Prenatal Exposure to PFAS and the Risk of Cerebral Palsy
Prenatal Exposure to PFAS and the Risk of Cerebral Palsy
We found a dose-response–like association between prenatal exposure to PFAS and the risks of CP in boys, and similar associations were seen for spastic unilateral or bilateral CP subphenotypes. No associations between PFASs and CP were found in girls, but the statistical power to estimate effects for girls was low because of small numbers. Recent evidence in animal and human studies suggests that PFASs interfere with maternal hormone function during pregnancy; deficiency of thyroid hormone during critical periods of brain development can damage the nervous system and cause neurodevelopment disorders such as CP.
Two previous studies used subsets of the DNBC samples and found no associations between prenatal exposures to PFOS/PFOA and scales of motor function and coordination of children at ages 18 months and 7 years. However, the study endpoints were self-reported by mothers and potentially prone to nondifferential measurement errors. More recently, in a birth cohort from Taiwan, trained physical therapists were asked to evaluate children's neurodevelopment, and the authors reported higher prenatal PFOS levels associated with lower gross motor function in children at 2 years of age, but the predictive value of the scores that were used may be low at these young ages.
Our study shows that PFAS exposures were correlated with CP risk only in boys, which could be a chance finding, but a possible sex-specific mechanism should be further investigated. There is some evidence suggesting that PFASs are sex-specific endocrine disruptors in vitro and in adults, and motor functions in PFAS-exposed mice were impaired in a sex-related manner. The vulnerability of different brain areas during different developmental windows may also differ by sex. Moreover, the male brain is suggested to be more vulnerable to white matter injuries and intraventricular hemorrhage, and males are, in general, at higher risk of CP.
CP risks were elevated among boys born at term to mothers with higher PFAS levels, but results are imprecise for boys born preterm. It should, however, be taken into consideration that gestational age may be a mediator in the causal pathway between PFAS exposure and CP, and stratification on preterm birth status could potentially introduce collider bias that could lead to either overestimated or underestimated risks.
The maternal PFAS values measured in our study are comparable to those previously reported during a similar time period in the US general population. The PFAS values below the lower limit of quantitation in our studies were estimated from multiple imputations, but the influence of estimation errors would be small for PFAS quartiles. Because concentrations for several PFASs were moderately correlated, it is difficult to disentangle whether specific compounds or the combination of substances are driving the associations. PFOS remained positively associated with CP after adjustment for the other types of PFAS in the same model. A recent in vitro assay found mixture-specific effects of 5 PFASs tested simultaneously for their ability to interfere with androgen receptors. Further experimental studies are needed to examine mechanisms of how different PFASs act on biological targets.
This study has several strengths. First, PFAS values were measured in prospectively collected maternal plasma samples. PFASs have a long biological half-life in humans, and it has previously been shown that PFAS measurements in serum and plasma samples are very comparable. High correlations between maternal and cord blood PFAS concentrations have been reported and suggest that PFAS in maternal plasma is also a valid marker of fetal exposure. Moreover, participants were selected from a well-defined nationwide cohort with a sufficient duration of follow-up (approximately 10 years, on average, in the DNBC) to catch all congenital CP cases, and CP cases were ascertained from records of the Danish National Cerebral Palsy Registry with unique civil registration numbers used for linkage. Because follow-up does not require the subject's active participation, selection bias due to differential response is not an issue. CP diagnoses were validated by experts' review of the children's medical records, which reduces disease misclassification. However, children must survive to at least 1 year of age to be diagnosed in the Danish National Cerebral Palsy Register; therefore, we likely underascertained the number of severe CP cases who died in pregnancy, at birth, or during early infancy. If PFAS exposure reduces fetal/neonatal survival, survival bias might occur, and we would expect an attenuation of the observed results.
We have no data for other endocrine-disrupting compounds; therefore, we could not evaluate possible confounding by organophosphates, bisphenol A, and phthalates. However, additional adjustment for dietary factors and household characteristics as proxies for common sources of exposure to endocrine-disrupting chemicals did not change our results and conclusions. Nonparticipation in the DNBC cohort would raise concerns if exposure has an influence on the selection of mothers who are at higher risk of having children with CP, and selective participation may also limit the generalizability of our results.
In summary, we found that prenatal exposure to some PFASs may increase the risk of CP in children. This finding raises concerns, because PFASs are ubiquitous and persistent in the environment, and CP has long-lasting impacts on patients, caregivers, and society. If this finding is causal, we have identified a potential preventable risk factor for CP, but further studies using other data sources are needed to reach such a conclusion.
