Effects of minimally invasive non-surgical therapy on C-reactive protein, lipoprotein-associated phospholipase A2, and clinical outcomes in periodontitis patients: A 1-year randomized, controlled clinical trial.

BACKGROUND: Growing evidence suggests the type of periodontal treatment could differentially influence the reduction of key cardiovascular risk mediators in periodontitis patients. This randomized, controlled clinical trial compared the impact of minimally invasive non-surgical therapy (MINST) with quadrant-wise subgingival instrumentation (Q-SI) on C-reactive protein (CRP) together with lipoprotein-associated phospholipase A2 (Lp-PLA2) levels, and clinical periodontal outcomes in patients with periodontitis. Moreover, it was evaluated if baseline CRP levels impacted the efficacy of non-surgical periodontal therapy protocols. METHODS: Forty-two periodontitis patients were enrolled and randomly treated by means of MINST (n = 21) or Q-SI (n = 21). The outcomes assessed were serum CRP and Lp-PLA2, and periodontal parameters (probing depth [PD], clinical attachment level [CAL], full-mouth bleeding score [FMBS]), at baseline and at follow-ups at 1, 3, and 6 months and at 1 year after treatment. RESULTS: At 1 year, MINST significantly reduced, among others, mean PD (p = 0.007), mean CAL (p = 0.007), the number of pockets >4 mm (p = 0.011) and ≥6 mm (p = 0.005), and FMBS (p = 0.048) compared to Q-SI. Generalized multivariate analysis evidenced that high baseline CRP (p = 0.039) and FMBS (p = 0.046) levels, together with MINST treatment (p = 0.007) were significant predictors of PD reduction at 1-year follow-up. Moreover, the Jonckheere-Terpstra test showed that patients with high baseline CRP levels gained more benefits from MINST treatment at 1-year follow-up than they did from Q-SI. CONCLUSION: Patients receiving MINST showed a greater reduction in CRP levels than patients with Q-SI after 1 year of follow-up. Moreover, patients with high baseline levels of CRP and Lp-PLA2 gained more benefits from the MINST approach at 1-year follow-up.

NLRP3 inflammasome activity and periodontal disease pathogenesis-A bidirectional relationship.

OBJECTIVE: Periodontitis is an inflammatory oral disease that occurs as a result of the damaging effects of the immune response against the subgingival microflora. Among the mechanisms involved, the nucleotide-binding oligomerization domain, leucine-rich repeat-containing proteins family member NLRP3 (NLR family pyrin domain-containing 3), proposed as the key regulator of macrophage-induced inflammation, is strongly associated with periodontal disease due to the bacterial activators. This paper aimed to present key general concepts of NLRP3 inflammasome activation and regulation in periodontal disease. METHOD: A narrative review was conducted in order to depict the current knowledge on the relationship between NLRP3 inflammasome activity and periodontal disease. In vitro and in situ studies were retrieved and commented based on their relevance in the field. RESULTS: The NLRP3 inflammasome activity stimulated by periodontal microbiota drive periodontal disease pathogenesis and progression. This occurs through the release of proinflammatory cytokines IL-1ß, IL-18, and DAMPs (damage-associated molecular pattern molecules) following inflammasome activation. Moreover, the tissue expression of NLRP3 is dysregulated by oral microbiota, further exacerbating periodontal inflammation. CONCLUSION: The review provides new insights into the relationship between the NLRP3 inflammasome activity and periodontal disease pathogenesis, highlighting the roles and regulatory mechanism of inflammatory molecules involved in the disease process.

Modeling longitudinal oral health status and pneumonia risk: secondary data analyses of an integrated dental-medical cohort.

