001 !.001 .06 .79 .04 .22
69 (7.3)
8 (11.9)
.16
146 (15.4) 164 (17.3) 37 (3.9)
21 (31.3) 20 (29.9) 11 (16.4)
!.001 .009 !.001
275 (28.9) 550 (57.9) 125 (13.2)
9 (13.4) 38 (56.7) 20 (29.9)
! 0.001
Data presented as number (percent) unless otherwise noted. * Student t test or c2 test where appropriate. y Defined as patient reported intravenous drug use, marijuana use, or cocaine use. z Defined as Neisseria gonorrhea and/or Chlamydia trachomatis by microbiologic testing. x Defined clinically in symptomatic women by vaginal pH 4.5 or greater and wet mount identification of clue cells.
Table II Final adjusted logistic regression model for delivery of an SGA infant* Adjusted RR (95th CI) y
Maternal age Married Use of public assistance Smoking Illicit substance use Pre-eclampsia Periodontal disease Mild Moderate/severe
1.3 0.6 1.6 1.0 1.8 3.2
(1.1-1.6) (0.3-1.2) (1.0-2.5) (0.6-1.8) (0.9-4.0) (1.7-6.1)
1.3 (0.7-2.5) 2.3 (1.1-4.5)
* Risk ratios approximated from odds ratios as described in text. y Decreasing in 5-year increments.
moderate/severe periodontal disease with serum C-reactive protein level greater than the 75th percentile in the model was 2.7 (1.1 to 6.8).
Comment Our data demonstrate that moderate/severe periodontal disease identified at less than 26 weeks’ gestation is associated with an increased risk for subsequent delivery of an SGA infant, independent of other risk factors for small fetal size. Thirty percent of women with moderate/
severe periodontal disease delivered SGA infants, a rate higher than expected and higher than observed among women with health and mild periodontal disease. We and others have previously reported an association between maternal periodontal disease and preterm birth7,8 preeclampsia9,19,20 and second-trimester miscarriage.10 Although it is unclear whether the relationship between maternal periodontal disease and adverse pregnancy outcomes is causal, several pilot intervention trials demonstrating the benefits of periodontal disease treatment during pregnancy suggest that controlling this source of maternal infection bears further consideration as a possible effective intervention to prevent preterm birth.21-23 The mechanism of periodontal disease associated adverse pregnancy outcomes remains speculative, but inflammatory responses are likely involved.12,14 We hypothesize that maternal periodontal disease presents an oral microbial challenge that results in a systemic inflammatory response in a subset of women and ultimately results in abnormal placental or fetal development that impacts fetal growth. C-reactive protein was selected as the inflammatory marker of interest for several reasons. First, inflammation as defined as moderate increases in C-reactive protein levels, has been associated with cardiovascular disease, implying that nonspecific inflammation has an
1320
Boggess et al Table III Unadjusted RRs (95th percentile CI) for delivery of an SGA infant, stratified by maternal periodontal disease status and C-reactive protein (CRP) category Observed RR (95th CI) Low CRP-health* Low CRP-mild periodontal disease Low CRP-moderate/severe disease High CRP-healthy High CRP-mild periodontal disease High CRP-moderate/severe disease
Figure 2 Population-based birth weight standards (n = 562, 393 births)16 to determine birth weight percentiles by gestational age week, adjusted for maternal race, parity, and infant gender. Center line in box plot represents median birth weight, upper and lower limits of box represent interquartile range of birth weight, and top and bottom of whiskers represent 90th and 10th percentile, respectively.
impact on systemic health.24 Second, there are data that individuals with periodontal disease have elevated serum C-reactive protein level,25 suggesting that a systemic response to the oral microbial burden may be 1 of the mechanisms of periodontal disease–associated adverse health outcomes. In our cohort of women, maternal periodontal disease was associated with increasing quartile serum C-reactive protein level, suggesting maternal systemic inflammation is associated with worsening oral health. We also found that among women with moderate/ severe periodontal disease, those with maternal serum C-reactive protein levels greater than the 75th percentile demonstrated a greater risk for delivery of an SGA infant, compared with those with serum C-reactive protein level less than the 75th percentile, and the combination of maternal serum C-reactive protein level greater than the 75th percentile and moderate/severe periodontal disease increased the risk for an SGA infant greater than either effect alone. Although we cannot determine in our study whether maternal systemic inflammation is occurring in response to oral infection, or some other maternal exposure, other data have shown that periodontal disease is associated with both local and systemic inflammation.11-13 Of note, maternal serum was collected on average, at 14 weeks’ gestation, many weeks prior to delivery of the infant, suggesting that a maternal systemic inflammatory response that occurs early in pregnancy may be important in the relationship between maternal periodontal disease and fetal growth. The timing and role of systemic inflammation as a mechanism of maternal
Expected RR (95th CI)
Reference 2.2 (0.9-5.9) 4.3 (1.4-12.5) 1.1 (0.1-9.2) 2.4 (0.8-7.3) 6.8 (2.4-19.4)
4.7z
* Low is less than the 75th percentile. y High is 75th percentile or greater. z Calculated by multiplying RR of low CRP-moderate/severe disease by high CRP-health.
