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Risk factors for Toxocara canis (T. canis) infection were evaluated in a prospective study of disadvantaged preschool children. In addition, the hypothesis that T. canis exposure is associated with lower intelligence was tested. Seropositivity was tested at 2 years, 3 years, and at 4 years 10 months (4-10). Intelligence was measured at age 4-10 by the Full Scale IQ of the Wechsler Preschool and Primary Scales of Intelligence (WPPSI). Pica and ownership of a dog were unrelated to seropositivity. Seropositive children had lower scores on the Mental Development Index (MDI) of the Bayley Scales of Infant Development at age 1 year (prior to likely exposure). They also had less favorable scores on a measure of the quality of childrearing. These findings suggest that, for disadvantaged children, lower initial intelligence and less advantageous child rearing are risk factors for T. canis exposure. Seropositive children also had higher blood lead levels, probably as a result of the common pathway of hand to mouth transmittal. Seropositivity at 3 years, at age 4-10, or, cumulatively, at any of the age 2, 3, or 4-10 assessments was associated with the WPPSI IQ after adjustment for sociodemographic factors. Exposure at age 4-10-years was significantly associated with reduced IQ scores (p = 0.030). However, when the age 1 year MDI score was controlled, the estimate became nonsignificant. We, thus, can neither confirm nor deny a relationship of T. canis and intelligence, but the importance of considering prior developmental status is emphasized.

A neonatal examination for fetal alcohol syndrome (FAS) should promote the guidance of parents, the planning of remediation for affected children, and the collection of prevalence data. A blinded examination of FAS characteristics conducted as part of a large prospective study of disadvantaged alcohol-exposed infants identified eight neonates who met the published criteria for FAS. These children were followed through the preschool years with a blinded assessment protocol. Seven of these children were found to have no impairment in cognitive and language development, when compared with their peers, and to be of average size. The one child who was mentally and growth retarded at follow-up who had been diagnosed as FAS might not have been diagnosed FAS using clinical criteria (as opposed to blinded research criteria), because his mother provided in-pregnancy reports of only low alcohol intake; she later acknowledged drinking an average of over 21 drinks/week during the pregnancy. The findings are positive in that they provide hope for children who present FAS at birth, although concern with adverse outcomes is certainly not dispelled. In particular, the possibility of later-emerging impairment in more complex tasks is not ruled out.

The relationship between circumpulpal dentine lead and IQ at age 4 years 10 months was examined in 164 urban children. Negative correlations were observed between dentine lead and IQ scores, but were reduced in magnitude after adjustment for social covariates. Analyses using errors-in-variables regression models indicated that the degree of this reduction depended on difficult-to-verify assumptions regarding the magnitudes of (i) measurement error in the lead variable and the covariates, and (ii) possible changes in the caretaking environment resulting from conjectured effect of lead on the child's cognitive and behavioral development. Sensitivity analyses were conducted in which estimates of the lead effect were repeatedly computed and compared for a range of possible values for factors (i) and (ii). It was found that the statistical significance of the lead effect on Full Scale IQ depended on the relative magnitudes of these factors, and that failure to incorporate measurement error in the analysis would have led to gross overestimation of the precision of the findings.

We believe that members of the scientific community have a primary obligation to promote integrity in research and that this obligation includes a duty to report observations that suggest misconduct to agencies that are empowered to examine and evaluate such evidence. Consonant with this responsibility, we became whistleblowers in the case of Herbert Needleman. His 1979 study (Needleman et al., 1979), on the effects of low-level lead exposure on children, is widely cited and highly influential in the formulation of public policy on lead. The opportunity we had to examine subject selection and data analyses from this study was prematurely halted by efforts to prevent disclosure of our observations. Nevertheless, what we saw left us with serious concerns. We hope that the events here summarized will contribute to revisions of process by which allegations of scientific misconduct are handled and that such revisions will result in less damage to scientists who speak out.

