Texto & Contexto Enfermagem

Objective: to assess whether maternal and paternal exposure to toxic agrochemicals throughout life causes congenital malformations. Method: a scoping review was carried out on the PUBMED, CINAHL, EBSCO, MEDLINE, LILACS, SciELO, BDENF, Web of Science and ATHENA databases between August and September 2019 and updated in December 2020. A cohort and case control study were included, which addressed the effects of parents’ exposure throughout their lives to toxic agrochemicals which caused congenital malformation outcomes. Results: the review covered 32 studies published between 2005 and 2020. The main malformations presented are related to the reproductive system, nervous system, musculoskeletal system, transverse limb deficiencies, digestive system and other malformations such as fetal growth restrictions, cleft palate and congenital heart disease. The most investigated toxic agrochemicals in the studies were the herbicides represented by atrazine. Conclusion: maternal and paternal exposure to toxic agrochemicals can be associated with greater chances of children being born with congenital malformations, especially those related to the male reproductive system. DESCRIPTORS: Congenital, hereditary and neonatal diseases and anomalies. Toxic agrochemicals. Pesticides. Review.


Grupo Hospita
ar Conceição. Porto Alegre
Rio Grande do SulBrasil

 Franciela 
Delazeri Carlotto 
Grupo Hospitalar Conceição. Porto Alegre
Rio Grande do SulBrasil

 Richard 
Santos Afonso 
Universidade Federal do Rio Grande do Sul
Instituto de Geociências. Porto Alegre
Rio Grande do SulBrasil

 Deise 
Lisboa Riquinho 
Escola de Enfermagem
Departamento de Assistência
Universidade Federal do Rio Grande do Sul



Orientação Profissional. Porto Alegre
Rio Grande do SulBrasil

EXPOSURE TO TOXIC AGROCHEMICALS AND DEVELOPMENT OF CONGENITAL MALFORMATIONS: A SCOPING REVIEW
1980-265X19A6718C3E539B37266DDD180D14A4A510.1590/1980-265X-TCE-2020-0372Received: Sepember 16, 2020. Approved: December 17, 2020.Enfermedades y anomalías congénitas, hereditarias y neonatalesAgrotóxicosPesticidasRevisió Objective: to assess whether maternal and paternal exposure to toxic agrochemicals throughout life causes congenital malformations.Method: a scoping review was carried out on the PUBMED, CINAHL, EBSCO, MEDLINE, LILACS, SciELO, BDENF, Web of Science and ATHENA databases between August and September 2019 and updated in December 2020.A cohort and case control study were included, which addressed the effects of parents' exposure throughout their lives to toxic agrochemicals which caused congenital malformation outcomes.Results: the review covered 32 studies published between 2005 and 2020.The main malformations presented are related to the reprodu tive system, nervous system, musculoskeletal system, transverse limb deficiencies, digestive system and other malformations such as fetal growth restrictions, cleft palate and congenital heart disease.The most investigated toxic agrochemicals in the studies were the herbicides represented by atrazine.Conclusion: maternal and paternal exposure to toxic agrochemicals can be associated with greater chances of children being born with congenital malformations, especially those related to the male reproductive system.DESCRIPTORS: Congenital, hereditary and neonatal diseases and anomalies.Toxic agrochemicals.Pesticides.Review.

INTRODUCTION

Diverse scientific evidence indicates that the environment can be related to the occurrence of congenital malformations such as anomaly of the limbs, orofacial fissures a

failur
in male urogenital development, in addition to spontaneous abortions, which can be accentuated when the parents are exposed to toxic agrochemicals.These congenital malformations are included in the list of congenital anomalies that can be defined as structural or functional changes that occur during intrauterine life [1][2] .Nearly 50% of the congenital anomalies are not linked to a specific conditioning factor.However, there are known causes that can be related, such as socioeconomic, demographic and environmental factors, infections, genetic factors and maternal nutritional status 3 .

