Isabelle Enderle
email: isabelle.enderle@chu-rennes.fr

Virginie De Lauzun

Marie-Astrid Metten

Marion Monperrus

Fleur Delva

Pauline Blanc-Petitjean

Brigitte Dananche

Christophe Paris

Cécile Zaros

Maela Le Lous

Rémi Beranger

Ronan Garlantezec

Pauline Blanc

Maternal occupational exposure to organic solvents and intrauterine growth in the ELFE cohort

Keywords: methodology, validation, formal analysis, resources, data curation, review fetal growth retardation, head circumference, solvents, occupational exposure, pregnancy

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Funding sources supporting the work described in the manuscript:

The ELFE survey is a joint project between the French Institute for Demographic Studies (INED) J o u r n a l P r e -p r o o f

INTRODUCTION

In developed countries, most women work during pregnancy [START_REF] Casas | Maternal occupation during pregnancy, birth weight, and length of gestation: combined analysis of 13 European birth cohorts[END_REF]; "Enquête nationale périnatale," 2016; "Maternity Leave and Employment Patterns of First-Time Mothers: 1961[START_REF] Shrier | Reducing bias through directed acyclic graphs[END_REF]," 2011). For example in France,70.8% of women included in the 2016 French perinatal survey did ("Enquête nationale périnatale," 2016), as well as 65.6% of those included in the 2008 Panel of the U.S. Census Bureau's Survey of Income and Program Participation ("Maternity Leave and Employment Patterns of First-Time Mothers: 1961[START_REF] Shrier | Reducing bias through directed acyclic graphs[END_REF]. During the first decade of this century, 14.7% of women workers were occupationally exposed to solvents [START_REF] Pilorget | Trends of occupational exposure to oxygenated, petroleum and chlorinated solvents in France between 1999 and[END_REF], defined as liquids with the property of dissolving, diluting, or extracting other substances without causing chemical modification of either those substances or themselves. These chemicals are present in a wide range of products, such as adhesives, paints, dyes, inks, cleaning products, and cosmetics. Solvents are classified into 3 major chemical families: oxygenated solvents (e.g., alcohols, esters, and ketones), petroleum solvents (e.g., benzene, aliphatic solvents, and aromatic solvents), and chlorinated solvents (e.g., perchloroethylene and trichloroethylene). Many of these can cross the placental barrier [START_REF] Donald | Customized and non-customized French intrauterine growth curves. I -Methodology[END_REF][START_REF] Elkin | Placenta as a target of trichloroethylene toxicity[END_REF][START_REF] Loch-Caruso | Trichloroethylene exposure in mid-pregnancy decreased fetal weight and increased placental markers of oxidative stress in rats[END_REF][START_REF] Ungváry | On the embryotoxic effects of benzene and its alkyl derivatives in mice, rats and rabbits[END_REF].

Small for gestational age (SGA) newborns are an important public health concern, because they are at higher risk of various immediate-, mid-, and long-term postnatal complications, including metabolic, immune, neurologic, respiratory, and endocrine adverse outcomes [START_REF] Kesavan | Intrauterine Growth Restriction: Postnatal Monitoring and Outcomes[END_REF][START_REF] Mayer | Fetal growth: a review of terms, concepts and issues relevant to obstetrics[END_REF]. The relation of maternal occupational solvent exposure to SGA status has thus far been explored in 6 studies [START_REF] Ahmed | Exposure to organic solvents and adverse pregnancy outcomes[END_REF][START_REF] Lipscomb | Pregnancy outcomes in women potentially exposed to occupational solvents and women working in the electronics industry[END_REF]Desrosiers et al., 2015;[START_REF] Seidler | Maternal occupational exposure to chemical substances and the risk of infants small-for-gestational-age[END_REF][START_REF] Seidler | Maternal occupational exposure to chemical substances and the risk of infants small-for-gestational-age[END_REF][START_REF] Zhu | Laboratory work and pregnancy outcomes: a study within the National Birth Cohort in Denmark[END_REF] and that to birthweight in 10 studies (Ish et al., 2022;Desrosiers et al., 2015;[START_REF] Burdorf | The effects of work-related maternal risk factors on time to pregnancy, preterm birth and birth weight: the Generation R Study[END_REF][START_REF] Snijder | Occupational exposure to chemicals and fetal growth: the Generation R Study[END_REF][START_REF] Ahmed | Exposure to organic solvents and adverse pregnancy outcomes[END_REF]Ronda et al., 2010;[START_REF] Axelsson | Exposure to solvents and outcome of pregnancy in university laboratory employees[END_REF][START_REF] Khattak | Pregnancy outcome following gestational exposure to organic solvents: a prospective controlled study[END_REF][START_REF] Ha | Parental exposure to organic solvents and reduced birth weight[END_REF][START_REF] Vaktskjold | Low birth weight in newborns to women employed in jobs with frequent exposure to organic solvents[END_REF]. Two of these studies reported a significantly higher risk of SGA status [START_REF] Ahmed | Exposure to organic solvents and adverse pregnancy outcomes[END_REF][START_REF] Lipscomb | Pregnancy outcomes in women potentially exposed to occupational solvents and women working in the electronics industry[END_REF], and three observed a significantly lower birth weight [START_REF] Khattak | Pregnancy outcome following gestational exposure to organic solvents: a prospective controlled study[END_REF][START_REF] Vaktskjold | Low birth weight in newborns to women employed in jobs with frequent exposure to organic solvents[END_REF][START_REF] Ha | Parental exposure to organic solvents and reduced birth weight[END_REF], but the others did not report significant associations. Among the reasons that may explain these inconsistent results, we note the lack of power in some studies, their different assessment methods (job-exposure matrices, expertise, or self-report), and the heterogenous definitions of solvents in most studies, without any investigation of these potential associations by solvent family, although these families may have different effects on fetal growth. Accordingly, among the 10 studies that investigated the impact of maternal occupational exposure to solvents in the general population [START_REF] Ahmed | Exposure to organic solvents and adverse pregnancy outcomes[END_REF][START_REF] Burdorf | The effects of work-related maternal risk factors on time to pregnancy, preterm birth and birth weight: the Generation R Study[END_REF]Ish et al., 2022;[START_REF] Khattak | Pregnancy outcome following gestational exposure to organic solvents: a prospective controlled study[END_REF][START_REF] Seidler | Maternal occupational exposure to chemical substances and the risk of infants small-for-gestational-age[END_REF][START_REF] Seidler | Maternal occupational exposure to chemical substances and the risk of infants small-for-gestational-age[END_REF][START_REF] Snijder | Occupational exposure to chemicals and fetal growth: the Generation R Study[END_REF][START_REF] Vaktskjold | Low birth weight in newborns to women employed in jobs with frequent exposure to organic solvents[END_REF][START_REF] Zhu | Laboratory work and pregnancy outcomes: a study within the National Birth Cohort in Denmark[END_REF]Desrosiers et al., 2015), nine explored the relation with solvents as a single group. Only the study by Desrosiers et al. investigated these relations separately J o u r n a l P r e -p r o o f for petroleum and chlorinated solvents (Desrosiers et al., 2015). It found a higherbut not statistically significantrisk of SGA status. Unfortunately, this study did not consider oxygenated solvents, although it is the most frequent family [START_REF] Pilorget | Trends of occupational exposure to oxygenated, petroleum and chlorinated solvents in France between 1999 and[END_REF].

In addition to SGA status and birthweight, measurement of head circumference (HC) at birth is another fetal growth parameter of particular interest as it is regularly used as a proxy for brain volume and intrauterine brain development [START_REF] Barbier | New reference curves for head circumference at birth, by gestational age[END_REF]. In addition, several publications have shown positive associations between HC and cognitive function, long-term memory storage and retrieval, and visuospatial ability [START_REF] Gale | The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years[END_REF][START_REF] Veena | Association of Birthweight and Head Circumference at Birth to Cognitive Performance in 9-to 10-Year-Old Children in South India: Prospective Birth Cohort Study[END_REF]. To the best of our knowledge, only one study [START_REF] Snijder | Occupational exposure to chemicals and fetal growth: the Generation R Study[END_REF] has investigated the relation between HC and maternal occupational exposure to solvents; it did not distinguish solvent families and did not report any associations.

While pregnant women remain frequently exposed to organic solvents at work, the question concerning their impact on fetal growth is still debated, especially in view of the lack of data by solvent family, as these different families may have different effects. Using data from a large sample of newborns from the French ELFE cohort, we aimed to assess the influence of occupational exposure to oxygenated, petroleum, and chlorinated solvents on SGA status, birthweight, and HC.

J o u r n a l P r e -p r o o f

MATERIALS AND METHODS

Study design

ELFE ("Etude Longitudinale Française depuis l'Enfance") is a French nationwide birth cohort intended to explore the influence of environmental and socioeconomic contexts on children's health and development from birth to the age of 20 years. The ELFE cohort has previously been described in detail [START_REF] Charles | Cohort Profile: The French National cohort of children ELFE: birth to 5 years[END_REF].

Overall, 349 maternity departments were randomly selected among the 544 with more than one delivery per day in mainland France, and 320 of these agreed to participate in recruiting the ELFE cohort. Women aged 18 years or older who gave birth to liveborn singletons or twins after 33 weeks of gestation were included in the study. Four inclusion periods occurred in 2011: April 1-4, June 27-July 4, September 27-October 4, and November 28-December 5. Written informed consent was required to participate, and women had to state that they did not plan to leave mainland France for the next three years. Overall, 51% (18,040 women with 18,329 newborns) agreed to participate in the cohort during their stay in the maternity ward. Because 55 families subsequently requested the destruction of their data, 18,274 children were finally included in the ELFE cohort follow-up.

