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Figure 1.
Analytic Framework: Screening and Treatment of Blood Lead Levels in Children
Analytic Framework: Screening and Treatment of Blood Lead Levels in Children

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions (KQs) that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes. A dashed line depicts a health outcome that follows an intermediate outcome. Refer to the USPSTF Procedure Manual for further details.8

aInterventions include counseling families to reduce lead exposure, nutritional interventions, residential hazard control techniques, and chelation therapy.

bIncluded outcomes measured in family members (eg, siblings, pregnant women in the same household) subsequently identified as having elevated blood lead levels after the index family member was found to have an elevated blood lead level during screening.

Figure 2.
Analytic Framework: Screening and Treatment of Blood Lead Levels in Pregnant Women
Analytic Framework: Screening and Treatment of Blood Lead Levels in Pregnant Women

Evidence reviews for the US Preventive Services Task Force (USPSTF) use an analytic framework to visually display the key questions (KQs) that the review will address to allow the USPSTF to evaluate the effectiveness and safety of a preventive service. The questions are depicted by linkages that relate interventions and outcomes.

aInterventions include counseling families to reduce lead exposure, nutritional interventions, residential hazard control techniques, and chelation therapy.

bIncluded outcomes measured in family members (eg, siblings, pregnant women in the same household) subsequently identified as having elevated blood lead levels after the index family member was found to have an elevated blood lead level during screening.

Figure 3.
Literature Search Flow Diagram: Childhood Key Questions
Literature Search Flow Diagram: Childhood Key Questions

KQ indicates key question; USPSTF, US Preventive Services Task Force.

aReasons for exclusion: Relevance: Study aim not relevant to key question. Setting: Study not conducted in a country relevant to US practice. Intervention: Study of an excluded intervention or screening approach. Comparator: Study lacked appropriate comparator group. Population: Study not conducted in an average-risk population. Outcomes: Study did not have relevant outcomes or had incomplete outcomes. Design: Study did not use an included design. Language: Study published in non-English language. Quality: Study did not meet criteria for fair or good quality. Unable to locate: Full-text article could not be located.

bArticles could appear in more than 1 KQ.

Figure 4.
Literature Search Flow Diagram: Pregnancy Key Questions
Literature Search Flow Diagram: Pregnancy Key Questions

aReasons for exclusion: Relevance: Study aim not relevant to key question. Setting: Study not conducted in a country relevant to US practice. Intervention: Study of an excluded intervention or screening approach. Comparator: Study lacked appropriate comparator group. Population: Study not conducted in an average-risk population. Outcomes: Study did not have relevant outcomes or had incomplete outcomes. Design: Study did not use an included design. Language: Study published in non-English language. Quality: Study did not meet criteria for fair or good quality. Unable to locate: Full-text article could not be located.

bArticles could appear in more than 1 KQ.

Figure 5.
Meta-analysis of Sensitivity and Specificity for the Centers for Disease Control and Prevention Questionnaire
Meta-analysis of Sensitivity and Specificity for the Centers for Disease Control and Prevention Questionnaire

The metandi command in Stata version 14.2 cannot be used to formally investigate heterogeneity or to compare the accuracy of 2 or more tests because it does not have an option for including a covariate in the bivariate model.

