Abstract
Objective
To assess the impact of prenatal exposure to polybrominated diphenyl ethers (PBDEs) and polyfluoroalkyl chemicals (PFCs) on early infant neurobehavior.
Study design
In a cohort of 349 mother/infant pairs, we measured maternal serum concentrations during pregnancy of PBDEs, including BDE-47 and other related congeners, as well as two common PFCs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS). At age five weeks, we measured infant neurobehavior using the NICU Network Neurobehavioral Scale (NNNS).
Results
Neither PBDE nor PFC exposures during gestation were associated with the 11 individual NNNS outcomes included in our study. However, using latent profile analysis to categorize infants into neurobehavioral profiles based on performance on the NNNS (“social/easygoing,” “high arousal/difficult,” or “hypotonic”), a ten-fold increase in prenatal PFOA concentrations significantly increased the odds of being categorized as hypotonic compared with social/easygoing (adjusted OR 3.79; 95% CI: 1.1–12.8).
Conclusions
Infants of mothers with higher serum concentrations of PFOA during pregnancy were more likely to be categorized as hypotonic. No association between PBDE concentrations and hypotonia was found. Additional studies should further investigate possible associations of prenatal PFC exposure and muscle tone in infants and children.
The central nervous system is the body system most vulnerable to developmental injury.(1) However, there is limited evidence of the potential neurological damage that may result from typical exposure levels to common environmental chemicals among pregnant women in the United States (US), such as polybrominated diphenyl ethers (PBDEs) and polyfluoroalkyl chemicals (PFCs). In the 1970's, PBDEs began being commercially produced for use as flame retardants in many consumer products, and they have since become pervasive and persistent organic pollutants.(2) A 2008 study reported measurable serum concentrations of PBDEs in 97% of a representative sample of U.S. residents between 2003 and 2004.(3) Despite discontinuation of the most common types of these chemicals in 2004 and 2013,(4, 5) levels of these persistent chemicals remain in the environment and in our homes. The high body burden in infants and toddlers has raised concerns for their potential developmental toxicity.(6) Recent studies indicate that prenatal exposure to PBDEs may have developmental effects, such as lower attention, adverse birth outcomes, lower scores tests of mental and physical development, and hyperactive behavior.(7-11)
PFCs, used to repel dirt, water and oils, have been used extensively since the 1950s in consumer products.(12-15) In a representative sample of the US population, Calafat et al detected perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), the most studied PFCs, in 98% of subjects.(13) Because of persistence in humans and the environment, widespread exposure in wildlife and people, and the potential adverse health impacts associated with such exposures,(16) in 2002, the main manufacturer of PFOS worldwide discontinued the production of PFOS precursors and related compounds in the United States. Ongoing efforts also exist to limit manufacturing emissions of PFOA.(13) Exposure to PFCs have been associated with lower weight and BMI, increased odds of developing attention deficit/hyperactivity disorder, impaired inhibition response, and, in infants, longer time to begin sitting without support.(17-20) However, some studies have found no association between prenatal PFC levels and Apgar score at birth or infant milestones (other than later sitting without support), behavioral and motor coordination problems at age seven, and performance on neuropsychological tests of cognition and language at 3-4 and 6-12 years of age.(14, 18, 21)
The results of studies assessing the effects of PBDEs and PFCs on neurological outcomes are limited, and findings are not consistent across studies or ages at which outcomes were measured. Further, the effects of PBDEs and PFCs on neurobehavioral outcomes in early infancy have not yet been studied. Our goal was to assess the impact of prenatal exposure to PBDEs and PFCs on the neurobehavioral organization of the young infant.
Methods
The study cohort comprised mother/infant pairs participating in the Health Outcomes and Measures of the Environment (HOME) Study, an ongoing, prospective pregnancy/birth cohort in the Cincinnati, Ohio, metropolitan area.(22-24) Recruitment of pregnant women took place between March 2003 and January 2006. Specific recruitment procedures have been described in detail elsewhere.(22, 23) Institutional review boards of four hospitals and two laboratories approved the study protocol, and all participating women provided informed consent for themselves and their infants.