Conclusion: Deliberate misrepresentation continues. Needleman attacks the whistleblowers, the NIH, and his own University to deflect attention from the indications of misconduct in his research. Federal agencies base policies on his research and on his assertions regarding the purported effects of low-level lead exposure on children. The policies divert resources and attention from the real needs of children. Misconduct issues will ultimately be resolved by the ORI and the courts. Public policy issues may require reconsideration in light of further evidence.

The relationship between blood lead level (PbB) and an array of socio-demographic, behavioral, caregiving and environmental risk factors was investigated in a cohort of socioeconomically disadvantaged urban children at ages 2, 3 and 4 years and 10 months. The risk factors were also related to dentine lead level (PbD) from shed deciduous teeth. Strong persistent pairwise relationships with PbB and PbD were observed for maternal IQ, parental education, examiner ratings of the condition and cleanliness of the physical environment, and the HOME scale, which assesses the quality of the caretaking environment. The association between dirt pica and PbB was strong at 2 years (r = 0.30), but was less pronounced in subsequent assessments as the prevalence of pica decreased. Insignificant or weak relationships were found for maternal assessments of paint-and-plaster peeling in the home and non-dirt pica. The HOME scale and the ratings of the condition of the physical environment were significantly related to PbB and PbD even after adjustment for socio-demographic factors. These two measures were also strongly related to an array of developmental outcomes. The results indicate that statistical adjustment specifically for the quality of the caretaking environment can lead to substantial reductions in estimates of adverse lead effects.

Studies of lead concentrations in blood during pregnancy are of interest because of the possibility of adverse effects on the fetus. One report of a single case suggested that blood lead concentrations are raised during pregnancy. This is consistent with the hypothesis of a pregnancy induced mobilisation of lead from bone. Data presented herein, however, indicate that blood lead measures are appreciably lower at delivery than they are at six months post partum. Other factors including but not limited to transmission to the fetus, may be influencing lead concentrations during pregnancy.

This report examines the effects of fetal alcohol exposure on size and growth in an urban cohort followed prospectively through early childhood. Indices of prenatal drinking were related to measurements of weight, stature (length), and head circumference obtained at birth and during five subsequent in-home assessments. Small but statistically significant relationships were detected between short-term recall estimates of drinking during pregnancy and weight and length at birth. The strength of these relationships diminished during the preschool assessments. However, estimates of catch-up growth associated with alcohol exposure were not statistically significant. With the exception of a single case with a profile of signs characteristic of fetal alcohol syndrome, an adverse effect of prenatal alcohol exposure on head circumference was not indicated.

Behavioral and developmental pediatric research often seeks to form causal inferences from associations between variables obtained in nonrandomized studies. To do this it is necessary to distinguish the effects of the independent variable of interest from other factors with which it is correlated. We review statistical adjustment procedures for assessing the effects of the independent variable after controlling for other variables, called cofactors. We present guidelines for cofactor adjustment for different patterns of causal relationships occurring in the developmental pediatric literature. We also review procedures for selecting a subset of cofactors from a larger array of candidate variables. Finally, we examine common methodological complications related to cofactor adjustment, including the presence of measurement error in the independent variable and/or the cofactors.

This report examines possible adverse effects on size and growth associated with subclinical prenatal and preschool age lead exposure in an urban cohort followed prospectively from birth through early childhood. Measurements of weight, stature (length), and head circumference were obtained at birth and during five subsequent in-home assessments. Prenatal lead exposure was assessed by cord (n = 185) and maternal (n = 162) blood lead levels at delivery. Preschool blood lead samples were obtained at ages six months (n = 151), two years (n = 165), three years (n = 165), and four years, ten months (n = 164). Multivariate longitudinal analyses incorporating adjustment for covariates revealed no statistically significant adverse effects of prenatal lead exposure on either neonatal size or on subsequent growth through age four years, ten months. Similarly, no statistically significant adverse effects were found between the preschool lead indices derived from blood collected at or after age two years and ensuing size measurements. We also found no evidence for an interaction between pre- and postnatal lead exposure. A marginal inverse association was exhibited between blood lead at six months and subsequent measures of head circumference. Limitations in the implications of this result in the context of many nonsignificant tests were discussed.

