0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation | Journal Club

Surgery and Neurodevelopmental Outcome of Very Low-Birth-Weight Infants FREE

Frank H. Morriss Jr, MD, MPH1; Shampa Saha, PhD2; Edward F. Bell, MD1; Tarah T. Colaizy, MD, MPH1; Barbara J. Stoll, MD3; Susan R. Hintz, MD, MS, Epi4; Seetha Shankaran, MD5; Betty R. Vohr, MD6; Shannon E. G. Hamrick, MD3; Athina Pappas, MD5; Patrick M. Jones, MD7; Waldemar A. Carlo, MD8; Abbot R. Laptook, MD6; Krisa P. Van Meurs, MD4; Pablo J. Sánchez, MD9,10; Ellen C. Hale, RN, BS, CCRC3; Nancy S. Newman, RN11; Abhik Das, PhD12; Rosemary D. Higgins, MD13 ; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
[+] Author Affiliations
1Department of Pediatrics, University of Iowa, Iowa City
2Social, Statistical and Environmental Sciences Unit, RTI International, Research Triangle Park, North Carolina
3Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, Georgia
4Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, California
5Department of Pediatrics, Wayne State University, Detroit, Michigan
6Department of Pediatrics, Women & Infants’ Hospital, Brown University, Providence, Rhode Island
7Department of Pediatrics, University of Texas Medical School, Houston
8Division of Neonatology, University of Alabama, Birmingham
9Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
10now Department of Pediatrics, College of Medicine, The Ohio State University, Columbus
11Department of Pediatrics, Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, Ohio
12Social, Statistical and Environmental Sciences Unit, RTI International, Rockville, Maryland
13Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
JAMA Pediatr. 2014;168(8):746-754. doi:10.1001/jamapediatrics.2014.307.
Text Size: A A A
Published online

Importance  Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine.

Objective  To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low-birth-weight infants.

Design, Setting, and Participants  A retrospective cohort analysis was conducted of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998 through 2009 and evaluated at 18 to 22 months’ corrected age. Twenty-two academic neonatal intensive care units participated. Inclusion criteria were birth weight 401 to 1500 g, survival to 12 hours, and availability for follow-up. A total of 12 111 infants were included in analyses.

Exposures  Surgical procedures; surgery also was classified by expected anesthesia type as major (general anesthesia) or minor (nongeneral anesthesia).

Main Outcomes and Measures  Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted mean scores of the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development, Second Edition, for patients born before 2006.

Results  A total of 2186 infants underwent major surgery, 784 had minor surgery, and 9141 infants did not undergo surgery. 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). For patients who had major surgery compared with those who had no surgery, the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% CI, 1.24-1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery, the adjusted risk of neurodevelopmental impairment was greater and the adjusted mean Bayley scores were lower.

Conclusions and Relevance  Major surgery in very low-birth-weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18 to 22 months’ corrected age. The role of general anesthesia is implicated but remains unproven.

Administration of general anesthetic agents to developing animals induces increased neuroapoptosis and subsequent neurocognitive or behavioral deficits.110 The toxic effects are widespread and affect both neurons and oligodendrocytes.11,12 The doses used to produce neurotoxic effects in the animals are analogous to those used in the clinical setting. The peak vulnerability to neuroapoptotic injury in rodents occurs at a stage of brain development equivalent to that of early gestation through infancy in humans.7 In contrast to general anesthesia, spinal anesthesia in developing rats does not produce increased neuroapoptosis and is not associated with recognized subsequent abnormality.13

These experimental observations raise concern that exposure of infants to general anesthesia for surgical procedures may increase the risk of subsequent neurodevelopmental impairment (NDI).1416 A study17 of infants who were born between 1985 and 1988 weighing less than 1000 g or who were less than 27 weeks’ gestational age found an adverse association of surgery requiring general anesthesia with moderate or severe disability at age 5 years, with an adjusted odds ratio (AOR) of 10.1 (95% CI, 2.3-44). However, a smaller study18 of infants born between 2001 and 2004 weighing less than 1250 g or less than 30 weeks’ gestational age found no significant effect on neurodevelopmental outcomes at age 2 years, although the infants exposed to surgery had relatively smaller brain volumes and more white matter injury. Several of the indications for surgical procedures in neonates, such as congenital malformations and necrotizing enterocolitis, have increased risk-adjusted odds of neonatal death as great as 3-fold.19 Postoperatively, neonates have a 40% increased adjusted risk of life-threatening infection.20 To determine, in a large cohort of very low-birth-weight (VLBW) infants exposed to surgical procedures, whether there was an increased adjusted risk for death or NDI at 18 to 22 months’ corrected age (CA), we conducted a retrospective analysis of the patients enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) Generic Database.

VLBW Infants

We studied VLBW infants enrolled in the NRN Generic Database from 1998 through 2009 who had birth weights (BWs) of 401 to 1500 g, survived for 12 hours, and were available for follow-up assessments at 18 to 22 months’ CA. We excluded patients who had certain conditions (Supplement [eTable 1]); among the excluded patients were those with congenital heart defects and those who had surgery for patent ductus arteriosus, conditions associated with NDI.2124 The follow-up evaluation included neurologic, hearing, vision, and developmental assessment.25 Participating centers received local institutional review board approval for data collection. The requirement for informed consent varied among the institutions; where required, it was obtained.

Sample Size

During 1998-2009, there were 12 111 infants of BW 401 to 1500 g with complete data who were included in the analyses (87% of those eligible), and 2970 of these infants had surgery during the initial hospitalization (Supplement [eFigure]).

Definitions

The primary outcome was death before follow-up assessment or NDI at 18 to 22 months’ CA. Because the NRN instrument used in neurodevelopmental assessment changed during the study period, NDI for infants born from 1998 to 2005 was defined as 1 or more of Bayley Scales of Infant Development, Second Edition (BSID-II),26 Mental Developmental Index (MDI) score of less than 70 or Psychomotor Developmental Index (PDI) score of less than 70, Gross Motor Function Classification System (GMFCS)27 level 2 or more, moderate or severe cerebral palsy, bilateral blindness, or hearing impairment with hearing aids in both ears. For infants born from 2006 to 2009, NDI was defined as 1 or more of BSID, Third Edition (BSID-III)28 cognitive composite score less than 80, GMFCS level 2 or more, moderate or severe cerebral palsy, deafness (permanent hearing loss that does not permit the child to understand the directions of the examiner and communicate despite amplification), or blindness (some or no useful vision in either eye). Secondary outcomes were NDI and its components among survivors and, for infants born before 2006, mean MDI and PDI scores.

