Medico-legal litigation in Obstetrics: a characterization analysis of a decade in Portugal

PURPOSE: It was to analyse the most critical areas in Obstetrics and to suggest measures to reduce or avoid the situations most often involved in these disputes. METHODS: Obstetrics cases submitted to the Medico-legal Council since the creation of the National Institute of Legal Medicine and Forensic Sciences in 2001 until 2011 were evaluated. A comprehensive characterization, determination of absolute/relative frequencies, hypothesis of a linear trend over the years and the association between each parameter was done. RESULTS: The analysis has shown no significantly linear trend. The most common reasons for disputes were perinatal asphyxia (50%), traumatic injuries of the newborn (24%), maternal sequelae (19%) and issues related to prenatal diagnosis and/or obstetric ultrasound (5.4%). Perinatal asphyxia showed no significantly linear trend (p=0.58) and was usually related to perinatal deaths or permanent neurologic sequelae in newborn children. Traumatic injuries of the newborn, mostly related to instrumented deliveries, shoulder dystocia or vaginal delivery in breech presentation, has shown a significantly increased linear trend (p<0.001), especially related to instrumented deliveries. The delay/absence of cesarean section was the clinical procedure questioned in a significantly higher number of cases of perinatal asphyxia (68.7%) and of traumatic lesions of the newborn due to instrumented deliveries (20.5%). CONCLUSION: It is important to improve and correct theoretical/practical daily clinical performance in these highlighted areas, in order to reduce or even avoid situations that could end up in medico-legal litigations.

Association between Lipid Accumulation Product and Hirsutism in Patients with Polycystic Ovary Syndrome

Objective Polycystic ovary syndrome (PCOS) is the most common endocrine metabolic disorder in women between menarche and menopause. Clinical hyperandrogenism is the most important diagnostic criterion of the syndrome, which manifests as hirsutism in 70% of cases. Hirsute carriers of PCOS have high cardiovascular risk. Lipid accumulation product (LAP) is an index for the evaluation of lipid accumulation in adults and the prediction of cardiovascular risk. The aim of this study was to evaluate the association between LAP and hirsutism in women with PCOS. Methods This was a cross-sectional observational study of a secondary database, which included 263 patients who had visited the Hyperandrogenism Outpatient Clinic from November 2009 to July 2014. The exclusion criteria were patients without Ferriman-Gallwey index (FGI) and/or LAP data. We used the Rotterdam criteria for the diagnosis of PCOS. All patients underwent medical assessment followed by measurement and recording of anthropometric data and the laboratory tests for measurement of the following: thyroid-stimulating hormone, follicle-stimulating hormone, prolactin, total testosterone, sex hormone binding globulin, 17-α-hydroxyprogesterone (follicular phase), glycohemoglobin A1c, and basal insulin. In addition, the subjects underwent lipid profiling and oral glucose tolerance tests. Other laboratory measurements were determined according to clinical criteria. LAP and the homeostatic model assessment index (HOMA-IR) were calculated using the data obtained. We divided patients into two groups: the PCOS group with normal LAP (< 34.5) and the PCOS group with altered LAP (> 34.5) to compare the occurrence of hirsutism. For statistical analysis, we used SPSS Statistics for Windows(r) and Microsoft Excel programs, with descriptive (frequencies, percentages, means, and standard deviations) and comparative analyses (Student's t-test and Chi-square test). We considered relations significant when the p-value was≤0.05. Results LAP was high in most patients (n = 177; 67.3%) and the FGI indicated that 58.5% of the patients (n = 154) had hirsutism. The analysis by LAP quartiles showed a positive correlation (p = 0.04) among patients with a high FGI and an upper quartile LAP (> 79.5) when compared with those with LAP < 29.0 (lower quartile). Conclusion This study demonstrated an association between high LAP and hirsutism. The FGI could represent a simple and low-cost tool to infer an increased cardiovascular risk in women with PCOS.