Although some of t e active ingredients of the agrochemicals are classified as moderately or slightly toxic, based on their acute effects, it is necessary to consider that the chronic effects can occur in months, years or even decades after exposure, manifesting in several diseases, such as tumors, congenital malformations, and endocrine, neurological and mental disorders 4 .In the vast areas of monocultures, agrochemica s are sprayed by means of tractors and airplanes on the crops, affecting not only the "pests" in the plantations, but also the soil, surface water, air, rain and food, as well as workers, surrounding residents and animals 5 .

The Brazil is the largest consumer of toxic agrochemicals in the world 5 .Based on this problem, the objective of this study was to assess whether maternal and paternal exposure to toxic agrochemicals throughout the life causes congenital malformations.This research included 32 studies, the quality of the evidence was considered as level 4, that is, with evidence from well-designed cohort and case control studies 6 .Among the papers selected in the research, there are 12 research studies carried out i the USA and 3 in Brazil, showing anomalies related to the reproductive system (hypospadias, cryptochidism and micropenis) [7][8][9][10][11][12][13][14][15][16][17] , to the nervous system 12,[18][19][20][21][22][23][24] and other malformations [25][26][27][28][29][30][31][32][33][34][35][36][37][38] .


METHOD

A scoping review was carried out following the method recommended by the Joanna Briggs Institute 39 according to the theoretical framework proposed by Arksey and O'Malley 40 .This type of research consists of an exploratory review aimed at mapping, in the scientific production, relevant studies in a given area, following the steps of the scoping review: 1. Identification of the research question; 2. Identification of relevant studies; 3. Selection of studies; 4. Data extraction; and 5. Summary and reporting of results.6.The sixth consultation step, considered optional, was not used in this study 39,41 .

The research question for this study was elaborated according to the PCC 39 mnemonic combination (P: Population -mother or father exposed to toxic agrochemicals; C: Concept -cong nital malformation; C: Context -the world), with the following guiding question being established: Is maternal and paternal exposure to toxic agrochemicals throughout life associated with congenital malformations in children?

One of the data sources consulted was the Virtual Health Library, which included the following databases: International Literature in Health Science (MEDLINE), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Base de dados da nfermagem (BDENF ), Cumulative Index to Nursing and Allied Health Literature (CINAHL).The searches for the publications indexed in the virtual libraries included: National Library of Medicine (PUBMED), EBSCO, Scientific Electronic Library Online (SciELO), Web of Science and Université Paris-Est Créteil Val de Marne (ATHENA.In order to guarantee research integrity, the researchers reviewed the reference lists of the selected articles to identify other possible relevant studies.

The following controlled terminology descriptors recommended by the Medical Subject Headings (MeSH) and/or the Health Sciences Descriptors (Descritores em Ciências da Saúde, DeCS) were 4/18 selected: Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Congenital diseases; Congenital malformations; Neonatal Diseases; Agrochemicals; Pesticides.All of these terms were searched for in their equivalences in Spanish, French and Portuguese.The search strategy used followed the definition of each corresponding database.The Boolean AND operator was used with the fol

es".The searches were perfo
med between August and September 2019 and updated in December 2020.

The refinement of the articles found was based on the eligibility criteria.The pre-established inclusion criteria were as follows: cohort and/or case control study, published in Portuguese, Spanish, English and French, which studied the effects of maternal and/or paternal exposure to toxic agrochemicals throughout life on congenital malformations.No time limit was established and duplicate studies, reviews, meta-analyses, theses, dissertations and books were excluded.

In addition to this, to systematize the process of inclusion of the studies, the PRISMA Extension for Scoping Reviews 42 methodology was chosen.The studies were pre-selected from reading the titles nd abstracts, and the final sample was reached based on reading the articles in full, according to the flowchart shown in Figure 1.In the data extraction stage, an instrument structured in Microsoft Excel was used, which allowed mapping the essential elements of the studies, such as author, year of publication, country where the study was conducted, journal, type of study, description of the sample, outcome and the level of evidence of the study 6 .The data were extracted in a double-independent fashion and, in case of dissent, a third reviewer was contacted.In this way, in order to present an overview of the entire material, the presenta

on of
the results was elaborated in a chart with the main characteristics of the studies, organizing a numerical description of the results and a thematic description according to the nature of the research.


