JAMA Pediatrics Journal Club Slides:
Surgery and Neurodevelopmental
Outcome of VLBW Infants
Morriss FH Jr, Saha S, Bell EF, et al; Eunice Kennedy Shriver
National Institute of Child Health and Human Development
Neonatal Research Network. Surgery and neurodevelopmental
outcome of very low-birth-weight infants. JAMA Pediatr. Published
online June 16, 2014. doi:10.1001/jamapediatrics.2014.307.
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Introduction
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Background
– Administration of general anesthetic agents to developing animals
induces increased neuroapoptosis and subsequent neurocognitive or
behavioral deficits. Both neurons and oligodendrocytes are affected.
– The peak vulnerability to neuroapoptotic injury in animal experiments
occurs at a stage of brain development equivalent to early gestation
through infancy in humans.
– Spinal anesthesia in developing animals does not produce increased
neuroapoptosis and is not associated with recognized adverse outcomes.
– Animal studies and some clinical studies raise concern about surgery with
general anesthesia in neonates.
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Study Objective
– To assess the association between surgery during the initial
hospitalization and death or neurodevelopmental impairment of very lowbirth-weight infants at 18-22 months’ corrected age.
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Methods
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Study Design
– Retrospective cohort analysis of patients enrolled in the Eunice Kennedy
Shriver National Institute of Child Health and Human Development
Neonatal Research Network Generic Database from 1998-2009 and
evaluated at 18-22 months’ corrected age.
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Setting
– 22 Academic neonatal intensive care units.
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Patients
– Inclusion criteria were birth weight 401-1500 g; survival to 12 hours;
available for follow-up. Some conditions were excluded. A total of 12 111
infants were included in analyses (87% of those eligible).
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Exposure of Interest
– Surgical procedures; surgery was also classified by expected anesthesia
type as major surgery (general anesthesia) or minor surgery (nongeneral
anesthesia).
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Outcomes
Methods
– Primary outcome: Risk-adjusted death or neurodevelopmental
impairment at 18-22 months’ corrected age was estimated by
multivariable logistic regression analyses in which either a 2- or 3-level
surgery variable was the predictor of interest. Additional covariables
were other risk factors as well as a propensity score adjustment.
– Risk-adjusted neurodevelopmental impairment at 18-22 months’
corrected age among survivors was estimated by similarly constructed
multivariable logistic regression analyses.
– Multivariable linear regression analyses were performed for the adjusted
means of the Mental Developmental Index and Psychomotor
Developmental Index of the Bayley Scales of Infant Development,
Second Edition, for patients born before 2006.
– Cognitive composite scores of the Bayley Scales of Infant Development,
Third Edition, and Gross Motor Function Classification System levels
were also evaluated.
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Methods
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Limitations
– Classification of surgery patients into subgroups is not confirmed by
documented type of anesthesia.
– Known and suspected risk factors for neurodevelopmental impairment
in very low-birth-weight infants, some associated with surgery, were
not available in the database. These include:
• Type and duration of exposure to anesthetic agents.
• Effects of pharmacologic agents other than anesthetics, such as
analgesics, administered to surgery patients.
• Physiological alterations associated with surgery, such as stress
and alterations in blood pressure and/or temperature.
– Retrospective cohort study design does not consider unknown
confounding factors.
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Results
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There were 2186 major and 784 minor surgery patients and 9141 patients
who did not undergo surgery.
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The risk-adjusted odds ratio of death or neurodevelopmental impairment
for all surgery patients compared with those who had no surgery was 1.29
(95% CI, 1.08-1.55).
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There were increasing risk-adjusted odds of death or neurodevelopmental
impairment with increasing number of separate surgeries.
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For patients who had major surgery compared with those who did not
undergo surgery, the risk-adjusted odds ratio of death or
neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87).
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Results
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For patients who had major surgery compared with those who had minor
surgery, the risk-adjusted odds ratio of death or neurodevelopmental
impairment was 1.45 (95% CI, 1.14-1.85).