The principal risk factor was surgery. For some analyses, surgery was classified into 2 subgroups: major and minor. The NRN Generic Database includes data for specific surgical procedures but not for anesthesia. Minor surgery was defined as a procedure that could have been performed under neuraxial, regional, or local anesthesia, such as gastrostomy, peritoneal drain placement, and inguinal hernia repair. Major surgery was defined as surgery that usually is performed with general anesthesia. Major surgery procedures also are more substantial than minor surgery procedures in aspects other than anesthetic agent, such as duration, physiological stress, and postoperative analgesia. The NRN Generic Database includes annotations regarding some circumstances under which surgery was performed, including general anesthesia used for procedures that are usually performed with nongeneral anesthesia.

Severe intracranial hemorrhage (ICH) was defined as parenchymal or intraventricular hemorrhage with ventricular dilatation, or cystic periventricular leukomalacia. Bronchopulmonary dysplasia was defined as requiring supplemental oxygen at 36 weeks. Necrotizing enterocolitis (NEC) was defined as modified Bell classification stage IIA or higher.29

Statistical Analysis

The χ2 and Fisher exact tests were used for categorical variables; analysis of variance tests were used for continuous variables. Separate bivariate analyses were performed to assess associations between the primary and secondary outcomes and the main predictors, as well as with potential confounders related to surgery and baseline covariates. To adjust for possible selection bias for performance of surgery, we developed a propensity score (PS) modeling approach.3033 We first attempted to develop a 3-level prediction model for the risk of surgery using proportional odds logistic regression. The proportionality assumption was not satisfied by the data, so we considered a polytomous logistic regression using a generalized logit model.

Once a prediction model for 3-level risk of surgery was developed by obtaining the PS for major, minor, and no surgery, we performed a multivariable logistic regression analysis of death or NDI, including adjustment with the PS of major and minor surgeries, as well as baseline covariates. We adjusted for NRN center and also for birth-year cohort effect to account for differences between the BSID-II and the BSID-III instruments.25,34We performed a similar multivariable logistic regression analysis for the outcome of NDI among survivors. In additional analyses of survivors who were evaluated with the BSID-II scales at 18 to 22 months’ CA, multivariable linear regression analyses were performed to separately determine the adjusted mean MDI and adjusted mean PDI for the significance and contribution of surgery. These analyses included the PS of major and minor surgery and all of the other variables associated with NDI from the bivariate analyses. Statistical analyses were conducted with SAS, version 9.2 (SAS Institute Inc).

Patient Characteristics

The analyses included 2186 patients with major surgery, 784 with minor surgery, and 9141 patients with no surgery. The patients in these 3 categories differed in most characteristics (Table 1). The 4649 procedures that we classified as major or minor surgery (Supplement [eTable 2]) were unequally distributed among anatomical systems (Supplement [eTable 3]). Most infants who underwent surgery had a single exposure, but 1080 had multiple exposures (Supplement [eTable 3]).

Table Graphic Jump LocationTable 1.  Characteristics of the Infants
Unadjusted Outcomes

Unadjusted associations of the 3-level surgery exposure and death or NDI, NDI among survivors, mean scores for BSID-II MDI and PDI and BSID-III cognitive composite score, GMFCS level 2 or more, moderate or severe cerebral palsy, blindness, and deafness are reported in Table 2. A progressively greater incidence of the adverse outcomes were exhibited from the no surgery to the minor surgery and then to the major surgery subgroups.

Table Graphic Jump LocationTable 2.  Unadjusted Associations of Neurodevelopmental Outcomes With Patient Subgroupsa
Multivariable Logistic Regression Analyses

In a multivariable logistic regression analysis of the primary outcome in which all surgery patients were combined as a risk factor (Table 3, model 1), infants who underwent surgery had significantly higher adjusted odds of death or NDI compared with those who had no surgery (AOR, 1.29; 95% CI, 1.08-1.55). The multivariable logistic regression analysis for the outcome NDI among survivors also indicated an increased risk for NDI among all survivors who had surgery (Supplement [eTable 4] , model 2).

Table Graphic Jump LocationTable 3.  Model 1: Multivariable Logistic Regression Analysis of the Primary Outcome of Death or Neurodevelopmental Impairment With 2-Level Surgery Predictor Variable

In a multivariable logistic regression analysis of the outcome death or NDI when surgery procedures were classified as major or minor (Table 4, model 3), patients who underwent major surgery had significantly higher adjusted odds of death or NDI compared with those who had no surgery (AOR, 1.52; 95% CI, 1.24-1.87) and with those who had minor surgery (AOR, 1.45; 95% CI, 1.14-1.85). There was no significant difference in death or NDI for patients who had minor surgery compared with those who had no surgery. There were increasing adjusted odds of death or NDI with an increasing number of separate surgeries. In a multivariable logistic regression analysis for the outcome NDI among survivors, there was an increased adjusted risk of NDI among survivors who underwent major surgery compared with those who had either no surgery or minor surgery (Supplement [eTable 5]; model 4). The Supplement (eTable 6) presents evidence that the PS achieved balanced distribution of covariates among the surgery groups.

Table Graphic Jump LocationTable 4.  Model 3: Multivariable Logistic Regression Analysis of the Primary Outcome of Death or Neurodevelopmental Impairment With 3-Level Surgery Predictor Variable

We performed a sensitivity analysis in which patients who had surgery for retinopathy of prematurity and were initially classified as major surgery patients were excluded, reasoning that there might be a strong possibility for confounding by indication. That is, patients who had retinopathy of prematurity sufficiently severe to warrant surgery had a high probability before surgery of having impaired vision and thus NDI. The exclusion of infants with retinopathy of prematurity who underwent surgery did not qualitatively change the primary outcome of death or NDI calculated using model 3. A second sensitivity analysis was performed in which we excluded 123 infants with severe ICH who had shunt procedures, and the primary outcome result was qualitatively unchanged. A third sensitivity analysis was performed in which the classification of 392 patients who had procedures to repair inguinal hernia, gastroschisis, or omphalocele was changed from minor to major surgery. With this change there was no significantly increased adjusted risk of death or NDI for major surgery patients compared with no surgery patients, using models 3 and 4, suggesting a relatively low risk of adverse outcomes for this group of procedures and also that the association between general anesthesia and the primary outcome is dependent on the specific surgical procedure (ie, effect modification). One possible explanation for the effect modification is the length of the procedure and exposure to anesthesia associated with various procedures.

BSID-II MDI and PDI

Among infants to whom the BSID-II was administered, the overall unadjusted mean MDI was 80.0, and the overall unadjusted mean PDI was 84.3. In multivariable linear regression analyses of mean BSID-II MDI and mean PDI between groups (Table 5, models 5 and 6), infants who underwent major surgery had an adjusted mean value for MDI of 3.3 (95% CI, 1.4-5.1) less than that for patients who had no surgery and 3.6 (95%, CI 1.5-5.3) less than that for those who had minor surgery. The adjusted mean value for PDI for infants with major surgery was 3.6 (95% CI, 1.8-5.4) less than that for patients who had no surgery and 3.1 (95% CI, 1.0-5.2) less than that for those who had minor surgery.

