THE ASSOCIATION BETWEEN PRENATAL PYRETHROIDS EXPOSURE AND CHILDREN’S HEALTH – CURRENT RESEARCH

Exposure to pyrethroids, a widely used agricultural, forestry, and household insecticide, is a major public health concern due to its potential health effects on children. The aim of this review was to summarize the current knowledge of the effects of prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children. A systematic and comprehensive search of the PubMed, Web of Science, and Scopus databases was conducted during January–February 2024. The review included original articles published in peer-reviewed English-language journals since 2015. Based on keywords, 198 studies were identified and screened for eligibility. Ultimately, the review analyzed 25 articles including 16 that assessed the effects of prenatal exposure to pyrethroids on children’s neurobehavioural development, 3 studies that assessed the effects on the course and outcome of pregnancy, and further 3 focused on respiratory disease. In addition, 1 study analyzed the development of obesity and 2 studies examined the effects on children’s growth, weight and body composition in early childhood. In conclusion, there is considerable uncertainty about the adverse effects of prenatal exposure to pyrethroids on children’s health. The strongest evidence has been reported for neurobehavioural development although results are also inconsistent. Further research is needed to understand the mechanisms of action and health effects of pyrethroids in susceptible populations. Int J Occup Med Environ Health. 2024;37(4)


INTRODUCTION
Pyrethroids, both natural and synthetic derivatives of pyrethrin, are widely use as insecticides not only in agricultureor forestry but also in many households.They are promoted as a safer alternative to many chemicals such as organophosphates the use of which has been limited due to higher acute toxicity rates and long-term health concerns including developmental neurotoxicity [1].Pyrethroids currently have an estimated 38% share of the global insecticide market [2,3].Exposure to pyrethroids in the general population is common, with the key route of exposure being the ingestion of contaminated food and to a lesser extent, inhalation and dermal absorption [4,5].The biomonitoring of exposure to pyrethroids is based on the measurement of the concentration of metabolites excreted in urine.Urine is a reliable marker for assessing integrated exposure from different sources and routes [6][7][8].The widespread use of pyrethroids raises concerns about potential adverse health effects at low levels of exposure, especially among vulnerable populations such as pregnant women and children.Importantly children have higher pyrethroids exposure rates comparing to adults which can result from greater food consumption per unit of body mass, higher minute ventilation, larger relative body surface area, or age-specific behaviors including putting hands in the mouth, spending more time on the floor or near surfaces where pyrethroids were applied [9,10].Moreover, pyrethroids can cross the placenta and the blood-brain barrier, raising concerns about health effects of in utero exposure, especially when combined with the potential greater susceptibility of the fetus and child (thereby impacting children's health and susceptibility to diseases later in life) [5,11,12].Results from existing studies, summarized in systematic and narrative reviews by Elser et al. [13] (papers published up to 2022), Andersen et al. [14] (papers published up to September 2021) and Bliznashka et al. [15] (papers published up to 2015), suggest that exposure to Selection process and data collection process A comprehensive and systematic search of the databases was performed independently by 2 reviewers.Based on the inclusion criteria using title and abstract, irrelevant reports were excluded and the full text was assessed.Verification of the search results and resolution of the resulting inconsistencies were discussed within the research team.The following significant information was extracted from publications meeting the eligibility criteria: first author's name, year of publication, study design and population description (study name, country, period of recruitment, sample size, age of children), period of maternal exposure, metabolites determined, health outcomes observed, diagnostic tool, confounders, urinary pyrethroid metabolite concentrations and the results of analysis.