The teratogenic effects of drinking during pregnancy on cognitive development were investigated in a cohort of disadvantaged mother-infant pairs. Three indices associated with maternal alcohol use were related to comprehensive cognitive measures obtained during five in-home assessments through age four years, ten months. Birth weight and a tally of craniofacial anomalies were also evaluated as early indicators of fetal alcohol damage. Multiple analyses relating the alcohol and cognitive measures provided no evidence of an adverse alcohol effect on cognitive development in the absence of Fetal Alcohol Syndrome. Assessments based on confidence intervals indicated that an average decrement of more than two points (IQ equivalent) on the five cognitive measures is unlikely for relatively heavy levels of maternal alcohol use or alcohol-related problems. Marginal relationships were observed between cognitive measures and the neonatal indicators, but depended heavily on the influence of a child exhibiting signs consistent with Fetal Alcohol Syndrome. This case therefore received special attention. The implications of the relationships involving the neonatal indicators were investigated using arguments based on path analysis.

The effects of fetal alcohol exposure on sustained attention in the preschool years were investigated in a sample of socioeconomically disadvantaged urban children. The 245 children examined were the 4-year 10-month-old follow-up cohort of a prospective study begun while their mothers were pregnant. Sustained attention was assessed by an automated, computer-administered vigilance task. Indices of fetal alcohol exposure included three measures of maternal drinking and two early indicators of fetal alcohol damage. The data were analyzed using univariate and multivariate regression techniques, both with and without adjustment for covariates. None of the analyses supported the hypothesis that fetal alcohol exposure adversely affects sustained attention performance in preschool children. We infer that, if there is an effect of prenatal alcohol exposure on vigilance task performance, that effect is small.

Fetal alcohol syndrome (FAS) is a cluster of features observed in some offspring of women who abuse alcohol in pregnancy. The defining features include intrauterine growth retardation, specific craniofacial dysmorphology, and central nervous system dysfunction. FAS is a full expression of a continuum of fetal alcohol effects. The assessment of alcohol abuse is one of several major problems in the study of the topic. Research findings are reviewed under a hypothesis of increasing effect in ordered categories: lethal effects, adverse obstetrical outcomes, malformations, growth retardation, reduced head circumference, and neuropsychological effects. Evidence of fetal alcohol effects may be found for each outcome category. The evidence across studies is not consistent nor is there any clear support for an effect order. The risk for psychological deficit may depend on the presence of dysmorphic effects.

The effects of fetal alcohol exposure on language and speech acquisition were investigated in a cohort of socioeconomically disadvantaged urban children. Language development was assessed by instruments derived from the Expressive and Receptive Scales of the Sequenced Inventory of Communication Development (SICD) at 1, 2, and 3 years, and by indices constructed from a taped speech sample at age 2 years. Three indices of maternal drinking were supplemented with birth weight and a tally of craniofacial anomalies as early indicators of fetal alcohol damage. No statistically significant relationships were found between the alcohol and language indices after statistical control for confounding variables. The anomalies tally was marginally related to reduced language scores. The statistical significance of this relationship, depended, however, on a single child with the characteristics of fetal alcohol syndrome. The pattern of results suggested that the anomalies tally, and to a lesser extent birth weight, are more sensitive indicators of fetal alcohol exposure than subsequent language development.