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There was no significant difference in risk of death or neurodevelopmental
impairment for patients who had minor surgery compared with those who
did not undergo surgery.
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Among survivors who had major surgery compared with those who did not
undergo surgery, the risk-adjusted odds ratio for neurodevelopmental
impairment was 1.56 (95% CI, 1.26-1.93) and the risk-adjusted mean
Mental Developmental Index and mean Psychomotor Developmental Index
values were lower.
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Results
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A sensitivity analysis in which the classification of patients who had
procedures to repair inguinal hernia, gastroschisis, or omphalocele was
changed from minor to major surgery resulted in no significantly increased
adjusted risk of death or neurodevelopmental impairment for major surgery
patients compared with patients who did not undergo surgery, suggesting a
relatively low adverse risk for this group of procedures as well as effect
modification.
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Results
Model 3: Multivariable Logistic Regression Analysis of the Primary Outcome of
Death or Neurodevelopmental Impairment With 3-Level Surgery Predictor Variable
Variable
Adjusted Odds Ratio,
Estimate (95% CI)
Major surgery vs no surgery
1.52 (1.24-1.87)
Major surgery vs minor surgery
1.45 (1.14-1.85)
Minor surgery vs no surgery
1.05 (0.83-1.33)
No. of surgeries (for each additional surgery)
1.17 (1.07-1.28)
Birth weight, for each 250-g increase in weight
0.73 (0.63-0.85)
Other covariables include small for gestational age, male, multiple birth cohort, white
race, 5-min Apgar score ≤3, antenatal corticosteroid exposure, postnatal corticosteroid
exposure, seizures, severe intracranial hemorrhage and/or cystic periventricular
leukomalacia, bronchopulmonary dysplasia, sepsis and/or meningitis, necrotizing
enterocolitis, patent ductus arteriosus (excluding surgically closed patients), highest
educational level attained by primary caregiver, birth year, inborn, center, and propensity
scores for major and minor surgery.
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Comment
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Very low-birth-weight infants who underwent surgical procedures during their
postnatal hospitalizations had increased adjusted risk of death or
neurodevelopmental impairment at 18-22 months’ corrected age, and
survivors had increased adjusted risk of neurodevelopmental impairment.
Classification to major or minor surgery groups based on expected type of
anesthesia resulted in increased adjusted risk of death or neurodevelopmental
impairment for those classified as major, but not for those classified as minor
surgery patients. The adjusted risk of neurodevelopmental impairment among
survivors was increased for major surgery patients.
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However, when procedures to repair inguinal hernia, gastroschisis, or
omphalocele were reclassified from minor to major surgery, we observed
effect modification, ie, the adverse risk for the major surgery group became
insignificant, suggesting a relatively low adverse risk for this group of
procedures that may be a consequence of length of exposure to anesthetic
agents or other factors.
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Comment
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This was a retrospective cohort study in which we were able to adjust for a
large number of potentially confounding variables, but important known
factors that are associated with the outcomes were not available. The type
of anesthesia used in each procedure was not documented, and the
classification into major and minor groups may be associated with factors
other than anesthesia type that are responsible for the observed results.
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This analysis supports the concern that surgery usually requiring general
anesthesia during a vulnerable period of infancy has an adverse effect on
neurodevelopmental outcome and extends that concern to very low-birthweight neonates. On the other hand, this analysis failed to demonstrate
increased risk of neurodevelopmental impairment after surgical procedures
that may have been performed under anesthesia other than general
anesthesia.
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Contact Information
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If you have questions, please contact the corresponding author:
– Frank H. Morriss Jr, MD, MPH, Department of Pediatrics,
University of Iowa, 200 Hawkins Dr, Iowa City, IA 52242
(frank-morriss@uiowa.edu).
Funding/Support
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The National Institutes of Health, the Eunice Kennedy Shriver National
Institute of Child Health and Human Development, the National Center
for Research Resources, and the National Center for Advancing
Translational Sciences provided grant support for the Neonatal
Research Network’s Generic Database Study through cooperative
agreements.
Conflict of Interest Disclosures
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None reported.
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