The NICU Network Neurobehavioral Scale (NNNS) is a comprehensive neurobehavioral assessment that evaluates neurological functioning, provides a behavioral profile, and measures signs of stress in young infants.(25) It is the most comprehensive validated assessment of infant neurobehavioral organization that currently exists.(26) The NNNS has been utilized in the past to assess the impact of in utero exposures to environmental toxicants, such as tobacco smoke and plastics.(25, 27, 28) NNNS exams were administered during a home visit by certified examiners trained to reliability against a gold standard and masked to all prenatal exposure information. Analysis of raw NNNS data yields scores describing 13 dimensions of neurobehavior: attention, self-regulation, quality of movement, arousal, excitability, special handling required to acquire orientation items, lethargy, non-optimal reflexes, asymmetrical reflexes, hypotonicity, stress/abstinence, habituation, and hypertonicity. Though each of the scales is somewhat different in its construction, for each of the 13 scales, a higher score indicates more of that quality during the exam, regardless of whether the quality is favorable or unfavorable. Higher scores are favorable for the scales habituation, attention, regulation, and quality of movement, and lower scores are favorable for the scales excitability, handling, lethargy, nonoptimal reflexes, asymmetry, hypertonicity, hypotonicity, and stress/abstinence.(29) For the arousal scale, a moderate score is optimal, as it describes an infant who is alert and responsive during the exam but not overly excited or agitated. A high arousal score indicates an infant who is easily aroused to fuss and cry during an exam, or who cries during the exam, and who is highly active while being handled and while left alone, and a low score indicates an infant who displays low levels of alertness and responsiveness during the exam.(30) The number of infants receiving scores on the habituation and hypertonicity scales of the NNNS was too small for meaningful interpretation, so we excluded these measurements from analyses, as we have in our previous work with the NNNS.(25, 27) Sucharew et al used latent profile analysis to classify infants in this cohort into three discrete profiles based on the scores of their NNNS exam.(31) The summary profiles that were identified were labeled as “social/easy going” (44% of infants), “high arousal/difficult” (32% of infants), and “hypotonic” (24% of infants). Social/easy-going infants showed the ‘best’ neurobehavioral performance during the NNNS examination. The high arousal/difficult infants had the highest mean standardized scores for handling, arousal, excitability and stress/abstinence and the lowest mean standardized scores for attention, self-regulation, non-optimal reflexes, asymmetric reflexes, and quality of movement. The hypotonic profile included infants with signs of hypotonia along with the highest mean standardized scores for lethargy and non-optimal reflexes.(31) Maternal serum obtained at one time point, about 16 weeks gestation, was analyzed for PBDEs. One maternal serum sample was also collected and analyzed for PFCs, although we were unable to collect all of these samples at about 16 weeks gestation. Therefore, we supplemented a small percentage of our PFC samples with those collected at about 26 weeks gestation (10%) and at delivery (5%). Although we measured several PFCs, we focus our analysis only on PFOA and PFOS, the two most commonly studied PFCs.
The serum concentrations of PBDEs and PFCs were measured at the Centers for Disease Control and Prevention (CDC) Environmental Health Laboratories using published methods.(32, 33) All samples were analyzed for ten PBDE-congeners. Of these, BDE-47, BDE-99, BDE-100, and BDE-153 were selected for inclusion, given that other studies found these congeners to be the most frequently detected PBDEs in pregnant mothers. As BDE-47 is detected most often, our analyses focused on serum BDE-47 individually, as well as the sum of the aforementioned four PBDE congeners (hereafter referred to as sum4BDE: -47, -99, -100, -153).(3, 8, 34) Serum PBDE concentrations were calculated on a lipid basis (ng/g lipid) to account for the PBDEs lipophilicity. For a small number of participants (2%) who had serum concentrations above zero but below the limit of detection (LOD) for PBDE congeners, values were replaced with the LOD divided by the square root of two.(35)
Due to the skewed distribution of PBDEs and PFCs concentrations we applied a log10 transformation to normalize the data. We conducted the analysis of bivariate associations between serum PBDEs and serum PFCs and NNNS outcomes. Various multivariate analytic methods were selected, depending upon the distributional properties of the outcome variable responses. The NNNS hypotonicity scale was dichotomized and analyzed with logistic regression due to a distribution in which the majority of infants received a score of zero, and very few infants had a score greater than one. The asymmetric reflexes scale was analyzed using Poisson regression because the outcome variable was distributed as a count. All other NNNS scales were analyzed using linear regression. Using the NNNS profiles (“Social/Easy Going,” “High arousal/Difficult,” or “Hypotonic”) developed by Sucharew et al from individual NNNS scales in this same cohort of children, we were also able to compare concentrations of PBDEs and PFCs by NNNS profile.(31) We used logistic regression to examine whether infants with higher maternal PBDEs and PFCs concentrations were more likely to be categorized into the “High arousal/Difficult” profile or the “Hypotonic” profile, as opposed to the “Social/Easy Going” profile.