BACKGROUND: Mounting evidence indicates potential associations between poor oral health status (OHS) and increased pneumonia risk. Relative pneumonia risk was assessed in the context of longitudinally documented OHS. METHODS: Electronic medical/dental patient data captured from 2007 through 2019 were retrieved from the integrated health records of Marshfield Clinic Health Systems. Participant eligibility initiated with an assessment of OHS, stratified into the best, moderate, or worst OHS groups, with the additional criterion of 'no pneumonia diagnosis in the past 90 days'. Pneumonia incidence was longitudinally monitored for up to 1 year from each qualifying dental visit. Models were assessed, with and without adjustment for prior pneumonia incidence, adjusted for smoking and subjected to confounding mitigation attributable to known pneumonia risk factors by applying propensity score analysis. Time-to-event analysis and proportional hazard modeling were applied to investigate relative pneumonia risk over time among the OHS groups. RESULTS: Modeling identified associations between any incident pneumonia subtype and 'number of missing teeth' (p < 0.001) and 'clinically assessed periodontal status' (p < 0.01), which remained significant following adjustment for prior pneumonia incidence and smoking. The hazard ratio (HR) for 'any incident pneumonia' in the best OHS group for 'number of missing teeth' was 0.65, 95% confidence interval (CI) [0.54 - 0.79] (unadjusted) and 0.744, 95% CI [0.61 - 0.91] (adjusted). The HR for 'any incident pneumonia' in the best 'clinically assessed periodontal status' group was 0.72, 95% CI [0.58 - 0.90] (unadjusted) and 0.78, 95% CI [0.62 - 0.97] (adjusted). CONCLUSION/CLINICAL RELEVANCE: Poor OHS increased pneumonia risk. Proactive attention of medical providers to patient OHS and health literacy surrounding oral-systemic disease association is vital, especially in high-risk populations.

Poor Oral Health in the Etiology and Prevention of Aspiration Pneumonia.

Aspiration pneumonia (AP), inflammation of the lung parenchyma initiated by aspirated microorganisms into the lower airways from proximal sites, including the oral cavity, is prevalent in, and problematic for, the elderly, especially those in institutions, and for those with several important risk factors. Many factors influence the pathogenesis of AP, including dysphagia, poor oral hygiene, diminished host defense, and underlying medical conditions. This article reviews the epidemiology, microbiology, pathogenesis, and prevention of AP, focusing on the role of poor oral health as a risk factor for, and on dental care for the prevention and management of, this important infection.

The association between accessing dental services and nonventilator hospital-acquired pneumonia among 2019 Medicaid beneficiaries.

In this 2019 cross-sectional study, we analyzed hospital records for Medicaid beneficiaries who acquired nonventilator hospital-acquired pneumonia. The results suggest that preventive dental treatment in the 12 months prior or periodontal therapy in the 6 months prior to a hospitalization is associated with a reduced risk of NVHAP.

Incidence, mortality, and cost trends in nonventilator hospital-acquired pneumonia in medicaid beneficiaries, 2015-2019.

Nonventilator hospital-acquired pneumonia is associated with substantial morbidity, mortality, and costs during an episode of acute care. We examined NVHAP incidence, mortality, and costs of Medicaid beneficiaries over a 5-year period (2015-2019). Overall NVHAP incidence was 2.63 per 1,000 patient days, and mortality was 7.76%, with an excess cost per NVHAP case of $20,189.

Mirdza E. Neiders: A pioneer in oral pathology, oral health science research, and education.

Over her near 60-year career, Mirdza E. (Mitzi) Neiders has served as a teacher, dentist, researcher, mentor, role-model, friend, and critic for thousands of faculty, students, and patients of the University at Buffalo School of Dental Medicine. One of the first women to serve on the dental school faculty, this article describes her journey and the great impact that she has made on dentistry and her community on the occasion of her retirement.

A Methodological Approach to Validate Pneumonia Encounters from Radiology Reports Using Natural Language Processing.

INTRODUCTION: Pneumonia is caused by microbes that establish an infectious process in the lungs. The gold standard for pneumonia diagnosis is radiologist-documented pneumonia-related features in radiology notes that are captured in electronic health records in an unstructured format. OBJECTIVE: The study objective was to develop a methodological approach for assessing validity of a pneumonia diagnosis based on identifying presence or absence of key radiographic features in radiology reports with subsequent rendering of diagnostic decisions into a structured format. METHODS: A pneumonia-specific natural language processing (NLP) pipeline was strategically developed applying Clinical Text Analysis and Knowledge Extraction System (cTAKES) to validate pneumonia diagnoses following development of a pneumonia feature-specific lexicon. Radiographic reports of study-eligible subjects identified by International Classification of Diseases (ICD) codes were parsed through the NLP pipeline. Classification rules were developed to assign each pneumonia episode into one of three categories: "positive," "negative," or "not classified: requires manual review" based on tagged concepts that support or refute diagnostic codes. RESULTS: A total of 91,998 pneumonia episodes diagnosed in 65,904 patients were retrieved retrospectively. Approximately 89% (81,707/91,998) of the total pneumonia episodes were documented by 225,893 chest X-ray reports. NLP classified and validated 33% (26,800/81,707) of pneumonia episodes classified as "Pneumonia-positive," 19% as (15401/81,707) as "Pneumonia-negative," and 48% (39,209/81,707) as "episode classification pending further manual review." NLP pipeline performance metrics included accuracy (76.3%), sensitivity (88%), and specificity (75%). CONCLUSION: The pneumonia-specific NLP pipeline exhibited good performance comparable to other pneumonia-specific NLP systems developed to date.