Table 1.  
Characteristics and Results of Questionnaire Screening Studiesa
Characteristics and Results of Questionnaire Screening Studiesa
Table 2.  
Characteristics and Results of Capillary Screening Studies
Characteristics and Results of Capillary Screening Studies
Table 3.  
Characteristics and Results of Randomized Clinical Trials of Treatmenta
Characteristics and Results of Randomized Clinical Trials of Treatmenta
Table 4.  
Summary of Evidence: Childhood Key Questions
Summary of Evidence: Childhood Key Questions
Table 5.  
Summary of Evidence: Pregnancy Key Questions
Summary of Evidence: Pregnancy Key Questions
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Dalton  MA, Sargent  JD, Stukel  TA.  Utility of a risk assessment questionnaire in identifying children with lead exposure.  Arch Pediatr Adolesc Med. 1996;150(2):197-202. doi:10.1001/archpedi.1996.02170270079012PubMedGoogle ScholarCrossref
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France  EK, Gitterman  BA, Melinkovich  P, Wright  RA.  The accuracy of a lead questionnaire in predicting elevated pediatric blood lead levels.  Arch Pediatr Adolesc Med. 1996;150(9):958-963. doi:10.1001/archpedi.1996.02170340072014PubMedGoogle ScholarCrossref
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Holmes  SE, Drutz  JE, Buffone  GJ, Rice  TD.  Blood lead levels in a continuity clinic population.  J Toxicol Clin Toxicol. 1997;35(2):181-186. doi:10.3109/15563659709001190PubMedGoogle ScholarCrossref
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Kazal  LA  Jr.  The failure of CDC screening questionnaire to efficiently detect elevated lead levels in a rural population of children.  J Fam Pract. 1997;45(6):515-518.PubMedGoogle Scholar
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Muñiz  MA, Dundas  R, Mahoney  MC.  Evaluation of a childhood lead questionnaire in predicting elevated blood lead levels in a rural community.  J Rural Health. 2003;19(1):15-19. doi:10.1111/j.1748-0361.2003.tb00536.xPubMedGoogle ScholarCrossref
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Robin  LF, Beller  M, Middaugh  JP.  Statewide assessment of lead poisoning and exposure risk among children receiving Medicaid services in Alaska.  Pediatrics. 1997;99(4):E9. doi:10.1542/peds.99.4.e9PubMedGoogle ScholarCrossref
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Snyder  DC, Mohle-Boetani  JC, Palla  B, Fenstersheib  M.  Development of a population-specific risk assessment to predict elevated blood lead levels in Santa Clara County, California.  Pediatrics. 1995;96(4, pt 1):643-648.PubMedGoogle Scholar
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Stefanak  MA, Bourguet  CC, Benzies-Styka  T.  Use of the Centers for Disease Control and Prevention childhood lead poisoning risk questionnaire to predict blood lead elevations in pregnant women.  Obstet Gynecol. 1996;87(2):209-212. doi:10.1016/0029-7844(95)00397-5PubMedGoogle ScholarCrossref
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Tejeda  DM, Wyatt  DD, Rostek  BR, Solomon  WB.  Do questions about lead exposure predict elevated lead levels?  Pediatrics. 1994;93(2):192-194.PubMedGoogle Scholar
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Holtrop  TG, Yee  HY, Simpson  PM, Kauffman  RE.  A community outreach lead screening program using capillary blood collected on filter paper.  Arch Pediatr Adolesc Med. 1998;152(5):455-458. doi:10.1001/archpedi.152.5.455PubMedGoogle ScholarCrossref
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Parsons  PJ, Raciti  K, Esernio-Jenssen  D.  Evaluation and Improvement of Sample Collection Procedures for the Determination of Blood Lead. Atlanta, GA: Centers for Disease Control and Prevention; 1993.
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Sargent  JD, Dalton  MA.  Rethinking the threshold for an abnormal capillary blood lead screening test.  Arch Pediatr Adolesc Med. 1996;150(10):1084-1088. doi:10.1001/archpedi.1996.02170350086015PubMedGoogle ScholarCrossref
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Sargent  JD, Brown  MJ, Freeman  JL, Bailey  A, Goodman  D, Freeman  DH  Jr.  Childhood lead poisoning in Massachusetts communities: its association with sociodemographic and housing characteristics.  Am J Public Health. 1995;85(4):528-534. doi:10.2105/AJPH.85.4.528PubMedGoogle ScholarCrossref
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Schlenker  TL, Fritz  CJ, Mark  D,  et al.  Screening for pediatric lead poisoning: comparability of simultaneously drawn capillary and venous blood samples.  JAMA. 1994;271(17):1346-1348. doi:10.1001/jama.1994.03510410058033PubMedGoogle ScholarCrossref
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Treatment of Lead-Exposed Children (TLC) Trial Group.  Safety and efficacy of succimer in toddlers with blood lead levels of 20-44 microg/dL.  Pediatr Res. 2000;48(5):593-599. doi:10.1203/00006450-200011000-00007PubMedGoogle ScholarCrossref
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Boreland  F, Lesjak  M, Lyle  D.  Evaluation of home lead remediation in an Australian mining community.  Sci Total Environ. 2009;408(2):202-208. doi:10.1016/j.scitotenv.2009.10.013PubMedGoogle ScholarCrossref
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Brown  MJ, McLaine  P, Dixon  S, Simon  P.  A randomized, community-based trial of home visiting to reduce blood lead levels in children.  Pediatrics. 2006;117(1):147-153. doi:10.1542/peds.2004-2880PubMedGoogle ScholarCrossref
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Dietrich  KN, Ware  JH, Salganik  M,  et al; Treatment of Lead-Exposed Children Clinical Trial Group.  Effect of chelation therapy on the neuropsychological and behavioral development of lead-exposed children after school entry.  Pediatrics. 2004;114(1):19-26. doi:10.1542/peds.114.1.19PubMedGoogle ScholarCrossref
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Liu  X, Dietrich  KN, Radcliffe  J, Ragan  NB, Rhoads  GG, Rogan  WJ.  Do children with falling blood lead levels have improved cognition?  Pediatrics. 2002;110(4):787-791. doi:10.1542/peds.110.4.787PubMedGoogle ScholarCrossref
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Markowitz  ME, Sinnett  M, Rosen  JF.  A randomized trial of calcium supplementation for childhood lead poisoning.  Pediatrics. 2004;113(1, pt 1):e34-e39. doi:10.1542/peds.113.1.e34PubMedGoogle ScholarCrossref
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O’Connor  ME, Rich  D.  Children with moderately elevated lead levels: is chelation with DMSA helpful?  Clin Pediatr (Phila). 1999;38(6):325-331. doi:10.1177/000992289903800602PubMedGoogle ScholarCrossref
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Rogan  WJ, Dietrich  KN, Ware  JH,  et al; Treatment of Lead-Exposed Children Trial Group.  The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead.  N Engl J Med. 2001;344(19):1421-1426. doi:10.1056/NEJM200105103441902PubMedGoogle ScholarCrossref
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Wolf  AW, Jimenez  E, Lozoff  B.  Effects of iron therapy on infant blood lead levels.  J Pediatr. 2003;143(6):789-795. doi:10.1067/S0022-3476(03)00540-7PubMedGoogle ScholarCrossref
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Nicholson  JS.  A community-based intervention for low-income families to reduce children’s blood lead levels between 3–9.9 μg/Dl.  Child Health Care. 2017:1-18. doi:10.1080/02739615.2017.1370673Google Scholar
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US Preventive Services Task Force
Evidence Report
April 16, 2019

Screening for Elevated Blood Lead Levels in Childhood and Pregnancy: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Author Affiliations
  • 1Pacific Northwest Evidence-based Practice Center, Departments of Medical Informatics and Clinical Epidemiology, Family Medicine, and Obstetrics and Gynecology, Oregon Health & Science University, Portland
  • 2Department of Emergency Medicine, Oregon Health & Science University, Portland
  • 3Pacific Northwest Evidence-based Practice Center, Portland, Oregon
JAMA. 2019;321(15):1510-1526. doi:10.1001/jama.2019.1004
Abstract

Importance  Elevated blood lead level is associated with serious, often irreversible, health consequences.