The population of this study excludes multiple pregnancies (n=287 twin pregnancies/574 children), major malformations as defined by the European surveillance of congenital anomalies ("European Platform on Rare Disease Registration," 2014) (n=303 children), and mothers who did not work during their pregnancies (n=4159 women). The study thus finally includes 13,238 mother-child pairs (Figure 1).

Data collection

During the maternity unit stay, trained midwives collected participants' sociodemographic, socioeconomic, and medical characteristics in face-to-face interviews and data about their pregnancies, deliveries, and medical histories from their medical records. Two months after childbirth, parents were asked to complete an email questionnaire about social and medical data. More details are available at: https://www.elfe-france.fr/en and https://pandora.vjf.inserm.fr/public/index.php. J o u r n a l P r e -p r o o f

Maternal occupational exposure to solvents

Information about maternal occupations and industrial activities was initially collected at the maternity ward and completed with the 2-month questionnaire when necessary. One single expert was in charge of occupational coding for all women, according the job title and the industry but also using tasks descriptions and type of contract (self-employment, employees…). The coding was made blind to the maternal and child health status, using standardized procedures (hierarchization of information used for coding and validation of homogeneity of coding with occupation and industrial activity) to limit classification bias. (INSEE, 2003). French National Public Health Agency (Santé Publique France) conducted the Matgéné project, resulting in developing three job-exposure matrices (JEMs), focusing respectively on oxygenated, petroleum, and chlorinated solvents [START_REF] Févotte | Matgéné: a program to develop job-exposure matrices in the general population in France[END_REF]. These JEMs also assessed exposures to subgroups of solvents within each family: alcohols, ketones and esters, ethylene glycol, diethyl ether and tetrahydrofuran for oxygenated solvents; benzene, fuel oil, industrial spirit, kerosene (lighting oil), diesel and fuel oils, white spirit and other light aromatic cuts for petroleum solvents; chloroform, methylene chloride, perchloroethylene, trichloroethylene; and 1,1,1-trichloroethane for chlorinated solvents. Exposures to each family or subgroup of were defined by a probability (per class of 10% for oxygenated and chlorinated solvents; 0%, 10%, 50%, 90%, and 100% for petroleum solvents) and level of exposure (very low, low, moderate, and high for oxygenated and chlorinated solvents; low, moderate, and high for petroleum solvents). These parameters are presented in the supplemental materials (Table S1).

Due to missing or imprecise data about maternal occupation or industrial activities, exposure assessment could not be performed for 212 women; 13,026 mothers had complete assessments. When mothers reported multiple jobs during pregnancy (n=15), we consider only the job with the highest level of exposure.

Before starting the main analysis, we recoded maternal occupational exposure to solvents according to the distribution of the exposure probability of each solvent family in our study population. Maternal occupational exposure to oxygenated solvents was classified according to probability of exposure: not exposed, likely exposed (probability below 90%) and certainly exposed (probability >90%). For women certainly exposed, we differentiated those exposed at a very low level from those exposed at J o u r n a l P r e -p r o o f least at a low level of intensity. The small numbers of combinations for maternal occupational exposures to petroleum and chlorinated solvents led us to group the JEM exposure assessments in two categories: not exposed and possibly exposed (any probability, any level) (Tables S2-S4).

Anthropometric parameters and small-for-gestational-age assessment

Birthweight and head circumference at birth were recorded in the medical files. SGA was defined as a birthweight under the 10 th percentile for gestational age and sex in France, by using the EPOPé charts (Ego et al., 2016). Among the 13,026 children for whom occupational exposure was assessed, SGA status was assessed for 12,676 (97.3%), while 12,756 newborns had information available for birthweight (97.9%) and 11,676 for head circumference (89.6%) (Figure 1).

Statistical analysis

We reviewed the relevant literature to develop a directed acyclic graph (DAG) [START_REF] Shrier | Reducing bias through directed acyclic graphs[END_REF], which was used to determine the minimally sufficient adjustment sets of variables for regression models to prevent for confounding and estimate the total effects of the studied exposure on the outcome (Figure S1). Based on this DAG, our models were systematically adjusted for maternal education level (primary and secondary education, passing baccalaureate, university level), smoking status (nonsmoker, stopped smoking during pregnancy, smoker), alcohol consumption during pregnancy (no, yes), and maternal body mass index (BMI<18.5 kg/m 2 , 18.5 kg/m 2 ≤ BMI <25 kg/m 2 , 25kg/m 2 ≤ BMI <30 kg/m 2 , BMI ≥30 kg/m 2 ). Statistical models for birthweight and head circumference were additionally adjusted for gestational age (in weeks of gestation; linear and quadratic form) and the newborn's sex.

Due to the small numbers of missing values for covariables, we imputed missing values by the mode: maternal education level (baccalaureate; n=43, 0.3%), smoking status (nonsmoker; n=141, 1.1%), alcohol consumption during pregnancy (none; n=60, 0.5%), and maternal body mass index (18.5 kg/m 2 ≤ BMI <25 kg/m 2 ; n=179, 1.4%).

We first studied the relation between each outcome and each maternal occupational exposure to each solvent family (oxygenated, petroleum, and chlorinated solvents) individually. In addition, if several exposures were significantly associated with the same outcome, mutual adjustments were performed in a subsequent analysis. We also performed analyses stratified by when mothers stopped working: in the first, second, or third trimester of pregnancy.

We used logistic regression to study associations with SGA status and multiple linear regression to study association with birthweight and HC. Results are presented as odds ratios (ORs) and beta coefficients with their 95% confidence intervals (95%CI).

J o u r n a l P r e -p r o o f

Three sensitivity analyses were performed to test the robustness of our results: 1) we changed the threshold for considering women to be certainly exposed to oxygenated solvents (probability of exposure above 50% rather than the 90% applied in the main analyses); 2) we aggregated women certainly exposed to oxygenated solvents at very low level and at a low level; and 3) we further adjusted the models studying HC for mode of delivery.

A p-value <0.05 was defined as statistically significant. SAS 9.4 and R version 3.6.2 were used for statistical analyses.

J o u r n a l P r e -p r o o f 10

RESULTS

Population characteristics

Table 1 describes the study population. The participants' mean age was 31 ± 5.0 years. Almost twothirds of them had attended at least some university (65.6%), 16.9% were overweight, and 8.2% obese; 16.9% smoked, and 19.6% had drunk alcohol during their pregnancy. Boys accounted for 51% of the newborns. On average, children were born at 39 weeks of gestation, weighed 3340 g ± 469 g and had a HC of 34.4 cm ± 1.4 cm at birth. Overall, 9.7% of newborns were SGA and 4% preterm. Half the women stopped working during their third trimester of pregnancy (n=6968, 52.6%), 28.9% (n=3825) during the second trimester, and 8.1% (n=1071) during the first. This information was unavailable for 10.4% of our population (n=1374).

Maternal occupational exposure to solvents

The mothers of children included in this analysis were employed mainly as clerical (n=3141; 24.1%), service (n=2203; 16.9%), and sales (n=1439; 11.0%) workers, as well as teachers (n=1426; 10.9%) (Table 2).

In all, 885 (6.9%) of the women included in this analysis were likely and 2037 (15.8%) certainly occupationally exposed during pregnancy to oxygenated solvents (Table 2). Among the certainly exposed women, 1785 (13.8% of those included in this analysis) were exposed at a very low level and 252 (2.0%) at least at a low level (Table S2). Mothers occupationally likely exposed to oxygenated solvents were mainly cleaners and helpers (70.0%) (Table 2). Those certainly exposed at a very low level were primarily health-related professionals (91.3%) and hairdressers (8.6 %), and those certainly exposed to at least a low level were chemists (49.6%) and hairdressers (32.9%) (Table 2). Alcohols were the most frequent subclass of oxygenated solvents in our study (6.3% of women were classified as likely exposed and 14.9% as certainly exposed), ahead of diethyl ether (13.4% as likely exposed, and none as certainly exposed), and ketones and esters (1.5% likely exposed and 1.3% certainly exposed) (Table S5).

For petroleum solvents, 861 women were classified as possibly occupationally exposed (6.7%), mainly at a low or very low level (n=858, 6.6%) (Table S4). Jobs mainly classified as possibly exposed to petroleum solvents were cleaners (60.2%) and chemists (17.7%). White spirit was the most frequent petroleum solvent exposure in our study (5.9% of the women were classified as possibly exposed) followed by special essence (1.6%) (Table S5).

Regarding chlorinated solvents, 190 women (1.5%) were classified as possibly occupationally exposed, at a low or very low level (Table S4). Mothers possibly occupationally exposed to chlorinated solvents were mostly chemists (83.2%) (Table 2). The most frequent chlorinated solvent J o u r n a l P r e -p r o o f exposures involved dichloromethane and trichloromethane (1.3% of women for both chemicals) (Table S5).