Table Graphic Jump LocationTable 5.  Models 5 and 6: Multivariable Linear Regression Analyses for Mean BSID-II MDI and Mean PDI With 3-Level Surgery Predictor Variables

Very low-birth-weight infants who underwent surgical procedures during their postnatal hospitalizations had an increased adjusted risk of death or NDI at 18 to 22 months’ CA, and survivors had an increased adjusted risk of NDI. Classification to major or minor surgery groups based on expected type of anesthesia also resulted in an increased adjusted risk of death or NDI for infants classified as undergoing major surgery, but not for those classified as having minor surgery. The adjusted risk of NDI among survivors was increased for major surgery patients. Infants whose surgery could have been conducted with neuraxial, regional, or local anesthesia (classified as minor surgery) did not have a significantly increased adjusted risk of either the primary or secondary outcome. Sensitivity analyses did not alter these outcomes, except when procedures to repair inguinal hernia, gastroschisis, or omphalocele were reclassified from minor to major surgery; this observation of effect modification suggests a relatively low risk of adverse outcomes for this group of procedures that may be a consequence of length of exposure to anesthetic agents. Alternatively, there may be other contributors to the adverse effects of surgical procedures on the primary outcome, such as stress, unidentified physiological alterations, or effects of pharmacologic agents other than anesthetics administered to patients who undergo surgery. The adjusted means for the BSID-II MDI and PDI scores at age 18 to 22 months’ CA were less for patients who had major surgery than for those who had minor surgery or no surgery.

These results were observed despite adjustment for many covariates that may reflect the level of illness. The covariates in the adjustments of the regression analyses included a PS for the likelihood of having a major or minor surgical procedure, as well as variables that may have independent effects on the outcomes in similar study populations. The PS method provides an alternative approach to covariate adjustment that reduces the entire collection of unbalanced baseline covariates to a single score that can be used for adjustment.

Although we excluded patients who had surgery for patent ductus arteriosus because the procedure in VLBW infants has been associated23,24 with subsequent NDI or neurosensory impairment, we retained patients who had patent ductus arteriosus but no surgical closure and observed no independent increased risk of death or NDI or of NDI among survivors.

The NRN has previously reported analyses of neurodevelopmental outcomes of VLBW infants following other selected surgical procedures. In a retrospective study35 of NRN patients, surgery for NEC was a significant independent risk factor for MDI scores less than 70, PDI scores less than 70, and NDI compared with medically treated NEC and no NEC. However, infants who underwent surgery for NEC had poorer growth compared with those in the other groups. Because surgical NEC was presumably associated with greater severity of the disease, an independent effect of surgery could not be demonstrated. In a separate prospective cohort pilot study,36 neonates with NEC or intestinal perforation who underwent laparotomy under general anesthesia were compared with those who received peritoneal drain placement without general anesthesia. The AOR for NDI or death by treatment group was not significant. In an NRN retrospective cohort analysis,37 children with severe ICH and ventriculoperitoneal shunts had significantly lower BSID-II MDI and PDI scores compared with those with severe ICH and no shunt.

Other retrospective analyses3849 have examined cohorts of more mature neonates or older children who were exposed to general anesthesia from as early as during the birthing process to as old as 5 years. The observed outcome measures ranged from individual neurodevelopmental testing at 18 to 22 months to learning disabilities identified during childhood and school achievement assessed by group testing at 19 years. Most,3846 but not all,4749 studies reported worse neurodevelopmental or achievement outcomes for patients who had surgery than for others, and some reported increasing risk with multiple surgical exposures.38,41,43

It is difficult to determine whether an adverse effect associated with surgery results from the anesthetic drug or from noxious effects of other perioperative drugs and/or events unrelated to the anesthetic. However, a meta-analysis50 of 7 selected observational studies of the effect of anesthesia with or without surgery in children aged 0 to 4 years on developmental or behavioral outcomes found that the summary odds ratio for adverse outcome was 1.4 (95% CI, 0.9-2.2) when adjusted outcomes were considered. Included among the studies selected for the meta-analysis was one51 that reported no increase in adjusted neurodevelopmental risk for preterm infants who received prolonged sedation and/or opioids for mechanical ventilation and/or surgery. Another included study52 examined sedation and analgesia drugs following surgery for congenital heart defects and found no association between dose and duration of sedation/analgesia drugs and adverse neurodevelopmental outcomes.

Major surgery and ICH, which includes cystic periventricular leukomalacia, are significant independent predictors of death or NDI and NDI among survivors (Table 4 and Supplement [eTable 5]). There are likely multiple pathways to NDI in preterm infants, as suggested previously53 by the detection of cystic periventricular leukomalacia by ultrasound in a minority of infants with abnormal neurodevelopmental outcomes.

For the present analysis, the type of anesthesia was not documented, and data on the anesthetic agents and doses used and perioperative analgesics, sedatives, and other drugs administered were not available. Of special concern is caffeine, a drug used frequently in VLBW infants, which has been shown54 to potentiate the neurotoxic effects of anesthetic agents in developing mice; potentiation in infants has not been studied. Data on perioperative events such as hypoxemia, hyperoxemia, hypotension, and hypothermia were not collected and could not be considered for adjustment. Notwithstanding these and other unrecognized potential confounders, this analysis supports the concern that surgery with general anesthesia during a vulnerable period of infancy has an adverse effect on neurodevelopmental outcome and extends that concern to VLBW neonates. On the other hand, this analysis failed to demonstrate increased risk of NDI after surgical procedures that may have been performed under anesthesia other than general anesthesia.

The strengths of this study include the large, prospectively enrolled cohort of VLBW infants with individual assessments at 18 to 22 months’ CA and adjustment for other risks. The major weaknesses are that the study is a retrospective cohort analysis for which the classification of surgery patients into subgroups is not confirmed by documented type of anesthesia, and there are potential confounders for which we were unable to adjust.

There have been no reported randomized clinical trials examining the potential adverse neurodevelopmental effects of general compared with spinal anesthesia for surgery, although at least 1 trial55 is under way for a selected procedure, inguinal herniorrhaphy. However, it currently is not feasible to conduct a trial of general vs nongeneral anesthesia for many procedures. Large retrospective analyses with extensive adjustment, including for selection bias, using innovative approaches such as propensity scoring, may provide the best obtainable evidence that there are risks associated with general anesthesia and surgery in VLBW infants. Additional information is required on specific agents and the doses and duration of administration to determine whether certain general anesthetic agents and/or practices carry greater risk and so should be avoided if alternatives are available. Meanwhile, potential neuroprotection strategies to ameliorate neurotoxicity may be investigated.56,57 Finally, postponement of elective procedures until the infants are older may be considered, especially if the procedure represents a second or subsequent anesthesia.