periodontal disease–associated adverse pregnancy outcomes is an area for future study. Limitations of our study merit discussion. Since periodontal status was the exposure of interest for this analysis, the correct identification of women with clinically or biologically significant periodontal disease is of paramount importance. We based our categories of periodontal disease status on characteristics that may have systemic effects during pregnancy, and include periodontal pockets that may harbor microorganisms and the inflammatory state indexed by bleeding on probing.6 We did not include attachment loss as part of our definition, although this is another common measure for periodontal disease. Other infections have been associated with fetal growth restriction or delivery of an SGA infant,1,3-5 and maternal periodontal disease may represent a surrogate for another infectious process that adversely affects fetal growth. In this analysis, symptomatic bacterial vaginosis or microbiologic proven sexually transmitted diseases were neither significantly associated with nor confounded the relationship between maternal periodontal disease and delivery of an SGA infant when assessed in the final model and thus are unlikely to be related to our findings. We did not examine other possible infectious challenges that might influence fetal growth. Many maternal factors other than infection can impact fetal growth. Although we attempted to identify and control for maternal medical and behavioral characteristics that might affect fetal growth, it is possible that not all factors were considered or identified. In particular, maternal body mass index (BMI), maternal weight, and maternal weight gain could negatively or positively affect fetal growth. We did not include BMI in
Boggess et al our model because the data were not consistently available. However, maternal weight at enrollment was similar between women with and without an SGA infant and did not confound the relationship between moderate/severe periodontal disease and delivery of an SGA infant. Another limitation was lack of information on the placenta. The placenta is critically involved in maintenance of normal fetal growth,26 and we did not assess placental weight or histology in this cohort of women. However, a recent study of very preterm births demonstrated that placental histology was no different between women with and without periodontal disease,27 suggesting that at least for preterm birth, any placental effects of periodontal disease are transient and likely occur remote from the time of delivery. Determination of appropriate fetal growth depends on accurate gestational dating. Estimates of gestational age by menstrual dating, ultrasound dating (when available), and postnatal dating all have inherent inaccuracies. Birth certificate data can be inaccurate, and birth certificate data do not specify what measurements were used to determine gestational age at delivery. This is a challenge for deriving birth weight curves. In the study by Zhang and Bowes28 describing birthweight-for-gestational-age patterns by race, sex, and parity in the United States, menstrual dating misclassified gestational age and elevated birth weight percentiles in preterm births and lowered birth weight percentiles in postterm births. However, ultrasound estimates also misclassified gestational age but in the opposite direction. Because there are currently no data to describe birth weight standard curves that arrives at dating by knowing date of ovulation or conception, we recognize that there are inaccuracies in defining SGA infants using any birth weight standard curve. Another limitation is using SGA as a surrogate for fetal growth restriction. Using a population-based birth weight standard to identify SGA fetuses misidentifies 24% of fetuses as normal and 28% as growth restricted.29 To try to overcome this limitation, we used North Carolina state-wide population standards. However, we recognize that several mechanisms contribute to fetal growth and are not accounted for when using population-based standards. The assessment of fetal weight using ultrasound and individually adjusted birth weight standards predicts growth restriction as a function of loss-of-growth potential and may be superior to using population-based standards to predict adverse perinatal events associated with hypoxia or diminished reserve. Compared with a population-based birth weight standard, a customized birth weight standard increases identification of fetuses at risk of stillbirth and neonatal death, probably because of improved identification of fetal growth restriction.30 Although we used a large
1321 population of women from which the study population was derived to generate birth weight standards, we did not explore using customized birth weight standards. Future study into the role of maternal periodontal disease and fetal growth will need to consider growth potential as well as absolute cut-points to identify fetuses at risk. Despite these limitations, our study provides new insight into the role of maternal periodontal disease and adverse pregnancy outcomes. Moderate/severe maternal periodontal disease identified early in pregnancy is a risk factor for delivery of an SGA infant that is independent of traditional risk factors. This risk may be mediated or exacerbated by a maternal systemic inflammatory response to the chronic challenge of oral pathogens. Further studies on the maternal and fetal inflammatory responses to chronic oral infection and on placental pathology in women with periodontal disease are ongoing to further elucidate the contribution of chronic oral infection on pregnancy outcomes. Maternal periodontal disease is a chronic exposure to oral pathogens that may represent a treatable condition that contributes to impaired in utero fetal growth.