Conservative Treatment of Stress Urinary Incontinence: A Systematic Review with Meta-analysis of Randomized Controlled Trials

We performed a systematic review and meta-analysis of randomized controlled trials that studied the conservative management of stress urinary incontinence (SUI). There were 1058 results after the initial searches, from which 37 studies were eligible according to previously determined inclusion criteria. For the primary outcomes, pelvic floor muscle training (PFMT) was more efficacious than no treatment in improving incontinence-specific quality of life (QoL) scales (SMD = [1]1.24SDs; CI 95% = [1]1.77 to [1]0.71SDs). However, its effect on pad tests was imprecise. Combining biofeedback with PFMT had an uncertain effect on QoL (MD = [1]4.4 points; CI 95% = [1]16.69 to 7.89 points), but better results on the pad test, although with elevated heterogeneity (MD = 0.9g; 95%CI = 0.71 to 1,10g); group PFMT was not less efficacious than individual treatment, and home PFMT was not consistently worse than supervised PFMT. Both intravaginal and superficial electrical stimulation (IES and SES) were better than no treatment for QoL and pad test. Vaginal cones had mixed results. The association of IES with PFMT may improve the efficacy of the latter for QoL and pad test, but the results of individual studies were not consistent. Thus, there is evidence of the use of PFMT on the treatment of SUI, with and without biofeedback.

Genetic variability in salt tolerance during germination of Stylosanthes humilis H.B.K. and association between salt tolerance and isozymes

Variation in salt tolerance of six natural populations of Stylosanthes humilis from three ecogeographic regions, Mata (wet tropical climate), Agreste and Sertão (semi-arid tropical climate) of Pernambuco State, Northeast Brazil, was evaluated on germination in 201 mM NaCl. There were significant differences among families of all populations for germination percentage and of five populations (except Tamandaré, from Mata) for germination rate. Populations from semi-arid regions presented high coefficients of genetic variation, those from Agreste being higher than those from Sertão. Populations from Mata showed low coefficients of genetic variation. The coefficients of genotypic determination were high for five populations, except Tamandaré, both for germination percentage ( > or = 0.89) and for germination rate ( > or = 0.79), indicating the possibility of selection for salt tolerance in these populations. An electrophoretic analysis of esterase and peroxidase isozymes was also performed in the six populations, and correlations were estimated between salt tolerance and allelic frequencies. The analysis of salt tolerant and salt sensitive families of populations from Agreste suggested an association of alleles of a peroxidase locus with salt tolerance during germination in the Caruaru population

Association of leprosy with HLA-DR2 in a Southern Brazilian population

The association between HLA specificities and leprosy was investigated in a Southern Brazilian population. One hundred and twenty-one patients and 147 controls were typed for HLA-A, B, Cw, DR and DQ. Patients were subdivided into the following subgroups, according to clinical, histological and immunological criteria: lepromatous (N = 55), tuberculoid (N = 32), dimorphous (N = 20), and indeterminate (N = 14). The frequencies of HLA specificities were compared between the total group of patients and controls, and between the same controls and each subgroup of patients. After correction of the probabilities, deviations were not significant, except for the DR2 specificity, which presented a frequency of 44.2% in the total group of patients and 56.3% in the subgroup of individuals with the tuberculoid form of the disease, compared to 23.3% in the controls. Stratified analysis showed that the increased DR2 frequency in the total group of patients was due to the subgroups with the tuberculoid and dimorphous forms. The relative risk of tuberculoid leprosy for DR2-positive individuals was 4.2, and the etiologic fraction of DR2 was 0.429. In conclusion, a positive association of the DR2 specificity with the tuberculoid form of leprosy, but not with the lepromatous, dimorphous, or indeterminate forms, was demonstrated in this Southern Brazilian population

Association between polyclonal B cell activation and the presence of autoantibodies in mice infected with Yersinia enterocolitica O:3

Eight-week old conventional female Swiss mice were inoculated intravenously with Yersinia enterocolitica O:3. A second group of normal mice was used as control. Five mice from each group were bled by heart puncture and their spleens were removed for spleen cell collection on the 3rd, 5th, 7th, 10th, 14th and 21st day after infection. Immunoglobulin-secreting spleen cells were detected by the isotype-specific protein A plaque assay. Total immunoglobulin levels were determined in mouse serum by single radial immunodiffusion and the presence of autoantibodies was determined by ELISA. We observed a marked increase in the total number of cells secreting immunoglobulins of all isotypes as early as on the 3rd day post-infection and the peak of secretion occurred on the 7th day. At the peak of the immunoglobulin response, the total number of secreting cells was 19 times higher than that of control mice and most immunoglobulin-secreting cells were of the IgG2a isotype. On the 10th day post-infection, total serum immunoglobulin values were 2 times higher in infected animals when compared to the control group, and continued at this level up to the 21st day post-infection. Serum absorption with viable Y. enterocolitica cells had little effect on antibody levels detected by single radial immunodiffusion. Analysis of serum autoantibody levels revealed that Y. enterocolitica infection induced an increase of anti-myosin and anti-myelin immunoglobulins. The sera did not react with collagen. The present study demonstrates that Y. enterocolitica O:3 infection induces polyclonal activation of murine B cells which is correlated with the activation of some autoreactive lymphocyte clones

