Amy Cantor

Risk Factors for Breast Cancer for Women Aged 40 to 49 Years: A Systematic Review and Meta-analysis

BACKGROUND Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions. PURPOSE To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor. DATA SOURCES MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium. STUDY SELECTION English-language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor. DATA EXTRACTION Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means. DATA SYNTHESIS Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk. LIMITATIONS Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered. CONCLUSION Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening. PRIMARY FUNDING SOURCE National Cancer Institute.

Harms of Breast Cancer Screening: Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation.

In 2009, the U.S. Preventive Services Task Force (USPSTF) recommended biennial mammography screening for women aged 50 to 74 years (1) on the basis of evidence of benefits and harms (2, 3). The USPSTF concluded that screening decisions for women aged 40 to 49 years should be based on individual considerations and that evidence was insufficient to assess benefits and harms for those aged 75 years or older (1). Although there is general consensus that mammography screening is beneficial for many women, benefits must be weighed against potential harms to determine the net effect of screening on individual women. Determining the balance between benefits and harms is complicated by several important considerations that are unresolved, including defining and quantifying potential harms; the optimal ages at which to begin and end routine screening; the optimal screening intervals; appropriate use of various imaging modalities, including supplemental technologies; values and preferences of women in regards to screening; and how all of these considerations vary depending on a womans risk for breast cancer. This systematic review updates evidence for the USPSTF on the harms of breast cancer screening, including false-positive mammography results, overdiagnosis, anxiety, pain during procedures, and radiation exposure, and how these adverse effects vary by age, risk factor, screening interval, and screening modality. Systematic reviews of the effectiveness of screening (4), performance characteristics of screening methods (5), and the accuracy of breast density determination and use of supplemental screening technologies (6) are provided in additional reports. Methods Scope, Key Questions, and Analytic Framework The USPSTF determined the scope and key questions for this review by using established methods (7, 8). A standard protocol was developed and publicly posted on the USPSTF Web site. A technical report further describes the methods and includes search strategies and additional information (4). Investigators created an analytic framework outlining the key questions, patient populations, interventions, and outcomes reviewed (Appendix Figure 1). Key questions include the harms of routine breast cancer screening and how they differ by age, risk factor, screening interval, and screening modality (mammography [film, digital, or tomosynthesis], magnetic resonance imaging [MRI], and ultrasonography). Harms include false-positive and false-negative mammography results, overdiagnosis, anxiety and other psychological responses, pain during procedures, and radiation exposure. Overdiagnosis refers to women receiving a diagnosis of ductal carcinoma in situ (DCIS) or invasive breast cancer when they have abnormal lesions that are unlikely to become clinically evident during their lifetime in the absence of screening. Overdiagnosed women may be harmed by unnecessary procedures and treatments as well as by the burden of receiving a cancer diagnosis. Appendix Figure 1. Analytic framework and key questions. KQ = key question. * Excludes women with preexisting breast cancer; clinically significant BRCA1 or BRCA2 mutations, Li-Fraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer, or other familial breast cancer syndrome; high-risk lesions (ductal carcinoma in situ, lobular carcinoma in situ, atypical ductal hyperplasia, or atypical lobular hyperplasia); or previous large doses of chest radiation (20 Gy) before age 30 y. False-positive and false-negative mammography results, biopsy recommendations due to false-positive mammography results, overdiagnosis and resulting overtreatment, anxiety, pain, and radiation exposure. Family history; breast density; race/ethnicity; menopausal status; current use of menopausal hormone therapy or oral contraceptives; prior benign breast biopsy; and, for women aged >50 y, body mass index. Mammography (film, digital, or tomosynthesis), magnetic resonance imaging, ultrasonography, and clinical breast examination (alone or in combination). The target population for the USPSTF recommendation includes women aged 40 years or older and excludes women with known physical signs or symptoms of breast abnormalities and those at high risk for breast cancer whose surveillance and management are beyond the scope of the USPSTF recommendations for preventive services (preexisting breast cancer or high-risk breast lesions, hereditary genetic syndromes associated with breast cancer, and previous large doses of chest radiation before age 30 years). Risk factors considered in this review are common among women who are not at high risk for breast cancer (9) (described in Appendix Figure 1). Data Sources and Searches A research librarian conducted electronic searches of the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE through December 2014 for relevant studies and systematic reviews. Searches were supplemented by references identified from additional sources, including reference lists and experts. Studies of harms included in the previous systematic review for the USPSTF (2, 3) were also included. Study Selection Two investigators independently evaluated each study to determine eligibility based on prespecified inclusion criteria. Discrepancies were resolved through consensus. We included recently published systematic reviews; randomized, controlled trials (RCTs); and observational studies of prespecified harms. When available, studies providing outcomes specific to age, risk factors, screening intervals, and screening modalities were preferred over studies providing general outcomes. Studies that were most clinically relevant to practice in the United States were selected; relevance was determined by practice setting, population, date of publication, and use of technologies and therapies in current practice. Studies meeting criteria for high quality and with designs ranked higher in the study designbased hierarchy of evidence were emphasized because they are less susceptible to bias (for example, RCTs were chosen over observational studies). Data Extraction and Quality Assessment Details of the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results were abstracted by one investigator and confirmed by another. Two investigators independently applied criteria developed by the USPSTF (7, 8) to rate the quality of each RCT, cohort study, casecontrol study, and systematic review as good, fair, or poor; criteria to rate studies with other designs included in this review are not available. Discrepancies were resolved through consensus. Data Synthesis Studies meeting inclusion criteria were qualitatively synthesized. Most studies in this review had designs for which quality rating criteria are not available, which limited data synthesis. When possible, we assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) by using methods developed by the USPSTF based on the number, quality, and size of studies; consistency of results between studies; and directness of evidence (7, 8). Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. The investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic frameworks, and key questions; resolve issues during the project; and finalize the report. The AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. The AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The AHRQ performed a final review of the manuscript to ensure that the analysis met methodological standards. The investigators are solely responsible for the content and the decision to submit the manuscript for publication. Results Of the 12004 abstracts identified by searches and other sources, 59 studies met inclusion criteria for key questions in this report, including 10 systematic reviews of 134 studies and 49 additional studies (Appendix Figure 2). Appendix Figure 2. Summary of evidence search and selection. RCT = randomized, controlled trial. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. False-Positive Mammography Results Two new observational studies estimated the cumulative probability of false-positive results after 10 years of screening with film and digital mammography, based on data from the Breast Cancer Surveillance Consortium, a large population-based database in the United States (Appendix Table 1) (10, 11). When screening began at age 40 years, the cumulative probability of receiving at least 1 false-positive mammography result after 10 years was 61% (95% CI, 59% to 63%) with annual screening and 42% (CI, 41% to 43%) with biennial screening (10). Estimates were similar when screening began at age 50 years. The cumulative probability of receiving a biopsy recommendation due to a false-positive mammography result after 10 years of screening was 7% (CI, 6% to 8%) with annual screening versus 5% (CI, 4% to 5%) with biennial screening for women who initiated screening at age 40 years and 9% (CI, 7% to 12%) with annual screening versus 6% (CI, 6% to 7%) with biennial screening for those who began at age 50 years. Appendix Table 1. U.S. Studies of Cumulative False-Positive Mammography and Biopsy Results In a separate analysis, rates of false-positive mammography results were highest among women receiving annual mammography who had extremely dense breasts and either were aged 40 to 49 years (65.5%) or used combination hormone therapy (65.8%) (11). The highest rates of biopsy due to false-positive mammography results were related to similar characteristics and ranged from 12% to 1