Exposure of VLBW infants to major surgery is associated with increased risk of death or NDI and of NDI among survivors, each by approximately 50%. The contribution of general anesthesia to this effect is suspected but not yet proven.

Accepted for Publication: February 5, 2014.

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).

Published Online: June 16, 2014. doi:10.1001/jamapediatrics.2014.307.

Author Contributions: Drs Saha and Das had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Morriss, Bell, Colaizy, Hintz, Hamrick, Jones, Higgins.

Acquisition, analysis, or interpretation of data: Saha, Bell, Colaizy, Stoll, Hintz, Shankaran, Vohr, Hamrick, Pappas, Laptook, Van Meurs, Sánchez, Hale, Newman, Das, Higgins.

Drafting of the manuscript: Morriss, Saha, Sánchez.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Morriss, Saha, Das.

Obtained funding: Bell, Stoll, Hintz, Shankaran, Carlo, Sánchez.

Administrative, technical, or material support: Stoll, Jones, Higgins.

Study supervision: Hintz, Shankaran, Hale, Das, Higgins.

Conflict of Interest Disclosures: None reported.

Funding/Support: The National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Center for Research Resources (NCRR), and the National Center for Advancing Translational Sciences (NCATS) provided grant support for the Neonatal Research Network’s Generic Database Study through cooperative agreements.

Role of the Sponsors: The NICHD staff had input into the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The NCRR and NCATS staff did not have input into this study.