Inconsistent results continue to be reported from studies linking low-level lead exposure and child development. This inconsistency is seen for both prenatal exposure and exposure in the preschool years. The primary outcome measures in most reports are indices of cognitive development, including IQ. Verbal skills may be particularly vulnerable to toxic insult. The fact that 2 y of age is both a time of peak exposure and also a time of rapid language development suggests that this may be a critical period for such an effect. The later prenatal and early infancy period, at which time the nervous system is developing rapidly, may also be critical exposure period. We examined the relationship of maternal and cord blood lead (PbB) at birth and venous PbB at 6 mo, 2 y, and 3 y with language measures at 1, 2, and 3 y of age. The sample consisted of disadvantaged urban children. Multivariate analyses revealed no statistically significant relationship of either prenatal PbB or early preschool PbB with language measures after control of cofactors. Supplementary partial correlations revealed a marginal relationship of cord PbB and mean length of utterance (MLU), which describes a child's ability to form meaningful word combinations. Because this analysis was one of a large number of analyses with both positive and negative regression coefficients, the possibility that this was a chance effect was considered. If there is an effect of low-level lead exposure on language development, that effect is not robust.

The relationship between breastfeeding and cognitive development in the first 2 years of life was examined in a cohort of children being followed in a study of risk factors in development. A significant difference between bottlefed children, children breastfed less than or equal to 4 months and those breastfed greater than 4 months was found on the Mental Development Index of the Bayley Scales at ages 1 and 2 years, favoring the breastfed children. At age 6 months, the direction of the relationship was the same but did not reach significance. Supplementary regression analyses examining the strength of the relationship between duration of breastfeeding and cognitive development similarly showed a small but significant relationship between duration of breastfeeding and scores on the Bayley at 1 and 2 years. Alternative explanations for the results are discussed.

Though the occurrence of alcohol-related birth defects is well documented in the human and in animal models, definition of specificity, critical period, and dose-response threshold with a precision adequate for clinical risk assessment and management has been lacking. Data from a cohort of 359 neonates, from a large prospective observational study in which chronic alcohol problems and maternal drinking were assessed during pregnancy and standardized neonatal examinations were blinded for prenatal information, were analyzed with the use of multivariate techniques, with uniform control for confounding by eight factors. Craniofacial abnormalities were found to be definitively related to prenatal alcohol exposure in a dose-response manner (p less than 0.001); a significant, but less striking, relationship was observed for other anomalies (p less than 0.01). The critical period for alcohol teratogenicity was confirmed to be around the time of conception. Risk for anatomic abnormalities in the offspring was clearly defined among the 5.6% of infants whose mothers drank more than three ounces of absolute alcohol, that is, more than six drinks, per day. Because of a trend toward an increase in craniofacial abnormalities with increasing embryonic alcohol exposure at lower levels, a clear threshold could not be defined. These are not experimental data and the results should not be overinterpreted. Nevertheless, pending further studies with larger samples, the findings suggest that to completely avoid alcohol-related anatomic abnormalities, advice to discontinue drinking or at least to reduce it to a minimal level before conception is clinically appropriate.

To determine long-term outcome of children with inapparent congenital cytomegalovirus infection, an assessment of congenitally infected children observed since birth was undertaken. Children with early postnatal acquisition of CMV infection were also evaluated. Cognitive, behavioral, neurologic, audiometric, and speech and language evaluations were performed in 48 patients, including 17 congenitally infected children, 10 children with postnatal infection, and 21 uninfected control subjects. Mean IQ of the three groups of children did not differ significantly. Behavioral, neurologic, speech and language examinations similarly failed to distinguish differences among the three groups. Audiologic abnormalities were present in four congenitally infected children, including one child with a severe unilateral sensorineural loss; in none of the children was hearing loss functionally significant. No hearing abnormalities were detected in postnatally infected children. Although inapparent CMV infection can result in audiologic sequelae, the continued lack of cognitive, behavioral, and neurologic sequelae in these school-age children reemphasizes the need to focus attention on prevention of primary maternal CMV infection to avoid the potentially devastating effects of intrauterine CMV infection.