Objective  To synthesize evidence on the effects of screening, testing, and treatment for elevated blood lead level in pregnant women and children aged 5 years and younger in the primary care setting to inform the US Preventive Services Task Force.

Data Sources  Cochrane CENTRAL and Cochrane Database of Systematic Reviews (through June 2018) and Ovid MEDLINE (1946 to June 2018); surveillance through December 5, 2018.

Study Selection  English-language trials and observational studies of screening for and treating elevated lead levels in asymptomatic children and pregnant women.

Data Extraction and Synthesis  Independent critical appraisal and data abstraction by 2 reviewers using predefined criteria.

Main Outcomes and Measures  Elevated blood lead level, morbidity, mortality, clinical prediction tools, test accuracy, adverse events.

Results  A total of 24 studies (N = 11 433) were included in this review. No studies evaluated the benefits or harms of screening vs no screening in children. More than 1 positive answer on the 5-item 1991 Centers for Disease Control and Prevention (CDC) screening questionnaire was associated with a pooled sensitivity of 48% (95% CI, 31.4% to 65.6%) and specificity of 58% (95% CI, 39.9% to 74.0%) for identifying children with a venous blood lead level greater than 10 μg/dL (5 studies [n = 2265]). Adapted versions of the CDC questionnaire did not demonstrate improved accuracy. Capillary blood lead testing demonstrated sensitivity of 87% to 91% and specificity greater than 90%, compared with venous measurement (4 studies [n = 1431]). Counseling and nutritional interventions or residential lead hazard control techniques did not reduce blood lead concentrations in asymptomatic children, but studies were few and had methodological limitations (7 studies [n = 1419]). One trial (n = 780) of dimercaptosuccinic acid (DMSA) chelation therapy found reduced blood lead levels in children at 1 week to 1 year but not at 4.5 to 6 years, while another trial (n = 39) found no effect at 1 and 6 months. Seven-year follow-up assessments showed no effect on neuropsychological development, a small deficit in linear growth (height difference, 1.17 cm [95% CI, 0.41 to 1.93]), and poorer cognitive outcomes reported as the Attention and Executive Functions subscore of the Developmental Neuropsychological Assessment (unadjusted difference, −1.8 [95% CI, −4.5 to 1.0]; adjusted P = .045) in children treated with DMSA chelation. Evidence was too limited to determine the accuracy of screening questionnaires or benefits and harms of treatment in pregnant women.

Conclusions and Relevance  Screening questionnaires were not accurate for identifying children with elevated blood lead levels. Chelating agents in children were not significantly associated with sustained effects on blood level levels but were associated with harms.

Introduction

Lead causes a number of adverse health effects primarily affecting the central nervous, hematopoietic, hepatic, and renal systems.1 Many health effects associated with chronic exposure to elevated blood lead levels are irreversible, with the nervous system being the most important.1 The severity of lead toxicity is correlated with higher blood lead levels, but manifestations may vary. Elevated blood lead levels in children are associated with IQ deficits, attention-related behaviors, and poor academic achievement.2,3 Lead exposure during pregnancy is associated with spontaneous abortion,4 reduced fetal growth, premature birth, blood pressure elevation,5 and cognitive deficiencies in the child.4

Elevated blood lead level is defined as greater than 5 µg/dL, according to the Centers for Disease Control and Prevention (CDC).3 Reference ranges are based on population levels from the National Health and Nutrition Examination Survey blood lead distribution; these do not define safe lead levels but are the level at which further clinical monitoring and treatment is recommended. The reference range may change with population prevalence.

In 2006, the US Preventive Services Task Force (USPSTF) found insufficient evidence for screening asymptomatic children at increased risk for elevated blood lead levels (I statement) and recommended against routine screening in asymptomatic pregnant women and children aged 1 to 5 years at average risk (D recommendations).6 Recommendations of other organizations are summarized in eTables 1 and 2 in the Supplement. This systematic review was commissioned by the USPSTF to update the prior review7 by synthesizing evidence on the benefits and harms of screening for elevated blood lead levels in asymptomatic pregnant women and children 5 years and younger.

Methods
Scope of the Review

Using established methods,8 this review addressed key questions (KQs) as shown in the analytic framework in Figure 1 and Figure 2. Methodological details, including study selection, search strategies, excluded studies, data analysis methods, and detailed results are available in the full evidence report at http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/elevated-blood-lead-levels-in-childhood-and-pregnancy-screening.9,10

Data Sources and Searches

Cochrane CENTRAL, the Cochrane Database of Systematic Reviews (through June 2018), and Ovid MEDLINE (1946 to June 2018) were searched, including all studies from prior reviews and reference lists of included studies.7 Since June 2018, we continued to conduct ongoing surveillance through article alerts and targeted searches of high-impact journals to identify major studies published in the interim that may affect the conclusions or understanding of the evidence and therefore the related USPSTF recommendation. The last surveillance was conducted on December 5, 2018, and identified no relevant new studies. Search strategies are listed in eAppendix 1 in the Supplement.