Group Information: The following investigators, in addition to those listed as authors, participated in this study: Neonatal Research Network Steering Committee Chairs: Alan H. Jobe, MD, PhD, College of Medicine, University of Cincinnati (2003-2006), and Michael S. Caplan, MD, University of Chicago, Pritzker School of Medicine (2006-2011). Alpert Medical School of Brown University and Women & Infants Hospital of Rhode Island (U10 HD27904): William Oh, MD; Robert T. Burke, MD, MPH; Bonnie E. Stephens, MD; Yvette Yatchmink, MD; Barbara Alksninis, RNC, PNP; Angelita M. Hensman, RN, BSN; Teresa M. Leach, Med, CAES; Martha R. Leonard, BA, BS; Lucy Noel; Rachel A. Vogt, MD; and Victoria E. Watson, MS, CAS. Case Western Reserve University, Rainbow Babies & Children's Hospital (U10 HD21364 and M01 RR80): Michele C. Walsh, MD, MS; Avroy A. Fanaroff, MD; Deanne E. Wilson-Costello, MD; Bonnie S. Siner, RN; and Harriet G. Friedman, MA. Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853 and M01 RR8084): Kurt Schibler, MD; Edward F. Donovan, MD; Kate Bridges, MD; Jean J. Steichen, MD; Kimberly Yolton, PhD; Barbara Alexander, RN; Estelle E. Fischer, MHSA, MBA; Cathy Grisby, BSN, CCRC; Marcia Worley Mersmann, RN; Holly L. Mincey, RN, BSN; Jody Hessling, RN; Teresa L. Gratton, PA; Lenora Denise Jackson, CRC; and Kristin Kirker, CRC. Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492 and M01 RR30): Ronald N. Goldberg, MD; C. Michael Cotten, MD, MHS; Ricki F. Goldstein, MD; Kathy J. Auten, MSHS; Kimberley A. Fisher, PhD, FNP-BC, IBCLC; Katherine A. Foy, RN; Kathryn E. Gustafson, PhD; and Melody B. Lohmeyer, RN, MSN. Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851 and M01 RR39): David P. Carlton, MD; and Ira Adams-Chapman, MD. Eunice Kennedy Shriver National Institute of Child Health and Human Development: Linda L. Wright, MD; Elizabeth M. McClure, MEd; and Stephanie Wilson Archer, MA. Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856 and M01 RR750): Brenda B. Poindexter, MD, MS; James A. Lemons, MD; Anna M. Dusick, MD; Carolyn Lytle, MD, MPH; Lon G. Bohnke, MS; Greg Eaken, PhD; Faithe Hamer, BS; Dianne E. Herron, RN; Lucy C. Miller, RN, BSN, CCRC; Heike M. Minnich, PsyD, HSPP; Leslie Richard, RN; and Leslie Dawn Wilson, BSN, CCRC. RTI International (U10 HD36790): W. Kenneth Poole, PhD; Dennis Wallace, PhD; Jamie E. Newman, PhD, MPH; Jeanette O’Donnell Auman, BS; Margaret M. Crawford, BS, CCRP; Betty K. Hastings; Elizabeth M. McClure, MEd; Carolyn M. Petrie Huitema, MS, CCRP; and Kristin M. Zaterka-Baxter, RN, BSN, CCRP. Stanford University, California Pacific Medical Center, Dominican Hospital, El Camino Hospital, and Lucile Packard Children's Hospital (U10 HD27880 and M01 RR70): David K. Stevenson, MD; Marian M. Adams, MD; Charles E. Ahlfors, MD; M. Bethany Ball, BS, CCRC; Joan M. Baran, PhD; Barbara Bentley, PhD; Lori E. Bond, PhD; Ginger K. Brudos, PhD; Alexis S. Davis, MD, MS; Maria Elena DeAnda, PhD; Anne M. DeBattista, RN, PNP; Barry E. Fleisher, MD; Jean G. Kohn, MD, MPH; Julie C. Lee-Ancajas, PhD; Andrew W. Palmquist, RN; Melinda S. Proud, RCP; Renee P. Pyle, PhD; Dharshi Sivakumar, MD; Robert D. Stebbins, MD; and Nicholas H. St. John, PhD. Tufts Medical Center, Floating Hospital for Children (U10 HD53119 and M01 RR54): Ivan D. Frantz III, MD; Elisabeth C. McGowan, MD; Brenda L. MacKinnon, RNC; Ellen Nylen, RN, BSN; Anne Furey, MPH; Cecelia Sibley, PT, MHA; and Ana Brussa, MS, OTR/L. University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216 and M01 RR32): Namasivayam Ambalavanan, MD; Myriam Peralta-Carcelen, MD, MPH; Kathleen G. Nelson, MD; Kirstin J. Bailey, PhD; Fred J. Biasini, PhD; Stephanie A. Chopko, PhD; Monica V. Collins, RN, BSN, MaEd; Shirley S. Cosby, RN, BSN; Mary Beth Moses, PT, MS, PCS; Vivien A. Phillips, RN, BSN; Julie Preskitt, MSOT, MPH; Richard V. Rector, PhD; and Sally Whitley, MA, OTR-L, FAOTA. University of California –San Diego Medical Center and Sharp Mary Birch Hospital for Women and Newborns (U10 HD40461): Neil N. Finer, MD; Maynard R. Rasmussen, MD; Yvonne E. Vaucher, MD, MPH; Paul R. Wozniak, MD; Kathy Arnell, RNC; Renee Bridge, RN; Clarence Demetrio, RN; Martha G. Fuller, RN, MSN; and Wade Rich, BSHS, RRT. University of Iowa Children's Hospital (U10 HD53109 and M01 RR59): John A. Widness, MD; Michael J. Acarregui, MD; Karen J. Johnson, RN, BSN; and Diane L. Eastman, RN, CPNP, MA. University of Miami, Holtz Children’s Hospital (U10 HD21397 and M01 RR16587): Charles R. Bauer, MD; Shahnaz Duara, MD; Ruth Everett-Thomas, RN, MSN; Amy Mur Worth, RN, MS; Mary Allison, RN; Alexis N. Diaz, BA; Elaine E. Mathews, RN; Kasey Hamlin-Smith, PhD; Lissa Jean-Gilles, BA; Maria Calejo, MS; Silvia M. Frade Eguaras, BA; Silvia Fajardo-Hiriart, MD; Yamiley C. Gideon, BA; Michelle Harwood Berkovits, PhD; Alexandra Stoerger, BA; Andrea Garcia, MA; Helena Pierre, BA; Georgette Roder, BSW; and Arielle Riguad, MD. University of New Mexico Health Sciences Center (U10 HD27881, U10 HD53089, and M01 RR997): Kristi L. Watterberg, MD; Andrea Freeman Duncan, MD, MScr; Janell Fuller, MD; Robin K. Ohls, MD; Lu-Ann Papile, MD; Conra Backstrom Lacy, RN; Sandra Brown, RN, BSN; Jean R. Lowe, PhD; and Rebecca Montman, RN, BSN. University of Rochester Medical Center, Golisano Children’s Hospital (U10 HD40521, M01 RR44, and NCRR UL1 024160): Dale L. Phelps, MD; Ronnie Guillet, MD, PhD; Gary J. Myers, MD; Linda J. Reubens, RN, CCRC, Erica Burnell, RN; Mary Rowan, RN; Cassandra A. Horihan, MS; Julie Babish Johnson, MSW; Diane Hust, MS, RN, CS; Rosemary L. Jensen; Emily Kushner, MA; Joan Merzbach, LMSW; Kelly Yost, PhD; and Lauren Zwetsch, RN, MS, PNP. University of Tennessee Health Science Center (U10 HD21415): Sheldon B. Korones, MD; Henrietta S. Bada, MD; Tina Hudson, RN, BSN; Marilyn Williams, LCSW; and Kimberly Yolton, PhD. University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System and Children’s Medical Center Dallas (U10 HD40689 and M01 RR633): Charles R. Rosenfeld, MD; Walid A. Salhab, MD; Luc P. Brion, MD; R. Sue Broyles, MD; Roy J. Heyne, MD; Sally S. Adams, MS, RN, CPNP; P. Jeannette Burchfield, RN, BSN; Cristin Dooley, PhD, LSSP; Alicia Guzman; Gaynelle Hensley, RN; Elizabeth T. Heyne, MS, MA, PA-C, PsyD; Jackie F. Hickman, RN; Melissa H. Leps, RN; Linda A. Madden, BSN, RN, CPNP; Nancy A. Miller, RN; Janet S. Morgan, RN; Susie Madison, RN; Lizette E. Torres, RN; Cathy Twell Boatman, MS, CIMI; and Diana M. Vasil, RNC-NIC. University of Texas Health Science Center at Houston Medical School, Children's Memorial Hermann Hospital, and Lyndon Baines Johnson General Hospital/Harris County Hospital District (U10 HD21373): Kathleen A. Kennedy, MD, MPH; Jon E. Tyson, MD, MPH; Patricia W. Evans, MD; Esther G. Akpa, RN, BSN; Magda Cedillo Guajardo, RN, BSN, FAACM; Susan E.Dieterich, PhD; Beverly Foley Harris, RN, BSN; Claudia I. Franco, RNC, MSN; Charles Green, PhD; Margarita Jiminez, MD, MPH; Anna E. Lis, RN, BSN; Terri Major-Kincade, MD, MPH; Sara C. Martin, RN, BSN; Georgia E. McDavid, RN; Brenda H. Morris, MD; Patricia Ann Orekoya, RN, BSN; Patti L. Pierce Tate, RCP; M. Layne Poundstone, RN, BSN; Stacey Reddoch, BA; Saba Khan Siddiki, MD; Maegan C. Simmons, RN; Laura L. Whitely, MD; and Sharon L. Wright, MT. University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children’s Medical Center (U10 HD53124 and M01 RR64): Roger G. Faix, MD; Bradley A. Yoder, MD; Michael Steffen, MS, CPM; Shawna Baker, RN; Karie Bird, RN; Jill Burnett, RN; Jennifer J. Jensen, RN, BSN; Karen A. Osborne, RN, BSN, CCRC; Cynthia Spencer, RNC; and Kimberlee Weaver-Lewis, RN, BSN. Wake Forest University Baptist Medical Center, Brenner Children’s Hospital, and Forsyth Medical Center (U10 HD40498 and M01 RR7122): T. Michael O’Shea, MD, MPH; Robert G. Dillard, MD; Nancy J. Peters, RN, CCRP; Korinne Chiu, MA; Deborah Evans Allred, MA, LPA; Donald J. Goldstein, PhD; Raquel Halfond, MA; Barbara G. Jackson, RN, BSN; Carroll Peterson, MA; Ellen L. Waldrep, MS; Melissa Whalen Morris, MA; and Gail Wiley Hounshell, PhD. Wayne State University, Hutzel Women’s Hospital, and Children’s Hospital of Michigan (U10 HD21385): Beena G. Sood, MD, MS; Yvette R. Johnson, MD, MPH; Rebecca Bara, RN, BSN; Laura Goldston, MA; Mary E. Johnson, RN, BSN; Deborah Kennedy, RN, BSN; and Geraldine Muran, RN, BSN. Yale University, Yale–New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, UL1 RR24139, M01 RR125, and M01 RR6022): Richard A. Ehrenkranz, MD; Christine Butler, MD; Harris Jacobs, MD; Patricia Cervone, RN; Nancy Close, PhD; Patricia Gettner, RN; Walter Gilliam, PhD; Sheila Greisman, RN; Monica Konstantino, RN, BSN; JoAnn Poulsen, RN; Elaine Romano, MSN; Janet Taft, RN, BSN; and Joanne Williams, RN, BSN.

Disclaimer: The comments and views of the authors do not necessarily represent the views of the NICHD.

Additional Contributions: We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study.