Effectiveness of Breast Cancer Screening: Systematic Review and Meta-analysis to Update the 2009 U.S. Preventive Services Task Force Recommendation

In 2009, the U.S. Preventive Services Task Force (USPSTF) recommended biennial mammography screening for women aged 50 to 74 years (1) on the basis of evidence of benefits and harms (2). The USPSTF concluded that screening decisions for women aged 40 to 49 years should be based on individual considerations, and that evidence was insufficient to assess benefits and harms for women aged 75 years or older (1). Mammography screening in the United States is generally opportunistic, unlike many screening programs organized as public health services in other countries. Despite changes in practice guidelines and variation in clinical practices (3), overall screening rates in the United States have remained relatively stable for the past decade (4, 5). Data from the Healthcare Effectiveness Data and Information Set indicate that mammography screening in 2014 in HMOs was performed for 74% of eligible women covered by commercial plans, 72% by Medicare, and 59% by Medicaid (6). This systematic review updates evidence for the USPSTF on the effectiveness of mammography screening in reducing breast cancer mortality, all-cause mortality, and advanced breast cancer for women at average risk; and how effectiveness varies by age, risk factors, screening intervals, and imaging modalities. Systematic reviews of harms of screening (7), performance characteristics of screening methods (8), and accuracy of breast density determination and use of supplemental screening technologies (9) are provided in separate reports. Methods Scope, Key Questions, and Analytic Framework The USPSTF determined the scope and key questions for this review by using established methods (10, 11). A standard protocol was developed and publicly posted on the USPSTF Web site. A technical report further describes the methods and includes search strategies and additional information (7). Investigators created an analytic framework outlining the key questions, patient populations, interventions, and outcomes reviewed (Appendix Figure 1). Key questions include the effectiveness of screening in reducing breast cancer mortality, all-cause mortality, and advanced breast cancer, and how effectiveness differs by age, risk factors, screening intervals, and modalities (mammography [film, digital, tomosynthesis], magnetic resonance imaging [MRI], and ultrasonography). Appendix Figure 1. Analytic framework and key questions. KQ = key question. * Excludes women with preexisting breast cancer; clinically significant BRCA1 or BRCA2 mutations, LiFraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer, or other familial breast cancer syndromes; high-risk lesions (ductal carcinoma in situ, lobular carcinoma in situ, atypical ductal hyperplasia, atypical lobular hyperplasia); or previous large doses of chest radiation (20 Gy) before age 30 y. Risk factors include family history; breast density; race/ethnicity; menopausal status; current use of menopausal hormone therapy or oral contraceptives; prior benign breast biopsy; and, for women aged >50 y, body mass index. Morbidity includes physical adverse effects of treatment, quality-of-life measures, and other measures of impairment. Screening modalities include mammography (film, digital, tomosynthesis), magnetic resonance imaging, ultrasonography, and clinical breast examination (alone or in combination). The target population for the USPSTF recommendation includes women aged 40 years or older, and excludes women with known physical signs or symptoms of breast abnormalities and those at high-risk for breast cancer whose surveillance and management are beyond the scope of the USPSTFs recommendations for prevention services (i.e., preexisting breast cancer or high-risk breast lesions, hereditary genetic syndromes associated with breast cancer, or previous large doses of chest radiation before age 30 years). Risk factors considered in this review are common among women who are not at high risk for breast cancer (12) (Appendix Figure 1). Data Sources and Searches A research librarian conducted electronic database searches of the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Ovid MEDLINE to 4 June 2015. Searches were supplemented by references identified from additional sources, including reference lists and experts. Additional unpublished data were provided by the investigators of the Canadian National Breast Screening Study (CNBSS) and Swedish Two-County Trial. Study Selection Two investigators independently evaluated each study to determine inclusion eligibility on the basis of prespecified criteria. Discrepancies were resolved through consensus. We included randomized, controlled trials (RCTs); observational studies of screening cohorts; and systematic reviews that compared outcomes of women exposed to screening versus not screening. For advanced cancer outcomes, studies that reported the incidence of late-stage disease among screened and unscreened populations were included, whereas those reporting comparisons of detection methods that did not capture a womans longitudinal screening experience were not included (e.g., rates of screen-detected vs. nonscreen-detected cancer). Studies providing outcomes specific to age, risk factors, screening intervals, and modalities were preferred over studies providing general outcomes, when available. Studies most clinically relevant to practice in the United States were selected over studies that were less relevant. Relevance was determined by practice setting, population, date of publication, and use of technologies and therapies in current practice. Studies meeting criteria for high quality and those with designs ranked higher in the study designbased hierarchy of evidence were emphasized because they are less susceptible to bias (e.g., RCTs over observational studies). Data Extraction and Quality Assessment Details of the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results were abstracted by one investigator and confirmed by a second. Two investigators independently applied criteria developed by the USPSTF (10, 11) to rate the quality of each study as good, fair, or poor for studies designed as RCTs, cohort studies, casecontrol studies, and systematic reviews; criteria to rate other study designs included in this review are not available. Discrepancies were resolved through consensus. Data Synthesis We conducted several meta-analyses to determine more precise summary estimates when adequate data were reported by trials rated as fair- or good-quality. In each meta-analysis, the number of included trials was counted as the number of discrete data sources contributing to the summary estimate using their most recent results. To determine the appropriateness of meta-analysis, we considered clinical and methodological diversity and assessed statistical heterogeneity. All outcomes were binary (breast cancer mortality, all-cause mortality, and advanced cancer incidence defined by stage and tumor size). We used a random-effects model to combine relative risks (RRs) as the effect measure of the meta-analyses, while incorporating variation among studies. A profile-likelihood model was used to combine studies in the primary analyses (13). We assessed the presence of statistical heterogeneity among the studies by using the standard Cochran chi-square test, and the magnitude of heterogeneity by using the I 2 statistic (14). To account for clinical heterogeneity and obtain clinically meaningful estimates, we stratified the analyses by age group whenever possible (39 to 49 years, 50 to 59 years, 60 to 69 years, 70 to 74 years, and 50 years). We obtained additional age-stratified data for the meta-analysis from the investigators of 3 trials (15, 16) (Tabr L. Personal communication). For breast cancer mortality, we used 2 methods of including cases to help clarify discrepancies between estimates. The long case accrual method counts all breast cancer cases contributing to breast cancer deaths. In this method, the case accrual time is equivalent to or close to the follow-up time. The short case accrual method includes only deaths that occur among cases of breast cancer diagnosed during the screening intervention period, and in some trials, within an additional defined case accrual period. The longest follow-up times available for each trial were selected for inclusion in the initial meta-analyses, and sensitivity analyses were conducted by using results of short case accrual methods. We calculated the absolute rate reduction for 100000 woman-years of follow-up (i.e., 10000 women followed for 10 years) for each age group on the basis of the combined RR and the combined cancer rate of the control group. We estimated combined cancer rates for each age group for controls with a random effects Poisson model using data from the trials. All analyses were performed by using Stata/IC, version 13.1 (StataCorp). We assessed the aggregate internal validity (quality) of the body of evidence for each key question as good, fair, or poor by using methods developed by the USPSTF that are based on the number, quality, and size of studies; consistency of results between studies; and directness of evidence (10, 11). Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. The investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic framework, and key questions; resolve issues during the project; and finalize the report. The AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. The AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The AHRQ performed a final review of the manuscript to ensure that the