Study Selection

Populations of asymptomatic children 5 years and younger and asymptomatic pregnant women were included, regardless of risk for elevated blood lead levels. Testing approaches included studies of screening questionnaires and venous or capillary blood lead testing. Comparisons for KQ1 were screening vs no screening; for KQ2a, a questionnaire against a reference standard (ie, venous lead level); for KQ2b, capillary vs venous blood lead level testing; and for treatment questions, treatment vs no treatment, placebo, or inactive control. Intermediate outcomes (eg, blood lead levels) were included, as well as clinical outcomes using validated measures of cognitive or neurobehavioral outcomes in children. Other outcomes were measures of diagnostic accuracy (KQ2) and harms of testing (eg, anxiety, distress, pain, or discomfort related to testing) and treatment. English-language articles were eligible for inclusion. Included studies were randomized clinical trials (RCTs), nonrandomized controlled intervention studies, and observational studies (for questions on screening and treatment); studies on the diagnostic accuracy of screening questionnaires or capillary sampling; and trials and observational studies of harms. Studies conducted in countries with a “very high” Human Development Index11 that evaluated interventions that focused on the individual or family (ie, counseling, nutritional interventions, residential hazard control techniques, and chelation therapy) were included. Studies of policies, laws, or community-based interventions focused on primary prevention of lead exposure were excluded.

Data Abstraction and Quality Rating

Data about study design, patient population, setting, screening method, interventions, analysis, and results were abstracted. Predefined criteria were used to assess the quality of individual controlled trials and observational studies using criteria developed by the USPSTF8; studies were rated as “good,” “fair,” or “poor.” For harms, results of poor-quality studies were included when no higher-quality studies were available (quality-rating methods are reported in eAppendix 2 in the Supplement). For each study, data abstraction and quality assessment were subject to dual review by study investigators. Disagreements were resolved by consensus.

Data Synthesis

Studies were qualitatively synthesized based on methods developed by the USPSTF8 and are summarized narratively. For diagnostic accuracy of clinical questionnaires, comparable studies were pooled using a random-effects model using the metandi command in Stata version 14.2 (StataCorp), and hierarchical summary receiver operating characteristic (ROC) plots were created using the metandiplot function.12,13 Forest plots without a summary measure and summary ROC plots were also created using Review Manager 5.3 (Cochrane Community).14 There were too few treatment studies to perform meta-analysis. Studies included in prior 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.

The overall strength of evidence was determined using methods described by the USPSTF.8 Based on the number, quality, and size of studies, consistency of results, and directness of evidence, overall evidence was rated “insufficient,” “low,” “moderate,” or “high.” The applicability of the findings to US primary care populations and settings was also assessed.

Results

Two reviewers evaluated 3147 unique citations and 233 full-text articles based on predefined criteria (eTables 3 and 4 in the Supplement). A total of 24 studies were included in this review (N = 11 433) (Figure 3 and Figure 4).

Screening and Treatment in Children 5 Years and Younger
Effectiveness of Screening

Key Question 1. Is there direct evidence that screening for elevated blood lead levels in asymptomatic children 5 years and younger improves health outcomes (ie, reduced cognitive or behavioral problems or learning disorders)?

No studies directly compared the effectiveness of screening vs no screening for elevated blood lead levels.

Diagnostic Accuracy of Questionnaires or Clinical Prediction Tools

Key Question 2a. What is the accuracy of questionnaires or clinical prediction tools that identify children who have elevated blood lead levels?

Nine fair-quality studies reported the diagnostic accuracy of questionnaires or clinical prediction tools for identifying asymptomatic children with elevated blood lead levels, defined as greater than 10 μg/dL (Table 1; eTable 5 in the Supplement).15-23,25 All studies used a blood lead level of 10 μg/dL or greater as the reference standard. Five studies evaluated the accuracy of the 1991 CDC questionnaire and 4 evaluated modified versions of the CDC questionnaire for specific populations and settings.15-23 The CDC questionnaire is a 5-question survey developed in 1991 that aims to assess residential, household, occupational, and personal risk factors for lead exposure in children. Sample sizes ranged from 167 to 2978 (total n = 6873). Where reported, mean age range was 9 to 31 months.18,19 Seven studies were conducted in urban or suburban communities, and 3 studies were from rural communities. Two studies identified the population as high risk16,23 and others did not specify risk level; however, many of the populations surveyed were from public programs, such as Medicaid or public health clinics. The prevalence of blood lead level 10 μg/dL or greater ranged from 0.6%15 to 29%.15 All studies were rated fair quality. Methodological shortcomings included unclear enrollment methods and exclusion of some patients from analysis. One poor-quality retrospective study was excluded from this analysis and was not included in the total number of studies.25

Five studies (n = 2265) conducted in mostly urban settings reported sensitivity of the CDC questionnaire that ranged from 32% to 83% and specificity that ranged from 32% to 80% (Table 1). The pooled sensitivity was 48% (95% CI, 31%-66%) and the pooled specificity was 58% (95% CI, 39%-74%) (Figure 5),15,16,19,21,23 for a positive likelihood ratio of 1.15 and a negative likelihood ratio of 0.89. Four studies17,18,20,22 (n = 4608) evaluated the 1991 CDC questionnaire modified to address local risk factors or adapted for specific populations. Two studies from urban settings had poor accuracy (sensitivity, 57%-68%; specificity, 51%-58%) for identifying children with elevated blood lead levels (Table 1).17,18 Two studies conducted in rural settings20,22 found that the adapted questionnaires had low accuracy (sensitivity, 25%; specificity, 49%) for detecting children with elevated blood lead levels (Table 1).

