Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials.

BACKGROUND: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis. METHODS: We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249. FINDINGS: We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference -8%, 95% CI -17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36-1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications. INTERPRETATION: Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. FUNDING: Canadian Institutes of Health Research.

Malignancy grading is no better than conventional histopathological grading in small squamous cell carcinoma of tongue and floor of mouth: retrospective study in 128 patients.

There is an ongoing debate about the predictive value of histopathological parameters in oral cancer. In the past decades, the emphasis was on the possible added value of the so-called malignancy grading system. In a retrospective study on 128 previously untreated patients with a T1 or T2 squamous cell carcinoma of the tongue and the floor of the mouth, the value of the classical Broders' grading system and the malignancy grading system were compared with regard to various outcome measures such as regional metastasis, local recurrence and 5-year survival. The results show that neither of the histological grading systems has a strong predictive value and that none is superior to the other.

Physicians' assessments versus measured symptoms of complex regional pain syndrome type 1: presence and severity.

OBJECTIVE: To assess the validity of physician's judgements of symptoms associated with Complex Regional Pain Syndrome Type 1. METHODS: The validity of physicians' judgments was assessed using measurements with regard to presence and severity of pain, temperature and volume asymmetry, and reduction in active range of motion in 66 Complex Regional Pain Syndrome Type 1 outpatients. Measurements were performed using Visual Analog Scales and McGill (number of words chosen total) for pain, infrared thermography for temperature differences, water displacement volumeters for volume differences, and hand-held goniometers for active range of motion. Physicians were blind to the outcomes of the measurements. RESULTS: In general, physicians were capable of determining presence or absence of measured symptoms and indicate the direction of the symptom asymmetry. Establishing presence of temperature and volume asymmetries was, however, inadequate. Poor to moderate correspondence was found for the severity of individual symptoms between physicians' judgments and measurements. For the total number of assessments, correlation coefficients ranged from 0.39 for Volume to 0.68 for Pain. In general, lower correlations and percentages of association for Volume and Temperature were found. Monitoring changes between consecutive patient assessments showed poor correspondence between both assessment methods, with correlation coefficients ranging from 0.25 for Volume to 0.37 for Pain. CONCLUSIONS: We conclude that establishing the presence of Complex Regional Pain Syndrome Type 1 symptoms, except for temperature and volume asymmetries, and monitoring of disease progression based on these symptoms can be performed by clinical judgment. The severity of the individual symptoms evaluated in this study should be measured with reliable and valid measurement instruments.

Conducting systematic reviews of diagnostic studies: didactic guidelines.

BACKGROUND: Although guidelines for critical appraisal of diagnostic research and meta-analyses have already been published, these may be difficult to understand for clinical researchers or do not provide enough detailed information. METHODS: Development of guidelines based on a systematic review of the evidence in reports of systematic searches of the literature for diagnostic research, of methodological criteria to evaluate diagnostic research, of methods for statistical pooling of data on diagnostic accuracy, and of methods for exploring heterogeneity. RESULTS: Guidelines for conducting diagnostic systematic reviews are presented in a stepwise fashion and are followed by comments providing further information. Examples are given using the results of two systematic reviews on the accuracy of the urine dipstick in the diagnosis of urinary tract infections, and on the accuracy of the straight-leg-raising test in the diagnosis of intervertebral disc hernia.

Muscle power development during the first year of life predicts neuromotor behaviour at 7 years in preterm born high-risk infants.