References 1. Creasy R, Resnick R. Intrauterine growth restriction. In: Creasy R, Resnick R, editors. Maternal-fetal medicine. Philadelphia: WB Saunders; 1999:569-84. 2. Piper JM, Xenakis EM, McFarland M, Elliott BD, Berkus MD, Langer O. Do growth-retarded premature infants have different rates of perinatal morbidity and mortality than appropriately grown premature infants? Obstet Gynecol 1996;87:169-74. 3. Embree JE, Krause VW, Embil JA, MacDonald S. Placental infection with Mycoplasma homonis and Ureaplasma urealyticum: clinical correlation. Obstet Gynecol 1980;56:475-81. 4. Germain M, Krohn MA, Hillier SL, Eschenbach DA. Genital flora in pregnancy and its association with intrauterine growth retardation. J Clin Microbiol 1994;32:2162-8. 5. Nieto A, Matorras R, Serra M, Valenzuela P, Molero J. Multivariate analysis of determinants of fetal growth retardation. Eur J Obstet Gynecol Reprod Biol 1994;53:107-13. 6. Lieff S, Boggess KA, Murtha AP, Jared H, Madianos PN, Moss K, et al. The oral conditions and pregnancy study: periodontal status of a cohort of pregnant women. J Periodontol 2004;75:116-26. 7. Offenbacher S, Katz V, Fertik G, Collins J, Boyd D, Maynor G, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol 1996;67:1103-13. 8. Jeffcoat MK, Geurs NC, Reddy MS, Cliver SP, Goldenerg RL, Hauth JC. Periodontal infection and preterm birth: results of a prospective study. J Am Dent Assoc 2001;132:875-80. 9. Boggess KA, Lieff S, Murtha AP, Moss K, Beck J, Offenbacher S. Maternal periodontal disease is associated with an increased risk for preeclampsia. Obstet Gynecol 2003;101:227-31. 10. Moore S, Ide M, Coward PY, Randhawa M, Borkowska E, Baylis R, et al. A prospective study to investigate the relationship between periodontal disease and adverse pregnancy outcome. Br Dent J 2004;197:251-8; discussion 247. 11. Scannapieco FA. Periodontal inflammation: from gingivitis to systemic disease? Compend Contin Educ Dent 2004;25:16-25.
1322 12. Slade GD, Ghezzi EM, Heiss G, Beck JD, Riche E, Offenbacher S. Relationship between periodontal disease and C-reactive protein among adults in the Atherosclerosis Risk in Communities study. Arch Intern Med 2003;163:1172-9. 13. Carta G, Persia G, Falciglia K, Iovenitti P. Periodontal disease and poor obstetrical outcome. Clin Exp Obstet Gynecol 2004;31:47-9. 14. Konopka T, Rutkowska M, Hirnle L, Kopec W, Karolewska E. The secretion of prostaglandin E2 and interleukin 1-beta in women with periodontal diseases and preterm low-birth-weight. Bull Group Int Rech Sci Stomatol Odontol 2003;45:18-28. 15. Offenbacher S, Boggess K, Murtha A, Jared H, Lieff S, McKaig R, et al. Active periodontal disease increases risk of very preterm delivery. Obstet Gynecol 2006, in press. 16. North Carolina Center for Vital Statistics. Selected vital statistics for 2001 and 1997-2001. Available at: www.schs.state.nc.us/SCHS/ vitalstats/volume1/2001/nc.html. Accessed May 1, 2005. 17. Zhang J, Yu KF. What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998;280:1690-1. 18. Belsley D, Kuh E, Welsch R. Regression diagnostics: identifying influential data and sources of collinearity. New York: John Wiley & Sons, Inc; 1980. 19. Oettinger-Barak O, Barak S, Ohel G, Oettinger M, Kreutzer H, Peled M, et al. Severe pregnancy complication (preeclampsia) is associated with greater periodontal destruction. J Periodontol 2005;76:134-7. 20. Canakci V, Canakci CF, Canakci H, Canakci E, Cicek Y, Ingec M, et al. Periodontal disease as a risk factor for pre-eclampsia: a case control study. Aust N Z J Obstet Gynaecol 2004;44:568-73. 21. Mitchell-Lewis D, Engebretson SP, Chen J, Lamster IB, Papapanou PN. Periodontal infections and pre-term birth: early findings
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from a cohort of young minority women in New York. Eur J Oral Sci 2001;109:34-9. Lopez NJ, Smith PC, Gutierrez J. Periodontal therapy may reduce the risk of preterm low birth weight in women with periodontal disease: a randomized controlled trial. J Periodontol 2002;73: 911-24. Jeffcoat MK, Hauth JC, Geurs NC, Reddy MS, Cliver SP, Hodgkins PM, et al. Periodontal disease and preterm birth: results of a pilot intervention study. J Periodontol 2003;74:1214-8. Veselka J, Prochazkova S, Duchonova R, Bolomova I, Urbanova T, Tesar D, et al. Relationship of C-reactive protein to presence and severity of coronary atherosclerosis in patients with stable angina pectoris or a pathological exercise test. Coron Artery Dis 2002;13:151-4. Slade GD, Offenbacher S, Beck JD, Heiss G, Pankow JS. Acutephase inflammatory response to periodontal disease in the U.S. population. J Dent Res 2000;79:49-57. Salafia CM. Placental pathology of fetal growth restriction. Clin Obstet Gynecol 1997;40:740-9. Goepfert AR, Jeffcoat MK, Andrews WW, Faye-Petersen O, Cliver SP, Goldenberg RL, et al. Periodontal disease and upper genital tract inflammation in early spontaneous preterm birth. Obstet Gynecol 2004;104:777-83. Zhang J, Bowes WA Jr. Birth-weight-for-gestational-age patterns by race, sex, and parity in the United States population. Obstet Gynecol 1995;86:200-8. Gardosi J, Chang A, Kalyan B, Sahota D, Symonds EM. Customised antenatal growth charts. Lancet 1992;339:283-7. De Jong CL, Francis A, Van Geijn HP, Gardosi J. Customized fetal weight limits for antenatal detection of fetal growth restriction. Ultrasound Obstet Gynecol 2000;15:36-40.