Diagnostic Accuracy of Capillary Blood Lead Testing in Children

Key Question 2b. What is the accuracy of capillary blood lead testing in children?

Four fair-quality cohort studies assessed the diagnostic accuracy of capillary testing compared with venous sampling for elevated blood lead levels (Table 2).26-28,30 All 4 studies were conducted in the urban United States and were published between 1994 and 1998. Sample sizes ranged from 124 to 513 (total n = 1431). Female participants comprised 41% to 47% of the sample in 3 studies; the fourth study did not report sex. Two studies predominately enrolled black children,26,30 and 1 study evaluated a more diverse study population (38% white, 28% black, 21% Hispanic, and 6% Asian27); the fourth study did not report race or ethnicity.28 Among the 3 studies reporting baseline lead levels, the proportion of children with blood lead level 10 μg/dL or greater ranged from 21% to 31%.26-28 Methodologic shortcomings included unclear enrollment methods and exclusion of some patients from analysis.

Three of 4 studies reported diagnostic accuracy of capillary sampling at a blood lead level cutoff of 10 μg/dL or greater (n = 1136) (Table 2). Sensitivities ranged from 87% to 91% and specificities ranged from 92% to 99%.26-28 For a blood lead level cutoff of 15 μg/dL or greater, 3 studies (n = 1136) reported sensitivities ranging from 36% to 83% and specificities from 95% to 98%.26-28 For a blood lead level cutoff of 20 μg/dL or greater, 3 studies (n = 918) reported sensitivities ranging from 78% to 96% and specificities from 91% to 100%.26,27,30

One study (n = 295) evaluated different preparation methods for capillary blood sampling.30 Using a capillary sampling threshold of greater than 20 μg/dL, the most commonly used sampling method (ie, soap and water plus alcohol) had the highest specificity (100%) compared with the other methods and similar sensitivity (88%) (Table 2).

Harms of Screening

Key Question 3. What are the harms of screening for elevated blood lead levels (with or without screening questionnaires) in children?

No studies evaluated the harms of screening vs not screening children for elevated blood lead levels.

Effectiveness of Interventions to Reduce Blood Lead Levels

Key Question 4. Do counseling and nutritional interventions, residential lead hazard control techniques, or chelation therapy reduce blood lead levels in asymptomatic children with elevated blood lead levels?

Seven RCTs31-40 (reported in 10 publications) evaluated the effects of interventions to reduce blood lead concentrations in asymptomatic children with elevated blood lead levels (Table 3). Two studies evaluated chelation, 3 studies evaluated home abatement, and 2 evaluated nutritional supplementation. Sample sizes ranged from 39 to 780 (total n = 1419). Mean age of participants was 1.6 to 3.6 years, with balanced sex distributions in the 3 studies that reported sex. One study was rated good quality, 4 fair quality, and 2 poor quality. Methodological limitations in the poor-quality studies included high loss to follow-up or failure to describe randomization, allocation concealment, or masking methods.

Chelation

Two trials (n = 819) found inconsistent effects of dimercaptosuccinic acid (DMSA) chelation therapy on blood lead level in asymptomatic children with baseline levels of 20 to 45 μg/dL (Table 3).31,34,35,37,38 Duration of follow-up was 6 years in 1 trial and 6 months in the other.

The Treatment of Lead-Exposed Children (TLC) study, a good-quality RCT (n = 780), evaluated children aged 12 to 33 months with blood lead levels between 20 and 44 μg/dL.31,34,35,38 All children received nutritional supplements and had home inspections with lead abatement. Children were randomized to treatment with DMSA (1050 mg/m2 per day for 7 days, then 700 mg/m2 per day for 19 days) or placebo and could be treated up to 3 times with a goal blood lead concentration of less than 15 μg/dL. DMSA was associated with a blood lead level at 1 week that was mean difference of 11 μg/dL lower than that of children in the placebo group (Table 3). However, blood lead levels increased once DMSA was discontinued, and at 52 weeks the blood lead level for the treatment group was only a mean difference of 2.7 μg/dL lower than that of the placebo group (95% CI, 1.9-3.5 μg/dL).38 In a follow-up study of 7-year-old TLC study participants (83% of original study population) 4.5 to 6 years after treatment, mean levels were similar in both groups (8.0 μg/dL).34

A small, fair-quality study (n = 39)37 randomized children aged 2.5 to 5 years with mean blood lead level between 30 and 45 μg/dL to 1 course of DMSA or control. DMSA was dosed according to weight and was administered 3 times daily for 5 days followed by twice daily for 14 days. There were no significant differences in mean blood lead level at 1 month (27.4 μg/dL [SD, 7.5] vs 33.2 μg/dL [SD, 10.3], P = .16) or 6 months (28.8 μg/dL [SD, 6.4] vs 25.1 μg/dL [SD, 6.8], P = .06) (Table 3).

