Proteomic signature of periodontal disease in pregnancy: Predictive validity for adverse outcomes

The rate of preterm birth is a public health concern worldwide because it is increasing and efforts to prevent it have failed. We report a Clinically Relevant Complex Systematic Review (CSCSR) designed to identify and evaluate the best available evidence in support of the association between periodontal status in women and pregnancy outcome of preterm low birth weight. We hypothesize that the traditional limits of research synthesis must be expanded to incorporate a translational component. As a proof-of-concept model, we propose that this CSCSR can yield greater validity of efficacy and effectiveness through supplementing its recommendations with data of the proteomic signature of periodontal disease in pregnancy, which can contribute to addressing specifically the predictive validity for adverse outcomes. For this CRCSR, systematic reviews were identified through The National Library of MedicinePubmed, The Cochrane library, CINAHL, Google Scholar, Web of Science, and the American Dental Association web library. Independent reviewers quantified the relevance and quality of this literature with R-AMSTAR. Homogeneity and inter-rater reliability testing were supplemented with acceptable sampling analysis. Research synthesis outcomes were analyzed qualitatively toward a Bayesian inference, and converge to demonstrate a definite association between maternal periodontal disease and pregnancy outcome. This CRCSR limits heterogeneity in terms of periodontal disease, outcome measure, selection bias, uncontrolled confounders and effect modifiers. Taken together, the translational CRCSR model we propose suggests that further research is advocated to explore the fundamental mechanisms underlying this association, from a molecular and proteomic perspective.     

Distribution of anaerobic bacteria among pregnant periodontitis patients who experience preterm delivery

The preterm delivery of low-birth-weight (PLBW) infants remains a significant public health issue and a leading cause of neonatal death and of long-term neurodevelopmental disturbances and health problems. Epidemiological and immunological studies have suggested that periodontal disease may be an independent risk factor for PLBW. The incidence of periodontal disease during pregnancy has been found to be associated with a significantly lower birth weight for gestational age after adjustment for race, parity and baby gender. The present case-control study, carried out to examine the distribution of anaerobes in pregnant women with periodontitis who experienced preterm delivery, provides microbial evidence that maternal periodontal disease and the presence of key pathogens are significant contributors to the obstetric risk of preterm delivery.     

A role for cellular senescence in birth timing

Senescence contributes to the local and systemic aging of tissues and has been associated with age-related diseases. Recently, roles for this process during pregnancy have come to light, the dysregulation of which has been associated with adverse pregnancy outcomes such as preterm birth. Here, we summarize recent advances that support a role for senescence in birth timing and propose new aspects of study in this emerging field.     

A simple point of care test can indicate the need for periodontal therapy to reduce the risk for adverse pregnancy outcomes in mothers attending antenatal clinics

Introduction: Although the association between periodontal disease (PD) and adverse pregnancy outcomes has gained recognition amongst antenatal healthcare workers, not much has changed in practice to address it. This prospective study tested the hypothesis that BANA (N-benzoyl-DL-arginine-2-naphthylamide), a diagnostic test for PD, may inform obstetricians and other antenatal healthcare practitioners, of the risk of adverse pregnancy outcomes in mothers attending antenatal clinics.

Methods: At first visit, the presence of suspected periodontopathogens was assessed by BANA testing of dental plaque from 443 mothers attending antenatal clinics in KwaZulu-Natal, South Africa and an association later sought with pregnancy outcomes. The accuracy of BANA to predict adverse pregnancy outcomes was evaluated by the calculation of likelihood ratios. The study complied with the Declaration of Helsinki.

Results: Significant differences were found between pregnancy outcomes of BANA-negative and BANA-positive mothers (p?<?0.0001). BANA showed sensitivity and negative predictive values of 87% and 91%; 75% and 78%; 87% and 94% in detecting low birth weight, preterm delivery, and preterm low birth weight delivery respectively.

Conclusion: This study confirms that BANA may indicate the need for periodontal therapy to reduce the risk of adverse pregnancy outcomes and could form part of the routine antenatal examination.     

Periodontal Treatment for Preventing Adverse Pregnancy Outcomes: A Meta- and Trial Sequential Analysis

Objectives

Periodontal treatment might reduce adverse pregnancy outcomes. The efficacy of periodontal treatment to prevent preterm birth, low birth weight, and perinatal mortality was evaluated using meta-analysis and trial sequential analysis.