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RESULTS

After the process of evaluation and selection of articles, 32 studies were included in the scoping review  . Thes were published between 2005 and 2018 (Chart 1).The results were presented with a description of the characteristics of the studies, and the main congenital malformations evidenced from the selected studies and the most frequently identified toxic agrochemicals in the studies are described.


Description of the studies

The largest number of publications was in the years 2014 12,21,[23][24][25]29,32 (n=7), 2020 [10][11]19,[34][35][36] (n=6), 2011 8,15,16,22,27-28 (n=6) and in 2010 7,9,13,18,33 (n=5). As fo the country where the studies were developed, most were from the United States 7,11,15,17,19,21,[23][24]26,29,32 , (n=10) f llowed by studies in Brazil 2,25,38 , (n=3), France 10,14,27 (n=3), India 20,31,16 (n=3) and Mexico 13,18 (n=2) (Chart 1).For being an inclusion criterion, most of the studies were case-control studies [7][8]10,[26][27][28][29][30][31][32][33][34][35][36][37][38] (n=29) and only three studies were cohort 8,10,27 (n=3) (Chart 1).In the 32 studies, the quality of the evidence was considered level 4, that is, with evidence from well-designed cohort and case control studies 6 .

Below are four categories generated to meet the study objective: malformations related to the reproductive system, in which the main malformation found was hypospadias, followed by cryptorchidism and micropenis; malformations related to the nervous system such as neural tube defects (anencephaly, spina bifida), cleft palate and other malformations, such as fetal growth, digestive and musculoskeletal system restrictions, such as gastroschisis, choanal stenosis, transverse limb defects, cleft palate were also found.A fo rth category with the toxic agrochemicals most frequently identified in the studies was also established.


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Malformations related to the reproductive system Among the 32 studies analyzed, twelve demonstrated an association between exposure to toxic agrochemicals and the occurrence of outcomes related to the reproductive system.Of these studies, hypospadias appeared more frequently (n=8) 7-9,12,14-17 , followed by cryptorchidism (n=3) 8,11,13 and micropenis (n=1) 8 .The association between prenatal expo ure to organochlorines and the occurrence of cryptorchidism was found through a case-control study.In addition to this, organophosphate levels in serum lipids of mother with children with cryptorchidism were analyzed, as well as in a control group of mothers of children with descending testicles; and the newborns' umbilical cord blood samples were studied.The levels of organochlorine metabolites w re found in greater amount among mothers of newborns with cryptorchidism than among mothers of children with testicular descent: OR=1.79, 95% CI (1.34 -2.24) 13 .

According to a cohort study carried out in northeastern Brazil, the prevalence of newborns diagnosed with micropenis with maternal and paternal exposure to household pesticides was investigated.Exposure was assessed using a questionnaire, testosterone analysis and molecular gene analysis.Of the newborns monitored, 56 m lformations were identified, with cryptorchidism (n=23), hypospadias (n=15) and micropenis (n=18).Most of the parents of these newborns reported exposure to toxic agrochemicals during paid and unpaid work, with 80.36% of the mothers and 58.63% of the fathers.This study indicated that exposure to disruptors of the endocrine system before and during pregnancy indicates that fetal contamination can be a risk factor for the development of male external genital malformation 8 .In the case control study carried out in Ethiopia, women exposed to pesticides during pregnancy were twice as prone to having children with congenital malformations (OR=3.19;95% CI=1.31, 10.96) 35 .

In a study carried out to assess the association between consumption of atrazine in

ater
nd hypospadias through a population-based control case, exposure to atrazine was measured using a maternal questionnaire on water and drinking water consumption (OR=1.00;95% CI), estimating the total maternal consumption of atrazine (OR=1.02;95% CI).In this study, the association between hypospadias and daily maternal exposure to atrazine during the critical window of genitourinary development was weak or null 17 .

