Neurodevelopmental Outcome After Prenatal Anesthesia

Neurodevelopmental Disorders Clinical Trial

Official title:

Association Between Prenatal Anesthesia Exposure and Neurodevelopmental Outcome : an Ambi-directional Cohort Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06052878
• Other study ID #: CHUCaen
• Status: Completed
• Start date: October 9, 2023
• Est. completion date: February 26, 2024

Study information

• Verified date: March 2024
• Source: University Hospital, Caen
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: February 26, 2024
• Est. primary completion date: February 23, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 5 Years to 12 Years

Eligibility

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

Related Conditions & MeSH terms

• Child Behavior
• Neurodevelopmental Disorders

Intervention

Other:
• Parental telephone interview with standardized parental questionnaire from the "Behaviour Rating Inventory of Executive Function" (BRIEF)
The "Behaviour Rating Inventory of Executive Function" (BRIEF) is a parental questionnaire that assesses the executive functions of children aged 5 to 18 years old. It consists of 86 questions grouped into 8 scales: inhibition, flexibility, emotional control, initiation, material organization, working memory, planning/organization, and monitoring. It provides information on a global scale (score) regarding subtle and subclinical changes in various executive functions.
• Parental questionnaire about their child's cognitive functioning in their daily life and medical history.
Standardized questionnaire includes : The child's medical history and cognitive functioning (at school, parental home, and during extracurricular activities), home environment, parent's child socioeconomic status and emotional climate.

Locations

Country	Name	City	State
France	University Hospital Caen Normandie	Caen	Normandy

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Caen

Country where clinical trial is conducted

France, 

References & Publications (30)

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Bleeser T, Devroe S, Lucas N, Debels T, Van de Velde M, Lemiere J, Deprest J, Rex S. Neurodevelopmental outcomes after prenatal exposure to anaesthesia for maternal surgery: a propensity-score weighted bidirectional cohort study. Anaesthesia. 2023 Feb;78(2):159-169. doi: 10.1111/anae.15884. Epub 2022 Oct 25. — View Citation

Bleeser T, Van Der Veeken L, Fieuws S, Devroe S, Van de Velde M, Deprest J, Rex S. Effects of general anaesthesia during pregnancy on neurocognitive development of the fetus: a systematic review and meta-analysis. Br J Anaesth. 2021 Jun;126(6):1128-1140. doi: 10.1016/j.bja.2021.02.026. Epub 2021 Apr 6. — View Citation

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Devroe S, Bleeser T, Van de Velde M, Verbrugge L, De Buck F, Deprest J, Devlieger R, Rex S. Anesthesia for non-obstetric surgery during pregnancy in a tertiary referral center: a 16-year retrospective, matched case-control, cohort study. Int J Obstet Anesth. 2019 Aug;39:74-81. doi: 10.1016/j.ijoa.2019.01.006. Epub 2019 Jan 12. — View Citation

DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg. 2011 Nov;113(5):1143-51. doi: 10.1213/ANE.0b013e3182147f42. Epub 2011 Mar 17. — View Citation

Dong C, Rovnaghi CR, Anand KJ. Ketamine exposure during embryogenesis inhibits cellular proliferation in rat fetal cortical neurogenic regions. Acta Anaesthesiol Scand. 2016 May;60(5):579-87. doi: 10.1111/aas.12689. Epub 2016 Jan 29. — View Citation

Ing C, Landau R, DeStephano D, Miles CH, von Ungern-Sternberg BS, Li G, Whitehouse AJO. Prenatal Exposure to General Anesthesia and Childhood Behavioral Deficit. Anesth Analg. 2021 Sep 1;133(3):595-605. doi: 10.1213/ANE.0000000000005389. — View Citation

Marchesini V, Disma N. Anaesthetic neuroprotection in children: does it exist or is it all just bad? Curr Opin Anaesthesiol. 2019 Jun;32(3):363-369. doi: 10.1097/ACO.0000000000000723. — View Citation

McCann ME, de Graaff JC, Dorris L, Disma N, Withington D, Bell G, Grobler A, Stargatt R, Hunt RW, Sheppard SJ, Marmor J, Giribaldi G, Bellinger DC, Hartmann PL, Hardy P, Frawley G, Izzo F, von Ungern Sternberg BS, Lynn A, Wilton N, Mueller M, Polaner DM, Absalom AR, Szmuk P, Morton N, Berde C, Soriano S, Davidson AJ; GAS Consortium. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019 Feb 16;393(10172):664-677. doi: 10.1016/S0140-6736(18)32485-1. Epub 2019 Feb 14. Erratum In: Lancet. 2019 Aug 24;394(10199):638. — View Citation

Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, Hanig JP, Patterson TA, Slikker W Jr, Wang C. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011 Mar-Apr;33(2):220-30. doi: 10.1016/j.ntt.2011.01.001. Epub 2011 Jan 15. — View Citation

Reitman E, Flood P. Anaesthetic considerations for non-obstetric surgery during pregnancy. Br J Anaesth. 2011 Dec;107 Suppl 1:i72-8. doi: 10.1093/bja/aer343. — View Citation

Robbins LS, Blanchard CT, Biasini FJ, Powell MF, Casey BM, Tita AT, Harper LM. General anesthesia for cesarean delivery and childhood neurodevelopmental and perinatal outcomes: a secondary analysis of a randomized controlled trial. Int J Obstet Anesth. 2021 Feb;45:34-40. doi: 10.1016/j.ijoa.2020.08.007. Epub 2020 Aug 25. — View Citation

Salaun JP, Chagnot A, Cachia A, Poirel N, Datin-Dorriere V, Dujarrier C, Lemarchand E, Rolland M, Delalande L, Gressens P, Guillois B, Houde O, Levard D, Gakuba C, Moyon M, Naveau M, Orliac F, Orliaguet G, Hanouz JL, Agin V, Borst G, Vivien D. Consequences of General Anesthesia in Infancy on Behavior and Brain Structure. Anesth Analg. 2023 Feb 1;136(2):240-250. doi: 10.1213/ANE.0000000000006233. Epub 2022 Oct 27. — View Citation

Shi Y, Hu D, Rodgers EL, Katusic SK, Gleich SJ, Hanson AC, Schroeder DR, Flick RP, Warner DO. Epidemiology of general anesthesia prior to age 3 in a population-based birth cohort. Paediatr Anaesth. 2018 Jun;28(6):513-519. doi: 10.1111/pan.13359. Epub 2018 Mar 13. — View Citation

Sprung J, Flick RP, Wilder RT, Katusic SK, Pike TL, Dingli M, Gleich SJ, Schroeder DR, Barbaresi WJ, Hanson AC, Warner DO. Anesthesia for cesarean delivery and learning disabilities in a population-based birth cohort. Anesthesiology. 2009 Aug;111(2):302-10. doi: 10.1097/ALN.0b013e3181adf481. — View Citation

Sun LS, Li G, Miller TL, Salorio C, Byrne MW, Bellinger DC, Ing C, Park R, Radcliffe J, Hays SR, DiMaggio CJ, Cooper TJ, Rauh V, Maxwell LG, Youn A, McGowan FX. Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA. 2016 Jun 7;315(21):2312-20. doi: 10.1001/jama.2016.6967. — View Citation

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Walkden GJ, Gill H, Davies NM, Peters AE, Wright I, Pickering AE. Early Childhood General Anesthesia and Neurodevelopmental Outcomes in the Avon Longitudinal Study of Parents and Children Birth Cohort. Anesthesiology. 2020 Nov 1;133(5):1007-1020. doi: 10.1097/ALN.0000000000003522. — View Citation

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* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The "Behavior Rating Inventory of Executive Function" composite score	The "Behaviour Rating Inventory of Executive Function" (BRIEF) is a parental questionnaire that assesses the executive functions of children aged 5 to 18 years old. It consists of 86 questions grouped into 8 scales: inhibition, flexibility, emotional control, initiation, material organization, working memory, planning/organization, and monitoring. It provides information on a global scale (score) regarding subtle and subclinical changes in various executive functions	Through the fourty minute phone call to the child's legal guardian. All phone calls will be conducted during the course of the study, which lasts an average of 2 months."
Secondary	The child's cognitif functioning (at school, parental home, and during extracurricular activities), and medical history.	Progress of pregnancy, history of general anesthesia during childhood, hospitalization during childhood, non-febrile seizure during childhood, history of chronic otolaryngological pathology, specialized neuro-pediatric or child psychiatry follow-up, psychological or speech therapy in childhood, use of psychotropic medication, occasional psychological consultation, Psychological follow-up in childhood, speech therapy follow-up, diagnosed developmental disorder, reported school delay, school difficulties reported by teachers, specialized class or institution, experience of traumatic life events (bullying, death of a loved one), child's well-being in daily life: at school, at home, engagement in extracurricular activities and child's well-being, amount of screen time	Through the fourty minute phone call to the child's legal guardian. All phone calls will be conducted the course during of the study, which lasts an average of 2 months."