Discussion
We found a dose-response–like association between prenatal exposure to PFAS and the risks of CP in boys, and similar associations were seen for spastic unilateral or bilateral CP subphenotypes. No associations between PFASs and CP were found in girls, but the statistical power to estimate effects for girls was low because of small numbers. Recent evidence in animal and human studies suggests that PFASs interfere with maternal hormone function during pregnancy; deficiency of thyroid hormone during critical periods of brain development can damage the nervous system and cause neurodevelopment disorders such as CP.
Two previous studies used subsets of the DNBC samples and found no associations between prenatal exposures to PFOS/PFOA and scales of motor function and coordination of children at ages 18 months and 7 years. However, the study endpoints were self-reported by mothers and potentially prone to nondifferential measurement errors. More recently, in a birth cohort from Taiwan, trained physical therapists were asked to evaluate children's neurodevelopment, and the authors reported higher prenatal PFOS levels associated with lower gross motor function in children at 2 years of age, but the predictive value of the scores that were used may be low at these young ages.
Our study shows that PFAS exposures were correlated with CP risk only in boys, which could be a chance finding, but a possible sex-specific mechanism should be further investigated. There is some evidence suggesting that PFASs are sex-specific endocrine disruptors in vitro and in adults, and motor functions in PFAS-exposed mice were impaired in a sex-related manner. The vulnerability of different brain areas during different developmental windows may also differ by sex. Moreover, the male brain is suggested to be more vulnerable to white matter injuries and intraventricular hemorrhage, and males are, in general, at higher risk of CP.
CP risks were elevated among boys born at term to mothers with higher PFAS levels, but results are imprecise for boys born preterm. It should, however, be taken into consideration that gestational age may be a mediator in the causal pathway between PFAS exposure and CP, and stratification on preterm birth status could potentially introduce collider bias that could lead to either overestimated or underestimated risks.
The maternal PFAS values measured in our study are comparable to those previously reported during a similar time period in the US general population. The PFAS values below the lower limit of quantitation in our studies were estimated from multiple imputations, but the influence of estimation errors would be small for PFAS quartiles. Because concentrations for several PFASs were moderately correlated, it is difficult to disentangle whether specific compounds or the combination of substances are driving the associations. PFOS remained positively associated with CP after adjustment for the other types of PFAS in the same model. A recent in vitro assay found mixture-specific effects of 5 PFASs tested simultaneously for their ability to interfere with androgen receptors. Further experimental studies are needed to examine mechanisms of how different PFASs act on biological targets.
This study has several strengths. First, PFAS values were measured in prospectively collected maternal plasma samples. PFASs have a long biological half-life in humans, and it has previously been shown that PFAS measurements in serum and plasma samples are very comparable. High correlations between maternal and cord blood PFAS concentrations have been reported and suggest that PFAS in maternal plasma is also a valid marker of fetal exposure. Moreover, participants were selected from a well-defined nationwide cohort with a sufficient duration of follow-up (approximately 10 years, on average, in the DNBC) to catch all congenital CP cases, and CP cases were ascertained from records of the Danish National Cerebral Palsy Registry with unique civil registration numbers used for linkage. Because follow-up does not require the subject's active participation, selection bias due to differential response is not an issue. CP diagnoses were validated by experts' review of the children's medical records, which reduces disease misclassification. However, children must survive to at least 1 year of age to be diagnosed in the Danish National Cerebral Palsy Register; therefore, we likely underascertained the number of severe CP cases who died in pregnancy, at birth, or during early infancy. If PFAS exposure reduces fetal/neonatal survival, survival bias might occur, and we would expect an attenuation of the observed results.
We have no data for other endocrine-disrupting compounds; therefore, we could not evaluate possible confounding by organophosphates, bisphenol A, and phthalates. However, additional adjustment for dietary factors and household characteristics as proxies for common sources of exposure to endocrine-disrupting chemicals did not change our results and conclusions. Nonparticipation in the DNBC cohort would raise concerns if exposure has an influence on the selection of mothers who are at higher risk of having children with CP, and selective participation may also limit the generalizability of our results.
In summary, we found that prenatal exposure to some PFASs may increase the risk of CP in children. This finding raises concerns, because PFASs are ubiquitous and persistent in the environment, and CP has long-lasting impacts on patients, caregivers, and society. If this finding is causal, we have identified a potential preventable risk factor for CP, but further studies using other data sources are needed to reach such a conclusion.
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