For the individual NNNS scales and NNNS profiles that demonstrated bivariate associations (p<0.15) with maternal serum concentrations of PBDEs and PFCs, multivariable models were constructed. Potential covariates included infant sex and age at NNNS exam (these variables were retained in all models as they are known contributors to NNNS performance), maternal age, race, household income, marital status, maternal depression, maternal body mass index at 13-19 weeks gestation, reported alcohol use during pregnancy, reported marijuana use during pregnancy, maternal serum cotinine, infant weight change per month from birth to five weeks, and maternal blood lead level during pregnancy (maternal blood lead was measured at 16 weeks gestation, 26 weeks gestation, and at delivery, and the maximum value was included for analyses). In addition, we included a variable that identified potentially high-risk infants based on gestational age less than 37 weeks, birth weight less than 2500 g, and/or stay in the neonatal intensive care unit (NICU) following birth. With the exception of infant sex and age at NNNS exam, covariates were removed from the multivariate model if they were insignificant and their removal did not modify the regression coefficient of PBDEs or PFCs by >10%. Each covariate was removed individually, beginning with the covariate that demonstrated the weakest association with the outcome. All statistical analyses were conducted using SAS, version 9.3 (SAS Institute, Cary, NC).
Results
Of the 389 women with singleton live births who comprised the cohort, measures of prenatal PBDE and PFC exposure were collected and NNNS exams were performed on 349 infants at approximately five weeks of age. Characteristics of the sample are displayed in Table I. Women averaged 29.6 years at delivery of the infant, and the majority of women were non-Hispanic, white and married. Infants averaged 34 days at the time of the five-week NNNS assessment.
Table 1.
Characteristics of the sample
| Full sample (N = 349) | ||
|---|---|---|
| Maternal characteristics | ||
| Maternal Age at Deliverya | 29.6 | 5.7 |
| Race | ||
| White, non-Hispanic | 222 | (64%) |
| Black, non-Hispanic | 105 | (30%) |
| Other | 22 | (6%) |
| Marital Status | ||
| Married | 235 | (67%) |
| Not married, living with someone | 46 | (13%) |
| Not married, living alone | 68 | (19%) |
| Household incomeb | 55 K | (28 K, 85 K) |
| Employed during prengnacy | 287 | (82%) |
| Education | ||
| ≤HS or GED | 46 | (22%) |
| Some college or college graduate | 195 | (56%) |
| Graduate or professional school | 77 | (22%) |
| Maternal BMI | ||
| Underweight | 2 | (1%) |
| Normal | 146 | (42%) |
| Overweight | 119 | (34%) |
| Obese | 82 | (24%) |
| Moderate to severe depression (during pregnancy or postpartum) | 83 | (24%) |
| Alcohol use during pregnancy | ||
| Never drank alcohol during pregnancy | 192 | (55%) |
| Drank <1 alcoholic drink per month | 106 | (30%) |
| Drank >1 alcoholic drink per month | 51 | (15%) |
| Marijuana use during pregnancy | 24 | (7%) |
| Maximum blood lead (μg/dL, geomean)c | 0.83 | (0.27 - 2.49) |
| Maximum serum cotinine (μg/L, geomean)c | 0.10 | (0.003 - 2.77) |
| Infant characteristics | - | - |
| Male | 164 | (47%) |
| Birth weight (grams)a | 3387.26 | (610.12) |
| Birth length (cms)a | 50.92 | (2.92) |
| Head circumference (cms)a | 34.21 | (1.85) |
| Gestational age (weeks)a | 39.03 | (1.70) |
| Age at 5-week exam (days)a | 34.50 | (5.03) |
| Birth order | ||
| First child | 152 | (44%) |
| Second child | 112 | (32%) |
| >Second child | 85 | (24%) |
| At risk for neurodevelopmental deficits | 43 | (12%) |
| Preterm (<37 weeks) | 31 | (9%) |
| Low birth weight (<2500 g) | 18 | (5%) |