When associated with exposure to organophosphates and hypospadias, through the analysis of organophosphate metabolites in the blood and hair collected from children with hypospadias and their parents, it was verified that they had higher values than the general population, sugges ing that exposure to organophosphate and organochlorine pesticides can be a potential risk factor for hypospadias 12 .

A study 9 verified the association between maternal environmental exposures to endocrine disrupting toxic agrochemicals and the occurrence of births diagnosed with hypospadias.Through a control case, an association was verified between maternal exposure to a class of endocrine disrupters (OR=2.44;95% CI) and (OR=4.11;95% CI)

r more than one class.The high plasma concen
ration of hexachlorobenzene (OR=2.44)can be related to the development of hypospadias in the newborn 9 .

Regarding exposure to organochlorines, scholars 16 conducted a case control study assessing the risk of hypospadias.The evaluation took place using the blood samples collected from the children to assess the levels of organochlorines and polymorphism in the CYP1A1, GSTM1 and GSTT1 genes.The results showed that exposure to high levels of organochlorines increased the risk of developing hypospadias 16 .In 2005, Morera et al 14 .conducted a case-control study, with 225 cases (n=225) and 225 controls (n=225), to assess exposure to pesticides during the prenatal period and the occurre ce of hypospadias.Thus, they concluded that exposure to toxic agrochemicals increased the chances of developing hypospadias in the newborn (OR=1.54;CI=0.83-2.84) 14.


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However, according to the other studies 715 ,, it was not possible to identify an association between exposure to toxic agrochemicals and the risk of hypospadias.Onde of the studies 15 concluded that occupational exposure to fungicides, insecticides and herbicides in the maternal periconceptional period was not associated with an increased risk of hypospadias (OR=0.78;95% CI=0.61-1.01),while other authors 7 showed no association between maternal exposure to toxic agrochemicals and hypospadias, as they found no statistically significant results when studying maternal exposure to brominated, polychlorinated biphenyls and other pestic des and the occurrence of hypospadias in their children.

In addition to this, in the case control study 11 , whose objective was to analyze maternal exposure in early pregnancy to organochlorines and an association with the risk of cryptorchidism, no statistically significant associations were found.As was the case in the cohort carried out by other authors 10 , where no association was also found between the use of this input and the occurrence of malformations related to the reproductive system.
Malformations related to the nervous system

Of the studies analyzed, seven [18][19][20][21][22][23][24] showed an association between exposure to toxic agrochemicals and the occurrence of outcomes related to the Central Nervous System (CNS) in newborns.The association between maternal exposure to organochlorines and neural tube defects in newborns was verified through a case-control study.Blood levels of dichlorodiphenyldichlorethylene (DDE), total hexachlorocyclohexane (t-HCH) and endosulfan in mothers in the case group and in newborns with neural tube defects were significantly higher.Mothers who had children with NTDs were 11.3 times more likely to have DDE levels above the median concentration of the control group 20 .

In China, conducted a study 22 to investigate the association between the occ rrence of neural tube defects in newborns due to the exposure of pregnant women to toxic agrochemicals.The levels of agrochemicals were analyzed in placentas of pregnant women who had chi

ren w
th neural tube defects.Placental concentrations of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides, polychlorinated biphenyls, dichlorodiphenyltrichloroethane (DDT) and hexachlorocyclohexane (HCH) were significantly higher in the placentas with newborn NTD outcome.Thus, the risk for increased PAH levels was 4.52 times greater (95% CI=2.10-9.74)for any neural tube defect, in addition to 5.84 (95% CI=2.28-14.96)and 3.71 times (95% CI=1.57-8.79) of increased risk of anencephaly and spina bifida, respectively 22 .

