Cross-trimester repeated measures testing for Down's syndrome screening: an assessment.

OBJECTIVES: To provide estimates and confidence intervals for the performance (detection and false-positive rates) of screening for Down's syndrome using repeated measures of biochemical markers from first and second trimester maternal serum samples taken from the same woman. DESIGN: Stored serum on Down's syndrome cases and controls was used to provide independent test data for the assessment of screening performance of published risk algorithms and for the development and testing of new risk assessment algorithms. SETTING: 15 screening centres across the USA, and at the North York General Hospital, Toronto, Canada. PARTICIPANTS: 78 women with pregnancy affected by Down's syndrome and 390 matched unaffected controls, with maternal blood samples obtained at 11-13 and 15-18 weeks' gestation, and women who received integrated prenatal screening at North York General Hospital at two time intervals: between 1 December 1999 and 31 October 2003, and between 1 October 2006 and 23 November 2007. INTERVENTIONS: Repeated measurements (first and second trimester) of maternal serum levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and pregnancy-associated plasma protein A (PAPP-A) together with alpha-fetoprotein (AFP) in the second trimester. MAIN OUTCOME MEASURES: Detection and false-positive rates for screening with a threshold risk of 1 in 200 at term, and the detection rate achieved for a false-positive rate of 2%. RESULTS: Published distributional models for Down's syndrome were inconsistent with the test data. When these test data were classified using these models, screening performance deteriorated substantially through the addition of repeated measures. This contradicts the very optimistic results obtained from predictive modelling of performance. Simplified distributional assumptions showed some evidence of benefit from the use of repeated measures of PAPP-A but not for repeated measures of uE3 or hCG. Each of the two test data sets was used to create new parameter estimates against which screening test performance was assessed using the other data set. The results were equivocal but there was evidence suggesting improvement in screening performance through the use of repeated measures of PAPP-A when the first trimester sample was collected before 13 weeks' gestation. A Bayesian analysis of the combined data from the two test data sets showed that adding a second trimester repeated measurement of PAPP-A to the base test increased detection rates and reduced false-positive rates. The benefit decreased with increasing gestational age at the time of the first sample. There was no evidence of any benefit from repeated measures of hCG or uE3. CONCLUSIONS: If realised, a reduction of 1% in false-positive rate with no loss in detection rate would give important benefits in terms of health service provision and the large number of invasive tests avoided. The Bayesian analysis, which shows evidence of benefit, is based on strong distributional assumptions and should not be regarded as confirmatory. The evidence of potential benefit suggests the need for a prospective study of repeated measurements of PAPP-A with samples from early in the first trimester. A formal clinical effectiveness and cost-effectiveness analysis should be undertaken. This study has shown that the established modelling methodology for assessing screening performance may be optimistically biased and should be interpreted with caution

Cross-Country Individual Participant Analysis of 4.1 Million Singleton Births in 5 Countries with Very High Human Development Index...

Background: Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice. Methods: We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and one comparator U.S. state (California) to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors. Findings: Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6–6.0 and 2.8–5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25–50% and 11–16% of excess population attributable risk, respectively (p < 0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted. Conclusions: We have quantified the causes of variation in preterm birth rates among countries with very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions

Renal obstructive dysplasia: Ultrasound diagnosis and therapeutic implications

57 cases of renal obstructive dysplasia (defined as the abnormal development of nephronic and ductal structures due to in utero obstruction of the urinary tract) were evaluated in terms of sonographic findings, renal and other associated anomalies, and current status of the child. More than one-third of the cases had bilateral disease and although not uniformly fatal bilateral involvement was associated with significant morbidity and mortality. In 12 of the 33 cases with unilateral dysplasia there was an association with contralateral renal problems including ureteropelvic junction obstruction, vesicoureteral reflux and aplasia. Almost one-half of the cases had congenital anomalies, these included VACTERL association, congenital heart disease, cranial abnormalities and gastrointestinal malformations. Fifteen stillborns and 12 of the patients with bilateral involvement and four with unilateral involvement have died. Four patients are on dialysis (two with bilateral involvement and two with unilateral renal obstructive dysplasia). Only one-quarter are otherwise normal. More serious problems are reported in this mixed age population of patients with obstructive renal dysplasia than has been identified in previous studies. Management decisions of the fetus and child must be based on this new age-expanded population.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46696/1/247_2005_Article_BF02018623.pd

Cross-Country Individual Participant Analysis of 4.1 Million Singleton Births in 5 Countries with Very High Human Development Index Confirms Known Associations but Provides No Biologic Explanation for 2/3 of All Preterm Births.