| NICU stay | 17 | (5%) |
Mean(SD)
Median (25th, 75th percentile)
Geometric Mean (95% confidence interval)
Maternal PBDE serum concentrations at 16 weeks gestation were measured for 326 women (326 for PBDE47, 292 for congeners -99, -100 and -153). Maternal PFC serum concentrations were measured for 327 women (279 at 16 weeks, 33 at 26 weeks, and 15 at delivery). Measurements are displayed in Table II. Serum concentrations of PBDE-47 and PFOS were similar to estimated national levels of pregnant females during 2003-04. During this time, PBDE levels were reported to be rising in North America, and PFC levels were reported to be decreasing.(13, 36) However, serum concentrations of PFOA were more than twice as high as estimated national levels of pregnant females during 2003-04.(37) With regard to the NNNS Summary Profiles, mean PBDE and PFC concentrations did not differ significantly between the three profiles. Mean scores of the NNNS subscales for these 349 infants were similar to those reported by Tronick and Lester in a normative sample of infants assessed at four weeks.(38, 39)
Table 2.
Polybrominated Diphenyl Ether (PBDE) and Polyfluoroalkyl Chemical Levels in HOME Study Maternal Serum and Urinary Samples in Comparison with National Levels of Pregnant Women during 2003-04
| Exposure | National Levels Pregnant Females 2003-04a | HOME Study | ||
|---|---|---|---|---|
| Geometric Meanb | Geometric Standard Error | Geometric Meanb | Geometric Standard Error | |
| PBDE47 | 23.90 | 0.24 | 19.96 | 0.05 |
| Sum4PBDEc | Not reported | 37.12 | 0.06 | |
| PFOAd | 2.39 | 0.24 | 5.49 | 0.03 |
| PFOSe | 12.29 | 1.02 | 13.25 | 0.03 |
| NNNS Summary Profile: Hypotonic (n = 84) | ||||
| PBDE47 | 18.72 | 0.10 | ||
| Sum4PBDEc | 35.55 | 0.11 | ||
| PFOAd | 6.06 | 0.06 | ||
| PFOSe | 13.6 | 0.05 | ||
| NNNS Summary Profile: High arousal/difficult (n = 108) | ||||
| PBDE47 | 21.05 | 0.10 | ||
| Sum4PBDEc | 39.39 | 0.11 | ||
| PFOAd | 5.54 | 0.06 | ||
| PFOSe | 13.55 | 0.07 | ||
| NNNS Summary Profile: Social/Easy going (n = 157) | ||||
| PBDE47 | 19.95 | 0.07 | ||
| Sum4PBDEc | 36.61 | 0.08 | ||
| PFOAd | 5.18 | 0.04 | ||
| PFOSe | 12.86 | 0.04 | ||
Environmental Chemicals in Pregnant Women in the United States: NHANES 2003-2004 Woodruff, et al., 2011
Reported as ng/g lipid for PBDEs and μg/L for PFCs
Sum of PBDE -47, -99, -100, -153
Perfluorooctanoic acid
Perfluorooctane sulfonic acid
Table III displays the bivariate and multivariable associations of each of the four chemical exposures examined (ie, sum4PBDE, PBDE47, PFOS, PFOA) with each of the 11 NNNS outcomes. Bivariately, a ten-fold increase in maternal serum concentration of BDE -47 was associated with a significantly decreased (more favorable) score in the asymmetry scale (p = 0.0499). No other bivariate associations were observed at the significance level of 0.05. Several other NNNS scales (arousal, lethargy, hypotonicity, and stress/abstinence) with p-values <0.15 were further examined in multivariable analyses. After adjustment of important covariates, neither PBDE nor PFC exposure measures were significantly associated with any of the NNNS scales. However, two near-significant trends (p<0.10) were observed. The first was the association of PFOA and the hypotonicity scale, in which increased serum concentrations of PFOA were associated with an increased odds of being categorized as hypotonic (p = 0.0613; adjusted odds ratio (aOR) 2.72; 95% CI: 0.95 – 8.785). The second near-significant trend was the association of PFOS and the NNNS stress/abstinence scale, in which serum concentrations of PFOS were positively associated with increased signs of stress/abstinence in the infant (p = 0.0532).