Maternal occupational solvent exposure and intrauterine fetal growth

We observed a nonsignificantly higher risk of SGA status among children of mothers likely exposed to oxygenated solvents (OR adjusted = 1.24; 0.99 to 1.55) but not for children of mothers who were certainly exposed (certainly exposed at a very low level: OR adjusted = 1.01; 0.85 to 1.20; certainly exposed at least at a low level: OR adjusted = 1.28; 0.86 to 1.90) (Table 3). The risk of an SGA newborn was statistically significantly higher among mothers who were occupationally exposed to petroleum solvents (OR adjusted = 1.26; 1.01 to 1.57), but the association was not statistically significant for maternal exposure to chlorinated solvents (OR adjusted = 1.31; 0.83 to 2.06) (Table 3). A significant excess risk for a SAG newborn appeared for women certainly exposed at least at a low level to oxygenated solvents who worked into the third trimester (OR adjusted = 1.75; 1.11 to 2.75) (Table 4). The estimates for exposure to petroleum solvents, although not significant, were in the same range as for the main analyses when stratifying for trimester of starting maternity leave (during the first or second trimester: OR adjusted = 1.34; 0.96 to 1.89; third trimester: OR adjusted = 1.20; 0.85 to 1.72) (Table 4).

No statistically significant associations were observed between maternal occupational exposure to oxygenated, petroleum, or chlorinated solvents and birthweight as a continuous variable (Table 3).

When trimester of maternal leave during pregnancy was considered, birthweight was significantly lower in the children of mother exposed to petroleum solvents who worked into the third trimester (β adjusted = -47.37g; -89.33 to -5.42) (Table 4).

HC was lower among children of mothers certainly exposed to at least a low level of oxygenated solvents (β adjusted = -0.27; -0.44 to -0.10) (Table 3) or exposed to chlorinated solvents (β adjusted = -0.25; -0.44 to -0.06) (Table 3). The association between petroleum solvents and HC was not statistically significant (β adjusted = -0.05; -0.15 to 0.04) (Table 3). After mutual adjustment for exposure to oxygenated and chlorinated solvents, oxygenated solvent exposure to at least a low level remained statistically significant (β adjusted = -0.25; -0.47 to -0.03), but chlorinated solvent exposure was not (β adjusted = -0.07; -0.32 to 0.18) (Table 5). HC was lower among the children of mothers certainly exposed to at least a low level of oxygenated solvents (β adjusted = -0.28; -0.49 to -0.07) or exposed to chlorinated solvents (β adjusted = -0.29; -0.53 to -0.05) for those mothers who worked into the third trimester (Table 4). These associations were not observed, however, when women stopped working during the first or second trimester of pregnancy (certainly exposed to oxygenated solvents at least at a low level: β adjusted = -0.16; -0.50 to 0.18; exposure to chlorinated solvents: β adjusted = -0.19; -0.55 to 0.17) (Table 4).

J o u r n a l P r e -p r o o f

Sensitivity analyses Results about SGA status and HC remained similar when we used a probability of exposure of 50% as the threshold for defining mothers certainly exposed to oxygenated solvents (Table S6).

We observed no statistically significant associations when children of mothers certainly exposed to oxygenated solvents were aggregated in the same group, regardless of the intensity of exposure (Table S7).

Additional adjustment for the mode of delivery did not change the associations between occupational exposure to oxygenated and chlorinated solvents, and HC at birth (Table S8).

J o u r n a l P r e -p r o o f

DISCUSSION

We report an increased risk of SGA newborn among mothers occupationally exposed during pregnancy to petroleum solvents, as well as among women who were occupationally exposed to oxygenated solvents at least at a low level and who worked into their third trimester of pregnancy. For birthweight as a continuous variable, a significantly lower birthweight was observed only for infants of mothers still working during the third trimester and exposed to petroleum solvents; no risk was observed for other solvents or other time periods. Finally, HC was lower among the children of mothers occupationally exposed to oxygenated or chlorinated solvents, especially those working into their third trimester. Our results remained stable in sensitivity analyses.

Our search found only one study that previously investigated the relation between maternal occupational exposure by solvent families and the risk of SGA status. Desrosiers et al. analyzed data from 2886 mothers and their infants born between 1997 and 2002 in the USA. In this study, industrial hygienists assessed the probabilities of exposure to ten organic solvents: six chlorinated, three aromatic and the petroleum-based mixture Stoddard solvents (also known as mineral spirits or white spirits), and SGA was defined as in our study as birthweight below the 10th centile for a given gestational age at delivery. They found a higher but not statistically significant risk of an SGA neonate when mothers were occupationally exposed to any solvents (OR=1.71; 95%CI: 0.86-3.40), chlorinated solvents (OR=1.70; 95%CI: 0.69-4.01), and aromatic solvents (OR=1.87; 95%CI: 0.78-4.50) but not with Stoddard solvent (OR=0.98; 95%CI: 0.44-2.18) (Desrosiers et al., 2015). This absence of statistical significance might be due to a lack of power (only 23 women (10.1%) with an SGA newborn were exposed to any solvent, 18 (7.9%) to chlorinated solvents, and 7 (3.1%) to aromatic solvents). These studies are partially consistent with our results for aromatic solvents but not for Stoddard solvents, which were the most frequent subclass of petroleum solvent in our study. In addition, Desrosiers et al. did not examine either occupational exposure to oxygenated solvents or the influence of the trimester when pregnancy leave began.

We also highlighted lower birthweight in the newborns of women exposed to petroleum solvents into the third trimester, in line with the study by [START_REF] Ha | Parental exposure to organic solvents and reduced birth weight[END_REF]. They investigated the association between birthweight and maternal and paternal exposure to organic solvents in 1222 couples employed in a large petrochemical corporation in Beijing, China [START_REF] Ha | Parental exposure to organic solvents and reduced birth weight[END_REF]. In this study, a trained interviewer assessed parental exposures to organic solvents considering only four petroleum solvents in their definition of organic solvents (benzene, toluene, xylene, and styrene). The authors concluded that maternal exposure to organic solvents is significantly associated with a lower birthweight (-81.7g, 95%CI: -106.3 to -3.1) [START_REF] Ha | Parental exposure to organic solvents and reduced birth weight[END_REF].

J o u r n a l P r e -p r o o f

Only one previous epidemiological study investigated the relation between maternal occupational exposure to solvents and newborn HC [START_REF] Snijder | Occupational exposure to chemicals and fetal growth: the Generation R Study[END_REF], analyzing data from 4680 pregnant women participating in the Generation R cohort study from early pregnancy onwards in the Netherlands (2002Netherlands ( -2006) ) [START_REF] Snijder | Occupational exposure to chemicals and fetal growth: the Generation R Study[END_REF]. Using the JEM developed by Brouwers et al. [START_REF] Brouwers | Occupational exposure to potential endocrine disruptors: further development of a job exposure matrix[END_REF], Snijder et al. estimated maternal occupational exposure to potential endocrinedisrupting chemicals that included an organic solvent category based on exposure to 6 organic solvents (ethylene glycol ethers, styrene, toluene, xylene, trichloroethylene, and perchloroethylene) but not on most oxygenated and chlorinated solvents. They observed no significant reduction in HC when mothers were exposed to organic solvents (221 pregnant women (4.7%) exposed, β adjusted : -0.00902, standard error: 0.00560, with the p-value and 95%CI not provided). No study has focused on a broader definition of organic solvents including oxygenated solvents, although it is the most frequent solvent family involved in occupational exposure [START_REF] Garlantézec | The study of the relation between maternal occupational exposure to solvents and birth defects should include oxygenated solvents[END_REF].

Our results about the impact of oxygenated and petroleum solvents on fetal growth are also consistent with animal studies that have reported associations with several alcohols (ethanol, methanol, propanol, glycol, etc.) [START_REF] Nelson | Developmental toxicology of industrial alcohols: a summary of 13 alcohols administered by inhalation to rats[END_REF] and with white spirit [START_REF] Carrillo | The sub-chronic toxicity of regular White Spirit in rats[END_REF], which respectively accounted for the vast majority of oxygenated and petroleum solvent exposures in our study. We think that these solvents might be deleterious at three different levelsat the maternal, placental, or directly at the fetal level, since many solvents can cross the placental barrier [START_REF] Donald | Customized and non-customized French intrauterine growth curves. I -Methodology[END_REF][START_REF] Elkin | Placenta as a target of trichloroethylene toxicity[END_REF][START_REF] Loch-Caruso | Trichloroethylene exposure in mid-pregnancy decreased fetal weight and increased placental markers of oxidative stress in rats[END_REF][START_REF] Ungváry | On the embryotoxic effects of benzene and its alkyl derivatives in mice, rats and rabbits[END_REF]. We have found no evidence that the different solvent families use common mechanisms; we have thus considered these exposures separately. The underlying mechanisms have rarely been investigated except for that of ethanol, which accounts for half of the oxygenated solvents used in France (INRS, 2009). Nelson summarized 13 alcohols administered by inhalation to rats [START_REF] Nelson | Developmental toxicology of industrial alcohols: a summary of 13 alcohols administered by inhalation to rats[END_REF], whereas other studies about fetal consequences of alcohol used ingestion models that correspond to the most common nonoccupational maternal exposure during pregnancy. Thus, ethanol ingestion has been reported to affect maternal levels of iron and zinc, creating maternal deficiencies [START_REF] Naik | Effects of nutrition and gestational alcohol consumption on fetal growth and development[END_REF] that can result in fetal growth restriction by reducing levels of insulin-like growth factor-1 and its receptor activity [START_REF] Naik | Effects of nutrition and gestational alcohol consumption on fetal growth and development[END_REF]. It also affects placental stress response [START_REF] Gårdebjer | Periconceptional alcohol consumption causes fetal growth restriction and increases glycogen accumulation in the late gestation rat placenta[END_REF] and disrupts trophoblast angiogenic factors [START_REF] Gualdoni | Perigestational alcohol consumption induces altered early placentation and organogenic embryo growth restriction by disruption of trophoblast angiogenic factors[END_REF]. Trichloroethylene ingestion (chlorinated solvent), on the other hand, increases placental oxidative stress markers in a rat model of fetal growth restriction [START_REF] Loch-Caruso | Trichloroethylene exposure in mid-pregnancy decreased fetal weight and increased placental markers of oxidative stress in rats[END_REF].