Oral health status and the etiology and prevention of nonventilator hospital-associated pneumonia.

Nonventilator hospital-associated pneumonia has recently emerged as an important preventable hospital-associated infection, and is a leading cause of healthcare-associated infection. Substantial accumulated evidence links poor oral health with an increased risk of pneumonia, which can be caused by bacterial, viral, or fungal pathogens, each with their own distinct mechanisms of transmission and host susceptibility. These infections are frequently polymicrobial, and often include microbes from biofilms in the oral cavity. Evidence documenting the importance of oral care to prevent nonventilator hospital-associated pneumonia is continuing to emerge. Reduction of oral biofilm in these populations will reduce the numbers of potential respiratory pathogens in the oral secretions that can be aspirated, which in turn can reduce the risk for pneumonia. This review summarizes up-to-date information on the role of oral care in the prevention of nonventilator hospital-associated pneumonia.

Identifying Pneumonia Subtypes from Electronic Health Records Using Rule-Based Algorithms.

BACKGROUND: The International Classification of Disease (ICD) coding for pneumonia classification is based on causal organism or use of general pneumonia codes, creating challenges for epidemiological evaluations where pneumonia is standardly subtyped by settings, exposures, and time of emergence. Pneumonia subtype classification requires data available in electronic health records (EHRs), frequently in nonstructured formats including radiological interpretation or clinical notes that complicate electronic classification. OBJECTIVE: The current study undertook development of a rule-based pneumonia subtyping algorithm for stratifying pneumonia by the setting in which it emerged using information documented in the EHR. METHODS: Pneumonia subtype classification was developed by interrogating patient information within the EHR of a large private Health System. ICD coding was mined in the EHR applying requirements for "rule of two" pneumonia-related codes or one ICD code and radiologically confirmed pneumonia validated by natural language processing and/or documented antibiotic prescriptions. A rule-based algorithm flow chart was created to support subclassification based on features including symptomatic patient point of entry into the health care system timing of pneumonia emergence and identification of clinical, laboratory, or medication orders that informed definition of the pneumonia subclassification algorithm. RESULTS: Data from 65,904 study-eligible patients with 91,998 episodes of pneumonia diagnoses documented by 380,509 encounters were analyzed, while 8,611 episodes were excluded following Natural Language Processing classification of pneumonia status as "negative" or "unknown." Subtyping of 83,387 episodes identified: community-acquired (54.5%), hospital-acquired (20%), aspiration-related (10.7%), health care-acquired (5%), and ventilator-associated (0.4%) cases, and 9.4% cases were not classifiable by the algorithm. CONCLUSION: Study outcome indicated capacity to achieve electronic pneumonia subtype classification based on interrogation of big data available in the EHR. Examination of portability of the algorithm to achieve rule-based pneumonia classification in other health systems remains to be explored.

Identifying oral disease variables associated with pneumonia emergence by application of machine learning to integrated medical and dental big data to inform eHealth approaches.