Authors 21 analyzed the occurrence of NTDs in newborns of pregnant women who were exposed to toxic agrochemicals in the preco ception and up to two months after conception.There was a positive, although not significant, association for the combined classes of insecticides and herbicides referring all types of NTDs.As for the joint classes of insecticides, herbicides and fungicides, there was a significant association for all NTD cases, with greater occurrence of anencephaly a

encephalocele 21 .
In relation to other malformations related to the nervous system, an increased risk of newborns having anencephaly, spina bifida, cleft lip without or with cleft palate or cleft palate was identified in pregnant women with early exposition to toxic agrochemicals.The estimate was made based on residential proximity in places with application of agrochemicals.Petrol um derivatives contributed to the increase in the occurrence of anencephaly; herbicides, specifically hydroxybenzonitrile, for spina bifida; and 2,6-dinitroaniline herbicides and dithiocarbamate methyl isothiocyanate, for cleft lip or palate.However, none of the 26 chemical products analyzed had an Odds Ratios with an associated confidence interval, although this environmental factor may be a condition for the onset of these diseases 23 .

In a case-control study c nducted in Mexico, authors 18 evaluated the exposure of pregnant women to toxic agrochemicals and the emergence of defects in the neural tube of their newborns.


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According to the authors, interviews were conducted with the women for research on education, smoking and folate use.The women who used some chemical substance in their backyards were twice as likely to have newborns with neural tube defects (95% CI=1.2-3.1) when compared to women without these reported exposures.In addition to this, the women in the case group also reported living less than 0.35 km from cultivated fields than women in the control group (OR=3.6;95% CI=1.7-7.6).Thus, the information regarding exposure to toxic agrochemicals increases the risk for the emergence of defects in the neural tube, especially of anencephaly in newborns 50 .

A study carried out in the USA identified an increased risk for the development of holoprosencephaly in children whose mothers were exposed to pesticides during the pre-conception period or during pregnancy (OR=2.60,95% CI=0.84-8.68).No association was found for occupational exposures to pesticides during pregnancy (OR=1.15,95% CI=0.11-11.42) 19.


Other malformations

In addition to malformations related to the reproductive and nervous systems, a ticles were also found referring to malformations related to fetal growth restrictions (n= 2) 27,31 , to the digestive system (n=3) 29,[32][33] , to the musculoskeletal system (n=1) 26 , to the circulatory system (n=2) 34,36 , and congenital anomalies in general (n=5) 25,27,30,35,37 .

In France in 2011, authors 27 conducted a study between 2012 and 2016, using urinary biomarkers to detect exposure to atrazine before the 19 th gestational week and its possible adverse events for pregnancy.As a result, they found metabolites of this herbicide in between 20% and 40% of the samples, and the presence of these metabolites was positively associated with fetal growth restriction and small head circumference according to gender and gestational age 27 .

Also on fetal growth restriction, authors 31 produced a study that sought to identify genes present in pregnant women with fetal growth restrictio

that i
teract with organochlorines, looking for the cause of the restriction.For this, the study used blood samples from the mother and the umbilical cord.Among these samples, significantly higher levels of organochlorines were found in the cases when compared to the controls 31 .

Regarding the digestive system, scholars 33 , conducted a case-control study to determine periconceptional exposure to toxic agrochemicals, finding an association between the development of gastroschisis and the distance of the maternal residence from places with high exposure to pesticides.As a result, gastroschisis was positively associated with those who lived <25 km from places with high exposure (OR=1.6).However, authors 32 verified that gastroschisis was also positively related to maternal occupational exposure to insecticides, herbicides and fungicides (OR=1.88;95% CI).However, contrary to the re ults found by scholars others 33 , the study carried out in California 32 did not identify any association between exposure to triazines and gastroschisis or a standard profile related to women having children with gastroschisis.

The study carried out in the USA 29 , sought to identify the residential exposure of women to toxic agrochemicals and its relationship with choanal atresia or stenosis; it was found that the children of mothers with high exposure accordingly had an increase in choanal atresia or stenosis (OR=1.79;95% CI) 29 .In relation to the occurrence of cleft palate and maternal occupational exposure to solvents and pesticides, a case-control study showed that maternal exposure to pesticides si nificantly increased the chance of developing cleft palate (OR=1.7;95% CI) 37 .