Preventing Dental Caries in Children <5 Years: Systematic Review Updating USPSTF Recommendation

BACKGROUND AND OBJECTIVE: Screening and preventive interventions by primary care providers could improve outcomes related to early childhood caries. The objective of this study was to update the 2004 US Preventive Services Task Force systematic review on prevention of caries in children younger than 5 years of age. METHODS: Searching Medline and the Cochrane Library (through March 2013) and reference lists, we included trials and controlled observational studies on the effectiveness and harms of screening and treatments. One author extracted study characteristics and results, which were checked for accuracy by a second author. Two authors independently assessed study quality. RESULTS: No study evaluated effects of screening by primary care providers on clinical outcomes. One good-quality cohort study found pediatrician examination associated with a sensitivity of 0.76 for identifying a child with cavities. No new trials evaluated oral fluoride supplementation. Three new randomized trials were consistent with previous studies in finding fluoride varnish more effective than no varnish (reduction in caries increment 18% to 59%). Three trials of xylitol were inconclusive regarding effects on caries. New observational studies were consistent with previous evidence showing an association between early childhood fluoride use and enamel fluorosis. Evidence on the accuracy of risk prediction instruments in primary care settings is not available. CONCLUSIONS: There is no direct evidence that screening by primary care clinicians reduces early childhood caries. Evidence previously reviewed by the US Preventive Services Task Force found oral fluoride supplementation effective at reducing caries incidence, and new evidence supports the effectiveness of fluoride varnish in higher-risk children.

Routine iron supplementation and screening for iron deficiency anemia in pregnancy: A systematic review for the U.S. preventive services task force