Nutritional Interventions

Two poor-quality studies provided insufficient evidence to determine the effects of calcium or iron nutritional supplementation interventions on blood lead level in children.36,39

Residential Lead Hazard Control Techniques

Three fair-quality RCTs found no clear effects of home lead abatement in lowering blood lead concentrations in asymptomatic children with elevated blood lead levels at baseline (Table 3).32,33,40 One trial (n = 175) randomized children younger than 28 months in Rhode Island with blood lead levels of 15 to 19 μg/dL33 to a home-based intervention or control. Blood lead levels in both groups decreased overall, but there was no significant difference between the intervention and control groups at 3, 6, or 12 months after baseline. A fair-quality trial (n = 90)32 randomized age-matched pairs of 12- to 60-month-old children with mean blood lead levels 15 to 30 μg/dL to home remediation and lead abatement or delayed intervention for 1 year. Despite reductions in home lead concentrations after the intervention, the effects of remediation on mean blood lead levels were small (17.5 vs 17.9 μg/dL; mean change, 1% [95% CI, −11% to 11%]), with no significant difference between groups. A fair-quality trial (n = 84)40 conducted in Florida enrolled asymptomatic children from the Women, Infants, & Children and Head Start programs with blood lead levels 3 to 10 μg/dL (mean, 5.29 μg/dL [range, 3.0-9.3 μg/dL]). Participants were randomized to receive an educational brochure, a home cleaning kit, or a formal home inspection and abatement. A passive control group received no intervention or information. All groups experienced a decrease in blood lead level of 2.26 to 2.99 μg/dL over 6 to 12 months, with no significant difference between groups.

Effectiveness of Interventions to Improve Health Outcomes

Key Question 5. Do counseling and nutritional interventions, residential lead hazard control techniques, or chelation therapy improve health outcomes in asymptomatic children with elevated blood lead levels?

The TLC34,35,38 trial of DMSA chelation therapy vs placebo (n = 780) was the only study to evaluate the effect of interventions for lowering elevated blood lead level on health outcomes by measuring children’s neuropsychological outcomes (Table 3). At 36 months, there were no significant differences between chelation therapy and placebo in the Wechsler Preschool and Primary Scale of Intelligence–Revised, the Developmental Neuropsychological Assessment (NEPSY), or the Conners Parent Rating Scale–Revised. In a follow-up study34 of the same children at age 7 years (4.5-6 years after treatment), chelation was associated with lower (worse) scores on the adjusted Attention and Executive Functions subscore of the NEPSY (unadjusted difference, −1.8 [95% CI, −4.5 to 1.0]; adjusted P = .045). There were no statistically significant effects on any other cognitive, neuropsychiatric, or behavioral outcome.

Harms of Interventions for Children With Elevated Blood Lead Levels

Key Question 6. What are the harms of interventions in asymptomatic children with elevated blood lead levels?

One good-quality RCT (Table 3) and 1 poor-quality study reported adverse effects of chelation therapy. The TLC trial (n = 780) compared DMSA chelation therapy with placebo in children aged 12 to 33 months with blood lead concentrations between 20 and 44 μg/dL.38 DMSA was associated with a small but statistically significant decrease in height growth over 34 months (difference, 0.35 cm [95% CI, 0.05-0.72 cm]) and slightly poorer scores on attention and executive function (unadjusted difference, −1.8; adjusted P = .045 for effect) tests at age 7 years.34 There were no significant differences in laboratory values, including neutrophil count, platelet count, aminotransferase concentrations, and alkaline phosphatase concentration after chelation.31,38 One poor-quality study42 reported adverse events associated with the less-commonly used chelator d-penicillamine, including leukopenia, thrombocytopenia, rashes, urinary incontinence, and gastrointestinal symptoms. No study identified harms of counseling, nutritional interventions, or residential lead hazard control techniques.

Screening and Treatment in Pregnancy

Evidence to determine effects of lead screening during pregnancy was extremely limited. There were no studies of screening in pregnant women and no studies reported health outcomes of interventions to reduce blood lead levels in asymptomatic pregnant women. One study reported the diagnostic accuracy of a clinical questionnaire for pregnant women,24 and 1 study reported effects of a nutritional intervention during pregnancy.41

Effectiveness of Screening

Key Question 1a. Is there direct evidence that screening for elevated blood lead levels in asymptomatic pregnant women improves health outcomes (ie, reduced cognitive problems in offspring, adverse perinatal outcomes, and adverse maternal outcomes)?

Key Question 1b. Does the effectiveness of screening in asymptomatic pregnant women vary by gestational age?

No studies directly evaluated clinical benefits and harms of screening pregnant women for elevated blood lead levels vs no screening or how effectiveness of screening varies according to the gestational age at which screening is performed.

Diagnostic Accuracy of Questionnaires or Clinical Prediction Tools

Key Question 2. What is the accuracy of questionnaires or clinical prediction tools that identify pregnant women who have elevated blood lead levels?

One fair-quality observational study24 evaluated the accuracy of a questionnaire for identifying pregnant women with elevated blood lead levels using 4 questions from the 5-question 1991 CDC questionnaire designed to identify children at risk (n = 314). Women with a positive response to at least 1 of the 4 questions were more likely to have elevated blood lead levels than those who answered negatively to all 4 questions (relative risk, 2.39 [95% CI, 1.17 to 4.89]; P = .01) (Table 1). However, diagnostic accuracy was poor, with a sensitivity of 75.7% and specificity of 46.2%. The single most predictive item was having a “home built before 1960.”

Harms of Screening

Key Question 3. What are the harms of screening for elevated blood lead levels (with or without screening questionnaires) in asymptomatic pregnant women?