Background: The objective of this study was to build models that define variables contributing to pneumonia risk by applying supervised Machine Learning-(ML) to medical and oral disease data to define key risk variables contributing to pneumonia emergence for any pneumonia/pneumonia subtypes. Methods: Retrospective medical and dental data were retrieved from Marshfield Clinic Health System's data warehouse and integrated electronic medical-dental health records (iEHR). Retrieved data were pre-processed prior to conducting analyses and included matching of cases to controls by (a) race/ethnicity and (b) 1:1 Case: Control ratio. Variables with >30% missing data were excluded from analysis. Datasets were divided into four subsets: (1) All Pneumonia (all cases and controls); (2) community (CAP)/healthcare associated (HCAP) pneumonias; (3) ventilator-associated (VAP)/hospital-acquired (HAP) pneumonias and (4) aspiration pneumonia (AP). Performance of five algorithms were compared across the four subsets: Naïve Bayes, Logistic Regression, Support Vector Machine (SVM), Multi-Layer Perceptron (MLP) and Random Forests. Feature (input variables) selection and ten-fold cross validation was performed on all the datasets. An evaluation set (10%) was extracted from the subsets for further validation. Model performance was evaluated in terms of total accuracy, sensitivity, specificity, F-measure, Mathews-correlation-coefficient and area under receiver operating characteristic curve (AUC). Results: In total, 6,034 records (cases and controls) met eligibility for inclusion in the main dataset. After feature selection, the variables retained in the subsets were: All Pneumonia (n = 29 variables), CAP-HCAP (n = 26 variables); VAP-HAP (n = 40 variables) and AP (n = 37 variables), respectively. Variables retained (n = 22) were common across all four pneumonia subsets. Of these, the number of missing teeth, periodontal status, periodontal pocket depth more than 5 mm and number of restored teeth contributed to all the subsets and were retained in the model. MLP outperformed other predictive models for All Pneumonia, CAP-HCAP and AP subsets, while SVM outperformed other models in VAP-HAP subset. Conclusion: This study validates previously described associations between poor oral health and pneumonia. Benefits of an integrated medical-dental record and care delivery environment for modeling pneumonia risk are highlighted. Based on findings, risk score development could inform referrals and follow-up in integrated healthcare delivery environment and coordinated patient management.

Associations between dental caries and systemic diseases: a scoping review.

BACKGROUND: The objective of this study was to evaluate and present evidence from animal and human clinical studies on associations between dental caries and systemic diseases, and to suggest potential mechanisms that might explain such associations. METHODS: An electronic search was conducted of PubMed, Embase and Cochrane Central Register of Controlled Trials for articles published from 2010 to 2020 in the English language. From the initial search, 404 full-text studies were assessed for eligibility. After excluding studies for technical and study limitations, a total of 67 studies were included in the summary tables and additional studies were included in the review to support evidence. RESULTS: Few systemic disease and conditions were found to be clinically meaningfully associated with caries experience. Best evidence from human and animal studies described association between metabolic diseases and dental caries. Several interesting animal studies were noted that could generate clinical hypotheses and further investigations in rodent models for cardiovascular injury and hyperglycemia. Inadequate data was found to suggest any modifications to current clinical practice or prevention guidelines. CONCLUSIONS: Limited clinical evidence was found connecting several systemic diseases and dental caries. Inadequate data was found to suggest any modifications to current clinical practice or prevention guidelines. CLINICAL SIGNIFICANCE: Understanding of associations between dental caries and systemic diseases play a crucial role in the treatment planning and education of the dental patient.

Comparative Pan-Genome Analysis of Oral Veillonella Species.

The genus Veillonella is a common and abundant member of the oral microbiome. It includes eight species, V. atypica, V. denticariosi, V. dispar, V. infantium, V. nakazawae, V. parvula, V. rogosae and V. tobetusensis. They possess important metabolic pathways that utilize lactate as an energy source. However, the overall metabolome of these species has not been studied. To further understand the metabolic framework of Veillonella in the human oral microbiome, we conducted a comparative pan-genome analysis of the eight species of oral Veillonella. Analysis of the oral Veillonella pan-genome revealed features based on KEGG pathway information to adapt to the oral environment. We found that the fructose metabolic pathway was conserved in all oral Veillonella species, and oral Veillonella have conserved pathways that utilize carbohydrates other than lactate as an energy source. This discovery may help to better understand the metabolic network among oral microbiomes and will provide guidance for the design of future in silico and in vitro studies.

Dysbiosis revisited: Understanding the role of the oral microbiome in the pathogenesis of gingivitis and periodontitis: A critical assessment.