The effects observed with reduced HC are also in accordance with what is known of the neurotoxicity of several alcohols [START_REF] Nelson | Developmental toxicology of industrial alcohols: a summary of 13 alcohols administered by inhalation to rats[END_REF] and tricholoromethane (Agency for Toxic Substances and Disease Registry, 1997). The effects observed in our study were broader for exposures lasting into the third trimester. In humans, intrauterine fetal growth is quite slow until the 23rd week of gestation, and J o u r n a l P r e -p r o o f then accelerates before peaking around the 34th week [START_REF] Lepercq | Physiologie de la croissance foetale[END_REF]. We can thus hypothesize that impairments during the period of fetal growth might have a greater impact on anthropometric parameters at birth. Solvent exposure in late gestation has been shown to cause greater effects in animal studies [START_REF] Donald | Customized and non-customized French intrauterine growth curves. I -Methodology[END_REF].

We used data from a large birth cohort (n= 13,026 women) with detailed information about a wide range of personal and medical characteristics that allowed us to control for various potential confounders [START_REF] Charles | Cohort Profile: The French National cohort of children ELFE: birth to 5 years[END_REF]. Including only women who worked during their pregnancy enabled us to avoid bias from the "healthy worker effect," since women who were not working might have a higher rate of adverse pregnancy outcomes [START_REF] Casas | Maternal occupation during pregnancy, birth weight, and length of gestation: combined analysis of 13 European birth cohorts[END_REF]. However, we have no data on possible sick leave during pregnancy (we only have the beginning of the maternity leave). Nonetheless, the population selection strategies might have led to some limitations. In particular, the ELFE cohort only included women who gave birth after 33 weeks of gestation, which might have resulted in excluding some premature newborns with severe SGA.

The JEMs we used to assess solvent exposure were developed for the general population in France by the French Institute for Public Health Surveillance during the same period as the ELFE pregnancies [START_REF] Févotte | Matgéné: a program to develop job-exposure matrices in the general population in France[END_REF]. Exposure misclassification is likely when using JEMs [START_REF] Vaktskjold | Low birth weight in newborns to women employed in jobs with frequent exposure to organic solvents[END_REF]. Most authors investigating the properties of generic JEMs have emphasized that they could plausibly underestimate variability in exposures, since the same probability and levels of exposure are allocated for a given combination (occupation and industrial sector) without considering between-worker variability (for specific tasks, material use, work environments, period or use of different protection devices) [START_REF] Fritschi | OccIDEAS -occupational exposure assessment in community-based studies[END_REF][START_REF] Ge | Use and Reliability of Exposure Assessment Methods in Occupational Case-Control Studies in the General Population: Past, Present, and Future[END_REF][START_REF] Teschke | Occupational exposure assessment in case-control studies: opportunities for improvement[END_REF]. By assigning the mean exposure level to the whole group, JEMs induce Berkson-type misclassification error, which tends to reduce study power, but leads to little or no bias in the estimators of logistic or linear regression coefficients [START_REF] Armstrong | Effect of measurement error on epidemiological studies of environmental and occupational exposures[END_REF].

Another limitation is that the low number of women classified as exposed to petroleum and chlorinated solvents in our study were not sufficient to benefit from the fine level of exposure probability and intensity available in the JEMs. Grouping together various types, probabilities, and intensities of exposure might have diluted possible associations [START_REF] Teschke | Occupational exposure assessment in case-control studies: opportunities for improvement[END_REF]. Finally, we could not rule out the possibility that associations observed in our study might be markers of association with other co-exposures that we did not evaluate study rather than the direct effect of solvents.

Among our neonatal outcomes, we defined SGA with the French EPOPé unadjusted intrauterine fetal growth charts, developed from the 2010 French Perinatal Survey (FPS). An alternative would have been to use customized charts that include in addition maternal characteristics (height, weight, parity) J o u r n a l P r e -p r o o f associated with fetal weight that better consider each infant's intrinsic growth potential [START_REF] Mamelle | Identification of newborns with Fetal Growth Restriction (FGR) in weight and/or length based on constitutional growth potential[END_REF]. However, these main variables were included in our adjustment strategy. Another key point in studying fetal growth is to date the pregnancy accurately. The American College of Obstetricians and Gynecologists, the American Institute of Ultrasound in Medicine, the Society for Maternal-Fetal Medicine and the French College of Fetal Echography recommend the use of the craniocaudal length measurement performed during the usual first trimester screening ultrasound ("Collège Français d'Échographie Foetale," 2022; The American College of Obstetricians and Gynecologists, 2014), as performed in ELFE cohort. But the inaccuracy of this method is ± 5-7 days (Obstetrics & Gynecology, 2017). Estimates based on menstrual dates are two to three days higher, on average, than those based on early ultrasound, a difference usually attributed to late ovulation [START_REF] Morin | Determinants and consequences of discrepancies in menstrual and ultrasonographic gestational age estimates[END_REF]. Nevertheless, the difference between the date of the last menstrual period and the ultrasound dating has been reported to be a marker of the risk of early growth restriction [START_REF] Källén | Increased risk of perinatal/neonatal death in infants who were smaller than expected at ultrasound fetometry in early pregnancy[END_REF][START_REF] Morin | Determinants and consequences of discrepancies in menstrual and ultrasonographic gestational age estimates[END_REF]. Thus, we cannot exclude the possibility that occupational exposure to solvents is responsible for early SGA status and that sonographic correction could have underestimated this effect. Other studies have used fetal growth trajectories based on ultrasound-estimated fetal growth to study SGA status [START_REF] Snijder | Occupational exposure to chemicals and fetal growth: the Generation R Study[END_REF]. Their method let them differentiate intrauterine growth retardation that occurred in the second or in the third trimester of pregnancy. But it also resulted in selective participation, with mothers with lower socioeconomic status less well represented and required suitable reference charts for fetal growth [START_REF] Snijder | Occupational exposure to chemicals and fetal growth: the Generation R Study[END_REF].

We planned in advance to adjust for potential confounders based on a directed acyclic graph, constructing an a priori model of the postulated relations between the maternal occupational solvent exposures, intrauterine growth, and the covariates [START_REF] Shrier | Reducing bias through directed acyclic graphs[END_REF] to enable theoretically and expert-based adjustment of sets of covariates. Moreover, in sensitivity analyses, we additionally chose to adjust the models studying HC for the mode of delivery to consider plastic deformation of the fetal head; after vaginal delivery, newborn heads can have a "sugar loaf" appearance because of its increased length and the reduction in its 2 largest dimensions (biparietal and suboccipito-bregmatic) [START_REF] Schaal | Engagement[END_REF]. Babies born by cesarean section will have a rather round head. We also performed two other sensitivity analyses: changing the threshold to consider women as certainly exposed to oxygenated solvent at a probability of exposure above 50% rather than the 90% in the main analyses, and aggregating women certainly exposed to oxygenated solvent at very low and low levels. These results were consistent with the main analyses.

J o u r n a l P r e -p r o o f

CONCLUSION

Our study based on job-exposure matrices highlighted an increased risk of SGA newborns when mothers were occupationally exposed to petroleum and oxygenated solvents. We also observed lower HC when mothers were occupationally exposed to oxygenated or chlorinated solvents. These results were strongest among women who worked into the third trimester of pregnancy. Other studies need to be conducted on this topic to confirm these results and investigate potential co-exposures in the workplace. If these results are confirmed, preventive measures should be reinforced for pregnant women occupationally exposed to solvents especially if they work into their third trimester of pregnancy.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

  and the National Institute of Health and Medical Research (INSERM), in partnership with the French blood transfusion service (Etablissement français du sang, EFS), Santé publique France, the National Institute for Statistics and Economic Studies (INSEE), the Direction générale de la santé (DGS, part of the Ministry of Health and Social Affairs), the Direction générale de la prévention des risques (DGPR, Ministry for the Environment), the Direction de la recherche, des études, de l'évaluation et des statistiques (DREES, Ministry of Health and Social Affairs), the Département des études, de la prospective et des statistiques (DEPS, Ministry of Culture), and the Caisse nationale des allocations familiales (CNAF), with the support of the Ministry of Higher Education and Research and the Institut national de la jeunesse et de l'éducation populaire (INJEP). Via the RECONAI platform, it receives a government grant managed by the National Research Agency under the "Investissements d'avenir" program (ANR-11-EQPX-0038).

  Each data collection received the necessary approvals from the French Consultative Committee for the Treatment of Information in Medical Research (n°10.623), the French National Commission for the Confidentiality of Computerized Data (n°910504), and the Committee for the Protection of Persons Participating in Biomedical Research (n°CPP-IDF IX-11-024).

FIGUREFigure 1 .

 1 FIGURE

  maternal education level, smoking status, alcohol consumption, and maternal body mass index ** Adjusted for gestational age (linear and quadratic form), newborn sex, maternal education level, smoking status, alcohol consumption, and maternal body mass index J o u r n a l P r e -p r o o f

  maternal education level, smoking status, alcohol consumption, and body mass index ** Adjusted for gestational age (linear and quadratic form), newborn sex, maternal education level, smoking status, alcohol consumption, and body mass index J o u r n a l P r e -p r o o f

  Maternal occupations were coded according to the International Standard

	Classification of Occupations from 1968 (ISCO 1968) (ISCO-International Standard Classification of
	Occupations, 1968) and the French classification of professions and socioprofessional categories from
	1994 (French PCS 1994) ("Nomenclatures des professions et catégories socioprofessionnelles | Insee,"
	1994). Industry activities were coded with the International Standard Industrial Classification of All
	Economic Activities from 1975 (ISIC 1975 classification) ("International Standard Industrial
	Classification of All Economic Activities," 1975) and the French classification of economic activities
	from 2003 (French NAF 2003)

Table 1 .