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Maternal periodontal disease in early pregnancy and risk for a small-for-gestational-age infant Kim A. Boggess, MD,a,b James D. Beck, PhD,b Amy P. Murtha, MD,c Kevin Moss,b Steven Offenbacher, DDS, PhDb Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicinea and Center for Oral and Systemic Diseases,b University of North Carolina, Chapel Hill, NC; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC c Received for publication June 29, 2005; revised November 29, 2005; accepted November 30, 2005
KEY WORDS Pregnancy Periodontal disease Small-for-gestationalage
Objective: The objective of the study was to determine whether periodontal disease is associated with delivery of a small-for-gestational-age infant. Study design: In a prospective study of oral health, periodontal disease was categorized as health, mild, or moderate/severe on the basis of clinical criteria. Small for gestational age was defined as birth weight less than the 10th percentile for gestational age. A risk ratio (95th percentile confidence interval) for a small-for-gestational-age infant among women with moderate or severe periodontal disease was calculated. Results: Sixty-seven of 1017 women (6.6%) delivered a small-for-gestational-age infant, and 143 (14.3%) had moderate or severe periodontal disease. The small-for-gestational-age rate was higher among women with moderate or severe periodontal disease, compared with those with health or mild disease (13.8% versus 3.2% versus 6.5%, P ! .001). Moderate or severe periodontal disease was associated with a small-for-gestational-age infant, a risk ratio of 2.3 (1.1 to 4.7), adjusted for age, smoking, drugs, marital and insurance status, and pre-eclampsia. Conclusion: Moderate or severe periodontal disease early in pregnancy is associated with delivery of a small-for-gestational-age infant. Understanding the mechanism of periodontal disease– associated adverse pregnancy outcomes could lead to interventions to improve fetal growth. Ó 2006 Mosby, Inc. All rights reserved.
Normal fetal growth is an important indicator of fetal well-being. Fetal growth restriction complicates 3% to 7% of all pregnancies, affecting almost 200,000 births annually. Fetal growth restriction contributes to
Supported by National Institutes of Health Grants K08 HD043284 and R01 DE12453 and the University of North Carolina General Clinical Research Center Grant RR00046. Reprints not available from the authors. 0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.11.059
one third of all cases of low birth weight in infants, resulting in significant economic and emotional burden.1 Infants who are small for gestational age (less than the 10th percentile for birth weight) have significantly higher neonatal mortality rates when compared with appropriate- and large-for-gestational-age infants.2 Although the mechanisms of intrauterine growth impairment are not fully elucidated, there are many maternal, placental, and fetal factors that function in concert to assure normal fetal growth.
Boggess et al Human data suggest a relationship between maternal infection and poor fetal growth. Congenital infection with cytomegalovirus, rubella, and Toxoplasma gondii is associated with growth-restricted and microcephalic infants.1 Pregnancies complicated by abnormal genital flora3,4, maternal urinary tract infection,5 or Ureaplasma urealyticum3 isolation from the placenta demonstrate increased rates of fetal growth restriction. Periodontal disease is a chronic oral infection commonly identified in pregnant women,6 which has recently been recognized as a risk factor for preterm birth, preeclampsia, and second-trimester miscarriage.7-10 Periodontal disease is characterized by an overgrowth of normal oral flora with a polymicrobial anaerobic and Gram-negative flora that results in local (gingival) and systemic inflammatory and immune responses.11,12 The causal mechanism of periodontal disease-associated adverse pregnancy outcomes is unknown, although maternal or fetal inflammatory responses to oral pathogens may be involved.13,14 The objectives of this study were to determine the relationship between maternal periodontal disease and delivery of a small-for-gestational-age (SGA) infant and to determine the role of maternal systemic inflammation in this relationship.