This commentary provides background, historical context, and a critical assessment of the concept that microbial dysbiosis drives the pathogenesis of periodontal diseases. It is long known that periodontal pathogenesis is dependent on tooth-borne microbial biofilms (dental plaque) that trigger host inflammation resulting in periodontal destruction and tooth loss in some patients. Ecological principles governing plaque biofilm development, along with localized host responses, are both rooted in evolution. Interpretation of available evidence suggests that, in most patients, alveolar bone loss results from interactions of a highly diverse commensal microbiota with the host, and not from "overgrowth" of a few "pathobionts" that results in a "dysbiosis." Most previously described dysbiotic chronic diseases, for example, inflammatory bowel diseases and dermatitis, are characterized by decreased microbial diversity (likely due to frank overgrowth of one or a few microbial taxa). Most common forms of periodontitis do not appear to conform to this general principle, and the associated microbiome in fact almost always shows increased bacterial diversity compared with periodontal health. This diversity is driven by interactions of genetic and environmental factors working in concert within specific windows of time. Periodontal pathogenesis is likely the result of "personalized pathology," insofar as each patient likely has a variable constellation of microbes and host risk factors influencing specific tissue sites where disease activity occurs, and during a limited window of time (a tissue-destructive "burst"). The concept of cooperative virulence of higher abundance commensals in periodontal pathogenesis, which does not conform to the model of dysbiosis observed for other diseases, is discussed.

Periodontitis and its higher levels of severity are associated with the triglyceride/high density lipoprotein cholesterol ratio.

BACKGROUND: Periodontitis and the Triglyceride/High Density Lipoprotein Cholesterol (TG/HDL-C) ratio have both been associated with cardiovascular disease, metabolic syndrome, and obesity. Additionally, the ratio is a possible substitute for predicting insulin resistance. This study investigated the association between periodontitis, its severity levels (exposures), and the TG/HDL-C ratio (outcome). METHODS: A cross-sectional study of public health service users in Brazil considered socioeconomic-demographic characteristics, lifestyle behavior, and general and oral health conditions. Anthropometric measurements and blood pressure were also measured. Systemic biomarker data were obtained, as well as assessment of periodontal diagnosis and its severity. The TG/HDL-C ratio was calculated using the serum triglyceride level over HDL cholesterol and the cut-off point, TG/HDL-C ≥2.3 serving as the cutoff indicting dyslipidemia. Logistic and linear regressions were used to statistically analyze the data. RESULTS: A total of 1011 participants were included, with 84.17% having periodontitis and 49.85% having a TG/HDL-C ratio ≥2.3. For individuals with periodontitis, the odds of TG/HDL-C ratio ≥2.3 were 1.47 times greater than in those without periodontitis (ORAdjusted  = 1.47, 95% CI: 1.02-2.14). Similar results were found for those with moderate and severe periodontitis, with a slight increase in the measurement magnitude with disease severity. CONCLUSION: A positive relationship between periodontitis and the TG/HDL-C ratio ≥2.3 was found, suggesting a possible association with periodontal disease severity.

Poor Oral Health in the Etiology and Prevention of Aspiration Pneumonia.

Aspiration pneumonia (AP), inflammation of the lung parenchyma initiated by aspirated microorganisms into the lower airways from proximal sites, including the oral cavity, is prevalent in, and problematic for, the elderly, especially those in institutions, and for those with several important risk factors. Many factors influence the pathogenesis of AP, including dysphagia, poor oral hygiene, diminished host defense, and underlying medical conditions. This article reviews the epidemiology, microbiology, pathogenesis, and prevention of AP, focusing on the role of poor oral health as a risk factor for, and on dental care for the prevention and management of, this important infection.

Moderate and severe periodontitis are positively associated with metabolic syndrome.

OBJECTIVE: This study investigated the association between periodontitis severity (exposure) and metabolic syndrome (MetS - outcome), using two criteria for diagnosis of the outcome, since this relationship remains unexplored. MATERIALS AND METHODS: A case-control study was conducted with 870 individuals: 408 with first MetS diagnosis (cases) and 462 without MetS (controls). Participants' general information was obtained using a questionnaire and laboratory data was collected from medical records. Periodontitis severity criteria followed the Center for Disease Control and Prevention: none, mild, moderate, and severe. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by logistic regression analysis. RESULTS: Findings showed a positive association between moderate and severe periodontitis and MetS: ORadjusted = 1.64 (95% CI: 1.01 to 2.68) and ORadjusted = 1.94 (95% CI: 1.19 to 3.16), respectively, after adjustment for age, sex, schooling level, smoking habit, and cardiovascular disease. The adjusted measurements showed that among individuals with moderate or severe periodontitis, the probability of having MetS was around two times greater than among those without periodontitis, and that the chance was greater among participants with severe periodontitis than those with moderate periodontitis. CONCLUSION: An association between the severity of periodontal status and MetS was found, suggesting a possible relationship between the two diseases. CLINICAL RELEVANCE: MetS influences the etiology of cardiovascular diseases, one of the leading causes of mortality worldwide. The findings suggest that the greater the severity of periodontitis, the greater is the association magnitude with MetS. The health professional needs to recognize that the importance of periodontal disease may play in MetS.