Iron deficiency is the most common pathologic cause of anemia in pregnancy. Increased risk during pregnancy is due to increased maternal iron needs and demands from the growing fetus and placenta; increased erythrocyte mass; and, in the third trimester, expanded maternal blood volume (15). Definitions of iron deficiency anemia (IDA) in pregnant women may be imprecise given pregnancy-associated physiologic changes and variable definitions in population subgroups (1, 2). Physiologic anemia, or dilutional anemia of pregnancy, is common in healthy pregnant women due to blood volume expansion to support the growing fetus and is associated with a modest decrease in hemoglobin levels. Iron deficiency occurs when the level of stored iron becomes depleted. Iron deficiency anemia occurs when iron levels are sufficiently depleted to produce anemia (1, 6). Serum ferritin is useful in diagnosing iron deficiency in pregnant women, who can have an elevated serum transferrin level in the absence of iron deficiency. As an acute-phase reactant, serum ferritin can be elevated in inflammatory conditions and may be of limited usefulness when concentrations decrease late in pregnancy (7). Overall prevalence of iron deficiency in pregnant women in the United States is near 18%, with anemia in 5% of pregnant women and rates of iron deficiency increasing across trimesters from 6.9% to 14.3% to 28.4% (5). Risk factors for iron deficiency or IDA in pregnant women include an iron-deficient diet, gastrointestinal issues affecting absorption, or a short pregnancy interval (8). Pregnant women with clinically significant iron deficiency or IDA may present with fatigue, weakness, pallor, tachycardia, and shortness of breath (9). Maternal iron requirements average 1000 mg/d (10). Because many pregnant women lack sufficient iron stores, iron supplementation may be included in prenatal care. Primary prevention for average-risk populations includes adequate intake of dietary iron and oral, low-dose (30 mg/d) iron supplements early in pregnancy (11). Suggested prophylaxis for IDA in high-risk populations is 60 to 100 mg of elemental iron daily (12). The association between iron status and negative outcomes for women and their infants is inconclusive. Although many older observational studies, including uncontrolled and cross-sectional studies, have shown an association between various measures of iron status and negative perinatal outcomes, such as low birthweight (1315), premature birth (1318), and perinatal death (14), more rigorous trial evidence is inconsistent. Screening for IDA may lead to earlier identification and earlier treatment, which may prevent serious negative health outcomes. The U.S. Preventive Services Task Force (USPSTF) last reviewed evidence on prenatal screening for IDA in 2006 and recommended routine screening (B recommendation) on the basis of fair-quality evidence (19). There was insufficient evidence (no studies) on the accuracy of screening in asymptomatic pregnant women but fair-quality evidence that treating asymptomatic IDA in pregnancy results in moderate health benefits. Evidence was also insufficient to recommend for or against routine iron supplementation for nonanemic pregnant women (I statement). This review was commissioned by the USPSTF to update the prior recommendations (19). We examined evidence from U.S.-relevant populations on the effectiveness of routine supplementation and screening for IDA in pregnancy. Methods Methods are described in detail in a technical report (20). On the basis of evidence gaps identified from prior reviews (21, 22), and in consultation with the USPSTF (23), we developed key questions and analytic frameworks for routine supplementation (Appendix Figure 1) and screening (Appendix Figure 2) for IDA during pregnancy. Key questions were as follows. Appendix Figure 1. Analytic framework for routine iron supplementation in pregnant women. KQ = key question. Appendix Figure 2. Analytic framework for screening for iron deficiency anemia in pregnant women. KQ = key question. Supplementation 1. What are the benefits of routine iron supplementation in pregnant women on maternal and infant health outcomes? 2. What are the harms of routine iron supplementation in pregnant women? Screening 1. What are the benefits of screening asymptomatic pregnant women for iron deficiency anemia on maternal and infant health outcomes? 2. What are the harms of screening for iron deficiency anemia in pregnant women? 3. What are the benefits of treatment for iron deficiency anemia in pregnant women on maternal and infant health outcomes? 4. What are the harms of iron treatment in pregnant women? 5. What is the association between a change in maternal iron status (including changes in ferritin or hemoglobin level) and improvement in newborn and peripartum outcomes in U.S.-relevant populations? Data Sources We searched the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE (1996 to August 2014) (Appendix Table 1). We also searched reference lists of relevant systematic reviews to identify studies published before 1996, the year that the prior reviews concluded. Appendix Table 1. Search Strategies Study Selection Abstracts were selected for full-text review if they included asymptomatic pregnant women receiving screening or supplementation for IDA, were relevant to a key question, and met predefined inclusion criteria (20). For the screening framework, key questions focused on the effectiveness of screening compared with not screening in preventing adverse health outcomes and reducing the incidence of complications, as well as the association of improvements in intermediate and clinical health outcomes with harms (including infant harms). Health outcomes included long- or short-term maternal and infant morbidity (including birth outcomes), infant mortality, and maternal quality of life (including postpartum depression) resulting from screening, supplementation, or treatment and related harms. Intermediate outcomes included iron status based on hematologic indices, including ferritin levels. Additional outcomes included the relationship between a change in maternal iron status and maternal and infant health outcomes. We focused on studies using iron supplementation and treatment regimens commonly used in clinical practice in the United States and those conducted in countries with high or very high human development based on the United Nations Human Development Index (24). We included only English-language articles and excluded studies published as abstracts or without original data. Two reviewers independently evaluated each study to determine inclusion eligibility. We included randomized, controlled trials; nonrandomized, controlled trials; and cohort studies for all key questions. When good- and fair-quality studies were available, poor-quality studies were excluded. The selection of studies is summarized in Figure 1 . Figure 1. Summary of evidence search and selection. KQ = key question. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. Prior reports, reference lists of relevant articles, and systematic reviews. Some studies are included for >1 KQ. Poor-quality studies were excluded because good- and fair-quality evidence was available. Data Abstraction and Quality Rating One investigator abstracted details about study design, patient population, setting, screening method, analysis, follow-up, and results. A second investigator reviewed the data abstraction for accuracy. Using predefined criteria developed by the USPSTF (23), 2 investigators rated the quality of studies (good, fair, or poor) (23) and resolved discrepancies by consensus. Data Synthesis and Analysis We assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) by using methods developed by the USPSTF, based on the number, quality, and size of studies; consistency of results among studies; and directness of evidence (23). Meta-analysis was performed when studies were available that used comparable dosages, durations, and timing of outcome assessment. We conducted meta-analyses using the MantelHaenszel random- or fixed-effects models in Review Manager, version 5.2 (Cochrane Collaboration), to calculate risk ratios of the effects of routine iron supplementation on incidence of preterm delivery, low birthweight, and maternal IDA and iron deficiency at term. Statistical heterogeneity was assessed using the I 2 statistic. Due to methodological shortcomings in the studies and differences across studies in design, interventions (timing and dosing), patient populations, and other factors, meta-analysis was not attempted for all outcome measures. Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. Investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic framework, and key questions; resolve issues arising during the project; and finalize the report. The AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. The AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The AHRQ performed a final review of the manuscript to ensure that the analysis met methodological standards. The investigators are solely responsible for the content and the decision to submit the manuscript for publication. Results Effectiveness of Routine Iron Supplementation in Pregnancy We identified a total of 12 good-quality (2527) and fair-quality (2836) trials comparing the effects of routine prenatal iron supplementation versus no supplementation (37, 38). Studies were conducted in the United States, Iran, Hong Ko

Screening and Routine Supplementation for Iron Deficiency Anemia: A Systematic Review