Table 3.
Association of Prenatal Exposure to Polybrominated Diphenyl Ethers (PBDEs) and Polyfluoroalkyl Chemicals (PFCs) on NICU Network Neurobehavioral Exam
| Variables | Bivariate | Multivariablea | |||||
|---|---|---|---|---|---|---|---|
| NNNS Outcome | Exposure | Beta | Standard Error | p-value | Beta | Standard Error | p-value |
| Attention | Sum4PBDEb | −0.07 | 0.06 | 0.2440 | |||
| PBDE47 | −0.08 | 0.06 | 0.1706 | ||||
| PFOA | 0.01 | 0.06 | 0.8129 | ||||
| PFOS | 0.01 | 0.06 | 0.8493 | ||||
| Self-Regulation | Sum4PBDE | −0.01 | 0.06 | 0.8157 | |||
| PBDE47 | −0.03 | 0.06 | 0.5888 | ||||
| PFOA | −0.02 | 0.06 | 0.6956 | ||||
| PFOS | −0.03 | 0.06 | 0.6277 | ||||
| Quality of Movement | Sum4PBDE | −0.02 | 0.06 | 0.7909 | |||
| PBDE47 | −0.04 | 0.06 | 0.4482 | ||||
| PFOA | −0.01 | 0.06 | 0.9194 | ||||
| PFOS | −0.01 | 0.06 | 0.9126 | ||||
| Arousal | Sum4PBDE | −0.02 | 0.06 | 0.7092 | |||
| PBDE47 | 0.00 | 0.06 | 0.9798 | ||||
| PFOA | 0.08 | 0.06 | 0.1262 | 0.09 | 0.06 | 0.1000 | |
| PFOS | 0.05 | 0.06 | 0.3886 | ||||
| Excitability | Sum4PBDE | −0.02 | 0.06 | 0.6738 | |||
| PBDE47 | 0.01 | 0.06 | 0.9192 | ||||
| PFOA | 0.06 | 0.06 | 0.2784 | ||||
| PFOS | 0.08 | 0.06 | 0.1707 | ||||
| Special Handling Required | Sum4PBDE | 0.03 | 0.06 | 0.6639 | |||
| PBDE47 | 0.05 | 0.06 | 0.3274 | ||||
| PFOA | 0.03 | 0.06 | 0.5886 | ||||
| PFOS | 0.05 | 0.06 | 0.3609 | ||||
| Lethargy | Sum4PBDE | 0.07 | 0.06 | 0.2541 | |||
| PBDE47 | 0.07 | 0.06 | 0.2144 | ||||
| PFOA | −0.09 | 0.06 | 0.0864 | −0.09 | 0.06 | 0.1126 | |
| PFOS | −0.10 | 0.06 | 0.0631 | −0.09 | 0.06 | 0.1244 | |
| Non-Optimal Reflexes | Sum4PBDE | 0.06 | 0.06 | 0.3252 | |||
| PBDE47 | 0.05 | 0.06 | 0.3743 | ||||
| PFOA | 0.02 | 0.06 | 0.6589 | ||||
| PFOS | 0.07 | 0.06 | 0.1908 | ||||
| Asymetrical Reflexes | Sum4PBDE | −0.09 | 0.05 | 0.0649 | −0.07 | 0.05 | 0.1256 |
| PBDE47 | −0.09 | 0.05 | 0.0499 | −0.09 | 0.05 | 0.0726 | |
| PFOA | 0.03 | 0.05 | 0.5108 | ||||
| PFOS | 0.07 | 0.05 | 0.1239 | 0.07 | 0.05 | 0.1355 | |
| Hypotonicity | Sum4PBDE | −0.03 | 0.08 | 0.6468 | |||
| PBDE47 | −0.05 | 0.07 | 0.4787 | ||||
| PFOA | 0.13 | 0.07 | 0.0720 | 0.14 | 0.07 | 0.0613 | |
| PFOS | 0.04 | 0.07 | 0.6170 | ||||
| Stress/Abstinence | Sum4PBDE | 0.04 | 0.06 | 0.4718 | |||
| PBDE47 | 0.05 | 0.06 | 0.3621 | ||||
| PFOA | 0.01 | 0.06 | 0.8163 | ||||
| PFOS | 0.08 | 0.06 | 0.1374 | 0.11 | 0.06 | 0.0532 | |
Assessed if univariate p-value <0.15.