Methods

An existing systematic review was updated and meta-analyses performed. Risk of bias, heterogeneity, and publication bias were evaluated, and meta-regression performed. Subgroup analysis was used to compare different studies with low and high risk of bias and different populations, i.e., risk groups. Trial sequential analysis was used to assess risk of random errors.

Results

Thirteen randomized clinical trials evaluating 6283 pregnant women were meta-analyzed. Four and nine trials had low and high risk of bias, respectively. Overall, periodontal treatment had no significant effect on preterm birth (odds ratio [95% confidence interval] 0.79 [0.57-1.10]) or low birth weight (0.69 [0.43-1.13]). Trial sequential analysis demonstrated that futility was not reached for any of the outcomes. For populations with moderate occurrence (<20%) of preterm birth or low birth weight, periodontal treatment was not efficacious for any of the outcomes, and trial sequential analyses indicated that further trials might be futile. For populations with high occurrence (≥20%) of preterm birth and low birth weight, periodontal treatment seemed to reduce the risk of preterm birth (0.42 [0.24-0.73]) and low birth weight (0.32 [0.15-0.67]), but trial sequential analyses showed that firm evidence was not reached. Periodontal treatment did not significantly affect perinatal mortality, and firm evidence was not reached. Risk of bias, but not publication bias or patients’ age modified the effect estimates.

Conclusions

Providing periodontal treatment to pregnant women could potentially reduce the risks of perinatal outcomes, especially in mothers with high risks. Conclusive evidence could not be reached due to risks of bias, risks of random errors, and unclear effects of confounding. Further randomized clinical trials are required.     

Maternal nativity status and pregnancy outcome among U.S.-born Filipinos.

Using 1979-87 Hawaii vital record data on single live births, this study compares by nativity status of the mother the maternal characteristics and pregnancy outcomes of resident Filipino women. Among ethnic minorities in the United States, the pregnancy outcomes of U.S.-born mothers have been reported to compare unfavorably to their foreign-born counterparts. In this study, unequivocally preferential pregnancy outcome indicators were not observed for foreign-born women. Contrary to expectations, a significant, but modest, increase in the risk of preterm delivery was found for infants of Philippines-born mothers, along with a less favorable mean birth weight and gestational age. As a growing minority population in the United States, the atypical determinants and patterns of pregnancy outcome in this population warrants further investigation.     

Risk of Adverse Pregnancy Outcomes among Women Practicing Poor Sanitation in Rural India: A Population-Based Prospective Cohort Study

BackgroundThe importance of maternal sanitation behaviour during pregnancy for birth outcomes remains unclear. Poor sanitation practices can promote infection and induce stress during pregnancy and may contribute to adverse pregnancy outcomes (APOs). We aimed to assess whether poor sanitation practices were associated with increased risk of APOs such as preterm birth and low birth weight in a population-based study in rural India.ConclusionsThis study provides the first evidence, to our knowledge, that poor sanitation is associated with a higher risk of APOs. Additional studies are required to elucidate the socio-behavioural and/or biological basis of this association so that appropriate targeted interventions might be designed to support improved birth outcomes in vulnerable populations. While it is intuitive to expect that caste and poverty are associated with poor sanitation practice driving APOs, and we cannot rule out additional confounders, our results demonstrate that the association of poor sanitation practices (open defecation) with these outcomes is independent of poverty. Our results support the need to assess the mechanisms, both biological and behavioural, by which limited access to improved sanitation leads to APOs.     

Does fetal sex affect pregnancy outcome?