BACKGROUND AND OBJECTIVES: Supplementation and screening for iron-deficiency anemia (IDA) in young children may improve growth and development outcomes. The goal of this study was to review the evidence regarding the benefits and harms of screening and routine supplementation for IDA for the US Preventive Services Task Force. METHODS: We searched Medline and Cochrane databases (1996–August 2014), as well as reference lists of relevant systematic reviews. We included trials and controlled observational studies regarding the effectiveness and harms of routine iron supplementation and screening in children ages 6 to 24 months conducted in developed countries. One author extracted data, which were checked for accuracy by a second author. Dual quality assessment was performed. RESULTS: No studies of iron supplementation in young children reported on the diagnosis of neurodevelopmental delay. Five of 6 trials sparsely reporting various growth outcomes found no clear benefit of supplementation. After 3 to 12 months, Bayley Scales of Infant Development scores were not significantly different in 2 trials. Ten trials assessing iron supplementation in children reported inconsistent findings for hematologic measures. Evidence regarding the harms of supplementation was limited but did not indicate significant differences. No studies assessed the benefits or harms of screening or the association between improvement in impaired iron status and clinical outcomes. Studies may have been underpowered, and control factors varied and could have confounded results. CONCLUSIONS: Although some evidence on supplementation for IDA in young children indicates improvements in hematologic values, evidence on clinical outcomes is lacking. No randomized controlled screening studies are available.

Screening for Syphilis: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

IMPORTANCE Screening for syphilis infection is currently recommended for high-risk individuals, including those with previous syphilis infection, an infected sexual partner, HIV infection, or more than 4 sex partners in the preceding year. OBJECTIVE To update a 2004 systematic review of studies of syphilis screening effectiveness, test accuracy, and screening harms in nonpregnant adults and adolescents. DATA SOURCES Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews through October 2015 and Ovid MEDLINE (January 2004 to October 2015), with updated search through March 2016. STUDY SELECTION English-language trials and observational studies of screening effectiveness, test accuracy, and screening harms in nonpregnant adults and adolescents. DATA EXTRACTION AND SYNTHESIS One investigator abstracted data, a second checked data for accuracy, and 2 investigators independently assessed study quality using predefined criteria. MAIN OUTCOMES AND MEASURES Transmission of disease, including HIV; complications of syphilis; diagnostic accuracy; and harms of screening. RESULTS No evidence was identified regarding the effectiveness of screening on clinical outcomes or the effectiveness of risk assessment instruments; the harms of screening; or the effectiveness of screening in average-risk, nonpregnant adolescents or adults or high-risk individuals other than men who have sex with men (MSM) or men who are HIV positive. Four non-US studies indicated higher rates of syphilis detection with screening every 3 months vs 6 or 12 months for early syphilis in HIV-positive men or MSM. For example, there was an increased proportion of asymptomatic, higher-risk MSM in Australia (n = 6789 consultations) receiving a diagnosis of early syphilis when tested every 3 months vs annually (53% vs 16%, P = .001), but no difference among low-risk MSM. Treponemal and nontreponemal tests were accurate in asymptomatic individuals (sensitivity >85%, specificity >91%) in 3 studies but required confirmatory testing. Reverse sequence testing with an initial automated treponemal test yielded more false reactive test results than with rapid plasma reagin in 2 studies, one with a low-prevalence US population (0.6% vs 0.0%, P = .03) and another in a higher-prevalence Canadian population (0.26% vs 0.13%). CONCLUSIONS AND RELEVANCE Screening HIV-positive men or MSM for syphilis every 3 months is associated with improved syphilis detection. Treponemal or nontreponemal tests are accurate screening tests but require confirmation. Research is needed on the effect of screening on clinical outcomes; effective screening strategies, including reverse sequence screening, in various patient populations; and harms of screening.

Screening for Gonorrhea and Chlamydia: A Systematic Review for the U.S. Preventive Services Task Force

In 2005, on the basis of epidemiologic studies of screening and studies of the diagnostic accuracy of screening tests (13), the U.S. Preventive Services Task Force (USPSTF) recommended screening for gonorrhea in all sexually active or pregnant women at increased risk for infection (4). It recommended against routine screening in low-risk men and nonpregnant women and found insufficient evidence to recommend for or against routine screening in high-risk men and low-risk pregnant women. In 2007, on the basis of studies of the effectiveness of screening, harms, and diagnostic accuracy of screening tests (13), the USPSTF recommended screening for chlamydia in all sexually active or pregnant women younger than 25 years and in older, high-risk women (5). It recommended against routine screening in low-risk women, regardless of pregnancy status, and found insufficient evidence to recommend for or against screening in men. Gonorrhea and chlamydia are the 2 most commonly reported sexually transmitted infections (STIs) in the United States (6). In 2012, totals of 334826 cases of gonorrhea and 1422976 cases of chlamydia were reported to the Centers for Disease Control and Prevention (6). However, the true incidence of gonorrhea and chlamydia is difficult to estimate because most infections are undetected. In women, gonococcal and chlamydial infections are most often asymptomatic but can cause cervicitis and complications of pelvic inflammatory disease (PID), ectopic pregnancy, infertility, and chronic pelvic pain (6, 7). In men, these infections can cause urethritis and epididymitis (6, 8). Most men with gonococcal urethritis are symptomatic, prompting timely treatment that prevents serious complications (9). However, gonococcal infections at extragenital sites, including the pharynx and rectum, and genital chlamydial infections are typically asymptomatic. Gonorrhea and chlamydia can also facilitate HIV transmission in both men and women (6, 10, 11). Infection with either gonorrhea or chlamydia in pregnant women can lead to adverse neonatal outcomes, including preterm birth and transmission of infection to the newborn. Chlamydial infection also causes neonatal ophthalmia and pneumonia in infants. Age is a strong predictor of risk for both gonorrhea and chlamydia, and infection rates are greatest among persons aged 15 to 24 years (6). Although rates are greater for women than men (108.7 cases of gonorrhea per 100000 women vs. 105.8 per 100000 men; 643.3 cases of chlamydia per 100000 women vs. 262.6 per 100000 men), rates have increased more rapidly among men in recent years (6). Other risk factors include having new or multiple sex partners or a partner with an STI, inconsistent condom use, and history of previous or coexisting STIs (1, 2). These risk factors are often used to define persons at increased risk in screening recommendations. Rates differ among population subgroups, and black and Hispanic persons generally have greater rates of infections compared with white persons (6, 12). Men who have sex with men who were tested in STD Surveillance Network clinics in 2012 had median prevalence rates of 16.4% for gonorrhea and 12.0% for chlamydia (6). This systematic review is an update of previous reviews for the USPSTF (13). It focuses on new studies of the effectiveness and adverse effects of gonorrhea and chlamydia screening in asymptomatic men and women, including pregnant women and adolescents, as well as the diagnostic accuracy of screening tests. Methods Methods are further described in a technical report (13). We followed a standard protocol consistent with the Agency for Healthcare Research and Quality (AHRQ) methods for systematic reviews (14). On the basis of evidence gaps identified from previous reviews (13), the USPSTF and AHRQ determined the key questions for this update (15). The investigators created analytic frameworks incorporating the key questions and outlining the patient populations, interventions, outcomes, and potential adverse effects (Supplements 1 and 2). A work plan was externally reviewed and modified but was not registered. Supplement 1. Analytic framework and key questions for screening men and nonpregnant women, including adolescents. Supplement 2. Analytic framework and key questions for screening pregnant women. The target populations were asymptomatic, sexually active men and women, including pregnant women and adolescents. The key questions focused on the effectiveness of screening compared with not screening in preventing adverse health outcomes, effectiveness of different screening strategies, diagnostic accuracy of screening tests, and potential harms of screening. Screening strategies included selective screening of high-risk groups, sampling from various anatomical sites, cotesting for concurrent STIs (including HIV), and using different screening intervals, among others. Outcomes included reduction of complications of infection and transmission or acquisition of disease, including gonorrhea, chlamydia, and HIV. For pregnant women, outcomes also included reduction in maternal complications and adverse pregnancy and infant outcomes. Harms of screening included labeling, anxiety, false-positive and false-negative test results, and other consequences of testing. The efficacy and harms of antibiotic treatments were well-established and were not further evaluated. Data Sources and Searches We searched Ovid MEDLINE (1 January 2004 to 13 June 2014), the Cochrane Central Register of Controlled Trials (May 2014), the Cochrane Database of Systematic Reviews (May 2014), the Health Technology Assessment Database (May 2014), the Database of Abstracts of Reviews of Effects (May 2014), and ClinicalTrials.gov (May 2014) and reviewed reference lists for additional citations (13). Search terms are provided in Supplement 3. Supplement 3. MEDLINE Search Strategies Study Selection Abstracts were selected for full-text review if they included asymptomatic, sexually active men and women, including pregnant women and adolescents; were relevant to a key question; and met additional prespecified inclusion criteria for each key question (13). Although this update was intended to evaluate studies published since the previous USPSTF reviews, the scope, key questions, and inclusion criteria differ across reviews, resulting in the inclusion of older studies that have not been previously reviewed. We included only English-language articles and excluded studies that were published as abstracts only or did not report original data. The selection of studies is summarized in a literature flow diagram Supplement 4. Two reviewers independently evaluated each study to determine inclusion eligibility. Supplement 4. Literature flow diagram. Only randomized, controlled trials (RCTs) and controlled observational studies were included to evaluate the effectiveness of screening, whereas uncontrolled observational studies were also included to determine adverse effects. Studies of screening strategies were included if they adequately described the study population and comparison groups, features of the screening program, and outcome measures. Inclusion criteria were less restrictive for effectiveness studies than diagnostic accuracy studies because the main comparison concerned outcomes related to the overall approach of screening compared with nonscreening rather than the characteristics of the individual tests. Studies of the accuracy of diagnostic tests were included if they evaluated screening tests in asymptomatic participants using technologies and methods that have been cleared by the U.S. Food and Drug Administration (FDA) and are available for clinical practice in the United States. These inclusion criteria reflect the scope of the USPSTF recommendations about technologies and medications. On the basis of these criteria, rectal, pharyngeal, and self-collected vaginal specimens obtained in nonclinical settings and point-of-care or in-house tests were excluded. Tests that were previously cleared and subsequently removed from the U.S. market (such as the ligase chain reaction test) were also excluded (16). Included studies used credible reference standards, adequately described the study population, defined positive test results, and reported performance characteristics of tests (such as sensitivity and specificity) or provided data to calculate them. Data Abstraction and Quality Rating A single investigator abstracted details about study design, patient population, comparison groups, setting, screening method, analysis, follow-up, and results. A second investigator reviewed data abstraction for accuracy. By using prespecified criteria for RCTs, cohort, and diagnostic accuracy studies developed by the USPSTF (14), 2 investigators independently rated the quality of studies (good, fair, or poor) and resolved discrepancies by consensus. Data Synthesis and Analysis Two independent reviewers assessed the internal validity (quality) of the body of evidence for the new studies for each key question using methods developed by the USPSTF, on the basis of the number, quality, and size of studies; consistency of results among studies; and directness of evidence (14, 15). Statistical meta-analysis was not done because of methodological limitations of the studies and heterogeneity in study designs, interventions, populations, and other factors. Studies included in previous reviews were reviewed for consistency with current results; however, lack of studies and differences in scope, key questions, and inclusion criteria limited aggregate synthesis with the updated evidence. Role of the Funding Source This research was funded by AHRQ under a contract to support the work of the USPSTF. The investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic frameworks, and key questions; resolve issues during the project; and finalize the report. AHRQ had no role in study selection, quality assessment, syn