 1 Description of the 12,676 women of the ELFE cohort who worked during pregnancy and for whom exposure was known for at least one organic solvent and their risk factors for a small-for-gestational-age (SGA)

	TABLES
	neonate.
			Total		Non-SGA	SGA
			N	%	N	%	N	%
		Total 12,676	100	11,444	90.3	1232	9.7
	Maternal age (years)	< 25	1237	9.8	1092	9.6		11.8
		25-29	4159	32.9	3744	32.8		33.8
		30-34	4682	37.0	4269	37.4		33.7
		≥ 35	2566	20.3	2312	20.2		20.7
	Maternal education level Body mass index (kg/m²) Parity Smoking during pregnancy Alcohol consumption during pregnancy High blood pressure during pregnancy Diabetes mellitus or J o u r n a l P r e -p r o o f Post-secondary education 8282 65.6 7527 66.0 Baccalaureate 2289 18.1 2047 17.9 Primary and secondary education 2065 16.3 1831 16.1 < 18.5 921 7.3 775 6.8 18.5-25 8475 67.6 7648 67.5 25-30 2113 16.9 1948 17.2 > 30 1034 8.2 957 8.5 0 children 5918 46.7 5172 45.2 1 or more children 6749 53.3 6265 54.8 Nonsmoker 10,307 82.0 9436 83.2 Stopped smoking during pregnancy 134 1.1 114 1.0 Smoker 2129 16.9 1797 15.8 No 10,160 80.4 9161 80.3 Yes 2476 19.6 2249 19.7 No 12,110 98.0 10,964 98.3 Yes 244 2.0 195 1.7 No 11,142 92.7 10,054 92.6	827 77 20 1146 49 1088	61.3 19.7 19.0 12.0 68.1 13.6 6.3 60.7 39.3 71.3 1.6 27.1 81.5 18.5 95.9 4.1 93.6
	gestational diabetes	Yes	874	7.3	799	7.4	75	6.4
	Prematurity	No	12,151	95.9	11,003	96.1	1148	93.2
		Yes	525	4.1	441	3.9	84	6.8
	Mode of delivery	Vaginal delivery	8639	69.2	7828	69.5		66.5
		Instrumental delivery	721	13.8	1564	13.9		12.9
		Cesarean section	2119	17.0	1867	16.6		20.6
	Infant's sex	Male	6466	51.0	5863	51.2		48.9
		Female	6210	49.0	5581	48.8		51.1

Table 2 .

 2 Description of occupational activities and solvent exposure among women of the ELFE cohort who worked during pregnancy and for whom organic solvent exposure is known for at least one solvent family (n = 13,026 women).

						Oxygenated (NA=116)				Petroleum (NA=129)		Chlorinated (NA=50)
							Certainly exposed at a	Certainly exposed at
			Not exposed Likely exposed	very low level	least a low level	Not exposed Possibly exposed Not exposed Possibly exposed
		Total (N)	N	%	N	%	N	%	N	%	N	%	N	%	N	%	N	%
		Total 13,026 9988 77.4	885	6.9	1785	13.8	252	2.0	12,036 93.3	861	6.7	12,786 98.5	190	1.5
	Professional, technical, and related workers	5355	3729 70.3	283	5.3	1125	21.2	165	3.1	5025 95.2	253	4.8	5163 96.8	172	3.2
	Medical, dental, veterinarians, pharmacists	700	201 28.7	235	33.6	238	34.0	26	3.7	700 100.0	0	0.0	700 100.0		0.0
	Nurses, midwives, medical x ray technicians	912	25	2.7	0	0.0	887	97.3	0	0.0	912 100.0	0	0.0	912 100.0		0.0
	Architects, engineers, and related technicians	382	346 90.8	25	6.6	0	0.0	10	2.6	314	82.2	68	17.8	367	97.3	10	2.7
	Statisticians, mathematicians, systems analysts	35	35	100.0	0	0.0	0	0.0	0	0.0	35	100.0	0	0.0	35	100.0		0.0
	Teachers	1426	1426 100.0	0	0.0	0	0.0	0	0.0	1426 100.0	0	0.0	1426 100.0		0.0
	Social workers	511	511 100.0	0	0.0	0	0.0	0	0.0	511 100.0	0	0.0	511 100.0		0.0
	Chemists, biologists, and related workers	180	41	23.6	8	4.6	0	0.0	125	71.8	27	15.1	152	84.9	19	10.7	158	89.3
	Jurists, journalists, and related workers

Table 3 .

 3 Relation between exposure to solvents by solvent family and the risk of SGA status, birthweight, and head circumference (N=13,026 children).

	SGA	Birthweight	Head circumference
	(OR (95% CI))	(β (95% CI))	(β (95% CI))

Table 4 .

 4 Relation between exposure to solvents by solvent family and the risk of SGA, birthweight, and head circumference for women who stopped working during the first, second (N= 4896 children), or third trimester of pregnancy (N= 6968 children).

	SGA	Birthweight	Head circumference

Table 5 .

 5 Relation between exposure to solvents and head circumference (solvents statistically associated with reduced head circumference, mutually adjusted) (N=13,026 children).

	Solvent	Exposure	Head circumference (β (95% CI)) **
	Oxygenated	Not exposed	ref
		Likely exposed	-0.04 (-0.13; 0.06)
		Certainly exposed at a very low level	-0.04 (-0.10; 0.03)
		Certainly exposed at least at a low level	-0.25 (-0.47; -0.03)
	Chlorinated	Not exposed	ref
		Possibly exposed	-0.07 (-0.32; 0.18)

**Adjusted for gestational age (linear and quadratic form), newborn sex, maternal education level, smoking status, alcohol consumption, maternal body mass index, oxygenated solvent exposure, and chlorinated solvent exposure.

Table S1 .

 S1 Notation of probability and level of exposure for each group of solvents in the JEM.

		Oxygenated solvents Petroleum solvents Chlorinated solvents
	Probability of exposure	0: not exposed	0: < 1 %	0: not exposed
		10: [1%-10%]	1: [1%-10%]	10: [1%-10%]
		20: ]10%-20%]	2: ]10%-50%]	20: ]10%-20%]
		30: ]20%-30%]	3: ]50%-90%]	30: ]20%-30%]
		40: ]30%-40%]	4: > 90 %	40: ]30%-40%]
		50: ]40%-50%]		50: ]40%-50%]
		60: ]50%-60%]		60: ]50%-60%]
		70: ]60%-70%]		70: ]60%-70%]
		80: ]70%-80%]		80: ]70%-80%]
		90: ]80%-90%]		90: ]80%-90%]
		100: > 90%		100: > 90%
	Level of exposure J o u r n a l P r e -p r o o f 1: very low 2: low 3: moderate 4: high 1: low 2: moderate 3: high 1: very low 2: low 3: moderate 4: high

Table S2 .

 S2 Probability and level of occupational exposure to oxygenated solvents for women of the ELFE cohort who worked during pregnancy (N=12,910 women).

	Oxygenated solvents	Level of exposure
	Probability of exposure	Not exposed (N) Very low (N) Low (N) Moderate (N) Total (N)
	Not exposed Not exposed	9988		9988
	]1%-10%]		15		15
	]10%-20%]		23		23
	]20%-30%]		18		18
	]30%-40%]		220	8	228
	]40%-50%]	Likely exposed	13		14
	]50%-60%] ]60%-0%] ]70%-80%] ]80%-90%] > 90% Total	516 2 51 1 1785 2644 J o u r n a l P r e -p r o o f 1 9 5 Certainly exposed 249 9988 272	516 3 62 6 2037 12,910

Table S3 .

 S3 Probability and level of occupational exposure to petroleum solvents for women of the ELFE cohort who worked during pregnancy (N=12,897 women).

	Petroleum solvents	Level of exposure
	Probability of exposure	Not exposed (N)	Low (N)	Moderate (N)	Total (N)
	Not exposed	Not exposed	12,036			12,036
	]1%-10%]			743		743
	]10%-50%]	Possibly exposed		79	1	80
	]50%-90%]			24		24
	> 90 % Total	12 858 J o u r n a l P r e -p r o o f 2 12,036 3	14 12,897
						32

Table S4 .

 S4 Probability and level of occupational exposure to chlorinated solvents for women of the ELFE cohort who worked during pregnancy (N=12,976 women).

	Chlorinated solvents		Level of exposure
	Probability of exposure		Not exposed (N) Very low (N)	Total (N)
	Not exposed	Not exposed	12,786		12,786
	]1%-5%]			164	164
	]5%-10%]	Possibly exposed		14	14
	]10%-50%]			1	1
	]50%-55%]			11	11
	Total		12,786	190	12,976
	J o u r n a l P r e -p r o o f

Table S5 .

 S5 Probability of occupational exposure to subgroups of solvents for women of the ELFE cohort who worked during pregnancy (N=13,026 women).