Background: In maternal fetal medicine, gender differences in outcome are often observed.Objective: This article reviews the fetal sex-dependent differences found in many aspects of pregnancy, from conception through birth.Methods: The MEDLINE, EMBASE, and Current Contents databases were searched, for the years 1985 to 2006, using the following Medical Subject Headings and text words: fetal gender, finale, female, sex ratio at birth, pregnancy outcome, preterm birth, and stillbirth. The search was not limited by language. In addition, the bibliographies of known relevant articles were examined to capture any reports not already identified in the electronic search. All reports that provided information on gender differences in pregnancy outcome were included for review.Results: An extremely high male-to-female ratio was found in fetuses born after very short-duration pregnancy; this level declined around the 20th week and stabilized at term. In the absence of manipulation, both the sex ratio at birth and the population sex ratio have been found to remain consistent. A higher incidence of preterm birth and premature preterm rupture of membranes has been observed in different populations among mothers of male newborns compared with mothers of females. It has been speculated that this higher incidence may be linked to the relatively greater weight at lower gestational age of male newborns versus females. Women carrying male fetuses had higher rates of gestational diabetes mellitus, fetal macrosomia, failure to progress during the first and second stages of labor, cord prolapse, nuchal cord, and true umbilical cord knots. Cesarean sections were also more frequently found among male neonates compared with females.Conclusions: Male sex is an independent risk factor for adverse pregnancy outcome. Evidence suggests that females have an advantage over males, with a better outcome in the perinatal period, particularly after preterm birth.Key words: fetal gender, male, female, sex ratio of birth, perinatal outcome.     

Maternal nativity status and pregnancy outcome among U.S.‐born Filipinos

Abstract

Using 1979–87 Hawaii vital record data on single live births, this study compares by nativity status of the mother the maternal characteristics and pregnancy outcomes of resident Filipino women. Among ethnic minorities in the United States, the pregnancy outcomes of U.S.‐born mothers have been reported to compare unfavorably to their foreign‐born counterparts. In this study, unequivocally preferential pregnancy outcome indicators were not observed for foreign‐born women. Contrary to expectations, a significant, but modest, increase in the risk of preterm delivery was found for infants of Philippines‐born mothers, along with a less favorable mean birth weight and gestational age. As a growing minority population in the United States, the atypical determinants and patterns of pregnancy outcome in this population warrants further investigation.     

Relationships between some maternal factors and pregnancy outcome

This study, carried out on mother-infant pairs in obstetric hospitals in Istanbul, was designed to investigate the impact of some maternal parameters on pregnancy outcome as well as to provide information on birth weight, and incidence of low birth weight, preterm birth, and small for gestational age birth. Low birth weight, preterm birth, and fetal malnutrition are among major risk factors influencing perinatal, neonatal, and postneonatal mortality and morbidity. Reported values for prepregnancy body weight and postpartum measurements of stature, weight, mid-upper arm circumference showed that the women in this series did not have caloric undernutrition, while nearly 9% were of low stature. Maternal stature, postpartum body weight, and postpartum weight and height values were found to be important determinants of birth weight. The frequency of preterm births in this series corresponds fairly well with that found in another group of Turkish mother-infant pairs in which gestational age was determined by Dubowitz scoring. In agreement with many previous studies, maternal stature and body weight stood out as important influences on the outcome of pregnancy in this series. Overall, the nutritional state of the mother prior to pregnancy is the most important determinant of birth weight.     

Genetic regulation of amniotic fluid TNF-alpha and soluble TNF receptor concentrations affected by race and preterm birth

Racial disparity in spontaneous preterm birth (PTB) between African Americans and Caucasians in the US is unexplained, but is probably related to differences in amniotic fluid (AF) inflammatory cytokine profiles. Therefore, this study analyzed the association of 34 single nucleotide polymorphisms (SNPs) in TNF-α and its receptor genes (TNFR1 and TNFR2) with AF TNF-α and soluble TNF receptor (R1 and R2) concentrations in PTB. Samples consisted of African American and Caucasian cases (PTB), and controls (term birth) for which both cytokine, and maternal and fetal genotype data were available. Analyses were performed with genotype, case, and maker-status interaction in the model for log transformed cytokine concentrations. In Caucasians, two interactions between genotype and pregnancy outcome associated with cytokine concentrations, whereas 14 gene variants in African Americans showed interactions with pregnancy outcome, and 13 showed association with genetic markers. In conclusion, cytokine concentrations in African American preterm births can be partially explained by interactions between pregnancy outcome, SNPs and infection. This does not appear to be the case in Caucasians. These findings may be important in understanding disparity in rates of PTB between the two populations. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Review on genetic variants and maternal smoking in the etiology of oral clefts and other birth defects

A spectrum of adverse pregnancy outcomes, including preterm birth, low birth weight, and birth defects has been linked with maternal smoking during pregnancy. This article includes a review of studies investigating interactions between genetic variants and maternal smoking in contributing to birth defects using oral clefting as a model birth defect. The primary gene-smoking studies for other major birth defects are also summarized. Gene-environment interaction studies for birth defects are still at an early stage with several mixed results, but evolving research findings have begun to document clinically and developmentally important interactions. As samples and data become increasingly available, more effort is needed in designing innovative analytical methods to study gene-environment interactions.     