Familial predisposition to hypertension and the association between urinary sodium excretion and blood pressure in a population-based sample of young adults

The reasons for the inconsistent association between salt consumption and blood pressure levels observed in within-society surveys are not known. A total of 157 normotensive subjects aged 18 to 35 years, selected at random in a cross-sectional population-based survey, answered a structured questionnaire. They were classified as strongly predisposed to hypertension when two or more first-degree relatives had a diagnosis of hypertension. Anthropometric parameters were obtained and sitting blood pressure was determined with aneroid sphygmomanometers. Sodium and potassium excretion was measured by flame spectrophotometry in an overnight urine sample. A positive correlation between blood pressure and urinary sodium excretion was detected only in the group of individuals strongly predisposed to hypertension, both for systolic blood pressure (r = 0.51, P<0.01) and diastolic blood pressure (r = 0.50, P<0.01). In a covariance analysis, after controlling for age, skin color and body mass index, individuals strongly predisposed to hypertension who excreted amounts of sodium above the median of the entire sample had higher systolic and diastolic blood pressure than subjects classified into the remaining conditions. The influence of familial predisposition to hypertension on the association between salt intake and blood pressure may be an additional explanation for the weak association between urinary sodium excretion and blood pressure observed in within-population studies, since it can influence the association between salt consumption and blood pressure in some but not all inhabitants.

Reporting on methods of subgroup analysis in clinical trials: a survey of four scientific journals

Results of subgroup analysis (SA) reported in randomized clinical trials (RCT) cannot be adequately interpreted without information about the methods used in the study design and the data analysis. Our aim was to show how often inaccurate or incomplete reports occur. First, we selected eight methodological aspects of SA on the basis of their importance to a reader in determining the confidence that should be placed in the author's conclusions regarding such analysis. Then, we reviewed the current practice of reporting these methodological aspects of SA in clinical trials in four leading journals, i.e., the New England Journal of Medicine, the Journal of the American Medical Association, the Lancet, and the American Journal of Public Health. Eight consecutive reports from each journal published after July 1, 1998 were included. Of the 32 trials surveyed, 17 (53%) had at least one SA. Overall, the proportion of RCT reporting a particular methodological aspect ranged from 23 to 94%. Information on whether the SA preceded/followed the analysis was reported in only 7 (41%) of the studies. Of the total possible number of items to be reported, NEJM, JAMA, Lancet and AJPH clearly mentioned 59, 67, 58 and 72%, respectively. We conclude that current reporting of SA in RCT is incomplete and inaccurate. The results of such SA may have harmful effects on treatment recommendations if accepted without judicious scrutiny. We recommend that editors improve the reporting of SA in RCT by giving authors a list of the important items to be reported.

Clinical signs of pneumonia in children: association with and prediction of diagnosis by fuzzy sets theory

The present study compares the performance of stochastic and fuzzy models for the analysis of the relationship between clinical signs and diagnosis. Data obtained for 153 children concerning diagnosis (pneumonia, other non-pneumonia diseases, absence of disease) and seven clinical signs were divided into two samples, one for analysis and other for validation. The former was used to derive relations by multi-discriminant analysis (MDA) and by fuzzy max-min compositions (fuzzy), and the latter was used to assess the predictions drawn from each type of relation. MDA and fuzzy were closely similar in terms of prediction, with correct allocation of 75.7 to 78.3% of patients in the validation sample, and displaying only a single instance of disagreement: a patient with low level of toxemia was mistaken as not diseased by MDA and correctly taken as somehow ill by fuzzy. Concerning relations, each method provided different information, each revealing different aspects of the relations between clinical signs and diagnoses. Both methods agreed on pointing X-ray, dyspnea, and auscultation as better related with pneumonia, but only fuzzy was able to detect relations of heart rate, body temperature, toxemia and respiratory rate with pneumonia. Moreover, only fuzzy was able to detect a relationship between heart rate and absence of disease, which allowed the detection of six malnourished children whose diagnoses as healthy are, indeed, disputable. The conclusion is that even though fuzzy sets theory might not improve prediction, it certainly does enhance clinical knowledge since it detects relationships not visible to stochastic models.