				Likely	Certainly	Certainly
				exposed	exposed at a	exposed	at
					very low level	least at a low
						level
	Solvents	Subgroups	N exposed (%) N exposed (%) N exposed (%) N exposed (%)
	Oxygenated	Alcohols	2758 (21.2)	815 (6.3)	93 (0.7)	1850 (14.2)
		Diethyl ether	1742 (13.4)	1742 (13.4)	0	0
		Ethylene glycol	1 (0.008)	1 (0.008)	0	0
		Ketones and esters	367 (2.8)	189 (1.5)	93 (0.7)	85 (0.6)
	Petroleum Chlorinated	Tetrahydrofurane Benzene Fuel Kerosene Special essence White spirit Dichloromethane Tetrachloroethylene Trichloroethylene Trichloromethane J o u r n a l P r e -p r o o f 30 (0.2) 30 (0.2) 0 8 (0.06) 7 (0.05) 0 19 (0.1) 18 (0.1) 0 16 (0.1) 16 (0.1) 0 206 (1.6) 205 (1.6) 0 748 (5.8) 737 (5.7) 0 166 (1.3) 166 (1.3) 0 13 (0.1) 13 (0.1) 0 9 (0.07) 9 (0.07) 0 163 (1.3) 163 (1.3) 0	0 1 (0.001) 1 (0.001) 0 1 (0.001) 11 (0.1) 0 0 0 0
							34

Table S6 .

 S6 Relation between exposure to oxygenated solvents and the risk of SGA status, birthweight, and head circumference (threshold with a probability of exposure > 50 %) (N=13,026 children).

					SGA	Birth weight	Head circumference
	Solvent	Exposure	Not SGA:	SGA:	Crude OR	Adjusted	Crude β	Adjusted β **	Crude β	Adjusted β **
			N (%)	N (%)	(95% CI)	OR*	(95% CI)	(95% CI)	(95% CI)	(95% CI)
						(95% CI)
	Oxygenated Not exposed	8783 (90.5)	924 (9.5)	ref	ref	ref	ref	ref	ref
		Likely exposed	256 (87.7)	36 (12.3)	1.34	1.33	-42.38	-24.75	-0.07	-0.03
					(0.94;1.91)	(0.93;1.91)	(-97.01; 12.25)	(-70.45; 20.95)	(-0.22; 0.12)	(-0.19; 0.12)
		Certainly	2068 (89.8) 236 (10.2)	1.08	1.06	-20.53	-1.87	-0.07	-0.03
		exposed at a very			(0.93;1.26)	(0.91;1.24)	(-41.79; 0.73)	(-20.24; 16.50)	(-0.13; -0.003)	(-0.09; 0.03)
		low level
		Certainly	229 (88.8)	29 (11.2)	1.20 (0.81;	1.19	-28.19	-34.21
		exposed at least			1.78)	(0.80;1.77)	(-85.66; 29.29)	(-83.49; 15.
		at a low level

Table S7 .

 S7 Relation between exposure to oxygenated solvents and the risk of SGA status, birthweight, and head circumference (certainly exposure to oxygenated solvent, aggregated) (N=13,026 children). Adjusted for maternal education level, smoking status, alcohol consumption, and body mass index ** Adjusted for gestational age (linear and quadratic form), newborn sex, maternal education level, smoking status, alcohol consumption, and body mass index J o u r n a l P r e -p r o o f 36

					SGA	Birthweight	Head circumference
	Solvent	Exposure	Not SGA:	SGA:	Crude OR	Adjusted	Crude β	Adjusted β **	Crude β	Adjusted β **
			N (%)	N (%)	(95% CI)	OR*	(95% CI)	(95% CI)	(95% CI)	(95% CI)
						(95% CI)
	Oxygenated Not exposed	8783 (90.5) 924 (9.5)	ref	ref	ref	ref	ref	ref
		Likely exposed	762 (6.7)	104 (8.4)	1.30	1.24	-39.42	-16.45	-0.09	-0.03
					(1.05-1.61)	(0.99-1.55)	(-71.96; -6.88)	(-44.49; 11.59)	(-0.19; 0.02)	(-0.13; 0.06)
		Certainly exposed	1791 (90.1) 197 (9.9)	1.05	1.04	-16.51	-8.42	-0.08	-0.06
					(0.89-1.23)	(0.89-1.23)	(-39.08; 6.07)	(-27.38; 10.55)	(-0.15; -0.01)	(-0.13; 0.01)

*

Table S8 .

 S8 Relation between exposure to solvents by family and head circumference (additionally adjusted for the mode of delivery) (N=13,026 children). Adjusted for gestational age (linear and quadratic form), newborn sex, maternal education level, smoking status, alcohol consumption, body mass index, and mode of delivery

	Solvent	Exposure	Head circumference (β (95% CI)) ***
	Oxygenated	Not exposed	ref
		Likely exposed	-0.04 (-0.13; 0.06)
		Certainly exposed at a	-0.03 (-0.09; 0.04)
		very low level
		Certainly exposed at least	-0.27 (-0.44; -0.10)
		at a low level
	Petroleum	Not exposed	ref
		Possibly exposed	-0.06 (-0.16; 0.03)
	Chlorinated	Not exposed	ref
		Possibly exposed	-0.25 (-0.43; -0.06)
	***

J o u r n a l P r e -p r o o f

SUPPLEMENTAL MATERIAL

J o u r n a l P r e -p r o o f

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:


Houssem E M Triki
email: houssem.triki@cirad.fr

Fabienne Ribeyre

Fabrice Pinard

Marc Jaeger

Coupling plant growth models, application on pest & disease models: an interaction structure proposal

Keywords: Complex systems, Plant growth model, pest & diseases model, model coupling, interaction

When a plant is attacked by a pest or a disease, different effects can be observed on the yield and/or on the different organs that have been affected by the pest. In order to represent and simulate these effects, different works were done on the interaction between plant growth model and its environment, or plant-pathogen (Qi et al., 2009), plant-climate or plant-plant (Gaudio et al., 2021). The literature on plant-pathogen coupling is poorer regarding combined biotic and abiotic stress dynamics (Louarn et al., 2020). A classic way to approach model interactions is to test them within each other, but this approach is specific to each use-case and difficult to generalize [START_REF] Garin | [END_REF]. Here, we propose to develop a formalism allowing to highlight all the coupling effects on the dynamics of all the models involved over a large timescale (theoretically, throughout the plant's lifespan). The proposed framework thus inherits the model coupling approach of (Siad et al., 2019).

We define an interaction platform structure as a model interaction framework, flexible in terms of number of models and types of models. The platform implements a specific behavioural design pattern called Mediator, defining how objects interact with each other. Mediator promotes loose coupling by preventing objects from referring to each other explicitly, and allows their interaction to vary independently [START_REF] Gamma | Reading[END_REF]. The interaction platform structure, as presented in figure 1, is organized around three main functions:

• Systems' states: This function deals with the state variables of the interacting models and the platform states. The relevant states of the models involved in the interactions are collected and "translated" into platform states (dedicated to the interaction). When executing the interaction models maintained in the platform, the function potentially alters the platform states. Conversely, these platform states are "translated" into the state variables of the linked models. • Cycle synchronisation: The platform defines and manages a scheduler because the temporal scales of each model can differ regarding its nature (e.g. calendar time, thermal time) and/or length (e.g. days, weeks …). This function launches the linked models, and of course, between two model calls, launches the interaction process updating the system states within the platform. This component also manages the priorities of the different interacting models according to their cycle durations (the fastest has a priority over the slower) or according to user controls. • State recording and Storage: This function ensures the integrity of interacting models and platform states. It also manages data and other dynamics that are not required for interaction but are requested by the user for observations. The storage of states and variables thus ensures a secure simulation, allowing stop-&-go. When setting up an interaction, few modifications are generally necessary on the models, which are supposed to be operational with a stop-and-go implementation. Moreover, the modular structure of the platform is designed to be easy to understand and to customize the low-level interactions descriptions: the user modeller defines how the state variable of the interface interacts, not the states of the models. This is an advantage during development, each module is independent, and we can modify each one independently, still guaranteeing the execution of the platform.

We are currently applying and developing this interaction frame between Coffee Berry Borer (CBB) attacks and Coffee trees models, calibrated from Indonesian data and tested on Latin America data. The platform aims to host other P&D models on Robusta species issued from experiments conducted in Uganda.

Supported by EU FOOD/2021/427-759 / DESIRA and French ANR-16-CONV-0004 / #DigitAg programs

Figure 1 :

 1 Figure 1: Interaction structure Schematics of P&D model and a plant growth model.

Pest & Disease Model

Plant Growth model

Modules


Corentin Chaumont

Raphaël P Martins

Guillaume Viart

Dominique Pavin

Brieuc Noirot-Cosson

David Huchette

Arnaud Savouré

Bénédicte Godin

Adrian Mirolo

Jorys Achard

Raphael P Martins

Brieuc Noirot- Cosson

Arnaud Savoure

Benedicte Godin

Simon Rivron

Hélène Eltchaninoff

Frédéric Anselme
email: frederic.anselme@chu-rouen.fr

RVOT premature ventricular contractions induce significant anatomical displacement during 3D mapping: A cause of mid-term ablation failure?

Keywords: Premature ventricular contraction, RVOT PVC, Radiofrequency ablation, 3D electroanatomical mapping system, Cardiac arrhythmia

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Premature ventricular complexes (PVCs) originating from the right ventricular outflow tract (RVOT) are a common arrhythmia. While RVOT PVCs are frequently benign, they can be symptomatic and disabling or even cause a cardiomyopathy with impaired left ventricular ejection fraction (LVEF) [START_REF] Yarlagadda | Reversal of cardiomyopathy in patients with repetitive monomorphic ventricular ectopy originating from the right ventricular outflow tract[END_REF].