No study directly compared the harms of screening pregnant women for elevated blood lead levels in a screened vs an unscreened population.

Effectiveness of Interventions to Reduce Blood Lead Levels and Gestational Hypertension

Key Question 4. Do counseling and nutritional interventions, residential lead hazard control techniques, or chelation therapy reduce blood lead levels and rates of gestational hypertension in asymptomatic pregnant women with elevated blood lead levels?

One fair-quality RCT (n = 670) of healthy pregnant women (mean baseline lead level, ≈4 μg/dL) in Mexico found calcium supplementation associated with reduced blood lead levels vs placebo (difference, 11%; P = .004; levels in each group not reported) (Table 3).41 Effects were more pronounced in women with baseline blood levels of 5 μg/dL or greater. Women were not required to have elevated blood levels at baseline. Limitations included unclear allocation methods, unblinded design, and some baseline between-group differences, including dietary calcium intake. Loss to follow-up was 14% (46/334) in the calcium group and 18% (59/336) in the placebo group. No harms were reported.

Effectiveness of Interventions to Improve Health Outcomes

Key Question 5. Do counseling and nutritional interventions, residential lead hazard control techniques, or chelation therapy improve health outcomes in asymptomatic pregnant women with elevated blood lead levels?

No studies reported health outcomes after interventions to reduce blood lead levels in asymptomatic pregnant women.

Harms of Interventions for Pregnant Women With Elevated Blood Lead Levels

Key Question 6. What are the harms of interventions in asymptomatic pregnant women with elevated blood lead levels?

One RCT on the effects of calcium supplementation on blood lead levels in pregnant women did not report harms (Table 3).41

Discussion

A summary of the evidence for this updated review is shown in Table 4 and Table 5 (summary of evidence tables from the full USPSTF reports are available in eTables 6 and 7 in the Supplement). Consistent with the prior USPSTF review,7 no evidence was found that directly evaluated benefits or harms of screening children for elevated blood lead levels compared with no screening. Based on studies available at the time of the prior USPSTF review, instruments to identify children at higher risk of elevated blood levels to guide targeted screening have poor diagnostic accuracy. This update confirms there are no clear effects of interventions for lowering elevated blood levels in affected children or to improve neurodevelopmental outcomes. Evidence to determine benefits and harms of screening or treating elevated lead levels during pregnancy remains extremely limited.

Given the decreased prevalence of elevated blood lead levels identified in the US pediatric population (from 88% between 1976 and 1980 to 0.8% from 2007 to 2010), targeted screening strategies have been suggested.2 The most commonly used risk assessment instrument is the CDC questionnaire; however, studies of this instrument or adapted versions have found poor diagnostic accuracy, with results that are not informative.17,18,20,22,43 Furthermore, the CDC questionnaire was created in 1991 and no study on its accuracy has been published since 1997, potentially limiting the applicability of available evidence to contemporary clinical practice. Accurate risk-assessment instruments would be helpful for guided targeted screening strategies. In lieu of accurate screening instruments, potential alternative strategies include universal screening15,19 or screening targeted at communities with a high prevalence of elevated lead levels.16 The findings regarding the poor accuracy of the CDC questionnaire are generally consistent with those from another recent systematic review44 on accuracy of screening questionnaires and with evidence from the prior USPSTF review.7

Evidence indicates that capillary sampling is slightly less sensitive than venous sampling, with comparable specificity,26-28,30 provided that contamination is avoided using standard techniques. Factors that may inform the decision to perform capillary sampling for screening include the trade-offs between slightly worse accuracy and greater convenience or patient preferences. Both methods require confirmation.

There is limited evidence on the effectiveness of interventions for elevated blood lead levels on neurodevelopmental outcomes and longer-term blood lead levels. One trial showed short-term (through 1 year) effects of DMSA chelation on lowering blood levels vs placebo in children with moderately elevated blood levels (20-44 μg/dL) at baseline, but no clear effects on longer-term lead levels or neurodevelopmental outcomes, with some data indicating potential harms.38 No trial evaluated effects of chelation in children with blood lead levels less than 20 μg/dL, but chelation is not recommended at this level in the absence of severe symptoms. Evidence on residential interventions was limited and showed no clear effects on blood lead concentrations. Evidence on calcium and iron nutritional interventions was poor quality and insufficient to determine effects on blood lead levels or clinical outcomes.

This review focused on evidence of screening and treatment of individuals in primary care settings. Community or public health–based approaches are other important strategies used to address lead exposures. Risk factors for lead exposure include socioeconomic disadvantage, living near lead industry, renovation or deterioration of older lead-painted houses, poor nutrition, and previously living in countries where leaded gasoline is used.2,45,46 Exposures may occur through water sources, lead pipes, or culturally linked sources, such as folk remedies, imported food and candy, and traditional pottery used for cooking.47,48 The CDC recommends that public health entities provide clinicians with community-specific risk factors that can be used to determine the need for screening.49

Elevated blood lead levels predominantly affect socioeconomically disadvantaged and minority children. Different sources of lead exposure than have been previously considered are emerging in these children, yet research on screening and prevention in these populations remains limited.47,48,50 Exposures related to community water sources, lead pipes in schools, and factory emissions affecting neighborhood soil quality are some of the relevant factors not captured by current screening questionnaires. Culturally linked sources of lead poisoning, such as imported candy, pottery, traditional medicines, and cosmetics, specific to subpopulations47,48 living in the United States also may pose additional risk, since little regulation exists to monitor, identify, and control these nonpaint exposures. Additional research is warranted to validate these potential associations in specific geographic locations. Children exposed to less common sources of lead exposure may live in areas with a higher risk for housing-related source exposures.50 The dual risk associated with these communities suggests a more focused strategy to deal with population-specific risks.