The aim of the study was to find if neurological function during the first year of life could predict neuromotor behaviour at 7 years of age in children born preterm with a high risk. A follow-up study of neuromotor behaviour in 52 children at a mean age of 3, 6, 12 months (corrected age) and 7 years was performed. All children were born with a gestational age less than 32 weeks and/or a birthweight under 1500 g and the infants were categorised according to their medical history in the three highest categories of the 'Neonatal Medical Index' (NMI, from category I to V, from few to serious complications). In addition, neonatal cerebral ultrasound abnormalities were used to divide the infants further into the different NMI categories. At 3 and 6 months, the relationship between active and passive muscle power was measured in shoulders, trunk and legs and (a)symmetry between right and left was noted. The results at 3 and 6 months were ranged from 1 for optimal to 5 for poor muscle power regulation. At 12 months of age, a neurological examination was done with special emphasis on the assessment of postural control, spontaneous motility, hand function and elicited infantile reactions with special attention to (a)symmetry. Outcome at 12 months was expressed as percentage of the optimal score on each subcategory. At 7 years, the motor behaviour study based on Touwen's examination for minor neurological dysfunction was performed. This investigation focuses on different functions, such as hand function, quality of walking, posture, passive muscle tone, coordination and diadochokinesis. The outcome was expressed as percentage of the optimal score on the combined subcategories. The best prediction of neuromotor behaviour at 7 years was assessed with stepwise linear multiple regression, using as potential predictors perinatal factors and outcome of motor behaviour at the corrected age of 3, 6 and 12 months. At 7 years none of the children scored 100% on the combined subcategories, 15 children (29%) scored between 75% and 99%, whereas 15 children scored less than 50%. Neuromotor behaviour at 7 years could be predicted by the NMI categorisation and gender with a sensitivity of 92% (specificity 47%; positive and negative predictive value 81% and 70%). No direct relation was found between neuromotor behaviour and cerebral ultrasound classification only, days on the ventilator and/or continuous positive airway pressure, birthweight, gestational age and dysmaturity. The best predictor of neuromotor behaviour at 7 years was the combination of outcome of muscle power in shoulders and legs at 3 months and postural control at 12 months, taking into account the gender of the child (sensitivity 95%; specificity 40%; positive predictive value 80%; negative predictive value 75%).

The urine dipstick test useful to rule out infections. A meta-analysis of the accuracy.

BACKGROUND: Many studies have evaluated the accuracy of dipstick tests as rapid detectors of bacteriuria and urinary tract infections (UTI). The lack of an adequate explanation for the heterogeneity of the dipstick accuracy stimulates an ongoing debate. The objective of the present meta-analysis was to summarise the available evidence on the diagnostic accuracy of the urine dipstick test, taking into account various pre-defined potential sources of heterogeneity. METHODS: Literature from 1990 through 1999 was searched in Medline and Embase, and by reference tracking. Selected publications should be concerned with the diagnosis of bacteriuria or urinary tract infections, investigate the use of dipstick tests for nitrites and/or leukocyte esterase, and present empirical data. A checklist was used to assess methodological quality. RESULTS: 70 publications were included. Accuracy of nitrites was high in pregnant women (Diagnostic Odds Ratio = 165) and elderly people (DOR = 108). Positive predictive values were >/=80% in elderly and in family medicine. Accuracy of leukocyte-esterase was high in studies in urology patients (DOR = 276). Sensitivities were highest in family medicine (86%). Negative predictive values were high in both tests in all patient groups and settings, except for in family medicine. The combination of both test results showed an important increase in sensitivity. Accuracy was high in studies in urology patients (DOR = 52), in children (DOR = 46), and if clinical information was present (DOR = 28). Sensitivity was highest in studies carried out in family medicine (90%). Predictive values of combinations of positive test results were low in all other situations. CONCLUSIONS: Overall, this review demonstrates that the urine dipstick test alone seems to be useful in all populations to exclude the presence of infection if the results of both nitrites and leukocyte-esterase are negative. Sensitivities of the combination of both tests vary between 68 and 88% in different patient groups, but positive test results have to be confirmed. Although the combination of positive test results is very sensitive in family practice, the usefulness of the dipstick test alone to rule in infection remains doubtful, even with high pre-test probabilities.

Predicting adherence to prophylactic medication in adolescents with asthma: an application of the ASE-model.

