We report on a mother who had a prenatal urinary BPA concentration two orders of magnitude higher than the mean or median urinary BPA levels documented in previous biomonitoring studies. We identified multiple potential sources of BPA exposure that could be avoided during vulnerable periods of development, including canned beverages and foods. Her infant had normal neurobehavior at birth followed by abnormal arousal, regulation, quality of movement, excitability, and lethargy at 1 month of age. The temporal relationship of the extremely high prenatal BPA value with the transient abnormal neurobehavioral findings is hypothesis generating and raises the question about whether these findings reflect BPA toxicity. However, the abnormal neurobehavior at 1 month might have been a result of another etiology, given that the infant had normal findings at birth and from 1 to 5 years of age. This case highlights a potential association between gestational BPA exposure and transient neurodevelopmental findings that can alert researchers to potential areas for examination in future investigations and epidemiologic studies.
The mother’s BPA concentration at 27 weeks of pregnancy was higher than any reported in the peer-reviewed literature for a person in the general population (CDC 2010
; Vandenberg et al. 2010
). Consumption of contaminated food and beverages is thought to be the single largest contributor to BPA exposure in the general population (Vandenberg et al. 2010
; von Goetz 2010). Recent data show that airborne BPA may also be an important source of exposure (Fu and Kawamura 2010
). The case mother reported eating canned ravioli daily during her second and third trimesters of pregnancy and eating canned or frozen vegetables one to three times per week in her prenatal questionnaire. Food can linings may contain BPA that can leach into foods (Vandenberg et al. 2007
). The degree of BPA leaching increases under acidic, basic, and high-temperature conditions. Canned beverages are also documented sources of BPA exposure (Cao et al. 2009
). The case mother reported drinking five canned beverages per week in the month before the 22-week questionnaire. This overall consumption pattern could have contributed to her high exposure concentration. A recent study showed that replacing canned and packaged foods with fresh foods in one’s diet significantly lowered urinary BPA concentrations (Rudel et al. 2011
). Consistently using and microwaving plastics (including plastic plates, cups, and food storage containers used to store and reheat foods) may have also led to the increased urinary BPA concentration. Hard polycarbonate plastic, cardboard food storage containers, and plastic stretch film can contain BPA (Vandenberg et al. 2007
Although we were unable to identify a specific exposure that led to the isolated high BPA concentration early in the third trimester, the combination of reported exposures may have contributed to the higher BPA concentration. BPA concentrations can vary considerably during the day based on multiple exposures and within person based on individual metabolism. Mahalingaiah et al. (2008)
found that single urine samples showed moderate sensitivity for predicting a pregnant woman’s exposure categorization over time, but it is possible that the case mother’s prenatal BPA concentration was a transient value that does not reflect exposures throughout the second and third trimesters of pregnancy. It is also possible that an unidentified source of BPA was the primary source of the elevated prenatal exposure concentration. Finally, recall bias may have affected answers to follow-up questions regarding prenatal exposures because the follow-up interview occurred 5 years after the infant was born. In 2004, we acquired data from the 22-week questionnaire on canned beverage consumption that asked about exposures in the month before completing the questionnaire. We did not have specific prenatal questionnaire data at the exact time when the 26-week urine sample was collected but did review responses from the 22-week questionnaire with the mother and confirmed reported lifestyle and dietary responses for the 26-week period.
Demographic factors can also be associated with overall exposure concentrations, and women from low socioeconomic backgrounds tend to have slightly higher urinary BPA concentrations than do women from higher socioeconomic strata (Braun et al. 2010
). Although she was unemployed and had a low HOME inventory score, her demographic profile did not stand out in any particular manner from the rest of the enrolled women ().
Data on prenatal BPA exposures and potential health impacts in humans are limited. An earlier study from this cohort showed a positive association between prenatal urinary BPA concentrations at 16 weeks of pregnancy and increased externalizing behavior, representing acting out styles that are categorized on hyperactivity and aggression scales, in female children at 2 years of age (Braun et al. 2009b
). The mother of the male case infant had a BPA concentration that was much higher than the median of the cohort and was therefore excluded from that analysis. The abnormalities in the case infant’s neurologic outcomes and behaviors at the 1-month examination were not observed in the overall cohort analysis for BPA exposure (data not shown). Ten singleton infants in the cohort were referred to a physician for abnormal NNNS findings after the 1-month examination. The geometric mean 26-week prenatal BPA concentrations for the 10 mothers of infants who were referred based on NNNS findings at the 1-month examination were higher than those for the mothers of 345 infants who were not referred (5.8 vs. 2.2 µg/g creatinine). The ratio of these values is 2.67 (95% confidence interval, 1.62–4.40). However, these results should be interpreted cautiously given the small number of referred infants.