Study selection
In the search process utilizing keywords, 198 studies were identified and subjected to inclusion/exclusion verification.In the initial phase, following the analysis of titles and abstracts, 16 duplicates, 106 irrelevant studies, and 3 reviews were excluded.Subsequently, all publications selected during the title and abstract assessment phase underwent full-text review.The primary reasons for exclusion included the absence of original data, the analysis of pyrethroid metabolite concentrations in biological materials other than urine, and the evaluation of postnatal exposure.Ultimately, 25 publications were included in the review.Figure 1 presents a detailed flowchart of the study selection process for the review.2).Table 3 shows the concentrations of pyrethroid metabolites in maternal urine samples collected during pregnancy, the limit of detection (LOD) and the percentage of samples below LOD.Three-phenoxybenzoic acid, which represents the exposure to most pyrethroids, was the most commonly used biomarker.Direct comparison of the concentrations of pyrethroid metabolites in urine samples is difficult due to differences in analytical methods and LOD.In all studies included in the review, adjustments for potential confounders were made, although the number of confounded varied (Table 4).The most commonly assessed confounders included the following data: maternal education, socioeconomic status, child sex and age.

Reference
Eleven studies analyzed the association between prenatal exposure to pyrethroids and children's cognitive and psychomotor development [25][26][27][28][29][30][31][32][33][34][35].It is important to note that these findings are not conclusive.Of these, 5 found an inverse relationship, indicating a reduction in cognitive function in children with increasing maternal exposure to pyrethroids [25][26][27][28][29]. Watkins et al. [25] observed a decrease in mental development index (MDI) scores among 2 years old children who were prenatally exposed to mean levels of 3-PBA.However, this relationship was not observed in children at 3 years of age, nor for PDI scores at either 2 or 3 years of age.Fluegge et al. [26] observed a reduction in MDI with higher levels of 3-PBA in maternal urine during the third trimester of pregnancy but not during second trimester of pregnancy.Increase of cis-DCCA, trans-DCCA or 3-PBA (10-fold) in maternal urine was associated with a decrease in Social-Emotional scores in children at 1 year of age.On the other hand, an increase in cis-DBCA levels (10-fold) resulted in a decrease Language Composite and Expressive Communication scores at 2 years of age [27].
In addition, prenatal exposure to mixtures of potentially neurotoxic substances, including 3-PBA, was associated with lower intellectual functioning in children at the age of 7, although the authors did not provide a separate estimate of the effect for 3-PBA [28].Four studies found no significant association between prenatal exposure and cognitive function in children [30][31][32][33].
Only Hisada et al. [34] demonstrated a positive correlation between maternal urinary 3-PBA levels and higher developmental quotient scores in children at 18 months of age.
of individual metabolites and birth weight and between the total metabolite level and the infant's birth length or head circumference [17].Dalsager et al. [18] demonstrated that higher concentrations of 3-PBA in maternal urine, collected during the third trimester of pregnancy, were associated with smaller abdominal circumference in girls.On the other hand, results from Jaacks et al. [19] suggest that mothers with detectable 3-PBA concentrations were less likely to give birth to a baby small for gestational age.

Prenatal exposure to pyrethroids and neurodevelopmental outcomes
Sixteen epidemiological studies were conducted to analyze the effects of prenatal pyrethroid exposure on child neurodevelopment (Table 6).The study population size ranged 102-1041 mother-child pairs.Neurodevelopmental assessments were carried out in a group of children using validated tools such as the Wechsler Intelligence Scale for Children (WISC), the Bayley Scales of Infant Development (BSID) and the Strengths and Difficulties Questionnaire (SDQ).
Four studies observed a significant association between prenatal pyrethroid exposure and poorer behavioural outcomes [20][21][22][23][24]. Furlong et al. [20] indicated an association between maternal urinary concentrations of 3-PBA, cis-DCCA and deficits in the Internalizing, Depression, Somatization, Behavioral Regulation, Emotional Control, Shifting, and Monitoring scales in children.Similarly, Viel et al. [21] found that maternal exposure to cis-DCCA was associated with the occurrence of more internalizing problems, particularly in girls.In contrast, Dalsager et al. [22] and Lee et al. [23] investigated potential associations between the exposure to pyrethroids and the incidence of attention deficit hyperactivity disorder (ADHD) in children.A doubling of 3-PBA concentrations in urine samples collected from mothers in the third trimester of pregnancy was associated with a 3% increase in ADHD score and a 13%

R E V I E W P A P E R
The study conducted by Qi et al. [35] provided inconsistent and inconclusive results.Maternal exposure to 3-PBA during the second trimester was inversely associated with cognitive and language outcomes, while exposure to cis-DBCA was inversely associated with adaptive behaviour outcomes of children at 1 year of age.It is important to note that no such associations were found for exposure during the first or third trimester.However, it should be noted that maternal exposure to 4F-3-PBA during the third trimester was found to have a positive association with language scores.Similarly, adaptive behaviour scores were positively associated with cis-DBCA and sum of pyrethroids [35].