Analysis of polymorphism at site -174 G/C of interleukin-6 promoter region in multiple myeloma

It is well established that interleukin-6 (IL-6) is an essential growth factor for multiple myeloma (MM) and patients with increased IL-6 levels have a poor prognosis. In healthy subjects, the presence of the C allele at a polymorphic site (-174 G/C) of the IL-6 gene is related to low IL-6 levels. In view of the potential association of this particular polymorphism with IL-6 concentration, and the relevance of IL-6 in MM pathogenesis, the objective of the present study was to investigate the prevalence of IL-6 (-174 G/C) promoter polymorphism and its association with development of MM in Brazilian individuals. We investigated the prevalence of these alleles in 52 patients and 60 healthy subjects (matched by age, sex, and race) of a Brazilian population. Thirty patients were male (42.4%), 24 (46.2%) were white and the median age at diagnosis was 58.5 years (range: 28 to 84 years). To determine the IL-6 (-174 G/C) polymorphism, molecular analysis was performed by polymerase chain reaction followed by endonuclease restriction digestion. The genotype distributions observed in the group of patients were 4% CC, 42% GC and 54% GG. The C allele frequency was 0.25. These results were similar to the control group, suggesting no impact of this polymorphism on the susceptibility to MM.

Association of the 894G>T polymorphism of the endothelial constitutive nitric oxide synthase gene with unstable angina

The 894G>T polymorphism of the endothelial constitutive nitric oxide synthase gene consists of the substitution of a guanine base by a thymine at the 894th nucleotide of the gene. An association of this polymorphism with acute coronary syndromes has been described, only when in combination with other polymorphisms of this gene. The aim of the present study was to search for an association between this polymorphism and unstable angina in a southern Brazilian population. In a case-control study, 156 patients (group 1 (N = 83): unstable angina, group 2 (N = 73): stable angina) were genotyped by PCR and digestion of the product. Univariate analysis demonstrated that the minimal luminal diameter and the degree of stenosis of the culprit lesion differed between groups (P = 0.006 and 0.005, respectively). In addition, the frequencies of the T allele and of the T allele carriers (combined TT and TG genotypes) were significantly higher in the group with unstable angina (41.6 vs 28.8%; P = 0.025, Pearson chi-square test, and 73.5 vs 45.2%; P = 0.001, Pearson chi-square test, respectively). Multivariate logistic regression showed that the frequency of the T allele carriers was the only variable with a predictive value for unstable angina, when controlled for the other variables (6.1 (95% CI = 2.55-14.43); P < 0.001). Thus, in a homogenous group of patients, the endothelial constitutive nitric oxide synthase 894G>T polymorphism was associated with unstable angina. We suggest that this polymorphism may be a genetic risk factor for unstable angina.

Association between the -174 G/C promoter polymorphism of the interleukin-6 gene and cardiovascular disease risk factors in Brazilian older women

In worldwide studies, interleukin-6 (IL-6) is implicated in age-related disturbances. The aim of the present report was to determine the possible association of IL-6 -174 C/G promoter polymorphism with the cytokine profile as well as with the presence of selected cardiovascular risk features. This was a cross-sectional study on Brazilian women aged 60 years or older. A sample of 193 subjects was investigated for impaired glucose regulation, diabetes, hypertension, and dyslipidemia. Genotyping was done by direct sequencing of PCR products. IL-6 and C-reactive protein were quantified by high-sensitivity assays. General linear regression models or the Student t-test were used to compare continuous variables among genotypes, followed by adjustments for confounding variables. The chi-square test was used to compare categorical variables. The genotypes were consistent with Hardy-Weinberg equilibrium proportions. In a recessive model, mean waist-to-hip ratio, serum glycated hemoglobin and serum glucose were markedly lower in C homozygotes (P = 0.001, 0.028, and 0.047, respectively). In a dominant hypothesis, G homozygotes displayed a trend towards higher levels of circulating IL-6 (P = 0.092). Non-parametric analysis revealed that impaired fasting glucose and hypertension were findings approximately 2-fold more frequent among G homozygous subjects (P = 0.042 and 0.043, respectively). Taken together, our results show that the IL-6 -174 G-allele is implicated in a greater cardiovascular risk. To our knowledge, this is the first investigation of IL-6 promoter variants and age-related disturbances in the Brazilian elderly population.