Sum4PBDE: sum of PBDE congeners -47, -99, -100, -153
Table IV displays the association of each of the four chemical exposures examined with the NNNS profiles. We did not find a significant association between maternal sum4BDE, BDE-47, PFOA, and PFOS serum concentrations and the likelihood of infants being categorized into the high arousal/difficult compared with the social/easy going profile on the NNNS at five weeks. We also did not find an association between maternal sum4BDE, BDE-47, and PFOS and likelihood of infants being categorized into the hypotonic compared with the social easy going NNNS profile. However, a ten-fold increase in maternal PFOA serum concentration significantly increased the odds of being categorized into the hypotonic profile compared with the social/easy going profile (aOR: 3.79; 95% CI: 1.1 – 12.8). Because the percentage of subjects represented by each profile is greater than 10%, in which case the use of the odds ratio may exaggerate the relative risk, we also calculated the adjusted relative risk (2.20; 95% CI: 1.06 – 4.59).
Table 4.
Association of Prenatal Exposure to Polybrominated Diphenyl Ethers (PBDEs) and Polyfluoroalkyl Chemicals (PFCs) on NICU Network Neurobehavioral Exam Profile Category
| Variables | Bivariate | Multivariablea | |||
|---|---|---|---|---|---|
| NNNS Profileb | Exposure | Odds Ratio | p-value | Odds Ratio | p-value |
| Difficult | Sum4PBDE | 1.216 | 0.5724 | ||
| PBDE47 | 1.147 | 0.6639 | |||
| PFOA | 1.657 | 0.3533 | |||
| PFOS | 1.488 | 0.4678 | |||
| Hypotonic | Sum4PBDE | 0.921 | 0.8236 | ||
| PBDE47 | 0.837 | 0.6138 | |||
| PFOA | 3.529 | 0.0399 | 3.785 | 0.0322 | |
| PFOS | 1.780 | 0.3996 | |||
Assessed if univariate p-value <0.15. Potential covariates included infant's sex and age at NNNS exam (retained in all models), maternal age, race, household income, marital status, maternal depression, maternal body mass index at 13-19 weeks gestation, maternal blood lead level during pregnancy, reported alcohol use during pregnancy, reported marijuana use during pregnancy, maternal serum cotinine, infant weight change per month from birth to five weeks, and a variable that identified potentially high-risk infants based on gestational age less than 37 weeks, birth weight less than 2500 g, and/or stay in the neonatal intensive care unit (NICU) following birth
Reference is Social/Easy Going profile
Discussion
We did not find significant associations between prenatal exposure to PBDEs or PFOS and infant neurobehavior as measured by the NNNS. However, we did find a significant association between prenatal exposure to PFOA and hypotonicity in infants at approximately five weeks of age. Infants born to mothers with higher serum PFOA concentration during pregnancy were at significantly higher risk of being categorized into a hypotonic profile versus a social/easy going profile (aOR: 3.79; 95% CI: 1.1 – 12.8) than other infants. Based on the individual NNNS scale, we found supportive evidence in that we observed a near-significant positive association of PFOA with an increased NNNS hypotonic score (aOR 2.72; 95% CI: 0.95 – 8.785). The hypotonic profile within this cohort, originally described by Sucharew et al(31) includes the 24% of infants who demonstrated reduced muscle tone during the NNNS assessment, which includes an evaluation of active and passive muscle tone, reflexes, and motor function. These hypotonic infants were also more lethargic during the exam and displayed more non-optimal reflexes. Fei et al evaluated infant developmental milestones at six and 18 months and did not find that increased prenatal exposure to PFOA or PFOS impacted these milestones.(18) However, Fei's outcome was measured by maternal report on a highly structured questionnaire, whereas our outcome was measured by individuals trained to conduct a comprehensive, standardized neurological exam. It should be noted, however, that Fei reported that children born to mothers with higher PFOS concentrations were slightly more likely to be sitting without support at a later age. Though we found an association with PFOA (rather than PFOS) with hypotonicity, together these studies do provide the evidence to suggest that PFC exposure may be associated with reduced muscle tone and increased hypotonicity during early and mid-infancy.