Ikonomidou  C, Bosch  F, Miksa  M,  et al.  Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70-74.
PubMed   |  Link to Article
Jevtovic-Todorovic  V, Hartman  RE, Izumi  Y,  et al.  Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23(3):876-882.
PubMed
Cattano  D, Young  C, Straiko  MM, Olney  JW.  Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg. 2008;106(6):1712-1714.
PubMed   |  Link to Article
Loepke  AW, Soriano  SG.  An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg. 2008;106(6):1681-1707.
PubMed   |  Link to Article
Brambrink  AM, Evers  AS, Avidan  MS,  et al.  Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology. 2010;112(4):834-841.
PubMed   |  Link to Article
Soriano  SG, Liu  Q, Li  J,  et al.  Ketamine activates cell cycle signaling and apoptosis in the neonatal rat brain. Anesthesiology. 2010;112(5):1155-1163.
PubMed   |  Link to Article
Yuede  CM, Wozniak  DF, Creeley  CE, Taylor  GT, Olney  JW, Farber  NB.  Behavioral consequences of NMDA antagonist–induced neuroapoptosis in the infant mouse brain. PLoS One. 2010;5(6):e11374. doi:10.1371/journal.pone.0011374.
PubMed   |  Link to Article
Paule  MG, Li  M, Allen  RR,  et al.  Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33(2):220-230.
PubMed   |  Link to Article
Palanisamy  A, Baxter  MG, Keel  PK, Xie  Z, Crosby  G, Culley  DJ.  Rats exposed to isoflurane in utero during early gestation are behaviorally abnormal as adults. Anesthesiology. 2011;114(3):521-528.
PubMed   |  Link to Article
Zou  X, Liu  F, Zhang  X,  et al.  Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey. Neurotoxicol Teratol. 2011;33(5):592-597.
PubMed   |  Link to Article
Brambrink  AM, Back  SA, Riddle  A,  et al.  Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012;72(4):525-535.
PubMed   |  Link to Article
Creeley  CE, Dikranian  KT, Dissen  GA, Back  SA, Olney  JW, Brambrink  AM.  Isoflurane-induced apoptosis of neurons and oligodendrocytes in the fetal rhesus macaque brain. Anesthesiology. 2014;120(3):626-638.
PubMed   |  Link to Article
Yahalom  B, Athiraman  U, Soriano  SG,  et al.  Spinal anesthesia in infant rats: development of a model and assessment of neurologic outcomes. Anesthesiology. 2011;114(6):1325-1335.
PubMed   |  Link to Article
Olney  JW, Young  C, Wozniak  DF, Ikonomidou  C, Jevtovic-Todorovic  V.  Anesthesia-induced developmental neuroapoptosis: does it happen in humans? Anesthesiology. 2004;101(2):273-275.
PubMed   |  Link to Article
Williams  RK.  The pediatrician and anesthesia neurotoxicity. Pediatrics. 2011;128(5):e1268-e1270. doi:10.1542/peds.2011-2489.
PubMed   |  Link to Article
Rappaport  B, Mellon  RD, Simone  A, Woodcock  J.  Defining safe use of anesthesia in children. N Engl J Med. 2011;364(15):1387-1390.
PubMed   |  Link to Article
Victorian Infant Collaborative Study Group.  Surgery and the tiny baby: sensorineural outcome at 5 years of age. J Paediatr Child Health. 1996;32(2):167-172.
PubMed   |  Link to Article
Filan  PM, Hunt  RW, Anderson  PJ, Doyle  LW, Inder  TE.  Neurologic outcomes in very preterm infants undergoing surgery. J Pediatr. 2012;160(3):409-414.
PubMed   |  Link to Article
Morriss  FH  Jr.  Increased risk of death among uninsured neonates. Health Serv Res. 2013;48(4):1232-1255.
PubMed   |  Link to Article
Boghossian  NS, Page  GP, Bell  EF,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births. J Pediatr. 2013;162(6):1120-1124, e1. doi:10.1016/j.jpeds.2012.11.089.
PubMed   |  Link to Article
Miller  SP, McQuillen  PS, Hamrick  S,  et al.  Abnormal brain development in newborns with congenital heart disease. N Engl J Med. 2007;357(19):1928-1938.
PubMed   |  Link to Article
Owen  M, Shevell  M, Majnemer  A, Limperopoulos  C.  Abnormal brain structure and function in newborns with complex congenital heart defects before open heart surgery. J Child Neurol. 2011;26(6):743-755.
PubMed   |  Link to Article
Madan  JC, Kendrick  D, Hagadorn  JI, Frantz  ID  III; National Institute of Child Health and Human Development Neonatal Research Network.  Patent ductus arteriosus therapy: impact on neonatal and 18-month outcome. Pediatrics. 2009;123(2):674-681.
PubMed   |  Link to Article
Kabra  NS, Schmidt  B, Roberts  RS, Doyle  LW, Papile  L, Fanaroff  A; Trial of Indomethacin Prophylaxis in Preterms Investigators.  Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants. J Pediatr. 2007;150(3):229-234.e1. doi:10.1016/j.jpeds.2006.11.039.
PubMed   |  Link to Article
Vohr  BR, Stephens  BE, Higgins  RD,  et al.  Are outcomes of extremely preterm infants improving J Pediatr. 2012;161(2):222-228.e3. doi:10.1016/j.jpeds.2012.01.057.
PubMed   |  Link to Article
Bayley  N. Bayley Scales of Infant Development.2nd ed. San Antonio, TX: Psychological Corp; 1993.
Palisano  R, Rosenbaum  P, Walter  S, Russell  D, Wood  E, Galuppi  B.  Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39(4):214-223.
Link to Article
Bayley  N. Bayley Scales of Infant Development.3rd ed. San Antonio, TX: Psychological Corp; 2006.
Walsh  MC, Kliegman  RM.  Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986;33(1):179-201.
PubMed
Rosenbaum  PR. Propensity score. In: Colton  T, Armitage  P, eds. Encyclopedia of Biostatistics.Vol 5. New York, NY: Wiley; 1998:3551-3555.
Rosenbaum  PR, Rubin  DB.  The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41-55.
Link to Article
D’Agostino  RB  Jr, D’Agostino  RB  Sr.  Estimating treatment effects using observational data. JAMA. 2007;297(3):314-316.
PubMed   |  Link to Article