The hypothesis that low level lead exposure in the fetal and early preschool years is related to neuropsychological deficit is being examined in a prospective study of development through the preschool years. Clear and consistent support for the hypothesis was not obtained in previously reported findings relating maternal and cord blood lead level (PbB) and PbB from venous samples through age three years to a series of developmental tests. It was concluded the relationship of lead level and cognitive development was primarily a function of the dependence of each on the quality of the caretaking environment. The cohort has now been examined at age four years, ten months, an age selected to assess development just prior to school age. The test used was the Wechsler Preschool and Primary Scale of Intelligence. We found statistically significant correlations between most of the PbB measures and the intelligence test scores, but these were attenuated, not statistically significant and not consistent in direction when relevant confounding variables were considered. Possible biases or threats to validity were reviewed. Effect sizes relating both prenatal and preschool lead exposure to intellectual development were small, not statistically significant, and not consistent in direction.

Scores on the McCarthy Scales of Children's Abilities, school reading tests, teacher ratings, and several exploratory measures were obtained for urban black school-aged children, first studied five years previously. These were related, for 63 children, to preschool blood lead, school-age blood lead, and free erythrocyte protoporphyrin levels, and, for 34 children, to dentine lead. Most outcome variables were not significantly related to the lead variables. Preliminary analyses indicated that results of several of the McCarthy Scales, including the critical General Cognitive Index and Verbal Scales, and the reading test were significantly impaired in higher lead level groupings. However, incorporating a brief measure of parent IQ into the analyses decreased variance associated with lead and led to a strong suspicion of the remaining significant results. Few investigators reporting positive effects have considered parent intelligence, which is known to be a major determinant of developmental status. For this and other admittedly difficult methodologic reasons, conclusions from prior studies are questioned.

Fetal alcohol effects in 359 infants born to disadvantaged women identified as having a history of alcohol abuse or as controls and who provided reports of alcohol use in pregnancy are being studied in a prospective design. Alcohol abuse was assessed with the Michigan Alcoholism Screening Test (MAST). Alcohol use (AA/day) was based on short-term recall covering 2-week periods prior to each antenatal visit. A tally of anomalies associated with fetal alcohol syndrome was obtained in a blinded examination of each infant. This tally was significantly related to the MAST classification and, for the MAST+ subjects, the tally was related to first trimester AA/day. Birth weight, length, and head circumference were negatively correlated with AA/day (entire pregnancy); however, the effect was attenuated and not statistically significant in models with covariate control. It is possible that these measures were near the threshold of effect. Scale scores of the Brazelton Neonatal Behavioral Assessment Scale and three scale scores of the Graham/Rosenblith Behavioral Examination of the Neonate were unrelated to the MAST classification and to AA/day.

The hypothesis that low level lead exposure in the fetal and early preschool years is related to neuropsychological deficit was examined in a prospective study of child development. We also tested the hypothesis of reverse causality, i.e., that lead level is a function of prior developmental status. Fetal lead exposure was measured in maternal and cord blood while preschool lead level was measured in venous blood samples at ages six months, two years and three years. These blood lead measures (PbB) were related to concurrent and ensuing scores on developmental measures at six months, one year, two years, and three years. With statistical control of covariate measures (age, sex, race, birth weight, birth order, gestational exposure to other toxic substances, maternal intelligence, and several indicators of the quality of the caretaking environment) as well as potentially confounding risk factors (gestational exposure to alcohol and other toxic substances), most statistically significant associations of PbB with concurrent and later development were completely attenuated. Effects of lead exposure, significant or not, were not consistent in direction. In reverse-causality analyses, PbB was not related significantly to prior measures of developmental retardation or acceleration. It was concluded that the relationship of lead level and measures of development in these early years was primarily a function of the dependence of each on the quality of the caretaking environment.