In Paraguay, a study 30 sought to determine the association between the prenatal risk factors and the occurrence of congenital anomalies.An association was observed between malformations with distance <1 km of the residence from fumigated fields (OR=3.75;95% CI) and direct maternal exposure to pesticides (OR=4.51;95% CI) 30 .


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In relation to congenital malformations in general, in a hospital in Mato Grosso

Sul, a Bra
ilian state that has agribusiness as the basis of its economy, one study 38 investigated the association between parental exposure to pesticides and the occurrence of congenital malformations in children.Thus, a positive association was observed between exposure to toxic agrochemicals and th occurrence of congenital anomalies, associated with low maternal education (OR=8.40;95% CI) 38 .Another Brazilian study carried out in Mato Grosso do Sul 25 sought to analyze the occurrence of congenital anomalies in the municipalities with the greatest exposure to toxic agro

emicals.Thu
, significant associations were observed related to exposure to agrochemicals in the post-fertilization period (OR=1.66;95% CI and OR=1.88; 95% CI) and in the periconceptional period (OR=2.04;95% CI).

In relation to paternal exposure to toxic agrochemicals and the occurrence of congenital anomalies, a case-control study 28 analyzed that certain occupations during the periconceptional period can increase the chances of the occurrence of congenital anomalies.Parental occupation with pesticides, solvents, solder smoke, lead, working with video displays and computer monitors was studied, with a verified greater chance of having children with congenital anomalies in occupations with exposure to pesticides (OR=3.42;95%CI=1.97-5.92),solvents (OR=5.63,95% CI=2.77-11.42)and solder smoke

OR=2.9
;95% CI=0.99-8.54), in addition to inbreeding, which was considered a risk factor (OR=1.91, 95% CI=1.25-2.92) 28.

Regarding the malformations related to the circulatory system, a case-control study carried out in Hungary found a positive association between paternal exposure to pesticides (OR=1.66,95% CI=1.03-2.69)and alkylphenolic compounds (OR=1.95,95% CI=1.30-2.93)and the occurrence of patent ductus arteriosus.However, another case-control study, conducted in the Netherlands, found no association between maternal occupational exposure to pesticides and the occurrence of cardiac abnormalities 34 .


Pesticides

As for the toxic agrochemicals most frequently identified in the studies, it is worth mentioning that the Atrazine herbicide was the most reported (n=11) 8,17,21,24,[26][27][29][30]33,[36][37] , followed by 11 studies that investigated organochlorines 7,[9][10][11]13,16,[20][21][22][23]31 .

The exposure to and/or application of toxic agrochemicals was verified in (n=8) studies [14][15]25,28,30,[37][38]52 . Insecticides was xamined in six studies 8,15,21,24,26,36 and fungicides, in four studies 15,24,26,37 .Only two studies investigated organophosphates 21,32 .


DISCUSSION

The toxic agrochemicals considered to be endocrine disruptors include insecticides, herbicides and fungicides.These inputs are used in agriculture, aquaculture and domestic uses, whose residues have been found in food, drinking water and water bodies 43 .Some classes of agrochemicals present estrogenic and/or anti-estrogenic activity, such as organochlor nes and pyrethroids; and androgenic and/or antiandrogenic activity, such as organochlorines, organophosphates and atrazine.The endocrine disrupting toxic agrochemicals act by binding to specific steroid hormone receptors (estradiol, testosterone and progesterone), thus being able to inhibit or activate enzymes that act in the synthesis and metabolism of hormones, disrupting the function of the hypothalamus and pituitary 44 .