An explanatory framework, referred to as the attitude/social influence/self-efficacy-model (ASE-model), was utilised to explain future self-reported adherence of adolescents to daily inhaled prophylactic asthma medication. The objective was to investigate the long-term influence of these earlier reported cognitive variables and other psychological and medical determinants on self-reported adherence 1 year later. Data were collected, via a questionnaire, from 86 adolescents with asthma (aged 11 through 18 years) recruited from outpatient clinics. Adherence was assessed by asking the patients to give themselves a report mark for adherence. The results of the multiple regression analyses showed that the three major ASE-variables were predictors of self-reported adherence to a moderate degree (R(2)=0.21). Previous self-reported adherence was found to be the best predictor of self-reported adherence to prophylactic asthma medication 1 year later (R(2)=0.45). The results of this study could be useful in the development of interventions to enhance adherence to asthma medication. In future, such interventions should focus on feelings of shame about having asthma and promoting healthy habits, such as adherence to medication.

[Congenital anomalies in Amsterdam: results of the 'Amsterdam-Born Children and their Development' study]. / Congenitale afwijkingen in Amsterdam: resultaten 'Amsterdam born children and their development'-studie.

OBJECTIVE: To describe the prevalence of congenital anomalies in children born in Amsterdam and to analyse potential differences between groups based on risk factors such as ethnicity and maternal age. DESIGN: Secondary analysis of a prospective cohort study. METHODS: Between 2003 and 2004, mothers filled in questionnaires on their newborn children on behalf of the Amsterdam-Born Children and their Development study (ABCD study). Data from 5,276 liveborn children in this cohort were used to calculate the prevalence rates of congenital anomalies in Amsterdam. These were compared with expected prevalence rates based on Eurocat data for the Northern region of the Netherlands during the years 2000-2005. Prevalence rates were compared between subgroups which had been divided according to risk factors: maternal ethnic origin, maternal age, parity, gender of child, inter-pregnancy interval, years of maternal education, smoking, alcohol use, and periconceptional folate use. RESULTS: The total prevalence of major congenital anomalies among liveborn children in the ABCD cohort was as expected based on the figures from the Eurocat registration. Digestive anomalies were reported significantly less frequently (n = 1) than expected (n = 10). Mothers of Surinam descent more frequently reported a child with a musculoskeletal anomaly. Older mothers were more likely to report congenital anomalies. No significant trends regarding other risk factors were observed. CONCLUSIONS: No significant trends regarding ethnicity and congenital anomalies were detected. The interpretation of the other results was hampered by methodological differences between the ABCD study and Eurocat. Nationwide registration with active case detection of congenital anomalies is therefore recommended.

Efficacy and safety of mesalazine (Salofalk) in an open study of 20 patients with ankylosing spondylitis.

OBJECTIVE: Mesalazine (Salofalk) was found to be effective and showed low toxicity in patients with inflammatory bowel disease. The association of gut lesions and spondyloarthropathy (SpA) is well known and we studied the efficacy and safety of a relatively high dose of mesalazine in patients with ankylosing spondylitis (AS). METHODS: In an open study, mesalazine (3-4 g/day) was prescribed for 24 weeks to 20 patients (aged 18-70 yrs) with active AS, defined as the presence of at least one clinical criterion (morning stiffness > 30 min, peripheral synovitis, enthesopathy, or pain score > 2 on a visual analog scale of 10 cm) and one laboratory criterion [erythrocyte sedimentation rate (ESR) > 20 mm/h or C-reactive protein (CRP) > 20 mg/l]. Data on toxicity and disease activity variables (ESR, CRP, BASDAI, BASFI, BASMI, global assessment, and joint count) were obtained at baseline and after 4, 12, and 24 weeks, and analyzed on an intention-to-treat basis. RESULTS: Study patients had a mean age of 41 years, with mean disease duration of 7.9 years and a mean ESR at baseline of 29 mm/h. After a mean of 9.3 weeks (range 2-22), 8 of the 20 patients prematurely stopped the medication because of adverse effects, mainly gastrointestinal complaints. Twelve patients completed the 24 weeks of the study using a mean dose of 3.2 g/day (range 1-4) mesalazine. Analysis of the data showed improvement in ESR, CRP, and physician's global assessment, but only the change in ESR (29 mm/h on baseline and 25 mm/h at week 24) reached statistical significance (p = 0.03). No change was observed in the other disease activity variables. CONCLUSION: No significant improvement in any disease activity variable of active AS was observed during treatment with Salofalk except for the ESR. Many side effects were seen.

Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission.

OBJECTIVE: To assess whether radiologic progression occurs during clinical remission in patients with rheumatoid arthritis (RA). METHODS: One hundred eighty-seven patients with RA in clinical remission were followed up clinically and radiologically for 2 years. Clinical remission was defined according to a modification of the American College of Rheumatology criteria (i.e., the criterion of fatigue was omitted, and patients had to fulfill 4 of the 5 remaining criteria). Radiologic joint damage was assessed by the Sharp/van der Heijde method. RESULTS: After 2 years of followup, remission persisted in 52% of patients. The median radiologic score for the total group of patients increased from 21 (interquartile range [IQR] 5, 65) at the time of entry to 25 (IQR 7, 72) after 2 years (P < 0.001). The median score for radiologic progression between baseline and 2 years was 0.5 (IQR 0, 2.5). Among patients with an exacerbation of RA (n = 86), the median score for progression over 2 years was 1.0 (IQR 0, 4.5) (P < 0.001), and in patients with a persistent remission (n = 93) it was 0 (IQR -0.5, 2.0) (P < 0.001). Clinically relevant progression of damage was more frequent in patients with exacerbation (23%) than in those with persistent remission (7%) (P = 0.001). However, in 15% of patients with persistent remission, an erosion developed in a previously unaffected joint. In the logistic regression analysis, the area under the curve of the Disease Activity Score, a continuous measure, was related to the chance of radiologic progression, regardless of the absolute disease activity level. Results were similar when other definitions of remission were used. CONCLUSION: Although rare, clinically relevant progression of joint damage does occur in patients with RA in prolonged remission. This suggests the need for markers that predict progression during periods of low disease activity and for drugs that prevent damage that is independent of disease activity.

Reliability and validity of lumbosacral spine radiograph reading by chiropractors, chiropractic radiologists, and medical radiologists.

STUDY DESIGN: A cross-sectional diagnostic study was conducted in two sessions. OBJECTIVE: To determine and compare the reliability and validity of contraindications to chiropractic treatment (infections, malignancies, inflammatory spondylitis, and spondylolysis-listhesis) detected by chiropractors, chiropractic radiologists, and medical radiologists on plain lumbosacral radiographs. SUMMARY OF BACKGROUND DATA: Plain radiography of the spine is an established part of chiropractic practice. Few studies have assessed the ability of chiropractors to read plain radiographs. METHODS: Five chiropractors, three chiropractic radiologists and five medical radiologists read a set of 300 blinded lumbosacral radiographs, 50 of which showed an abnormality (prevalence, 16.7%), in two sessions. The results were expressed in terms of reliability (percentage and kappa) and validity (sensitivity and specificity). RESULTS: The interobserver agreement in the first session showed generalized kappas of 0.44 for the chiropractors, 0.55 for the chiropractic radiologists, and 0.60 for the medical radiologists. The intraobserver agreement showed mean kappas of 0.58, 0.68, and 0.72, respectively. The difference between the chiropractic radiologists and medical radiologists was not significant. However, there was a difference between the chiropractors and the other professional groups. The mean sensitivity and specificity of the first round, respectively was 0.86 and 0.88 for the chiropractors, 0.90 and 0.84 for the chiropractic radiologists, and 0.84 and 0.92 for the medical radiologists. No differences in the sensitivities were found between the professional groups. The medical radiologists were more specific than the others. CONCLUSIONS: Small differences with little clinical relevance were found. All the professional groups could adequately detect contraindications to chiropractic treatment on radiographs. For this indication, there is no reason to restrict interpretation of radiographs to medical radiologists. Good professional relationships between the professions are recommended to facilitate interprofessional consultation in case of doubt by the chiropractors.