BACKGROUND: Preterm birth is the most common single cause of perinatal and infant mortality, affecting 15 million infants worldwide each year with global rates increasing. Understanding of risk factors remains poor, and preventive interventions have only limited benefit. Large differences exist in preterm birth rates across high income countries. We hypothesized that understanding the basis for these wide variations could lead to interventions that reduce preterm birth incidence in countries with high rates. We thus sought to assess the contributions of known risk factors for both spontaneous and provider-initiated preterm birth in selected high income countries, estimating also the potential impact of successful interventions due to advances in research, policy and public health, or clinical practice. METHODS: We analyzed individual patient-level data on 4.1 million singleton pregnancies from four countries with very high human development index (Czech Republic, New Zealand, Slovenia, Sweden) and one comparator U.S. state (California) to determine the specific contribution (adjusting for confounding effects) of 21 factors. Both individual and population-attributable preterm birth risks were determined, as were contributors to cross-country differences. We also assessed the ability to predict preterm birth given various sets of known risk factors. FINDINGS: Previous preterm birth and preeclampsia were the strongest individual risk factors of preterm birth in all datasets, with odds ratios of 4.6-6.0 and 2.8-5.7, respectively, for individual women having those characteristics. In contrast, on a population basis, nulliparity and male sex were the two risk factors with the highest impact on preterm birth rates, accounting for 25-50% and 11-16% of excess population attributable risk, respectively (p<0.001). The importance of nulliparity and male sex on population attributable risk was driven by high prevalence despite low odds ratios for individual women. More than 65% of the total aggregated risk of preterm birth within each country lacks a plausible biologic explanation, and 63% of difference between countries cannot be explained with known factors; thus, research is necessary to elucidate the underlying mechanisms of preterm birth and, hence, therapeutic intervention. Surprisingly, variation in prevalence of known risk factors accounted for less than 35% of the difference in preterm birth rates between countries. Known risk factors had an area under the curve of less than 0.7 in ROC analysis of preterm birth prediction within countries. These data suggest that other influences, as yet unidentified, are involved in preterm birth. Further research into biological mechanisms is warranted. CONCLUSIONS: We have quantified the causes of variation in preterm birth rates among countries with very high human development index. The paucity of explicit and currently identified factors amenable to intervention illustrates the limited impact of changes possible through current clinical practice and policy interventions. Our research highlights the urgent need for research into underlying biological causes of preterm birth, which alone are likely to lead to innovative and efficacious interventions

Further evidence of psychological factors underlying choice of elective cesarean delivery (ECD) by primigravidae

Objective: Requests for elective cesarean delivery (ECD) have increased in Iran. While some sociodemographic and fear-related factors have been linked with this choice, psychological factors such as self-esteem, stress, and health beliefs are under-researched. Methods: A total of 342 primigravidae (mean age = 25 years) completed questionnaires covering psychological dimensions such as self-esteem, perceived stress, marital relationship quality, perceived social support, and relevant health-related beliefs. Results: Of the sample, 214 (62.6%) chose to undergo ECD rather than vaginal delivery (VD). This choice was associated with lower self-esteem, greater perceived stress, belief in higher susceptibility to problematic birth and barriers to an easy birth, along with lower perceived severity of ECD, fewer perceived benefits from VD, lower self-efficacy and a lower feeling of preparedness. No differences were found for marital relationship quality or perceived social support. Conclusions: The pattern suggests that various psychological factors such as self-esteem, self-efficacy, and perceived stress underpin the decision by primigravidae to have an ECD

Down syndrome serum screening also identifies an increased risk for multicystic dysplastic kidney, two-vessel cord, and hydrocele

The FASTER trial compared 1st and 2nd trimester screening methods for aneuploidy. We examined relationships between maternal serum markers and common congenital anomalies in the pediatric outcome data set of 36,837 subjects

Preconceptional Folate Supplementation and the Risk of Spontaneous Preterm Birth: A Cohort Study

In an analysis of a cohort of pregnant women, Radek Bukowski and colleagues describe an association between taking folic acid supplements and a reduction in the risk of preterm birth

Mitral valve surgery for mitral regurgitation caused by Libman-Sacks endocarditis: a report of four cases and a systematic review of the literature

Libman-Sacks endocarditis of the mitral valve was first described by Libman and Sacks in 1924. Currently, the sterile verrucous vegetative lesions seen in Libman-Sacks endocarditis are regarded as a cardiac manifestation of both systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). Although typically mild and asymptomatic, complications of Libman-Sacks endocarditis may include superimposed bacterial endocarditis, thromboembolic events, and severe valvular regurgitation and/or stenosis requiring surgery. In this study we report two cases of mitral valve repair and two cases of mitral valve replacement for mitral regurgitation (MR) caused by Libman-Sacks endocarditis. In addition, we provide a systematic review of the English literature on mitral valve surgery for MR caused by Libman-Sacks endocarditis. This report shows that mitral valve repair is feasible and effective in young patients with relatively stable SLE and/or APS and only localized mitral valve abnormalities caused by Libman-Sacks endocarditis. Both clinical and echocardiographic follow-up after repair show excellent mid- and long-term results

TSH and FT4 reference interval recommendations and prevalence of gestational thyroid dysfunction: quantification of current diagnostic approaches

Context Guidelines recommend use of population- and trimester-specific TSH and FT4 reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. Methods We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using non-pregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. Results The study population comprised 52,496 participants from 18 cohorts. Compared to the use of trimester-specific reference intervals, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction and non-pregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. Conclusion Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable over- and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy

Risk factors for thyroid dysfunction in pregnancy: an individual participant data meta-analysis

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction