Marian McDonagh

Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Spine Fusion: A Systematic Review and Meta-analysis

BACKGROUND Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used as a bone graft substitute in spinal fusion, which unites (fuses) bones in the spine. The accuracy and completeness of journal publications of industry-sponsored trials on the effectiveness and harms of rhBMP-2 has been called into question. PURPOSE To independently assess the effectiveness and harms of rhBMP-2 in spinal fusion and reporting bias in industry-sponsored journal publications. DATA SOURCES Individual-patient data (IPD) from 17 industry-sponsored studies; related internal documents; and searches of MEDLINE (1996 to August 2012), other databases, and reference lists. STUDY SELECTION Randomized, controlled trials (RCTs) and cohort studies of rhBMP-2 versus any control and uncontrolled studies of harms. DATA EXTRACTION Effectiveness outcomes in IPD were recalculated using consistent definitions. Study characteristics and results were abstracted by 1 investigator and confirmed by another. Two investigators independently assessed quality using predefined criteria. DATA SYNTHESIS Thirteen RCTs and 31 cohort studies were included. For lumbar spine fusion, rhBMP-2 and iliac crest bone graft were similar in overall success, fusion, and other effectiveness measures and in risk for any adverse event, although rates were high across interventions (77% to 93% at 24 months from surgery). For anterior lumbar interbody fusion, rhBMP-2 was associated with nonsignificantly increased risk for retrograde ejaculation and urogenital problems. For anterior cervical spine fusion, rhBMP-2 was associated with increased risk for wound complications and dysphagia. At 24 months, the cancer risk was increased with rhBMP-2 (risk ratio, 3.45 [95% CI, 1.98 to 6.00]), but event rates were low and cancer was heterogeneous. Early journal publications misrepresented the effectiveness and harms through selective reporting, duplicate publication, and underreporting. LIMITATIONS Outcome assessment was not blinded, and ascertainment of harms in trials was poor. No trials were truly independent of industry sponsorship. CONCLUSION In spinal fusion, rhBMP-2 has no proven clinical advantage over bone graft and may be associated with important harms, making it difficult to identify clear indications for rhBMP-2. Earlier disclosure of all relevant data would have better informed clinicians and the public than the initial published trial reports did. PRIMARY FUNDING SOURCE Yale University and Medtronic.

Systematic review of the incidence and consequences of uterine rupture in women with previous caesarean section.

Abstract Objective To evaluate the incidence and consequences of uterine rupture in women who have had a delivery by caesarean section. Design Systematic review. Data sources Medline, HealthSTAR, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Centre for Reviews and Dissemination, reference lists, and national experts. Studies in all languages were eligible if published in full. Review methods Methodological quality was evaluated for each study by using criteria from the United States Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination. Uterine rupture was categorised as asymptomatic or symptomatic. Results We reviewed 568 full text articles to identify 71 potentially eligible studies, 21 of which were rated at least fair in quality. Compared with elective repeat caesarean delivery, trial of labour increased the risk of uterine rupture by 2.7 (95% confidence interval 0.73 to 4.73) per 1000 cases. No maternal deaths were related to rupture. For women attempting vaginal delivery, the additional risk of perinatal death from rupture of a uterine scar was 1.4 (0 to 9.8) per 10 000 and the additional risk of hysterectomy was 3.4 (0 to 12.6) per 10 000. The rates of asymptomatic uterine rupture in trial of labour and elective repeat caesarean did not differ significantly. Conclusions Although the literature on uterine rupture is imprecise and inconsistent, existing studies indicate that 370 (213 to 1370) elective caesarean deliveries would need to be performed to prevent one symptomatic uterine rupture.

Vaginal birth after cesarean: New insights on maternal and neonatal outcomes

OBJECTIVE: To systematically review the evidence about maternal and neonatal outcomes relating to vaginal birth after cesarean (VBAC). DATA SOURCES: Relevant studies were identified from multiple searches of MEDLINE, DARE, and the Cochrane databases (1980 to September 2009) and from recent systematic reviews, reference lists, reviews, editorials, Web sites, and experts. METHODS OF STUDY SELECTION: Inclusion criteria limited studies to the English-language and human studies conducted in the United States and developed countries specifically evaluating birth after previous cesarean delivery. Studies focusing on high-risk maternal or neonatal conditions, including breech vaginal delivery, or fewer than 10 patients were excluded. Poor-quality studies were not included in analyses. TABULATION, INTEGRATION, AND RESULTS: We identified 3,134 citations and reviewed 963 articles for inclusion; 203 articles met the inclusion criteria and were quality rated. Overall rates of maternal harms were low for both trial of labor and elective repeat cesarean delivery. Although rare in both elective repeat cesarean delivery and trial of labor, maternal mortality was significantly increased for elective repeat cesarean delivery at 0.013% compared with 0.004% for trial of labor. The rates of maternal hysterectomy, hemorrhage, and transfusions did not differ significantly between trial of labor and elective repeat cesarean delivery. The rate of uterine rupture for all women with prior cesarean was 0.30%, and the risk was significantly increased for trial of labor (0.47% compared with 0.03% for elective repeat cesarean delivery). Perinatal mortality was also significantly increased for trial of labor (0.13% compared with 0.05% for elective repeat cesarean delivery). CONCLUSION: Overall the best evidence suggests that VBAC is a reasonable choice for the majority of women. Adverse outcomes were rare for both elective repeat cesarean delivery and trial of labor. Definitive studies are lacking to identify patients who are at greatest risk for adverse outcomes.

Comparative benefits and harms of competing medications for adults with attention-deficit hyperactivity disorder: a systematic review and indirect comparison meta-analysis

RationaleRecommended medication prescribing hierarchies for adult attention-deficit hyperactivity disorder (ADHD) vary between different guideline committees. Few trials directly compare competing ADHD medications in adults and provide little insight for clinicians making treatment choices.ObjectiveThe objective of this study was to assess comparative benefits and harms of competing medications for adult ADHD using indirect comparison meta-analysis.Materials and methodsEligible studies were English-language publications of randomized controlled trials comparing ADHD drugs to placebo. Data sources were electronic bibliographic databases, Drugs@FDA, manufacturer data, and reference lists. Two reviewers independently abstracted data on design, internal validity, population, and results. Benefits and harms were compared between drug types using indirect comparison meta-regression (ratio of relative risks).ResultsTwenty-two placebo-controlled trials were included (n = 2,203). Relative benefit of clinical response for shorter-acting stimulants, primarily immediate release methylphenidate, was 3.26 times greater than for patients taking longer-acting stimulants (95% CI 2.03, 5.22) and 2.24 times greater than for patients taking longer-acting forms of bupropion (95% CI 1.23, 4.08). Immediate release methylphenidate is also the only drug shown to reduce ADHD symptoms in adults with substance abuse disorders. Neither non-stimulants nor longer-acting stimulants reduced adverse effects compared to shorter-acting stimulants. Key gaps in evidence were academic, occupational, social functioning, cardiovascular toxicity, and longer-term outcomes, influences of ADHD subtype and/or comorbidities, and misuse/diversion of the drugs.ConclusionsCurrent best evidence supports using immediate release methylphenidate as first-line treatment for most adults with ADHD.

Reporting Discrepancies between the ClinicalTrials.gov Results Database and Peer Reviewed Publications

Medical decision makers who use clinical trial evidence most often rely on findings that are published in peer-reviewed journals. Selective reporting of clinical trial results is a well-documented problem that raises concerns about using journal publications (1). Clinical trial registration is one mechanism aimed at reducing the effect of dissemination biases. Although many clinical trial registries exist, the single largest publicly accessible trial registry, and the only one with a results database, is ClinicalTrials.gov (2). Administered through the National Library of Medicine, ClinicalTrials.gov was developed to provide the public with a Web-based, searchable source of information about trials conducted within the United States. In September 2007, the Food and Drug Administration Amendments Act (FDAAA) was passed, greatly expanding the legal requirements for trial registration and mandating the creation of a publicly accessible clinical trial results database (3). According to FDAAA section 801, as of September 2008, basic summary results must be submitted for certain trials (called applicable clinical trials in the statute). Applicable clinical trials include most phase 2 through 4 trials of drugs, devices, or biologics regulated by the FDA having at least 1 site in the United States or conducted under an investigational new drug application or investigational device exemption (4). Several elements are required to be reported, including number of participants entering and completing the study; number of participants analyzed; demographic data, such as age and sex; summary results for all prespecified primary and secondary outcome measures; and anticipated and unanticipated adverse events by organ system. Results are generally required to be reported within 1 year of study completion, although submission may be delayed if the drug or device is not yet approved or if an application for a new use is to be submitted. The ClinicalTrials.gov results database has the potential to be a great asset for clinicians, patients, and researchers, but the ultimate validity of posted results is unclear. In contrast to the scientific scrutiny trials undergo during peer review for journals, results posted to ClinicalTrials.gov go through a quality assurance process focusing on internal consistency and logic. Although a gold standard repository of clinical trial results does not exist, inconsistencies between the ClinicalTrials.gov results database and other sources of clinical trial data suggest validity problems in 1 or both sources. The goal of this study was to assess the consistency of results reported in the ClinicalTrials.gov results database compared with those summarized in peer-reviewed journal publications. Methods Trial Selection Studies were eligible for inclusion if they posted results to ClinicalTrials.gov, were interventional, and were phase 3 or 4. To allow sufficient time for publication, we limited our search to trials with a primary completion date before 1 January 2009 or a start date before 1 July 2008 if the primary completion date field was not populated. Completed trials with results were sequenced in random order using Excel 2010 (Microsoft, Redmond, Washington) and were screened for the presence of a matching publication until a 10% random sample of trials with results was obtained. Trials were excluded if they did not assign participants to 2 or more interventional groups. We identified matching publications in a sequential process, first examining citations provided within ClinicalTrials.gov and then using a manual search of 2 electronic bibliographic databases. PubMed citations embedded within ClinicalTrials.gov can be provided by the investigator or the National Library of Medicine on the basis of matching National Clinical Trial (NCT) identifiers (5). We considered a publication to be a match if the intervention was the same and 1 or more groups in the trial had an identical number of participants. If relevant studies were not identified using citations provided within ClinicalTrials.gov, an electronic search of MEDLINE and the Cochrane Central Register of Controlled Trials was conducted using the study interventions, condition, principal investigator (if supplied), and date of trial completion as search criteria. Data Abstraction and Comparisons The following elements were abstracted and compared between the ClinicalTrials.gov results record and its corresponding publications: trial design, number of groups, primary outcome measure (POM) descriptions, secondary outcome measure (SOM) descriptions, total enrollment, and primary outcome results. We also abstracted the number of individuals affected by at least 1 adverse event (AE) and the number of individuals at risk, as reported to ClinicalTrials.gov. Comparisons of counts (such as enrollment, participants analyzed for the primary outcome, and number with an AE) were considered discrepant if they were not an exact match. The primary outcome result was required to be consistent to 1 decimal place. In cases of multiple publications, inconsistencies between the ClinicalTrials.gov results record and descriptions in any of the associated publications were considered a discrepancy. We classified POM description inconsistencies by using an existing framework describing the specificity of outcome reporting in ClinicalTrials.gov (6). The POM could deviate entirely in the domain measured or the number reported, the measurement tool used (for example, change in low-density lipoprotein cholesterol level vs. change in total cholesterol level), how the measure was used (for example, percentage change from baseline vs. absolute value), or the method of aggregation (for example, hemoglobin A1c level <7% vs. <8%). We considered SOMs to be consistent if they were mentioned in the results or methods section of the publication and were listed in the ClinicalTrials.gov results record. For trials with multiple publications, we considered the aggregate number of SOMs across all associated publications. When evaluating POM reporting consistency, we first determined whether the descriptions were consistent in both sources. When they were, we looked for discrepancies in the reported value (for example, mean response or count with outcome) or the number of individuals analyzed for the outcome (for example, denominator or number analyzed). For trials with more than 1 POM specified in both sources, any inconsistency in the result numerator or denominator was considered a discrepancy. If discrepancies in trial features resulted in downstream inconsistencies, we compared only the highest-order feature to avoid double counting. Adverse events did not become a mandatory reporting element until September 2009 and are summarized in the ClinicalTrials.gov results record in 2 tables: serious AEs (SAEs) and other (nonserious) AEs (OAEs). The FDA defines an SAE as any event that results in death, is life-threatening, requires or extends hospitalization, results in significant incapacity or interferes with normal life functions, or causes a congenital anomaly or birth defect (7). We compared the total number of SAEs reported in ClinicalTrials.gov with the total reported in the corresponding publications. In cases where the SAE counts differed, we compared the risk difference (experimental group risk minus control group risk) reported in ClinicalTrials.gov with the published estimate. For trials with multiple experimental groups, we selected the group of primary interest stated in the paper; if multiple FDA-approved dosing groups were assessed, we combined these for comparison with the control group. For OAEs, we restricted our comparison to specific AEs that could be matched to the publication without ambiguity and that were not also reported as an SAE in order to eliminate the possibility of double counting participants who may have had both a serious and nonserious AE. We distinguished publications reporting only treatment-related (attributable) AEs because ClinicalTrials.gov requires reporting of AEs regardless of attribution. Finally, we compared the number of deaths reported in each source. In ClinicalTrials.gov, deaths can be reported as an outcome, in the participant flow section, or as an SAE. If death was not a primary or secondary outcome, we compared the number of deaths reported in the participant flow or SAE section of ClinicalTrials.gov with the number reported in the publication. We classified the sources as discrepant only if counts of death differed between them. A second reviewer independently assessed reporting discrepancies between the ClinicalTrials.gov results record and the matched publication in a 20% random sample (22 trials) for all comparisons. Agreement between the primary and secondary abstractors was high, with an average of 0.98 across categories and no single category with a less than 0.91. Role of the Funding Source This work was supported by the National Library of Medicine and the Agency for Healthcare Research and Quality. The funding sources had no role in the design or execution of the study. Results The Figure describes the flow of trials from the initial ClinicalTrials.gov candidate pool to the final study sample. A total of 1669 phase 3 and 4 trials with posted results were initially identified through a query of ClinicalTrials.gov on 15 February 2011. After exclusion of trials with a primary completion date after 1 January 2009 and those not completed or terminated, 1120 trials remained. We randomly screened 357 potentially includable trials until a 10% sample (n= 110) was achieved. Three trials reported results in multiple publications. Table 1 describes the characteristics of the 110 matched trials and the 195 unmatched trials. Most studies were industry-funded, parallel-design trials of drugs. Unmatched trials were more likely to investigate something other than a drug or device and less likely to be cardiovascular trials. Twenty-nine t

Safety of vaginal birth after cesarean: A systematic review

OBJECTIVE: To evaluate the benefits and harms of vaginal birth after cesarean compared with repeat cesarean delivery. DATA SOURCES: The computerized databases MEDLINE, EMBASE, HealthSTAR, Cochrane CENTRAL, and National Centre for Reviews and Dissemination Database of Abstracts of Reviews of Effectiveness, along with reference lists and national experts, were used to conduct this review. METHODS OF STUDY SELECTION: All studies that reported data for maternal or infant outcomes in women with prior cesarean delivery were eligible. Methodological quality was evaluated for each study with the criteria of the United States Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination. Twenty of 6,828 potentially relevant articles (55,506 patients) were included in the analysis. TABULATION, INTEGRATION, AND RESULTS: Two authors independently abstracted information on study design, sample size, participant characteristics, and maternal and fetal health outcomes by using a standardized protocol. Rates of vaginal delivery in women undergoing a trial of labor ranged from 60% to 82%. There was no significant difference in maternal deaths or hysterectomy between trial of labor and repeat cesarean. Uterine rupture was more common in the trial-of-labor group, but rates of asymptomatic uterine dehiscence did not differ. Studies conflicted on the effect of induction of labor on these outcomes. Data regarding infant outcomes were poor. CONCLUSION: Safety in childbirth for women with prior cesarean is a major public health concern. Methodological deficiencies in the literature evaluating the relative safety of vaginal birth after cesarean compared with repeat cesarean delivery are striking. The identification of high-risk and low-risk groups of women and settings for morbidity remains a key research priority.

Systematic Review of the Benefits and Risks of Metformin in Treating Obesity in Children Aged 18 Years and Younger

IMPORTANCE Childhood obesity is an important public health problem with increasing prevalence. Because treatment often has limited success, new approaches must be identified. OBJECTIVE To evaluate the effectiveness and safety of metformin for treating obesity in children aged 18 years and younger without a diagnosis of diabetes mellitus. EVIDENCE REVIEW We included randomized clinical trials identified through searches of MEDLINE, the Cochrane Library, and ClinicalTrials.gov. Our primary outcome measure was change in body mass index (BMI, calculated as weight in kilograms divided by height in meters squared). We assessed study quality, pooled data using a random-effects model, and performed subgroup and sensitivity analyses. FINDINGS Fourteen randomized clinical trials were eligible. For BMI, moderate-strength evidence indicated a reduction of -1.38 (95% CI, -1.93 to -0.82) from baseline compared with control at 6 months. A similar, if less dramatic, effect was observed in studies less than 6 months, but the pooled estimate from studies of 1 year of treatment was not statistically significant. Subgroup analyses indicated smaller, but significant, effects for those with baseline BMI below 35, those of Hispanic ethnicity, those with acanthosis nigricans, those who had tried and failed diet and exercise programs, and in studies with more girls or higher mean age (adolescents). Moderate-strength evidence indicated that with metformin, 26% reported a gastrointestinal event compared with 13% in control groups (relative risk, 2.05; 95% CI, 1.19-3.54), although there was no difference in discontinuations due to adverse events. No serious adverse events were reported. CONCLUSIONS AND RELEVANCE Metformin provides a statistically significant, but very modest reduction in BMI when combined with lifestyle interventions over the short term. A large trial is needed to determine the benefits to subgroups or impacts of confounders. In the context of other options for treating childhood obesity, metformin has not been shown to be clinically superior.

A systematic review of the efficacy and safety of atypical antipsychotics in patients with psychological and behavioral symptoms of dementia

Although the Food and Drug Administration (FDA) has not approved atypical antipsychotics for use in patients with dementia, they are commonly prescribed in this population. Recent concerns about increased risk of cerebrovascular events and mortality have led to warnings. A systematic review was conducted to assess the benefits and harms of atypical antipsychotics when used in patients with behavioral and psychological symptoms of dementia. Electronic searches (through March 2005) of the Cochrane Library, Medline, Embase, and PsycINFO were supplemented with hand searches of reference lists, dossiers submitted by pharmaceutical companies, and a review of the FDA Website and industry‐sponsored results database. Using predetermined criteria, each study was assessed for inclusion, and data about study design, population, interventions, and outcomes were abstracted. An overall quality rating (good, fair, or poor) was assigned based on internal validity.

New Insights on Vaginal Birth After Cesarean: Can It Be Predicted?

OBJECTIVE: To evaluate existing vaginal birth after cesarean (VBAC) screening tools and to identify additional factors that may predict VBAC or failed trial of labor. DATA SOURCES: Relevant studies were identified through MEDLINE, Database of Abstracts of Reviews of Effectiveness, and the Cochrane databases (1980-September 2009), and from recent systematic reviews, reference lists, reviews, editorials, web sites, and experts. METHODS OF STUDY SELECTION: Inclusion criteria limited studies to those of humans, written in English, studies conducted in the United States and developed countries, and those rated good or fair quality by the U.S. Preventive Services Task Force criteria. Studies of individual predictors were combined using a random effects model when the estimated odds ratios were comparable across included studies. TABULATION, INTEGRATION, AND RESULTS: We identified 3,134 citations and reviewed 963 papers, of which 203 met inclusion criteria and were quality-rated. Twenty-eight provided evidence on predictors of VBAC and 16 presented information on scored models for predicting VBAC (or failed trial of labor). Six of the 11 scored models for predicting VBAC (or failed trial of labor) were validated by separated dataset, cross-validation, or both. Whereas accuracy remained high across all models for predicting VBAC, with predictive values ranging from 88% to 95%, accuracy for predicting failed trial of labor was low, ranging from 33% to 58%. Individual predictors including Hispanic ethnicity, African-American race, advanced maternal age, no previous vaginal birth history, birth weight heavier than 4 kg, and use of either augmentation or induction were all associated with reduced likelihood of VBAC. CONCLUSION: Current scored models provide reasonable predictability for VBAC, but none provides consistent ability to identify women at risk for failed trial of labor. A scoring model is needed that incorporates known antepartum factors and can be adjusted for current obstetric factors and labor patterns if induction or augmentation is needed. This would allow women and clinicians to better determine individuals most likely to require repeat cesarean delivery.

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