Analysis of preterm deliveries below 35 weeks' gestation in a tertiary referral hospital in the UK. A case-control survey

Background

Preterm birth remains a major public health problem and its incidence worldwide is increasing. Epidemiological risk factors have been investigated in the past, but there is a need for a better understanding of the causes of preterm birth in well defined obstetric populations in tertiary referral centres; it is important to repeat surveillance and identify possible changes in clinical and socioeconomic factors associated with preterm delivery. The aim of this study was to identify current risk factors associated with preterm delivery and highlight areas for further research.

Findings

We studied women with singleton deliveries at St Michael's Hospital, Bristol during 2002 and 2003. 274 deliveries between 23-35 weeks' gestation (preterm group), were compared to 559 randomly selected control deliveries at term (37-42 weeks) using standard statistical procedures. Both groups were >80% Caucasian. Previous preterm deliveries, high maternal age (> 39 years), socioeconomic problems, smoking during pregnancy, hypertension, psychiatric disorders and uterine abnormalities were significantly associated with preterm deliveries. Both lean and obese mothers were more common in the preterm group. Women with depression/psychiatric disease were significantly more likely to have social problems, to have smoked during pregnancy and to have had previous preterm deliveries; when adjustments for these three factors were made the relationship between psychiatric disease and pregnancy outcome was no longer significant. 53% of preterm deliveries were spontaneous, and were strongly associated with episodes of threatened preterm labour. Medically indicated preterm deliveries were associated with hypertension and fetal growth restriction. Preterm premature rupture of the membranes, vaginal bleeding, anaemia and oligohydramnios were significantly increased in both spontaneous and indicated preterm deliveries compared to term controls.

Conclusions

More than 50% of preterm births are potentially preventable, but remain associated with risk factors such as increased uterine contractility, preterm premature rupture of the membranes and uterine bleeding whose aetiology is unknown. Despite remarkable advances in perinatal care, preterm birth continues to cause neonatal deaths and long-term morbidity. Significant breakthroughs in the management of preterm birth are likely to come from research into the mechanisms of human parturition and the pathophysiology of preterm labour using multidisciplinary clinical and laboratory approaches.

     

Estimating perinatal critical windows of susceptibility to environmental mixtures via structured Bayesian regression tree pairs

Maternal exposure to environmental chemicals during pregnancy can alter birth and children's health outcomes. Research seeks to identify critical windows, time periods when exposures can change future health outcomes, and estimate the exposure–response relationship. Existing statistical approaches focus on estimation of the association between maternal exposure to a single environmental chemical observed at high temporal resolution (e.g., weekly throughout pregnancy) and children's health outcomes. Extending to multiple chemicals observed at high temporal resolution poses a dimensionality problem and statistical methods are lacking. We propose a regression tree–based model for mixtures of exposures observed at high temporal resolution. The proposed approach uses an additive ensemble of tree pairs that defines structured main effects and interactions between time-resolved predictors and performs variable selection to select out of the model predictors not correlated with the outcome. In simulation, we show that the tree-based approach performs better than existing methods for a single exposure and can accurately estimate critical windows in the exposure–response relation for mixtures. We apply our method to estimate the relationship between five exposures measured weekly throughout pregnancy and birth weight in a Denver, Colorado, birth cohort. We identified critical windows during which fine particulate matter, sulfur dioxide, and temperature are negatively associated with birth weight and an interaction between fine particulate matter and temperature. Software is made available in the R package dlmtree.     