Catheter ablation has become a first-line treatment for symptomatic and frequent RVOT PVCs because of the high acute success and low complication rates [START_REF] Morady | Long-term results of catheter ablation of idiopathic right ventricular tachycardia[END_REF][START_REF] Zeppenfeld | ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death[END_REF]. In a retrospective study in 510 patients, catheter ablation significantly reduced PVC burden and improved LVEF compared with antiarrhythmic drug therapy [START_REF] Zhong | Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: a single-center retrospective study[END_REF]. Over the past few years, the development of 3-dimensional (3D)electroanatomical mapping systems has given the opportunity to study the ventricular electrical activation pattern with a high degree of precision and has further increased the efficiency of catheter ablation. However, 30% of patients may experience PVC recurrence within 12 months of the ablation procedure [START_REF] Abraham | Similar outcomes with manual contact force ablation catheters and traditional catheters in the treatment of outflow tract premature ventricular complexes[END_REF]. Whereas it was assumed that the chamber geometry remained identical during both sinus rhythm and PVCs, Andreu D et al. [START_REF] Andreu | Displacement of the target ablation site and ventricles during premature ventricular contractions: relevance for radiofrequency catheter ablation[END_REF] were the first to show the existence of a displacement of the ventricles and the ablation target site during a PVC beat compared with that in the sinus rhythm position. As ablation lesions are often delivered during sinus rhythm, this PVC-induced displacement could deceive the operator about the true location of the PVC site of origin. The aim of this study was, therefore, to analyse the extent of displacement induced by RVOT PVCs and its implications for the ablation sites and mid-term efficacy of ablation.

Methods

This study was conducted in four hospitals in France. We retrospectively included all consecutive patients referred over the past 12 months for ablation of idiopathic ventricular ectopies originating from the RVOT using the CARTO 3D electroanatomical mapping system. All ablation procedures were performed with the Pentaray® catheter for mapping and a contact-force open-irrigation radiofrequency catheter for ablation. The "Tissue Proximity Index" filter was activated in all cases. Exclusion criteria were age less than 18 years, mapping procedures performed using only pace mapping, and activation maps for which less than 100 points were obtained. Acute success was defined as abolition of PVC activity at baseline and during isoprenaline infusion, after a 30-min wait following the last radiofrequency delivery.

The local ethics committee approved the study and all patients provided informed consent for the procedure and data collection.

Follow-up

Clinical evaluation and 24-h Holter monitoring were performed in all patients 3-6 months after the ablation procedure. Afterwards, patients continued usual follow-up with their refering cardiologist and general practicioner. Clinical follow-up included review of the patients' medical records and telephone contact with their referring physicians, if necessary. Documented recurrence was defined as PVCs with the same electrocardiographic pattern as that recorded preablation. Patients with more than 3000 PVCs on 24-h Holter monitoring performed during follow-up were considered to have recurrence of frequent PVCs.

Technical approach of 3D-map analysis and reannotation of activation points

All activation maps were analysed retrospectively. We first verified that the morphology of the PVC was unique and constant throughout the acquisition of all the activation points. Activation points taken on bursts of more than two PVCs were excluded. Activation times during PVCs were automatically determined using the CARTO® WAVEFRONT ANNOTATION™ Module (Biosense Webster, Issy-Les-Moulineaux, France), a dedicated annotation algorithm that considers both unipolar and bipolar signals. All activation points were then manually checked and adjusted if needed.

The initial local activation time (LAT) map was used as a reference (the raw PVC map). A copy was generated, on which each point was manually reannotated considering the previous sinus rhythm beat 3D location (the corrected PVC map). This manoeuvre did not modify the activation times of reannotated points. Of importance, only the original activation points (raw PVC maps) were visualized during the ablation procedures as this reannotation method was performed retrospectively.

We finally checked that raw and corrected PVC activation maps had the same number of points. The 10 best activation points were identified and used for analysis. The 3D location of each point was extracted from the CARTO system for both maps. Spatial point coordinates (i.e. x, y and z coordinates) for raw and corrected PVC maps were generated and recorded in a calculation workbook. The Euclidean distance between each point on both maps, representing the PVC-induced displacement, was calculated. The total number of VISITAGs (ablation sites) and their location, either VISITAG location represents a single ablation site, accumulating consecutive catheter positions recorded during application of radiofrequency energy while the ablation catheter is stable in a specific area. In our study, VISITAG apparition filters were established as follow: minimum distance change below 3 mm; minimum application time up to 3 s; and minimum force contact up to 3 g. We also collected the corresponding ablation index (AI), a visual indication based on evaluation of power, force and time parameters according to an equation and coefficients. VISITAGS were classified into two groups according to an ablation index threshold set at 450, in accordance with what has already been shown as producing an effective lesion in PVC ablation [START_REF] Casella | Ablation Index as a predictor of long-term efficacy in premature ventricular complex ablation: A regional target value analysis[END_REF]. Colouring threshold was accordingly fixed to 450 (i.e. red for AI ≥ 450 and pink for < 450).

Statistical analysis

Continuous variables are expressed as mean ± standard deviation (SD) for normally distributed data and as median and interquartile range (IQR) for non-normally distributed data. Normal distribution was assessed by a Shapiro-Wilk test. Categorical variables are expressed as counts and percentage.

Results

Fifty-four patients underwent RVOT PVC ablation procedures at four hospitals in France from January 2019 to January 2020. Fifteen patients whose ablation procedures were performed using a 3D mapping system other than CARTO were excluded. Thirty-nine patients were screened for inclusion, 21 of whom did not meet the study criteria (i.e. activation map with < 100 points [n = 14] or ablation procedure performed using pace mapping only [n = 7]). The study population therefore comprised 18 patients (Fig. 1).

Patient baseline characteristics are shown in Table 1. All patients had symptomatic frequent

PVCs and 1 had PVC-induced cardiomyopathy. Mean LVEF was 58 ± 9% and 1 patient had an LVEF of < 40%. From these patients, 18 unique chamber maps and a total of 2049 individual mapped points were analysed.

Acute procedural outcomes

Mean procedure duration was 65 ± 19 min. Acute procedural success was obtained in all patients.

Mean PVC duration was 130 ± 13 ms and mean coupling interval was 494 ± 93 ms. The site of origin within the RVOT was septal in 9 patients, lateral in 2, anterior in 3 and posterior in 4. The direction of map shift during PVCs relative to the map in sinus rhythm occurred along a craniocaudal axis in 16 of 18 patients (Fig. A.1). For those patients, the corrected PVC site of origin was located superior to the initial site of origin. The displacement was lateral in 2 patients. Considering all activation points, the mean displacement for each of the 18 mapped chambers was 5.6 ± 2.2 mm. The maximal displacement for each mapped chamber was 13.9 ± 3.2 mm. Considering only the 10 best activation points, for each of the 18 mapped chambers, the mean displacement distance was 5.1 ± 1.8 mm and the maximal displacement was 8.2 ± 3.4 mm.

Mid-term follow up

At 3-6-month follow up (mean 4.4 ± 1.9 months), 13 patients remained free from symptoms, with less than 500 PVCs on 24-h Holter monitoring. Recurrence of frequent and symptomatic RVOT PVCs 2. Of note, they all underwent a successful redo procedure. The sites of interest were in the same area within the RVOT.

There was no significant difference in the mean displacement distance between patients who remained free from arrhythmias and those with recurrence (5.3 ± 1.8 vs 6.3 ± 3.0, respectively).

However, when considering these 5 patients, none had a VISITAG ≥ 450 AI on the area including the 10 best LAT corrected points, whereas all had significant ablation lesions on the initial best points (Central illustration). Conversely, 8 of 13 patients free from PVCs had a VISITAG ≥ 450 AI on the 10 best LAT corrected points (0/5 vs 8/13) (Fig. 2). In the remaining 5 patients without recurrence, none of the recorded VISTAGS were ≥ 450 AI, but most of the VISITAGs (mean of 6) were on the area including the 10 best LAT corrected points.

Discussion

Spatial displacement during 3D electroanatomical mapping of RVOT PVCs

3D geometry volume acquisition as well as radiofrequency ablation lesions are mainly performed during sinus rhythm whereas the PVC activation map is, by definition, performed during PVC beats.

Consequently, in case of anatomical displacement of the heart chamber during PVC, points mapped during PVCs would be spatially displaced with regards to their true location on the map in sinus rhythm and could potentially be misleading for ablation.

Our study confirms the existence of a PVC-induced anatomical displacement during 3D mapping and ablation of RVOT PVCs. PVC-induced anatomical displacement could be explained by two phenomena: the short coupling interval between PVC and the previous sinus beat, and a mechanical activation pattern of the ventricle during PVC that differs from sinus rhythm. Other studies have demonstrated a significant spatial displacement between the activation point position in sinus rhythm and during PVC beats, regardless of the origin of the PVC [START_REF] Andreu | Displacement of the target ablation site and ventricles during premature ventricular contractions: relevance for radiofrequency catheter ablation[END_REF]8,[START_REF] Steyers | Ablation using 3D maps adjusted for spatial displacement of premature ventricular complexes relative to sinus beats: Improving precision by correcting for the shift[END_REF]. Interestingly, this displacement has been shown to increase with the shortening of the PVC coupling interval and to be greater in the right than in the left ventricle [START_REF] Andreu | Displacement of the target ablation site and ventricles during premature ventricular contractions: relevance for radiofrequency catheter ablation[END_REF]. In a study including 55 consecutive patients undergoing PVC ablation and a total of 7000 points from 71 electroanatomical activation maps, a median distance of 9 mm was found between the points position during sinus rhythm and PVC [START_REF] Andreu | Displacement of the target ablation site and ventricles during premature ventricular contractions: relevance for radiofrequency catheter ablation[END_REF]. De Potter et al. [8] also showed that PVCs caused a position shift in 3D mapping systems due to motion of the heart within the established geometry. In this study, the mean shift was also 9 mm. In another study, the earliest annotated PVC location was spatially displaced from the corresponding successful ablation site annotated during sinus rhythm by a mean of 6.7 mm (range 3.3-13.0 mm) [START_REF] Steyers | Ablation using 3D maps adjusted for spatial displacement of premature ventricular complexes relative to sinus beats: Improving precision by correcting for the shift[END_REF].