Material and methods This study was a planned secondary analysis of data collected as part of the prospective, observational Oral Conditions and Pregnancy study, which was a study of the relationship between maternal periodontal disease and preterm birth risk. The sample size was determined by the primary analysis. The overall study population and methods, and findings for the primary outcome of preterm birth, have been previously published.6,15 The current analysis to determine the relationship between maternal periodontal disease and delivery of an SGA infant was not considered in estimating sample size or calculating power to detect differences in SGA rates among women with varying degrees of periodontal disease. Institutional Review Board approval was granted to conduct the study, and written informed consent was obtained from all study participants. Eligible healthy women with a singleton pregnancy were enrolled prior to 26 weeks’ gestation. Gestational age was assigned based on last menstrual period confirmed by a first- or second-trimester ultrasound. Demographic, health behavior, and medical history data were obtained by patient questionnaire at the first visit and were reviewed by a physician at the first prenatal visit. Information on events of the pregnancy, labor and delivery, and health of the neonate were collected from the medical record, laboratory and pathology data, and the infant’s medical record and entered into the Oral Conditions and Pregnancy Study database (Microsoft Access, 1997 SR2, Microsoft, Redmond, WA).
1317 An oral health examination was performed at the first or second prenatal visit, with detailed methodology previously reported.6 Five certified dental hygienists were trained by a standard examiner and calibrated at the start of the study and at 6-month intervals, using pocket depth and attachment loss measurements. All weighted kappa scores were greater than 85% and intraclass correlation coefficients were 0.9 or higher.6 Gingival pocket depths, degree of attachment loss, and gingival bleeding on probing at 6 sites per tooth for all teeth present, including third molars, were measured and recorded. Clinical periodontal status was categorized based on pocket depth and bleeding criteria. Periodontal health or the absence of periodontal disease was defined as absence of gingival pocket depths greater than 4 mm and no gingival pocket depths greater than 3 mm that also bled on probing. Mild periodontal disease was defined as 1 or more tooth sites with greater than 4-mm pocket depth or 1 or more tooth pockets greater than 3 mm that bled on probing, up to 15 tooth sites. Moderate/severe periodontal disease was defined as 15 or more tooth sites with pocket depths greater than 4 mm. Maternal serum was collected at the enrollment visit and stored 80(C for future measurement of maternal inflammatory and immune responses. For this analysis, maternal serum C-reactive protein levels were measured using a commercially available ultrasensitive enzymelinked immunosorbent assay (R & D Systems, Minneapolis, MN). The lower and upper limits of detection are 1.0 pg/mL and 50 pg/mL, respectively. The inter- and intra-assay variability of the assay is 3% and 15%, respectively. The maternal serum C-reactive protein levels were measured with no knowledge of oral health exam results or birth outcomes. Small-for-gestational age was defined as a birth weight less than the 10th percentile for gestational age based on population standards. To determine 10th percentiles for birth weight for the population, birth certificate data were obtained from the North Carolina Center for Health Statistics.16 All singleton live births for the years of the study period (1997 to 2001) were entered into a database to develop population standard birth weight curves. Birth certificates with missing data were excluded, resulting in 562,393 birth certificate records available. For gestational ages between 32 and 45 weeks, the 10th percentile for birth weight at each week was determined after adjusting for maternal race, parity, and infant gender. Below 32 weeks’ gestation, maternal race, parity, and baby gender did not have a significant impact on birth weight percentiles because of sample sizes, so an unadjusted 10th percentile for gestational age week was determined for births less than 32 weeks’ gestation (Figure 1). All analyses were performed using Statistical Analytical Systems 8.0 (SAS Institute, Cary, NC). Bivariate
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Boggess et al
Results
Figure 1 Rate of delivery of an SGA infant by maternal periodontal disease category (health versus mild versus moderate/ severe) and serum C-reactive protein quartile (Q1, less than the 25th percentile; Q2, 25th to 49th percentile or greater; Q3, 50th to 74th percentile or greater; Q4, 75th percentile or greater).