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Congenital malformations are the second leading cause of infant death in Latin America according to data from the World Health Organization 45 .A Brazilian study identified that the largest association found between the increase in the cryptorchidism malformation from the 1993-2004 period to the 2004-2014 period was in the state of Paraná.The researchers suggest that, or being endocrine disruptors, some toxic agrochemicals are suspected of influencing the sexual differentiation of the fetus and other sex hormone-dependent outcomes and that they can be related to the fluctuation of female and male hormones during pregnancy 46 .

In the USA, it was verified 47 that women exposed to different classes of toxic agrochemicals obtained different levels of significant risk associated with the having children with hypospadias.A study 48 from Spain, on the other hand, evidenced that most of the agricultural workers studied had a high relative risk of fetal death due to congenital nomalies.In a case-control research study in the Netherlands 49 , paternal exposure to pesticides was significantly associated with cryptorchidism.A research study conducted in Paraguay 9 found a relationship between congenital anomalies and exposure to toxic agrochemicals.A Brazilian study 10 also found that maternal exposure to toxic agrochemicals during pregnancy was associated with congenital anomalies in the cities studied in the state of Mato Grosso, suggesting that populations intensely exposed to agrochemicals are at higher risk of fetal malformations.

In Mexico, a study 13 evaluated mothers and children born with cryptorchidism and exposure to organochlorines and concluded th t exposure to toxic agrochemicals was higher among the mothers with children who were born with cryptorchidism than among mothers of children with descended testicles.In a study 30 carried out in Argentina, some risk factors for the emergence of congenital malformations were identified, among them distance of the house from the fumigated fields being less than 1 km (OR=3.75;95% CI=0.98-14.31)and direct maternal exposure to pesticides (OR=4.51;95% CI=1.77-11.46).This corroborates the articles 18,23 which identified that homes close to crops and direct contact of pregnant women to toxic agrochemicals can cause neural tube defects and consequences for the nervous system.

In an ecological study conducted in Brazil, it was concluded that Brazilian states with high consumption of toxic agrochemicals presented an increase of 100% and 75%, and that those with mean consumption, an increase of 65% and 23%, respectively, in the risk of congenital anomalies in the CNS and in the Cardiovascular System at birth, when compared to low use states 51 .Thus, it is reinforced that the environmental factors, especially exposure to toxic agrochemicals, can contribute to the emergence of congenital malformations related to the central nervous system, according to the articles 18,[20][21]23 .

In this context, in a case-control study 24 parental exposure to toxic agrochemicals and the onset of spina bifida in newborns were analyzed.The parents' joint occupational exposure to agrochemicals (herbicides, fungicides and insecticides) was positively associated with spina bifida (OR=1.5;95% CI=0.9-2.4) when compared to the infants without parental exposure 24 .Among the articles of this study, herbicides were the most reported for the occurrence of congenital malformations together with insecticides and fungicides, not only for neural tube defects 21,23 , but also for other malformations such as those relat d to the reproductive system and to the gastrointestinal tract 15,26 .

Corroborating the findings of this study, a systematic review 53 that sought to identify the risk factors related to maternal exposure and congenital malformations found similar results, as well as higher prevalence of cardiovascular, gastrointestinal, genitourinary, musculoskeletal and nervous system malformations 53

Regarding t
e results found related to gastroschisis, a study carried out in the USA identified the prevalence of this malformation in cases coming from places with excessive use of pesticides for restricted use.In addition, a study 54 carried out in Campinas, São Paulo, also linked exposure to toxic agrochemicals during pregnancy with the occurrence of gastroschisis.


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In a Brazilian study 55 carried out between 2004 and 2006 in Nova Fribu go, state of Rio de Janeiro, higher prevalence of congenital malformations, low birth weight and low Apgar score in newborns in rural areas of the city were identified.The study also highlighted the occurrence of cleft palate as the third most prevalent outcome 55 .

The occurrence of congenital anomalies related to exposure to pesticides was also reported in a study conducted in South Africa.Through a control case study, it was concluded that newborns from mothers exposed to toxic agrochemicals were seven times more likely to develop some congenital anomaly when compared to newborns from mothers who di