In a prospective study of 3,253 pregnant adolescents, 1,404 were seronegative for cytomegalovirus (CMV). Specimen collection at each antenatal visit, including urine for viral culture and serum for complement-fixing antibody, allowed definition of primary CMV infection in 14 subjects (1%). Seven of 14 subjects delivered congenitally infected infants, including 5/7 subjects with third trimester infections, and 2/5 subjects with second trimester infections. The single mother with a first trimester infection delivered an uninfected infant, despite recurrent maternal viremia. The mean birth weight of congenitally infected infants did not differ significantly from the mean birth weight of uninfected infants. None of the infants had stigmata of cytomegalic inclusion disease. One infected infant died suddenly at 6 weeks of age from pneumonia. Follow-up examinations of the six living children failed to detect cognitive, behavioral, or audiologic sequelae. These data demonstrate that primary maternal CMV infection occurs in 1% of susceptible women and is associated with a 50% risk of intrauterine infection. Fetal infection, particularly if it occurs late in pregnancy, is not invariably accompanied by fetal damage.

Definitive evidence of neuropsychological effects of low level Pb exposure continues to be sought in prospective studies of child development. The period from mid-infancy to age three years is important because behavioral and physiological characteristics of that age are associated with the intake and retention of environmental Pb. In the Cleveland study, we measured blood Pb (PbB) at ages six months, two years, and three years. At ages six months, one year and two year, the Mental Development Index (MDI) of the Bayley Scales of Infant Development was administered. The Stanford Binet Intelligence Scale IQ was obtained at age three years. Eight multiple regression analyses tested the relationship of each of the three PbB measures with the respective current and each ensuring developmental assessment. Demographic data and measures of the caretaking environment were selected as covariates for the control of confounding factors. Six months PbB was not related significantly to any of five assessments with or without control of confounding variables. The remaining three analyses were significant in the initial analyses, but the effect was completely attenuated with statistical control of confounding variables. These results suggest that obtained correlations between lead exposure and preschool intelligence depend on the caretaking environment.

Assessment of alcohol-related fetal risk is complicated by difficulties in assessing alcohol exposure. We previously described considerable underreporting of alcohol use during pregnancy, particularly among problem drinkers. This report is of the relationship between severity of drinking problems and the magnitude of underreporting. Pregnant disadvantaged women responded to the Michigan Alcoholism Screening Test (MAST) at the first antenatal visit and provided self-report data regarding alcohol use at each antenatal visit. Five years later, 238 of these women again provided self-report information about drinking during the target pregnancy. Underreporting was defined as a positive difference between the indices computed from the retrospective and the in-pregnancy data. The relationship of underreporting to the MAST score was highly significant and indicated a 20-fold increase in underreporting from the lowest to highest MAST score. However, the marked individual variability seen in this relationship indicates that while the MAST may be a better indicator of risk than self-reports of drinking, it is also not sufficient for the purpose. Further work examining other measures and techniques for obtaining drinking information is indicated.

Studies of alcohol-related birth defects in humans rely heavily on maternal self-reports of alcohol use. The accuracy of self-reports, and thus of related risk levels, is of concern to investigators, to public health professionals, and to persons advising pregnant women. We contrasted quantitative reports of drinking in pregnancy by 238 women with retrospective reports obtained 5 years later. Although correlated (r = 0.67, p less than 0.0001), marked discrepancies suggested underreporting during pregnancy by a significant proportion of the women. The validity of the retrospective index was indicated in that it was somewhat more highly related to scores on the Michigan Alcoholism Screening Test (MAST) and to a tally of alcohol-related craniofacial anomalies in the neonate than was the in-pregnancy index. Furthermore, the retrospective index and the MAST score were significant predictors of other neonatal anomalies; the in-pregnancy index was not. The only variable related to underreporting was MAST score, i.e., the higher the MAST score the greater the underreporting. The results suggest that previously reported thresholds of effect based on self-report data may be underestimates. The results also suggest that questions regarding alcohol-related problems may be more effective than direct consumption questions in the identification of women who drink heavily in pregnancy.