Pregnancy and periodontal tissues

Periodontitis is today considered to be a serious disease of periodontal tissues, one caused in most cases by bacterial infection which stimulates proteolysis and osteolysis of the tissues. Typical for the disease is formation of periodontal pockets and a chronic destructive inflammation which impacts on the whole organism. Periodontopathic bacteria colonized in a subgingival biofilm cannot be removed by common oral hygiene. Overproduction of bacteria and other pro-inflammatory mediators can increase the total pro-inflammatory state of the organism in pregnant women. Increased levels of some pro-inflammatory cytokines (PGE2) and cells in fetoplacental space can lead to premature rupture of membranes and subsequent delivery of immature babies. An increasing number of studies in this field provide evidence that good professional care and personal oral hygiene can bring benefits through a decreased prevalence of preterm low birth weight infants (PLBWI) in women suffering periodontitis, although definitive conclusions have not yet been reached. Future mothers with periodontitis can run not only an increased risk of PLWBI but often also suffer pre-eclampsia - a state called acute atherosis - which can be ethiopathogenetically associated with high concentrations of various pro-inflammatory mediators. An increased production of female hormones during pregnancy contributes to the development of gingivitis and periodontitis because vascular permeability and possible tissue edema are both increased.     

Roles of maternal HDL during pregnancy

BackgroundHigh density lipoproteins (HDL) were first linked to cardiovascular disease (CVD) over 30 years ago when an inverse relationship was shown between CVD and HDL-cholesterol levels. It is now apparent that HDL composition and function, not cholesterol levels, are the pertinent measurements describing HDL's role in various disease processes, especially those with subclinical or overt inflammation.Scope of reviewPregnancy is also an inflammatory state. When inflammation becomes excessive during pregnancy, there is an increased risk for adverse outcomes that affect the health of the mother and fetus, including preterm birth and preeclampsia. Though studies on HDL during pregnancy are limited, recent evidence demonstrates that HDL composition and function change during pregnancy and in women with adverse outcomes.General significanceIn this review, we will discuss how HDL may play a role in maintaining a healthy pregnancy and how impairments in function could lead to pregnancies with adverse outcomes.     

Evaluation of preterm births and birth defects in liveborn infants of US military women who received smallpox vaccine

BACKGROUND: Women serving in the US military have some unique occupational exposures, including exposure to vaccinations that are rarely required in civilian professions. When vaccinations are inadvertently given during pregnancy, such exposures raise special concerns. These analyses address health outcomes, particularly preterm births and birth defects, among infants who appear to have been exposed to maternal smallpox vaccination in pregnancy. METHODS: This retrospective cohort study included 31,420 infants born to active‐duty military women during 2003–2004. We used Department of Defense databases to define maternal vaccination and infant health outcomes. Multivariable regression models were developed to describe associations between maternal smallpox vaccination and preterm births and birth defects in liveborn infants. RESULTS: There were 7,735 infants identified as born to women ever vaccinated against smallpox, and 672 infants born to women vaccinated in the first trimester of pregnancy. In multivariable modeling, maternal smallpox vaccination in pregnancy was not associated with preterm or extreme preterm delivery. Maternal smallpox vaccination in the first trimester of pregnancy was not significantly associated with overall birth defects (OR 1.40; 95% CI: 0.94, 2.07), or any of seven specific defects individually modeled. CONCLUSIONS: Results may be reassuring that smallpox vaccine, when inadvertently administered to pregnant women, is not associated with preterm delivery or birth defects in liveborn infants. Birth Defects Research (Part A) 2008. © 2008 Wiley‐Liss, Inc.     

Early pregnancy azathioprine use and pregnancy outcomes

BACKGROUND: Azathioprine (AZA) is used during pregnancy by women with inflammatory bowel disease (IBD), other autoimmune disorders, malignancy, and organ transplantation. Previous studies have demonstrated potential risks. METHODS: The Swedish Medical Birth Register was used to identify 476 women who reported the use of AZA in early pregnancy. The effect of AZA exposure on pregnancy outcomes was studied after adjustment for maternal characteristics that could act as confounders. RESULTS: The most common indication for AZA use was IBD. The rate of congenital malformations was 6.2% in the AZA group and 4.7% among all infants born (adjusted OR: 1.41, 95% CI: 0.98–2.04). An association between early pregnancy AZA exposure and ventricular/atrial septal defects was found (adjusted OR: 3.18, 95% CI: 1.45–6.04). Exposed infants were also more likely to be preterm, to weigh <2500 gm, and to be small for gestational age compared to all infants born. This effect remained for preterm birth and low birth weight when infants of women with IBD but without AZA exposure were used as a comparison group. A trend toward an increased risk of congenital malformations was found among infants of women with IBD using AZA compared to women with IBD not using AZA (adjusted OR: 1.42, 95% CI: 0.93–2.18). CONCLUSIONS: Infants exposed to AZA in early pregnancy may be at a moderately increased risk of congenital malformations, specifically ventricular/atrial septal defects. There is also an increased risk of growth restriction and preterm delivery. These associations may be confounded by the severity of maternal illness. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Preterm or Not – An Evaluation of Estimates of Gestational Age in a Cohort of Women from Rural Papua New Guinea