Martens  EP, Pestman  WR, de Boer  A, Belitser  SV, Klungel  OH.  Systematic differences in treatment effect estimates between propensity score methods and logistic regression. Int J Epidemiol. 2008;37(5):1142-1147.
PubMed   |  Link to Article
Anderson  PJ, De Luca  CR, Hutchinson  E, Roberts  G, Doyle  LW; Victorian Infant Collaborative Group.  Underestimation of developmental delay by the new Bayley-III scale. Arch Pediatr Adolesc Med. 2010;164(4):352-356.
PubMed   |  Link to Article
Hintz  SR, Kendrick  DE, Stoll  BJ,  et al; NICHD Neonatal Research Network.  Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics. 2005;115(3):696-703.
PubMed   |  Link to Article
Blakely  ML, Tyson  JE, Lally  KP,  et al; NICHD Neonatal Research Network.  Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants. Pediatrics. 2006;117(4):e680-e687. doi:10.1542/peds.2005-1273.
PubMed   |  Link to Article
Adams-Chapman  I, Hansen  NI, Stoll  BJ, Higgins  R; NICHD Research Network.  Neurodevelopmental outcome of extremely low birth weight infants with posthemorrhagic hydrocephalus requiring shunt insertion. Pediatrics. 2008;121(5):e1167-e1177.
PubMed   |  Link to Article
Wilder  RT, Flick  RP, Sprung  J,  et al.  Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796-804.
PubMed   |  Link to Article
Sprung  J, Flick  RP, Wilder  RT,  et al.  Anesthesia for cesarean delivery and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;111(2):302-310.
PubMed   |  Link to Article
Flick  RP, Lee  K, Hofer  RE,  et al.  Neuraxial labor analgesia for vaginal delivery and its effects on childhood learning disabilities. Anesth Analg. 2011;112(6):1424-1431.
PubMed   |  Link to Article
Flick  RP, Katusic  SK, Colligan  RC,  et al.  Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128(5):e1053-e1061. doi:10.1542/peds.2011-0351.
PubMed   |  Link to Article
DiMaggio  C, Sun  LS, Kakavouli  A, Byrne  MW, Li  G.  A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21(4):286-291.
PubMed   |  Link to Article
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;113(5):1143-1151.
PubMed   |  Link to Article
Ing  C, DiMaggio  C, Whitehouse  A,  et al.  Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130(3):e476-e485. doi:10.1542/peds.2011-3822.
PubMed   |  Link to Article
Block  RI, Thomas  JJ, Bayman  EO, Choi  JY, Kimble  KK, Todd  MM.  Are anesthesia and surgery during infancy associated with altered academic performance during childhood? Anesthesiology. 2012;117(3):494-503.
PubMed   |  Link to Article
Walker  K, Badawi  N, Halliday  R,  et al.  Early developmental outcomes following major noncardiac and cardiac surgery in term infants: a population-based study. J Pediatr. 2012;161(4):748-752.e1. doi:10.1016/j.jpeds.2012.03.044.
PubMed   |  Link to Article
Kalkman  CJ, Peelen  L, Moons  KG,  et al.  Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology. 2009;110(4):805-812.
PubMed   |  Link to Article
Bartels  M, Althoff  RR, Boomsma  DI.  Anesthesia and cognitive performance in children. Twin Res Hum Genet. 2009;12(3):246-253.
PubMed   |  Link to Article
Hansen  TG, Pedersen  JK, Henneberg  SW,  et al.  Academic performance in adolescence after inguinal hernia repair in infancy. Anesthesiology. 2011;114(5):1076-1085.
PubMed   |  Link to Article
DiMaggio  C, Sun  LS, Ing  C, Li  G.  Pediatric anesthesia and neurodevelopmental impairments. J Neurosurg Anesthesiol. 2012;24(4):376-381.
PubMed   |  Link to Article
Rozé  JC, Denizot  S, Carbajal  R,  et al.  Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants. Arch Pediatr Adolesc Med. 2008;162(8):728-733.
PubMed   |  Link to Article
Guerra  GG, Robertson  CM, Alton  GY,  et al; Western Canadian Complex Pediatric Therapies Follow-up Group.  Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth. 2011;21(9):932-941.
PubMed   |  Link to Article
Hamrick  SE, Miller  SP, Leonard  C,  et al.  Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants. J Pediatr. 2004;145(5):593-599.
PubMed   |  Link to Article
Yuede  CM, Olney  JW, Creeley  CE.  Developmental neurotoxicity of alcohol and anesthetic drugs is augmented by co-exposure to caffeine. Brain Sci. 2013;3(3):1128-1152.
PubMed   |  Link to Article
A multi-site randomized controlled trial comparing regional and general anesthesia for effects on neurodevelopmental outcome and apnea in infants (GAS). http://clinicaltrials.gov/ct2/show/NCT00756600?term=NCT00756600&rank=1. Accessed November 6, 2012.
Reddy  SV.  Effect of general anesthetics on the developing brain. J Anaesthesiol Clin Pharmacol. 2012;28(1):6-10.
PubMed   |  Link to Article
Costantine  MM, Weiner  SJ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.  Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants. Obstet Gynecol. 2009;114(2, pt 1):354-364.
PubMed   |  Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1.  Characteristics of the Infants
Table Graphic Jump LocationTable 2.  Unadjusted Associations of Neurodevelopmental Outcomes With Patient Subgroupsa
Table Graphic Jump LocationTable 3.  Model 1: Multivariable Logistic Regression Analysis of the Primary Outcome of Death or Neurodevelopmental Impairment With 2-Level Surgery Predictor Variable
Table Graphic Jump LocationTable 4.  Model 3: Multivariable Logistic Regression Analysis of the Primary Outcome of Death or Neurodevelopmental Impairment With 3-Level Surgery Predictor Variable
Table Graphic Jump LocationTable 5.  Models 5 and 6: Multivariable Linear Regression Analyses for Mean BSID-II MDI and Mean PDI With 3-Level Surgery Predictor Variables