The prevention of periodontal disease-An overview.

It is widely accepted that common diseases of the oral cavity, such as gingivitis and periodontitis, are preventable. Based on a large body of scientific evidence, a number of preventive strategies are known to prevent these diseases, but only if routinely implemented. Unfortunately, while most preventive strategies are theoretically simple to understand, they are often difficult to employ in practice at individual and public health levels. This volume of Periodontology 2000 provides the most current information on the state of the science and the evidence base supporting a preventive perspective for the management of periodontal disease, including evidence for proven interventions as well as cutting-edge ideas for potential future interventions. In addition to well-established and scientifically proven approaches (tooth and implant cleansing, topical chemotherapeutics, reduction in risk factors such as tobacco smoking), a number of new ideas are now under investigation, including antioxidant agents, probiotics, vaccines, and slow-release alternative chemotherapeutics. Furthermore, there are new ideas to alter patient behaviors with the aim to improve adherence to preventive strategies. Finally, examples from implementation science and public health are provided that suggest novel approaches to bring new ideas into clinical practice.

Oral-lung microbiome interactions in lung diseases.

The proximity and continuity of the oral cavity and the lower respiratory tract allows the oropharyngeal microbiome to be a major determinant of the lung microbiome. In addition, host-pathogen interactions related to the oropharyngeal microbiome or its metabolites could propagate systemic inflammation or modulate host defense mechanisms that could affect other organs, including the lung. There is increasing appreciation of the pathophysiologic significance of the lung microbiome, not only in the classical infection-related diseases, pneumonia, bronchiectasis, and cystic fibrosis, but also in chronic noninfectious lung diseases, such as chronic obstructive pulmonary disease, asthma, and pulmonary fibrosis. In this review, we will explore the relationship of the oral microbiome with lung diseases, such as pneumonia, chronic obstructive pulmonary disease, asthma, and cystic fibrosis.

Obesity and periodontitis are not associated in pregnant women.

OBJECTIVE: The objective of this study was to investigate an association between obesity (exposure) and periodontitis (outcome) in pregnant women. BACKGROUND: This association was investigated and only five studies were identified as showing a positive association. However, some of these studies had limitations such as reduced sample sizes, inadequate exposure criteria and outcome measures, which question the internal validity of these investigations. METHODS: A cross-sectional study was carried out with a sample of 644 pregnant women of the public health service of the municipality of Santo Antônio de Jesus, Bahia, Brazil. Data were obtained by collecting of socioeconomic-demographic information, health behavior, health conditions, and reproductive history through an interview. Obesity was evaluated using body mass index adjusted for gestational age and expected weight gain. The diagnosis of periodontitis followed two criteria: (a) Center for Disease Prevention and Control and American Academy of Periodontology (CDC/AAP); (b) Gomes-Filho et al (2018) using criterion that also evaluated bleeding upon probing; Prevalence ratios and respective 95% confidence intervals were obtained by Poisson regression analysis. RESULTS: In accordance with the outcome diagnostic criterion, the frequency of periodontitis was 17.24% (Gomes-Filho et al) and 66.92% (CDC/AAP). The participants were classified as low weight (19.72%), adequate weight (42.39%), overweight (24.84%), and obesity (13.04%), based on the exposure diagnostic criterion. The low weight and overweight groups were excluded from the data analysis, giving a final sample of 357 pregnant women. The association between obesity in pregnant women and periodontitis was not statistically significant, after adjusting for confounders such as age, schooling level, alcoholic beverage consumption, alimentary and nutritional orientation, urinary infection, and dental flossing. CONCLUSIONS: The findings showed a high frequency of periodontitis, obesity, and overweight in the studied population but no association between obesity and periodontitis in pregnant women was found.