BackgroundKnowledge of accurate gestational age is required for comprehensive pregnancy care and is an essential component of research evaluating causes of preterm birth. In industrialised countries gestational age is determined with the help of fetal biometry in early pregnancy. Lack of ultrasound and late presentation to antenatal clinic limits this practice in low-resource settings. Instead, clinical estimators of gestational age are used, but their accuracy remains a matter of debate.MethodsIn a cohort of 688 singleton pregnancies from rural Papua New Guinea, delivery gestational age was calculated from Ballard score, last menstrual period, symphysis-pubis fundal height at first visit and quickening as well as mid- and late pregnancy fetal biometry. Published models using sequential fundal height measurements and corrected last menstrual period to estimate gestational age were also tested. Novel linear models that combined clinical measurements for gestational age estimation were developed. Predictions were compared with the reference early pregnancy ultrasound (<25 gestational weeks) using correlation, regression and Bland-Altman analyses and ranked for their capability to predict preterm birth using the harmonic mean of recall and precision (F-measure).ResultsAverage bias between reference ultrasound and clinical methods ranged from 0–11 days (95% confidence levels: 14–42 days). Preterm birth was best predicted by mid-pregnancy ultrasound (F-measure: 0.72), and neuromuscular Ballard score provided the least reliable preterm birth prediction (F-measure: 0.17). The best clinical methods to predict gestational age and preterm birth were last menstrual period and fundal height (F-measures 0.35). A linear model combining both measures improved prediction of preterm birth (F-measure: 0.58).ConclusionsEstimation of gestational age without ultrasound is prone to significant error. In the absence of ultrasound facilities, last menstrual period and fundal height are among the more reliable clinical measures. This study underlines the importance of strengthening ultrasound facilities and developing novel ways to estimate gestational age.     

Developmental Exposure of Mice to Dioxin Promotes Transgenerational Testicular Inflammation and an Increased Risk of Preterm Birth in Unexposed Mating Partners

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly known as dioxin) is a ubiquitous environmental contaminant and known endocrine disruptor. Using a mouse model, we previously found that adult female mice exposed in utero to TCDD (F1 generation) as well as multiple subsequent generations (F2-F4) exhibited reduced fertility and an increased incidence of spontaneous preterm birth. Additional studies revealed that male F1 mice with a similar in utero/developmental TCDD exposure also exhibited diminished fertility and conferred an increased risk of preterm birth to their unexposed mating partners. Herein, we extend these previous observations, reporting that reduced fertility in male F1 mice is linked to testicular inflammation which coincides with apoptosis of developing spermatocytes, sub-fertility and an increased risk of preterm birth in their unexposed mating partners. Significantly, in the absence of additional toxicant exposure, testicular inflammation and reduced fertility persisted in F2 and F3 males and their control mating partners also frequently exhibited spontaneous preterm birth. Although a steady, global decline in male fertility has been noted over the last few decades, the reasons for these changes have not been firmly established. Likewise, the PTB rate in the U.S. and other countries has paralleled industrial development, suggesting a possible relationship between environmental toxicant exposure and adverse pregnancy outcomes. Most current clinical strategies to prevent preterm birth are focused solely on the mother and have yielded limited benefits. In contrast, our studies strongly suggest that the preconception testicular health of the father is a critical determinant of pregnancy outcomes in mice. Future clinical studies should examine the potential contribution of the male to gestation length in women and whether efforts to reduce the incidence of preterm birth should be initiated in both parents prior to pregnancy.