Children's health
The review included 6 studies that analyzed the impact of prenatal exposure to pyrethroids on the children's health, assessed based on anthropometric parameters and body composition analysis, the occurrence of respiratory diseases, including asthma, wheezing, or allergies (Table 7 and 8).Inconsistent and inconclusive results have been provided by studies focusing on the association between prenatal exposure to pyrethroids and anthropometric and body composition parameters (Table 7).According to Lee et al. [36], there is no correlation between maternal urinary 3-PBA concentrations during pregnancy and growth and adiposity parameters in early childhood.On the other hand, maternal concentrations of pyrethroid metabolites, specifically cis-DBCA and trans-DCCA, were negatively associated with body weight and composition in boys [37].In contrast, Kim et al. [38] highlighted that prenatal exposure to pyrethroids can reduce body fat in children at 5 years.Three studies focused on the association between exposure to pyrethroids during pregnancy and the frequency of respiratory diseases in children (      [40] suggested no association between prenatal exposure to pyrethroids and respiratory health outcomes.Only Hu et al. [41] indicated that maternal urinary 3-PBA concentrations were associated with a small decrease in FEV 1 /FVC in school-aged children.

Interpretation of the results
In summary, the reviewed studies demonstrated a variable relationship between maternal exposure to pyrethroids during pregnancy and the occurrence of adverse health effects in children.
The strongest evidence was noted for an increased risk of adverse behavioural outcomes and cognitive decline, which was also supported by the findings in the narrative review by Elser et al. [13] (papers published 2011-2022) and the systematic review by Andersen et al. [14] (papers published 2011-2021).However, the authors emphasize the need for further research to fully understand the neurodevelopmental effects of prenatal exposure on the compounds in question.The results should be interpreted with caution because of the limited number of studies that met the inclusion criteria and the variable effects of pyrethroid exposure during pregnancy on the course and outcome of pregnancy, weight and height of the child, and the incidence of respiratory diseases.We found no papers with previous works (before 2015) with the reviewed literature on the effects of prenatal exposure to pyrethroids on the occurrence of respiratory diseases or the development of obesity in children.In contrast, the results of 15 studies (papers published in 2003-2020) which analysed the relationship between prenatal exposure to pyrethroids and pregnancy outcome yielded mixed results [13].
Limited evidence and inconsistent results may be due to, the magnitude of exposure, the main routes of exposure, analytical methods, and the inability to separate remember all relevant details regarding symptoms, time of onset and response to treatment), flawed questionnaire design (questions in the questionnaire may be interpreted differently by respondents, resulting in inconsistencies in responses).Therefore, it is worth noting that to address the above limitations, Islam et al. [40] used a standard questionnaire (ISAAC study) to assess children's health status and Gilden et al. [42] and Hu et al. [41] additionally used clinical tests (spirometry).
The main limitation of the review is the small number of epidemiological studies that examined the association between prenatal exposure to pyrethroids and effects on pregnancy and pregnancy outcomes, weight and height, and incidence of respiratory disease in children, which did not allow firm conclusions to be drawn about the prevalence of associations.In addition, the characterization of exposure based on a single urine sample collected at different stages of pregnancy (pre-delivery, first, second, third trimester), different age groups of the children and different tools and methods used to assess the health outcomes analyzed may be a limitation that affects, the reliability of the exposure assessment and, the reliability of the observed health effects.

CONCLUSIONS
In conclusion, there is a considerable uncertainty regarding the adverse effects of prenatal exposure to pyrethroids on children's health.Further research is needed to understand the mechanisms of action and the effects of pyrethroids on the health of susceptible populations.