analysis was performed on a priori candidate risk factors to determine variables associated with the delivery of an SGA infant using Student t test or c2 test. All variables associated with delivery of an SGA infant (P ! .2) were then entered into a multivariable logistic regression model and then removed in a step-wise fashion if P ! .2 by the backward elimination procedure. Variables were also assessed for confounding by testing to see whether the point estimate for the relationship between delivery of an SGA infant and moderate/severe periodontal disease changed by more than 5% by inclusion of that variable in the model. After construction of the final model, the odds ratio was used to estimate the risk ratio (RR) for SGA using a macro application in SAS, which approximates the correction described by Zhang and Yu.17 All variables included in the final model were determined to be independent by assessing for collinearity by calculating the condition index for the model. A condition index greater than 30 reflects moderate to severe collinearity and would reduce confidence in the analysis.18 A separate analysis was conducted to examine the role of maternal inflammation in the relationship between moderate/severe periodontal disease and delivery of an SGA infant. To determine whether confounding was present, the final model excluding maternal serum C-reactive protein level greater than the 75th percentile was compared with a model including serum C-reactive protein level greater than the 75th percentile. Risk ratios (95th percentile confidence interval [CI]) for delivery of an SGA infant were calculated using multivariable logistic regression analysis and stratified by maternal serum C-reactive protein level less than the 75th percentile versus greater than the 75th percentile and the maternal periodontal disease category.
One thousand one hundred seventeen women enrolled at an average of 14 weeks’ gestation had complete data available and comprise the study cohort for this analysis. Maternal demographic characteristics, candidate risk factor and obstetric data, and clinical periodontal disease status are shown in Table I. The incidence of the delivery of an SGA infant was 6.6% (67 of 1017) and was more frequent among preterm, compared with term, deliveries (11% versus 5.6%, P ! .01). Two hundred eighty-four of 1017 (28.0%) had periodontal health, 588 (57.8%) had mild periodontal disease, and 145 (14.3%) had moderate/severe periodontal disease. Women with an SGA infant were also more likely to have moderate/severe periodontal disease than women without an SGA infant (29.9% versus 13.2%, P ! .001). The SGA rate was higher among women with moderate/severe periodontal disease, compared with those with health or mild disease (13.8% versus 6.5% versus 3.2%, P ! .001). The final model and adjusted RRs (95th percentile) for delivery of an SGA infant are shown in Table II. The condition index for the final model was 14.3. The mean serum C-reactive protein level for the cohort was 16.1 G 25.1 pg/mL, and the median (interquartile range) was 4.8 (1.0 to 15.8) pg/mL. Women who delivered an SGA infant had a significantly higher mean serum C-reactive protein level and were more likely to have serum C-reactive protein in the upper quartile than women without an SGA infant (22.9 pg/mL G 29.8 versus 15.8 pg/mL G 24.8, P = .05 and 34.6% versus 24.7%, P = .11, respectively). Women with moderate/severe periodontal disease had a significantly higher mean serum C-reactive protein level and were also more likely to have serum C-reactive protein in the upper quartile than those with periodontal health or mild disease (29.3 pg/mL G 32.4 versus 9.5 pg/mL G 17.7 versus 16.1 pg/mL G 24.9, P ! .0001 and 41.2% versus 15.2% versus 26%, P ! .0001, respectively). The rate of delivery of an SGA infant stratified by maternal periodontal disease and serum C-reactive protein quartile is shown in Figure 2. Among women with serum C-reactive protein level in the upper quartile, those with moderate/severe periodontal disease had a significantly higher rate of delivery of an SGA infant, compared with those with health and mild periodontal disease (19.6% versus 3.2% versus 6.8%, P ! .02). Risk ratios (95th percentile) for delivery of an SGA infant, stratified by maternal C-reactive protein category and periodontal disease category, are shown in Table III. Addition of maternal serum C-reactive protein level in the final model changed the point estimate for moderate/severe periodontal disease to predict the delivery of an SGA infant by 15%. The adjusted RR (95th percentile CI) for an SGA infant among women with
Boggess et al Table I
1319
Demographic, candidate risk factor and obstetric data, and periodontal disease status of cohort
Gestational age at study enrollment, wk (mean G SD) Maternal age, y (mean G SD) Maternal weight, kg (mean G SD) Unmarried Uninsured Use of public assistance Smoking Alcohol use Illicit substance usey Sexually transmitted diseasez during pregnancy Bacterial vaginosis during pregnancyx Previous delivery less than 37 wk Delivery less than 37 wk Preeclampsia Periodontal disease at enrollment Health Mild Moderate/severe
Non-SGA infant (n = 950)
SGA infant (n = 67)
14.9 G 4.9
15.9 G 4.7
28.4 73.4 445 483 159 145 158 36 133
24.9 70.6 50 51 24 16 12 6 13
(6.6) (19.9) (46.8) (50.8) (16.7) (15.2) (16.2) (3.8) (14.1)
(5.9) (17.6) (74.6) (76.1) (35.8) (23.9) (17.9) (8.9) (19.4)
P value* .74 !.001 .22 !.001 !.001 !.001 .06 .79 .04 .22
69 (7.3)
8 (11.9)
.16
146 (15.4) 164 (17.3) 37 (3.9)
21 (31.3) 20 (29.9) 11 (16.4)
!.001 .009 !.001
275 (28.9) 550 (57.9) 125 (13.2)
9 (13.4) 38 (56.7) 20 (29.9)
! 0.001
Data presented as number (percent) unless otherwise noted. * Student t test or c2 test where appropriate. y Defined as patient reported intravenous drug use, marijuana use, or cocaine use. z Defined as Neisseria gonorrhea and/or Chlamydia trachomatis by microbiologic testing. x Defined clinically in symptomatic women by vaginal pH 4.5 or greater and wet mount identification of clue cells.