Dimensionality of the premenstrual syndrome: confirmatory factor analysis of premenstrual dysphoric symptoms among college students

Premenstrual syndrome and premenstrual dysphoric disorder (PMDD) seem to form a severity continuum with no clear-cut boundary. However, since the American Psychiatric Association proposed the research criteria for PMDD in 1994, there has been no agreement about the symptomatic constellation that constitutes this syndrome. The objective of the present study was to establish the core latent structure of PMDD symptoms in a non-clinical sample. Data concerning PMDD symptoms were obtained from 632 regularly menstruating college students (mean age 24.4 years, SD 5.9, range 17 to 49). For the first random half (N = 316), we performed principal component analysis (PCA) and for the remaining half (N = 316), we tested three theory-derived competing models of PMDD by confirmatory factor analysis. PCA allowed us to extract two correlated factors, i.e., dysphoric-somatic and behavioral-impairment factors. The two-dimensional latent model derived from PCA showed the best overall fit among three models tested by confirmatory factor analysis (c²53 = 64.39, P = 0.13; goodness-of-fit indices = 0.96; adjusted goodness-of-fit indices = 0.95; root mean square residual = 0.05; root mean square error of approximation = 0.03; 90%CI = 0.00 to 0.05; Akaike's information criterion = -41.61). The items "out of control" and "physical symptoms" loaded conspicuously on the first factor and "interpersonal impairment" loaded higher on the second factor. The construct validity for PMDD was accounted for by two highly correlated dimensions. These results support the argument for focusing on the core psychopathological dimension of PMDD in future studies.

No evidence of association of MUC-1 genetic polymorphism with embryo implantation failure

Pregnancy loss can be caused by several factors involved in human reproduction. Although up to 50% of cases remain unexplained, it has been postulated that the major cause of failed pregnancy is an error of embryo implantation. Transmembrane mucin-1 (MUC-1) is a glycoprotein expressed on the endometrial cell surface which acts as a barrier to implantation. The gene that codes for this molecule is composed of a polymorphic tandem repeat of 60 nucleotides. Our objective was to determine if MUC-1 genetic polymorphism is associated with implantation failure in patients with a history of recurrent abortion. The study was conducted on 10 women aged 25 to 35 years with no history of successful pregnancy and with a diagnosis of infertility. The control group consisted of 32 patients aged 25 to 35 years who had delivered at least two full-term live children and who had no history of abortions or fetal losses. MUC-1 amplicons were obtained by PCR and observed on agarose and polyacrylamide gel after electrophoresis. Statistical analysis showed no significant difference in the number of MUC-1 variable number of tandem repeats between these groups (P > 0.05). Our results suggest that there is no effect of the polymorphic MUC-1 sequence on the implantation failure. However, the data do not exclude MUC-1 relevance during embryo implantation. The process is related to several associated factors such as the mechanisms of gene expression in the uterus, specific MUC-1 post-translational modifications and appropriate interactions with other molecules during embryo implantation.

The search for circadian clock components in humans: new perspectives for association studies

Individual circadian clocks entrain differently to environmental cycles (zeitgebers, e.g., light and darkness), earlier or later within the day, leading to different chronotypes. In human populations, the distribution of chronotypes forms a bell-shaped curve, with the extreme early and late types _ larks and owls, respectively _ at its ends. Human chronotype, which can be assessed by the timing of an individual's sleep-wake cycle, is partly influenced by genetic factors - known from animal experimentation. Here, we review population genetic studies which have used a questionnaire probing individual daily timing preference for associations with polymorphisms in clock genes. We discuss their inherent limitations and suggest an alternative approach combining a short questionnaire (Munich ChronoType Questionnaire, MCTQ), which assesses chronotype in a quantitative manner, with a genome-wide analysis (GWA). The advantages of these methods in comparison to assessing time-of-day preferences and single nucleotide polymorphism genotyping are discussed. In the future, global studies of chronotype using the MCTQ and GWA may also contribute to understanding the influence of seasons, latitude (e.g., different photoperiods), and climate on allele frequencies and chronotype distribution in different populations.