Preeclampsia Screening: Evidence Report and Systematic Review for the US Preventive Services Task Force

Importance Preeclampsia is a complex disease of pregnancy with sometimes serious effects on maternal and infant morbidity and mortality. It is defined by hypertension after 20 weeks’ gestation and proteinuria or other evidence of multisystem involvement. Objective To systematically review the benefits and harms of preeclampsia screening and risk assessment for the US Preventive Services Task Force. Data Sources MEDLINE, PubMed, and Cochrane Central Register of Controlled Trials databases from 1990 through September 1, 2015. Surveillance for new evidence in targeted publications was conducted through October 5, 2016. Study Selection English-language trials and observational studies, including externally validated prediction models, of screening effectiveness, benefits, and harms from routine preeclampsia screening during pregnancy. Data Extraction and Synthesis Independent dual review of article abstracts and full texts against a priori inclusion criteria. Meta-analysis was not performed because of clinical and statistical heterogeneity of included studies. Main Outcomes and Measures Maternal and infant health outcomes, including eclampsia, stroke, stillbirth, preterm birth, and low birth weight; screening and risk prediction test performance; harms of screening and risk assessment. Results Twenty-one studies (13 982 participants) were included. No studies directly compared the effectiveness of preeclampsia screening in a screened population vs an unscreened population; 1 US trial (n = 2764) found no difference in benefits or harms with fewer prenatal visits but was underpowered for rare, serious outcomes. For harms, a before-after comparison cohort noninferiority study of urine protein screening for specific indications compared with routine screening (n = 1952) did not identify harms with fewer urine screening tests. Four studies (n = 7123) reported external validation performance of 16 risk prediction models, 5 of which had good or better discrimination (c statistic >0.80) for prediction of preeclampsia, and positive predictive values of 4% in the largest, most applicable validation cohorts. Calibration was not reported despite being a key model performance measure. There were no studies of urine screening test performance conducted in asymptomatic primary care populations; 14 studies of protein urine test performance among women being evaluated for suspected preeclampsia (n = 1888) had wide-ranging test accuracy (sensitivity, 22%-100%; specificity, 36%-100%) and high statistical and clinical heterogeneity in tests used, eligibility criteria, and proteinuria prevalence (8.7%-93.8%). Conclusions and Relevance Evidence to estimate benefits and harms of preeclampsia screening and the test performance of different screening approaches over the course of pregnancy was limited. Externally validated risk prediction models had limited applicability and lacked calibration and clinical implementation data needed to support routine use. Further research is needed to better inform risk-based screening approaches and improve screening strategies, given the complex pathophysiology and clinical unpredictability of preeclampsia.

Pesticide-related Symptoms among Farm Workers in Rural Honduras

Abstract A survey of 96 families in a rural region of Honduras, conducted in 1998, showed that 80 of these predominantly (95 or 96) farming families used pesticides in their work or at home. Paraquat was used most often, and safety measures were very rarely taken in its use. Seventy-seven families stored pesticide containers in their homes, often within the reach of children. Every worker who used paraquat had at least one symptom potentially related to its use, and the prevalences of childhood disorders in the region are abnormally high compared with national averages.