Table II Final adjusted logistic regression model for delivery of an SGA infant* Adjusted RR (95th CI) y
Maternal age Married Use of public assistance Smoking Illicit substance use Pre-eclampsia Periodontal disease Mild Moderate/severe
1.3 0.6 1.6 1.0 1.8 3.2
(1.1-1.6) (0.3-1.2) (1.0-2.5) (0.6-1.8) (0.9-4.0) (1.7-6.1)
1.3 (0.7-2.5) 2.3 (1.1-4.5)
* Risk ratios approximated from odds ratios as described in text. y Decreasing in 5-year increments.
moderate/severe periodontal disease with serum C-reactive protein level greater than the 75th percentile in the model was 2.7 (1.1 to 6.8).
Comment Our data demonstrate that moderate/severe periodontal disease identified at less than 26 weeks’ gestation is associated with an increased risk for subsequent delivery of an SGA infant, independent of other risk factors for small fetal size. Thirty percent of women with moderate/
severe periodontal disease delivered SGA infants, a rate higher than expected and higher than observed among women with health and mild periodontal disease. We and others have previously reported an association between maternal periodontal disease and preterm birth7,8 preeclampsia9,19,20 and second-trimester miscarriage.10 Although it is unclear whether the relationship between maternal periodontal disease and adverse pregnancy outcomes is causal, several pilot intervention trials demonstrating the benefits of periodontal disease treatment during pregnancy suggest that controlling this source of maternal infection bears further consideration as a possible effective intervention to prevent preterm birth.21-23 The mechanism of periodontal disease associated adverse pregnancy outcomes remains speculative, but inflammatory responses are likely involved.12,14 We hypothesize that maternal periodontal disease presents an oral microbial challenge that results in a systemic inflammatory response in a subset of women and ultimately results in abnormal placental or fetal development that impacts fetal growth. C-reactive protein was selected as the inflammatory marker of interest for several reasons. First, inflammation as defined as moderate increases in C-reactive protein levels, has been associated with cardiovascular disease, implying that nonspecific inflammation has an
1320
Boggess et al Table III Unadjusted RRs (95th percentile CI) for delivery of an SGA infant, stratified by maternal periodontal disease status and C-reactive protein (CRP) category Observed RR (95th CI) Low CRP-health* Low CRP-mild periodontal disease Low CRP-moderate/severe disease High CRP-healthy High CRP-mild periodontal disease High CRP-moderate/severe disease
Figure 2 Population-based birth weight standards (n = 562, 393 births)16 to determine birth weight percentiles by gestational age week, adjusted for maternal race, parity, and infant gender. Center line in box plot represents median birth weight, upper and lower limits of box represent interquartile range of birth weight, and top and bottom of whiskers represent 90th and 10th percentile, respectively.
impact on systemic health.24 Second, there are data that individuals with periodontal disease have elevated serum C-reactive protein level,25 suggesting that a systemic response to the oral microbial burden may be 1 of the mechanisms of periodontal disease–associated adverse health outcomes. In our cohort of women, maternal periodontal disease was associated with increasing quartile serum C-reactive protein level, suggesting maternal systemic inflammation is associated with worsening oral health. We also found that among women with moderate/ severe periodontal disease, those with maternal serum C-reactive protein levels greater than the 75th percentile demonstrated a greater risk for delivery of an SGA infant, compared with those with serum C-reactive protein level less than the 75th percentile, and the combination of maternal serum C-reactive protein level greater than the 75th percentile and moderate/severe periodontal disease increased the risk for an SGA infant greater than either effect alone. Although we cannot determine in our study whether maternal systemic inflammation is occurring in response to oral infection, or some other maternal exposure, other data have shown that periodontal disease is associated with both local and systemic inflammation.11-13 Of note, maternal serum was collected on average, at 14 weeks’ gestation, many weeks prior to delivery of the infant, suggesting that a maternal systemic inflammatory response that occurs early in pregnancy may be important in the relationship between maternal periodontal disease and fetal growth. The timing and role of systemic inflammation as a mechanism of maternal
Expected RR (95th CI)
Reference 2.2 (0.9-5.9) 4.3 (1.4-12.5) 1.1 (0.1-9.2) 2.4 (0.8-7.3) 6.8 (2.4-19.4)
4.7z
* Low is less than the 75th percentile. y High is 75th percentile or greater. z Calculated by multiplying RR of low CRP-moderate/severe disease by high CRP-health.
periodontal disease–associated adverse pregnancy outcomes is an area for future study. Limitations of our study merit discussion. Since periodontal status was the exposure of interest for this analysis, the correct identification of women with clinically or biologically significant periodontal disease is of paramount importance. We based our categories of periodontal disease status on characteristics that may have systemic effects during pregnancy, and include periodontal pockets that may harbor microorganisms and the inflammatory state indexed by bleeding on probing.6 We did not include attachment loss as part of our definition, although this is another common measure for periodontal disease. Other infections have been associated with fetal growth restriction or delivery of an SGA infant,1,3-5 and maternal periodontal disease may represent a surrogate for another infectious process that adversely affects fetal growth. In this analysis, symptomatic bacterial vaginosis or microbiologic proven sexually transmitted diseases were neither significantly associated with nor confounded the relationship between maternal periodontal disease and delivery of an SGA infant when assessed in the final model and thus are unlikely to be related to our findings. We did not examine other possible infectious challenges that might influence fetal growth. Many maternal factors other than infection can impact fetal growth. Although we attempted to identify and control for maternal medical and behavioral characteristics that might affect fetal growth, it is possible that not all factors were considered or identified. In particular, maternal body mass index (BMI), maternal weight, and maternal weight gain could negatively or positively affect fetal growth. We did not include BMI in
Boggess et al our model because the data were not consistently available. However, maternal weight at enrollment was similar between women with and without an SGA infant and did not confound the relationship between moderate/severe periodontal disease and delivery of an SGA infant. Another limitation was lack of information on the placenta. The placenta is critically involved in maintenance of normal fetal growth,26 and we did not assess placental weight or histology in this cohort of women. However, a recent study of very preterm births demonstrated that placental histology was no different between women with and without periodontal disease,27 suggesting that at least for preterm birth, any placental effects of periodontal disease are transient and likely occur remote from the time of delivery. Determination of appropriate fetal growth depends on accurate gestational dating. Estimates of gestational age by menstrual dating, ultrasound dating (when available), and postnatal dating all have inherent inaccuracies. Birth certificate data can be inaccurate, and birth certificate data do not specify what measurements were used to determine gestational age at delivery. This is a challenge for deriving birth weight curves. In the study by Zhang and Bowes28 describing birthweight-for-gestational-age patterns by race, sex, and parity in the United States, menstrual dating misclassified gestational age and elevated birth weight percentiles in preterm births and lowered birth weight percentiles in postterm births. However, ultrasound estimates also misclassified gestational age but in the opposite direction. Because there are currently no data to describe birth weight standard curves that arrives at dating by knowing date of ovulation or conception, we recognize that there are inaccuracies in defining SGA infants using any birth weight standard curve. Another limitation is using SGA as a surrogate for fetal growth restriction. Using a population-based birth weight standard to identify SGA fetuses misidentifies 24% of fetuses as normal and 28% as growth restricted.29 To try to overcome this limitation, we used North Carolina state-wide population standards. However, we recognize that several mechanisms contribute to fetal growth and are not accounted for when using population-based standards. The assessment of fetal weight using ultrasound and individually adjusted birth weight standards predicts growth restriction as a function of loss-of-growth potential and may be superior to using population-based standards to predict adverse perinatal events associated with hypoxia or diminished reserve. Compared with a population-based birth weight standard, a customized birth weight standard increases identification of fetuses at risk of stillbirth and neonatal death, probably because of improved identification of fetal growth restriction.30 Although we used a large
1321 population of women from which the study population was derived to generate birth weight standards, we did not explore using customized birth weight standards. Future study into the role of maternal periodontal disease and fetal growth will need to consider growth potential as well as absolute cut-points to identify fetuses at risk. Despite these limitations, our study provides new insight into the role of maternal periodontal disease and adverse pregnancy outcomes. Moderate/severe maternal periodontal disease identified early in pregnancy is a risk factor for delivery of an SGA infant that is independent of traditional risk factors. This risk may be mediated or exacerbated by a maternal systemic inflammatory response to the chronic challenge of oral pathogens. Further studies on the maternal and fetal inflammatory responses to chronic oral infection and on placental pathology in women with periodontal disease are ongoing to further elucidate the contribution of chronic oral infection on pregnancy outcomes. Maternal periodontal disease is a chronic exposure to oral pathogens that may represent a treatable condition that contributes to impaired in utero fetal growth.
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