Elevated blood lead levels are associated with serious, often irreversible, health consequences. Effective screening could identify lead-contaminated residential environments and abate them, not only to improve the health of the individual child but also of others in the household. While remediation of lead exposures in a specific residence may be too late for an individual child who already is exposed, the downstream effect could prevent exposure for subsequent generations of children. Development of questionnaires that incorporate current risk factors for elevated lead levels with validation in contemporary populations of children in the United States is necessary. Research evaluating effectiveness of treatments for elevated lead levels, such as counseling, nutritional interventions, and residential lead hazard control techniques, in trials with adequate sample sizes may also inform treatment strategies. While there is limited evidence on the clinical benefit of nutritional supplementation in reducing lead levels in children, epidemiologic evidence suggests potential benefits and is supported by studies of the toxicokinetics of lead in childhood. Effects of nutrition could be further validated by well-designed research studies. Ideally, randomized trials would recruit children from a range of racial, ethnic, and socioeconomic strata and evaluate the effects of screening on improving health outcomes as well as short- and long-term harms. However, ethical issues of trials in the context of environmental health exposures would limit feasibility. Research on newer methods for testing blood lead levels, such as point-of-care testing, and on the intraindividual and interlaboratory reliability of blood lead level testing would be helpful for informing testing strategies.

Limitations

This review has several limitations. First, there was an overall lack of evidence to address all key questions. Second, despite searching for updated data, the available studies evaluating the effectiveness of the risk-based questionnaires were published between 1994 and 2003 and may not assess contemporary risk factors. Current clinical practice uses a reference blood lead level greater than 5 μg/dL based on updated CDC guidance, but several of the studies included for this review used the older reference value of 10 μg/dL or greater. Third, nonrandomized studies were included to evaluate the effectiveness of interventions for elevated blood levels but are more susceptible to confounding and bias, leading to downgrading of study quality. Fourth, direct correlation of environmental exposures with longer-term health outcomes is difficult to study and characterize, since these exposures often have subtle clinical effects. Fifth, the review focused on screening and treatment of individuals in primary care settings, excluding community and public health approaches that could inform screening practices at the population level.

Conclusions

Screening questionnaires were not accurate for identifying children with elevated blood lead levels. Chelating agents in children were not associated with sustained effects on blood level levels but were associated with harms.

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Article Information

Corresponding Author: Amy G. Cantor, MD, MPH, Pacific Northwest Evidence-based Practice Center, Departments of Medical Informatics and Clinical Epidemiology, Family Medicine, and Obstetrics and Gynecology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Mail Code BICC, Portland, OR 97239 (cantor@ohsu.edu).

Accepted for Publication: January 29, 2019.

Author Contributions: Dr Cantor had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Cantor, Griffin, McDonagh.

Acquisition, analysis, or interpretation of data: Cantor, Hendrickson, Blazina, Griffin, Grusing, McDonagh.

Drafting of the manuscript: Cantor, Hendrickson, Griffin, Grusing.

Critical revision of the manuscript for important intellectual content: Cantor, Hendrickson, Blazina, McDonagh.

Statistical analysis: Cantor.

Obtained funding: Cantor.

Administrative, technical, or material support: Cantor, Hendrickson, Blazina, Griffin, Grusing.

Supervision: Cantor, McDonagh.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded under contract HHSA290201500009I, Task Order No. 7, from the Agency for Healthcare Research and Quality (AHRQ), US Department of Health and Human Services, under a contract to support the USPSTF.

Role of the Funder/Sponsor: Investigators worked with USPSTF members and AHRQ staff to develop the scope, analytic framework, and key questions for this review. AHRQ had no role in study selection, quality assessment, or synthesis. AHRQ staff provided project oversight, reviewed the report to ensure that the analysis met methodological standards, and distributed the draft for peer review. Otherwise, AHRQ had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript findings. The opinions expressed in this document are those of the authors and do not reflect the official position of AHRQ or the US Department of Health and Human Services.

Additional Contributions: We thank AHRQ medical officer Iris Mabry-Hernandez, MD, MPH, as well as current and former members of the US Preventive Services Task Force who contributed to topic discussions. USPSTF members did not receive financial compensation for their contributions.

Additional Information: A draft version of this evidence report underwent external peer review from 5 content experts (Lynn Goldman, MD, MS, MPH, George Washington University; Ruth Etzel, MD, PhD, United States Environmental Protection Agency; Suril Mehta, MPH, National Institute of Environmental Health Sciences; Matthew Strickland, PhD, MPH, University of Nevada, Reno; Jennifer Lowry, MD, Children’s Mercy Kansas City) and 1 federal partner (Centers for Disease Control and Prevention [CDC]). Comments from reviewers were presented to the USPSTF during its deliberation of the evidence and were considered in preparing the final evidence review. Peer reviewers and those commenting on behalf of partner organizations dd not receive financial compensation for their contributions.

Editorial Disclaimer: This evidence report is presented as a document in support of the accompanying USPSTF Recommendation Statement. It did not undergo additional peer review after submission to JAMA.

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