Multiple animal studies cite neurologic abnormalities in offspring after in utero
BPA exposures (Chapin et al. 2008
; NTP 2008
). In mice, high-dose (50 mg/kg) prenatal BPA exposures were associated with increased anxiety in male offspring compared with females, and Cox et al. (2010)
postulated that this could be attributable to impacts on the dopaminergic or estrogen receptor-β pathways. Kawai et al. (2003)
found that prenatal low-dose (2 ng/g and 20 ng/g) BPA exposures were associated with a transient increased aggression score in male rats at 8 weeks of age that resolved at 12 weeks and thereafter. This transient nature of the neurobehavioral changes is similar to that of our case infant, whose symptoms of increased hypertonicity, tremors, abnormal movements, and extreme irritability at 1 month of age resolved in later testing.
Other environmental chemicals and endocrine-disrupting compounds, such as phthalates, lead, mercury, polychlorinated biphenyls, and pesticides, can also play a role in neurodevelopment. In a multiethnic cohort study of newborns in New York City, third-trimester urinary concentrations of some phthalate metabolites were associated with decreased orientation and alertness scores in girls and improved motor performance in boys assessed with the Neonatal Behavioral Assessment Scale at 5 days of age (Engel et al. 2009
). These exposures were also associated with elevated scores on conduct and aggression problem scales in children at 4 and 9 years of age (Engel et al. 2010
). The same urinary phthalate metabolites were measured in this case study mother () and were within the interquartile ranges of those reported for the women in the New York City cohort. Few animal and human studies examine prenatal exposure to mixtures of chemicals and subsequent neurodevelopmental health impacts. Therefore, it is difficult to know whether the mother’s exposures to other environmental chemicals may have played a role in the infant’s neurologic development.
The NNNS is a validated tool to assess neurobehavior during early infancy (Lester and Tronick 2004
). It was originally designed to assess neurobehavioral effects of prenatal exposure to drugs of abuse and prematurity, but it can also be used to assess healthy and at-risk infants (Lester and Tronick 2004
). The clinical significance of an abnormal NNNS exam in the neonatal period for functioning in later childhood has yet to be determined, but Liu et al. (2010)
reported the NNNS to be highly predictive of behavior problems, school readiness, and intelligence through age 4.5 years in at-risk children. Additional studies are necessary to validate the predictive ability of the NNNS in representative samples. Neonatal neurobehavior can be quite variable depending on timing of the examination as well as environmental factors, but the 1-month assessment time has been used in many published studies and is a more stable time point for evaluating newborn neurobehavior (Xu et al. 2011
). Normal physical examinations of newborn infants by medical providers quickly assess neurologic status by examining reflexes, tone, and general behavior but do not sensitively assess the specific of neurologic and behavioral factors that are assessed by the NNNS. Other infants within the HOME Study had abnormal neurologic examinations, but some of these mothers did not have elevated prenatal urinary BPA concentrations. These cases may have resulted from other etiologies of abnormal neurobehavior that have not yet been explored. The case infant displayed abnormal neurologic signs and behaviors at the 1-month examination, with no obvious etiology, which prompted us to conduct this case study. It is unclear how long these symptoms were present after the NNNS assessment. These abnormal findings were not noted by any other medical assessments performed by health care providers, including the primary medical doctor for the infant.
Other potential causes of abnormal neurobehavioral findings in an infant include brain injury due to hypoxic injury at birth, genetic causes, or some kind of postbirth neurologic insult (Paine 1961
; Volpe 2008
). The birth record documented a normal labor and delivery without insult, and there was no known family history of abnormal neurologic disease. Signs and symptoms of these types of insults can present immediately or take several days to manifest. Neurologic deficits with known etiology tend to persist past the neonatal period and take considerable time to resolve, if they resolve at all. The case infant had an isolated abnormal neurobehavioral examination at 1 month of age but without any apparent sequelae. No significant medical history that could have contributed to neurologic disease is noted in the medical record, and the mother stated that her infant had a normal course after discharge from the hospital. We did not identify an alternative etiology for the abnormal neurobehavioral findings from the medical record/questionnaire from 2004 or maternal interview in 2009.
This case study highlights a high prenatal urinary BPA concentration at 26-week gestation and an abnormal neurobehavioral examination at 1 month of age. It is likely that multiple sources of BPA exposure, which may have been avoided with appropriate education and resources, contributed to the mother’s elevated urinary concentration during pregnancy. This case raises the intriguing possibility that gestational BPA exposure may be associated with abnormal infant neurobehavior, because BPA is a suspected neurotoxicant that has elicited transient abnormal findings in toxicologic studies. Case reports or series of high-dose BPA exposures during fetal development offer a unique approach to study sources of BPA exposure and potential targets of toxicity. It is reassuring that the infant’s neurologic status was normal at follow-up, but the long-term health impacts of in utero BPA exposure remain to be determined by future studies that assess longitudinal developmental outcomes.