Agnieszka Brzozowska
Collecting material: Agnieszka Jankowska, Maja Ścieszko, Alicja Polańska reduced lung function in late childhood and even adulthood [46,47].The mechanisms linking prenatal pyrethroid exposure to anthropometric parameters and body composition are also unclear, possibly due to the small number of studies published available and inconsistent results in this area.
The adverse effects of pyrethroid exposure on pregnancy outcome may be due to greater susceptibility to toxicity in rapidly growing and developing fetal organs and lower levels of detoxifying enzymes than in adults.However, it should be noted that the exact mechanism of the potential effects of prenatal exposure to pyrethroids on the course and outcome of pregnancy is not fully understood [48].Knowledge and understanding of the mechanisms of action of pyrethroids is essential for both risk assessment and the development of strategies to minimize the occurrence of adverse health effects.

Strengths and limitations
This review aims to synthesize recent reports on the association between prenatal exposure to pyrethroids and the occurrence of adverse health outcomes in children.The majority of the studies included in this review are prospective cohort studies, which permit the tracking of changes in exposure levels and may provide evidence of a causal relationship between exposure and outcomes.Furthermore, a number of publications included in this review assessed multiple health effects and disorders (e.g., low birth weight, overweight/obesity, respiratory diseases, neurobehavioural and cognitive development) in children.This is crucial for a complete health risk assessment of prenatal exposure to pyrethroids.The use of questionnaires to collect data on the prevalence and course of respiratory diseases and allergies in children has some important limitations, i.e., reduced reliability of the data (answers given by parents may be subjective and may not reflect the child's true health status), incompleteness of the data (parents may not

Table 1 .
Characteristics of studies published in 2015-2024 included in the review on the effects of prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children

Table 1 .
Characteristics of studies published in 2015-2024 included in the review on the effects of prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children -cont.

assessment PYRETHROIDS EXPOSURE AND CHILDREN'S HEALTH R E V I E W P A P E RTable 2 .
Pyrethroids and their metabolites

Table 3 .
Concentrations of the pyrethroid metabolites in maternal urine in studies on prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children published in 2015-2024 -cont.

Table 3 .
Concentrations of the pyrethroid metabolites in maternal urine in studies on prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children published in 2015-2024 -cont.
R E V I E W P A P E RA. JANKOWSKA ET AL.