In a study of the same cohort, Chen et al found that prenatal exposure to PBDEs was associated with cognitive deficits at five years of age, as well as externalizing behavior problems, yet prenatal PBDE exposure was not associated with the infant neurobehavior in our analyses.(7) However, Chen did not find that PBDE exposure was associated with cognitive and motor development measured at one to three years, which may partially explain why no significant association was found at five weeks of age. Some studies have demonstrated that expression of a deficit caused by early neuron loss may lead to increased functional impairment at older age, and that the expression of the deficit may not occur for some time after the injury.(40, 41) This may partially explain the delayed effect that is observed with this cohort. As developmental stage may be an important factor in the relationship between PBDEs and neurological outcomes, we plan to conduct additional analyses of neurobehavioral outcomes at later time points in development within this cohort of children.
This study has several limitations that should be taken into consideration. One limitation is that PFC measurements were not taken at consistent time points during the pregnancy for all women. Some studies have shown that the effect of prenatal exposures on neurological outcomes can vary depending on the developmental stage of the organism.(1, 41, 42) However, greater than 85% of our 327 subjects who provided samples for PFC measurements did so at the first collection time point at 16 weeks gestation. We were also limited by our moderate sample size, and the fact that women in our sample were older, more highly educated, and more affluent than the general population, and of prima gravidas in particular. Younger, more impoverished women may be more likely to live in areas with greater environmental toxicants, and their total body burden of toxicants may therefore be greater. This could potentially lead to a greater frequency and/or severity of developmental problems and a higher correlation with the targeted toxicants. However, maternal age and household income were included as potential covariates in each of our multivariate models. Finally, we found a single significant effect and a marginal effect out of the numerous tests that were conducted, and it is possible that our findings reflect a type I error. However, given similar findings by Fei et al,(18) we feel that it is important that our findings be represented in the literature. A major strength of our study is that the neurobehavioral outcome assessed is based on a validated, standardized exam that was performed by a trained examiner, rather than relying on parental report.
As PBDEs and PFCs are ubiquitous in our environment, with various exposure routes,(43-45) it is critical that we understand their impact on human health. Some studies have attempted to identify potential risk factors for prenatal and neonatal exposure to PBDEs and PFCs, but additional studies are needed to confirm these findings as well as to identify the most relevant sources of exposure.(46, 47) Further studies should be conducted in order to better understand primary exposure routes of these substances. The specific source contributions of PFCs are not well characterized,(20) and the relative concentration of PBDE sources to overall body burden has not yet been well established.(48) In addition, studies should further investigate the impact of prenatal exposure of PBDEs and PFCs on neurological outcomes, and to determine the significance of aging in this relationship. Also, there are many different PBDE congeners that are likely to differ in their developmental toxicity.(45) Therefore, in the future it will be important to more clearly elucidate the different effects that each of the congeners may have.(45) Finally, additional studies should be conducted in order to further investigate the effect of prenatal PFC exposure on hypotonic behavior in infants and children.
Acknowledgments
Supported by the National Institute of Environmental Health Sciences (R01 ES015517, T32 HP10027).
Abbreviations and Acronyms
- PBDE
polybrominated diphenyl ether
- PFC
polyfluoroalkyl chemical
- NNNS
NICU Network Neurobehavioral Scale
Footnotes
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The authors declare no conflicts of interest.
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