In the present study focusing solely on RVOT PVCs, we confirmed a significant displacement of 5.6 ± 2.2 mm, and first demonstrated that the targeted ablation site displacement occurs predominantly along a craniocaudal axis. In 15 of 18 patients, the corrected PVC site of origin was located superiorly to the initial site of origin, likely due to an inferior displacement of the heart chamber during PVC beats (Central illustration and Fig. 2). In a study using a home-made algorithm, a systematic and similar displacement in terms of axis was found in a subgroup of 9 patients with RVOT PVCs. The corrected area was located superior and posterior to the initial site of interest [8]. Another study including 21 patients (only 8 with RVOT PVCs) found an overall direction of map shift during PVC leftwards and inferior relative to the map for sinus rhythm. However, all types of PVCs were included in this study and the displacement direction was not detailed for each patient and for each PVC origin [START_REF] Steyers | Ablation using 3D maps adjusted for spatial displacement of premature ventricular complexes relative to sinus beats: Improving precision by correcting for the shift[END_REF].

Clinical efficacy of PVC ablation

Our study also focused on the clinical efficacy of PVC ablation. We first investigated the impact of this displacement on clinical efficacy of radiofrequency PVC ablation. The mid-term success rate was 72%, similar to what has been described in the literature [START_REF] Zhong | Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: a single-center retrospective study[END_REF]. Our results also showed that the midterm arrhythmia recurrences were most likely related to PVC-induced displacement, as ablation lesions were delivered remote from the area of interest in all these cases (Central illustration). Despite acute success, those mid-term reccurences might also be explained by insufficient radiofrequency delivery on site of origin (i.e. low AI and/or deep foci). Taking this displacement into account during the index PVC ablation procedure could therefore affect the outcome.

Considering that irrigated radiofrequency application generally induces a lesion 5-6 mm wide (2.5 mm of radius), the mean displacement of 5.6 mm could very well be of clinical relevance except if additional application lesions are systematically performed around the site of origin.

The amount of shift was not correlated with the mid-term success of ablation. However, the lack of significant ablation lesions (i.e. ablation index ≥ 450) within the corrected area including the 10 best points seemed to be associated with clinical recurrences. To our knowledge, this association between mid-term PVC recurrence and the absence of spatial overlap between the ablation points and the corrected site of origin has not previously been described.

Of importance, only the original activation points (raw PVC maps) were visualized during the ablation procedures. Looking at maps recorded in patients with mid-term success, we found that ablation lesions were always delivered within the corrected PVC site of origin area. In some patients, radiofrequency lesions were first delivered at the initial site of origin on the geometry and then, due to lack of efficacy, were delivered slightly above (Fig. 2). In others, ablation was directely applied at the corrected site of origin, mainly guided by the online analysis of the PVC signal rather than looking at the site of origin on the map.

Clinical applications of this new approach

While the manual approach used in our study is extremely time-consuming, the recent version of the CARTO system incorporates a so-called LAT Hybrid module. This new algorithm automatically adjusts the points considering the 3D location during the sinus beat while preserving the local activation time J o u r n a l P r e -p r o o f 10 of the PVC beat. Our method, although performed manually, corresponds to the algorithm as evidenced by recent cases performed with both approaches (Fig. 3). In case of PVC ablation performed with other 3D mapping system, it could be wise to pay attention to the PVC electrogram orphology and its prematurity at the site located just cranially to the initial best site of origin, particularly if initial ablation lesions do not lead to immediate PVC disappearance. Further studies will be needed to evaluate whether this new approach will lead to better long-term clinical efficacy.

Limitations

This was a retrospective study with its inherent biases. The population was also highly selected (i.e. limited to ablation procedures using the CARTO 3D electroanatomical mapping system and activation maps of > 100 points).

Conclusions

RVOT PVCs induce an anatomical shift that can mislead physicians about the true location of the arrhythmia's site of origin. This displacement occurs predominantly on a craniocaudal axis. Our study highlights the association between mid-term PVC recurrence and the absence of spatial overlap between the ablation points and the corrected site of origin. Taking this phenomenon into account may improve PVC ablation outcomes.

Sources of funding

None.

Disclosure of interest

  occurred in 5 patients (Fig. A.2). The characteristics of these patients are shown in Table

FFiguresFigure 1 .

 1 Figures

  Figure 1. Flow chart. PVCs: premature ventricular complexes; RVOT: right ventricular outflow tract.

Figure 2 .

 2 Figure 2. 3D map showing the 10 best activation points of a RVOT PVC (left anterior oblique view) and the locations of the ablation lesions. Panel A: 3D map of the targeted PVC showing the 10 best activation times; initial points (raw PVC map) are shown in orange and manually reannotated points (corrected map) in green. The displacement direction is craniocaudal and the mean distance is 8.2 mm. Panel B: During the radiofrequency applications, only the initial points (orange area) were visualized by the operator. Note that the operator first targeted the initial points and, due to the lack of efficacy, ablation lesions with ablation index ≥ 450 were then applicated higher within the corrected PVC map (green area). This patient remained free from PVCs at 4-month follow-up. VISITAGS are shown in size 2 (2 mm radius). 3D: three-dimensional; PVCs: premature ventricular complexes; RVOT: right ventricular outflow tract.

Figure 3 .

 3 Figure 3. Comparison between the manual reannotation method used in the study and the new LAT hybrid algorithm. Panel A: 3D map of targeted PVCs showing the 10 best activation times; initial points (raw PVC map) are shown in orange and manually reannotated points (corrected PVC map) in green. Panel B: Initial points are shown in orange and automatically reannotated points (using the LAT hybrid algorithm) in green. The displacement (6.2 mm) is similar to that observed using the manual method. Panel C: 3D map showing the ablation lesions (VISITAGS). Note that ablation lesions with significant ablation index (i.e. AI ≥ 450) were applied directly within the corrected PVC area (green area), above the raw PVC area. This patient remained free from PVCs at 4-month follow-up. VISITAGS are shown in size 2 (2 mm radius). AI: ablation index; LAT: local activation time; PVCs: premature ventricular complexes; RVOT: right ventricular outflow tract.

Table 1 .

 1 Patient baseline characteristics (n = 18)

	Characteristic
	Baseline characteristics
	Age (years)	46 ± 15
	Body mass index (kg/m 2 )	27.6 ± 3.8
	Female sex	9 (50)
	Symptoms
	Palpitations	13 (72)
	Dyspnoea	5 (28)
	Syncope or lightheadedness	4 (22)
	Antiarrhythmic drugs
	Beta-blockers	13 (72)
	Amiodarone	1 (6)
	Calcium-channel blocker	1 (6)
	Echocardiography
	Underlying structural heart disease	0 (0)
	PVC-induced LVEF impairment	1 (6)
	LVEF (%)	58 ± 9
	24-h Holter monitoring
	Number of PVCs	23 461 ± 10 815
	Monomorphic PVC	18 (100)
	PVC characteristics
	PVC duration (ms)	130 ± 13
	Mean coupling interval (ms)	493 ± 90
	Fixed coupling interval	10 (55)
	Data are expressed as number (%) or mean ± standard deviation. LVEF: left ventricular ejection
	fraction; PVCs: premature ventricular complexes.

Table 2 .

 2 Characteristics of patients who needed a redo-procedure

		Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
	Baseline characteristics
	Age (years)	23	48	58	59	20
	Body mass index (kg/m 2 )	25	27	31	23	33
	Female sex	Male	Male	Female	Female	Female
	Symptoms
	Palpitations	1	1	0	1	1
	Dyspnoea	1	0	1	0	0
	Syncope or lightheadedness	0	0	0	1	0
	Echocardiography
	PVC-induced LVEF impairment	1	0	0	0	0
	LVEF (%)	38	55	61	76	64
	PVC characteristics
	Number of PVCs/24 h	12,000	30,000	32,500	31,000	19,000
	PVC duration (ms)	148	127	115	146	139
	Mean coupling interval (ms)	570	612	445	511	346
	Fixed coupling interval	0	0	1	0	1
	Procedure characteristics
	VISITAGS (AI ≥ 450) on 10 best	2	1	1	1	2
	LAT initial points
	VISITAGS (AI ≥ 450) on 10 best	0	0	0	0	0
	LAT corrected points
	Shift direction	CC a	Lateral	CC	CC	CC
	Mean displacement (mm)	7.9 ± 2.5	4.3 ± 2.7	10.7 ± 3.9	5.0 ± 1.9	3.4 ± 2.4
	Maximal displacement (mm)	16.5	13	18.7	9.5	14.2
	Mean displacement for 10 best	6.6 ± 2.3	2.9 ± 1.0	9.6 ± 4.7	4.3 ± 0.9	3.9 ± 1.6
	LAT (mm)
	Post-ablation data

Data are expressed as number (%) or mean ± standard deviation. LVEF: left ventricular ejection fraction; PVCs: premature ventricular complexes. a Craniocaudal axis.

Table 3 .

 3 Characteristics of patients without recurrences