Table 4 .
[37]ounders included in the analyzes of the effects of prenatal exposure to pyrethroids on child development and health published in 2015-2024 scores included age, sex, gestational age, mid-parental height Z-score, paternal education, total energy intake, weekly physical activity, pre-and postnatal concentration of 3-PBA weight Z-scores included age, sex, gestational age, birth weight Z-score, maternal and paternal BMI, paternal education level, physical activity, total energy intake, pre-and postnatal concentration of 3-PBA BMI Z-scores included age, sex, gestational age, birth weight Z-score, maternal and paternal BMI, paternal education level and 3-PBA concentrationsKim et al., 2022 [38]maternal education, maternal age, height, post-delivery weight, household food poverty, food insecurity, wealth index, marital status, energy intake during pregnancy, alcohol use during pregnancy, HIV status at delivery, duration of exclusive breastfeeding, parity, child sex Coker et al., 2019[37]maternal education, maternal age, maternal BMI, maternal parity, household poverty status, maternal HIV status maternal education, child sex, concentration of pyrethroid metabolites in childhood, urinary concentration of creatinine (mother and child), maternal concentrations of organophosphate metabolitesHisada et al., 2017 [34]maternal age, gestational week, birth weight, maternal BMI, parity, child sex, concentration of TSH in the child's blood 5 days after birth, breastfeeding duration, age of child at examination, Index of Child Care Environment score; a second model also included fish consumption Furlong et al., 2017 [20] maternal education, maternal marital status, race/ethnicity, quality of the home environment -HOME scores, organophosphate metabolites (ΣDMPs), urinary concentration of creatinine visit, child sex Eskenazi et al., 2018 [27] maternal education, age, poverty status and marital status at delivery, breastfeeding, Raven's Coloured Progressive Matrices Z-score for the mother/caregiver, preterm birth, birth weight Z-scores, maternal depression risk score, U.S. Department of Agriculture Food Insecurity Score, modified HOME Z-score, the psychometrician administering the BSID-III Dalsager et al., 2019 [22] maternal educational, parental psychiatric diagnosis, child age, child sex, urinary concentration of creatinine Tanner et al., 2020 [28] maternal education, maternal IQ, weight, smoking status, child sex, urinary concentration of creatinine Guo et al., 2020 [31] maternal education, age of the mother at birth, family income, passive smoking during pregnancy, breastfeeding duration, child sex, doctors performing IQ assessment, marital status at assessment, urinary concentration of creatinine Andersen et al. 2021 [32] maternal education, breastfeeding duration, child sex, urinary concentration of creatinine Qi et al., 2022 [35] maternal education, maternal age, poverty status, perceived stress, weight gain, urine concentration of cotinine during pregnancy, child sex, birth weight Z-scores, primary caregiver and parenting time for children, Hu et al., 2022 [41] maternal education, maternal age, pre-pregnancy BMI, family income, child's age, child sex, BMI, height, and passive smoking, urinary concentration of creatinine Islam et al., 2023 [40] maternal smoking during pregnancy, child sex, parity, breastfeeding, maternal history of asthma PYRETHROIDS EXPOSURE AND CHILDREN'S HEALTH R E V I E W P A P E R tration of the sum of cis-DCCA, trans-DCCA and 3-PBA metabolites in maternal urine was associated with a significant reduction in the infant's birth weight, whereas no association was observed between the concentration Only 3 studies met the inclusion criteria and were included in this review [17-19] (Table 5).Ding et al. [17] and Dalsager et al. [18] observed a negative association for the relationship in question.An increase in the concen-BSID-III -Bayley Scales for Infant Development, 3 edition; HOME -Health Outcomes and Measures of the Environment.3-PBA -3-phenoxybenzoic acid; TCPy -3,5,6-trichloro-2-pyridinol (metabolite of chlorpyrifos).TSH -thyroid stimulating hormone.n.a.-not available.

Table 5 .
Associations between prenatal pyrethroid levels and birth outcomes -review of studies on prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children published in 2015-2024

Table 4 .
Confounders included in the analyzes of the effects of prenatal exposure to pyrethroids on child development and health published in 2015-2024 -cont.

Table 6 .
Associations between prenatal pyrethroid levels and neurodevelopmental outcomes in children in studies on prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children published in 2015-2024 Reference

Table 6 .
Associations between prenatal pyrethroid levels and neurodevelopmental outcomes in children in studies on prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children published in 2015-2024 -cont.

Table 8 )
. To diagnose respiratory diseases and allergies, the recommendations of the International Study of Asthma and Allergies in

Table 7 .
Associations between prenatal pyrethroid levels and anthropometric parameters and body composition in children in on prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children studies published in 2015-2024

Table 8 .
Associations between prenatal pyrethroid levels and respiratory and allergic diseases in children in studies on prenatal exposure to pyrethroids on the course and outcome of pregnancy, health status, and neurobehavioural development of children published in 2015-2024 the effects of exposure during fetal life from those occurring after birth.In addition, studies varied in the choice of health outcomes assessed (e.g., birth weight, low birth weight), the tools used to assess them (particularly in relation to neurodevelopmental outcomes and respiratory disease), and the age groups of children.It should also be noted that many studies characterized exposure based on the common metabolite for most pyrethroids, 3-PBA, which may makes it difficult to identify specific health effects for individual insecticides.In addition, most studies have relied on a single urine sample to assess exposure, which may not fully describe the exposure given the short half-life of pyrethroids in the body.The mechanisms linking the occurrence of adverse health effects in children to prenatal exposure to pyrethroids are not fully understood.Studies in animal models have provided evidence of the effects of pyrethroids on systems and processes critical for brain and nervous system development.