In 2016, the US Food and Drug Administration raised concerns about the potential negative effects of anesthesia exposure on neurodevelopment in children during pregnancy or before the age of three.

The impact of exposure to anesthetic agents on neurodevelopmental outcome however remains debated: clinical studies on the subject do not allow for unequivocal conclusions to be drawn, given their methodological heterogeneity and the numerous confounding environmental factors.

To this date, only two studies have focused on the potential neurodevelopmental effects of general anesthesia during the prenatal period, even though general anesthesia for non-obstetric surgery during pregnancy affects up to 3% of pregnant women.

This observational ambidirectional study would be the first to investigate the potential neurodevelopmental effects of prenatal exposure to anesthesia, whether general or regional, for surgery during pregnancy. It would thus differentiate between the contribution of surgical stress and that of anesthetic agents in any observed modifications.

The aim of the study is:

Are there any subtle modifications of executive functions associated with prenatal exposure to anesthesia during non-obstetric surgery during pregnancy?

To investigate this, parents of the participating children will be asked to complete a standardized parental telephone questionnaire from the "Behaviour Rating Inventory of Executive Function" (BRIEF). This parental questionnaire allows for evaluating children's behaviors related to executive functions.

Researchers will compare the score derived from the "BRIEF" parental questionnaire (BRIEF score) between three groups of children aged from 5 to 12 years old, born between 2011 and 2018 at Caen University Hospital:

• The " General anesthesia " group: children whose mothers underwent general anesthesia for non-obstetric surgery during pregnancy (N: 62).
• The " Locoregional anesthesia " group: children whose mothers underwent regional anesthesia for non-obstetric surgery during pregnancy (N: 31).
• The " Control " group: children whose mothers did not undergo any surgical intervention during pregnancy (N: 62).

The first aim of our study is to investigate the presence of a significant difference in the BRIEF score between the three groups.

The seconds aims are to assess the cognitive functioning of patients in their daily lives (school, parental home, and extracurricular activities).

The study : "Association Between Prenatal Anesthesia Exposure and Neurodevelopmental Outcome : an Ambidirectional Cohort Study" is a single-center, ambidirectional, observational cohort study conducted at the University Hospital Center of Caen (CHU Caen).

Inclusion criteria :

The study groups "General Anesthesia" (GA group) and "Locoregional Anesthesia" (LRA group) are derived from a previous Caen University Hospital cohort, consisting of children whose mothers underwent general or regional anesthesia for non-obstetric surgery during pregnancy.

This previous cohort was established in 2021 for an unpublished research project consisting of 179 patients who underwent non-obstetric surgeries during pregnancy. These pregnant women who underwent surgery were identified through the Caen University hospital electronic database spanning from 2011 to 2020, as surgical procedures for pregnant women started to be documented since 2011 in the medical database of this hospital.

The "control group" will be formed by including children born at Caen University Hospital, the same day, right before and right after the children in the LRA group, but whose mothers did not undergo any surgical intervention during pregnancy.

The number of exposed patients (N=93) is comparable to prospective studies investigating the effect of postnatal general anesthesia on neurodevelopmental outcomes. It is also comparable to and higher than the two studies investigating the effect of prenatal general anesthesia on neurodevelopmental outcomes.

Matching :

The matching of the GA and LRA groups will be done based on the following three adjustment factors:

• Socio-economic level (parental monthly net income within a range of 500 euros)
• Age at the time of testing
• Gender of the child

Inclusion process:

After providing the information sheet and receiving the signed consent form from the legal guardian of the child, the elements of the parental telephone interview will be collected from the child's parents, prospectively, on a standardized data collection sheet during an estimated phone call duration of approximately forty minutes.

The phone call will consist of two parts :

• The standardized parental questionnaire from the "Behaviour Rating Inventory of Executive Function" (BRIEF).
• The parental hetero-questionnaire about their child's cognitive functioning in their daily life and medical history.

Both the parental standardized BRIEF questionnaire and our parental hetero-questionnaire will contribute to fulfilling the study objectives.

The parental hetero-questionnaire is the result of a discussion between clinicians specialized in pediatric and obstetric anesthesia and researchers specialized in the neurocognitive development of children.

Several anamnestic data from the medical records of the patients and their child such as progress of pregnancy, childbirth history, history of general anesthesia during childhood, hospitalization during childhood,, will also be collected retrospectively on a standardized data collection sheet.

Statistical Methodology:

The number of subjects included in the Caen University Hospital cohort comprises : 31 patients in the "locoregional anesthesia" (LRA) group with a 1:2 matching with the "general anesthesia" (GA) group, resulting in 62 patients.

The "control" group is also matched with a 1:2 ratio with the "LRA" group, resulting in 62 patients.

The significance level is set at 5%. Data will be collected using Excel 2022 software (Microsoft Corporation, Redmond, WA, USA). Discrete variables will be expressed as number of cases (%). Continuous variables will be presented as mean ± standard deviations for normally distributed data or as median (95% confidence interval) for non-normally distributed data.

The statistical software used will be Statistica 12, Statsoft®.

Data Management:

The data will be entered into a spreadsheet for statistical analysis of the collected values. These data will only be used for this study, and the sponsor undertakes not to disclose them to third parties. The data processing will comply with the General Data Protection Regulation (GDPR) guidelines.

Inclusion Criteria:

• Children born between 2011 and 2018 at Caen University Hospital
• Children whose mothers underwent surgery for non-obstetrical reasons under general or locoregional anesthesia, or did not undergo any surgical intervention.

Exclusion Criteria:

• Lost to follow-up
• Incomplete medical files
• Refusal of either parent or legal guardian
• Children with condition presenting independent risk factors for impaired neurocognitive development such as : neonatal hypoxia-ischemia, neurological disorder, neuromuscular disorder, complex cardiac or genetic disorders
• Children with a known or suspected genetic syndrome
• Preterm-born children (defined as birth at less than 37 weeks of amenorrhea)
• Cesarean-born children

Children born between 2011 and 2018 at Caen University Hospital :

• Whose mothers underwent general anesthesia for non-obstetric surgery during pregnancy (the "general anesthesia" group).
• Whose mothers underwent locoregional anesthesia for non-obstetric surgery during pregnancy (the "locoregional anesthesia" group).
• Whose mothers who did not undergo any surgical intervention during pregnancy (the "control" group).