References

Ikonomidou  C, Bosch  F, Miksa  M,  et al.  Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70-74.
PubMed   |  Link to Article
Jevtovic-Todorovic  V, Hartman  RE, Izumi  Y,  et al.  Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23(3):876-882.
PubMed
Cattano  D, Young  C, Straiko  MM, Olney  JW.  Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg. 2008;106(6):1712-1714.
PubMed   |  Link to Article
Loepke  AW, Soriano  SG.  An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg. 2008;106(6):1681-1707.
PubMed   |  Link to Article
Brambrink  AM, Evers  AS, Avidan  MS,  et al.  Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology. 2010;112(4):834-841.
PubMed   |  Link to Article
Soriano  SG, Liu  Q, Li  J,  et al.  Ketamine activates cell cycle signaling and apoptosis in the neonatal rat brain. Anesthesiology. 2010;112(5):1155-1163.
PubMed   |  Link to Article
Yuede  CM, Wozniak  DF, Creeley  CE, Taylor  GT, Olney  JW, Farber  NB.  Behavioral consequences of NMDA antagonist–induced neuroapoptosis in the infant mouse brain. PLoS One. 2010;5(6):e11374. doi:10.1371/journal.pone.0011374.
PubMed   |  Link to Article
Paule  MG, Li  M, Allen  RR,  et al.  Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33(2):220-230.
PubMed   |  Link to Article
Palanisamy  A, Baxter  MG, Keel  PK, Xie  Z, Crosby  G, Culley  DJ.  Rats exposed to isoflurane in utero during early gestation are behaviorally abnormal as adults. Anesthesiology. 2011;114(3):521-528.
PubMed   |  Link to Article
Zou  X, Liu  F, Zhang  X,  et al.  Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey. Neurotoxicol Teratol. 2011;33(5):592-597.
PubMed   |  Link to Article
Brambrink  AM, Back  SA, Riddle  A,  et al.  Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Ann Neurol. 2012;72(4):525-535.
PubMed   |  Link to Article
Creeley  CE, Dikranian  KT, Dissen  GA, Back  SA, Olney  JW, Brambrink  AM.  Isoflurane-induced apoptosis of neurons and oligodendrocytes in the fetal rhesus macaque brain. Anesthesiology. 2014;120(3):626-638.
PubMed   |  Link to Article
Yahalom  B, Athiraman  U, Soriano  SG,  et al.  Spinal anesthesia in infant rats: development of a model and assessment of neurologic outcomes. Anesthesiology. 2011;114(6):1325-1335.
PubMed   |  Link to Article
Olney  JW, Young  C, Wozniak  DF, Ikonomidou  C, Jevtovic-Todorovic  V.  Anesthesia-induced developmental neuroapoptosis: does it happen in humans? Anesthesiology. 2004;101(2):273-275.
PubMed   |  Link to Article
Williams  RK.  The pediatrician and anesthesia neurotoxicity. Pediatrics. 2011;128(5):e1268-e1270. doi:10.1542/peds.2011-2489.
PubMed   |  Link to Article
Rappaport  B, Mellon  RD, Simone  A, Woodcock  J.  Defining safe use of anesthesia in children. N Engl J Med. 2011;364(15):1387-1390.
PubMed   |  Link to Article
Victorian Infant Collaborative Study Group.  Surgery and the tiny baby: sensorineural outcome at 5 years of age. J Paediatr Child Health. 1996;32(2):167-172.
PubMed   |  Link to Article
Filan  PM, Hunt  RW, Anderson  PJ, Doyle  LW, Inder  TE.  Neurologic outcomes in very preterm infants undergoing surgery. J Pediatr. 2012;160(3):409-414.
PubMed   |  Link to Article
Morriss  FH  Jr.  Increased risk of death among uninsured neonates. Health Serv Res. 2013;48(4):1232-1255.
PubMed   |  Link to Article
Boghossian  NS, Page  GP, Bell  EF,  et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.  Late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births. J Pediatr. 2013;162(6):1120-1124, e1. doi:10.1016/j.jpeds.2012.11.089.
PubMed   |  Link to Article
Miller  SP, McQuillen  PS, Hamrick  S,  et al.  Abnormal brain development in newborns with congenital heart disease. N Engl J Med. 2007;357(19):1928-1938.
PubMed   |  Link to Article
Owen  M, Shevell  M, Majnemer  A, Limperopoulos  C.  Abnormal brain structure and function in newborns with complex congenital heart defects before open heart surgery. J Child Neurol. 2011;26(6):743-755.
PubMed   |  Link to Article
Madan  JC, Kendrick  D, Hagadorn  JI, Frantz  ID  III; National Institute of Child Health and Human Development Neonatal Research Network.  Patent ductus arteriosus therapy: impact on neonatal and 18-month outcome. Pediatrics. 2009;123(2):674-681.
PubMed   |  Link to Article
Kabra  NS, Schmidt  B, Roberts  RS, Doyle  LW, Papile  L, Fanaroff  A; Trial of Indomethacin Prophylaxis in Preterms Investigators.  Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants. J Pediatr. 2007;150(3):229-234.e1. doi:10.1016/j.jpeds.2006.11.039.
PubMed   |  Link to Article
Vohr  BR, Stephens  BE, Higgins  RD,  et al.  Are outcomes of extremely preterm infants improving J Pediatr. 2012;161(2):222-228.e3. doi:10.1016/j.jpeds.2012.01.057.
PubMed   |  Link to Article
Bayley  N. Bayley Scales of Infant Development.2nd ed. San Antonio, TX: Psychological Corp; 1993.
Palisano  R, Rosenbaum  P, Walter  S, Russell  D, Wood  E, Galuppi  B.  Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39(4):214-223.
Link to Article
Bayley  N. Bayley Scales of Infant Development.3rd ed. San Antonio, TX: Psychological Corp; 2006.
Walsh  MC, Kliegman  RM.  Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986;33(1):179-201.
PubMed
Rosenbaum  PR. Propensity score. In: Colton  T, Armitage  P, eds. Encyclopedia of Biostatistics.Vol 5. New York, NY: Wiley; 1998:3551-3555.
Rosenbaum  PR, Rubin  DB.  The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41-55.
Link to Article
D’Agostino  RB  Jr, D’Agostino  RB  Sr.  Estimating treatment effects using observational data. JAMA. 2007;297(3):314-316.
PubMed   |  Link to Article
Martens  EP, Pestman  WR, de Boer  A, Belitser  SV, Klungel  OH.  Systematic differences in treatment effect estimates between propensity score methods and logistic regression. Int J Epidemiol. 2008;37(5):1142-1147.
PubMed   |  Link to Article
Anderson  PJ, De Luca  CR, Hutchinson  E, Roberts  G, Doyle  LW; Victorian Infant Collaborative Group.  Underestimation of developmental delay by the new Bayley-III scale. Arch Pediatr Adolesc Med. 2010;164(4):352-356.
PubMed   |  Link to Article
Hintz  SR, Kendrick  DE, Stoll  BJ,  et al; NICHD Neonatal Research Network.  Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics. 2005;115(3):696-703.
PubMed   |  Link to Article
Blakely  ML, Tyson  JE, Lally  KP,  et al; NICHD Neonatal Research Network.  Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants. Pediatrics. 2006;117(4):e680-e687. doi:10.1542/peds.2005-1273.
PubMed   |  Link to Article
Adams-Chapman  I, Hansen  NI, Stoll  BJ, Higgins  R; NICHD Research Network.  Neurodevelopmental outcome of extremely low birth weight infants with posthemorrhagic hydrocephalus requiring shunt insertion. Pediatrics. 2008;121(5):e1167-e1177.
PubMed   |  Link to Article
Wilder  RT, Flick  RP, Sprung  J,  et al.  Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796-804.
PubMed   |  Link to Article
Sprung  J, Flick  RP, Wilder  RT,  et al.  Anesthesia for cesarean delivery and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;111(2):302-310.
PubMed   |  Link to Article
Flick  RP, Lee  K, Hofer  RE,  et al.  Neuraxial labor analgesia for vaginal delivery and its effects on childhood learning disabilities. Anesth Analg. 2011;112(6):1424-1431.
PubMed   |  Link to Article
Flick  RP, Katusic  SK, Colligan  RC,  et al.  Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2011;128(5):e1053-e1061. doi:10.1542/peds.2011-0351.
PubMed   |  Link to Article
DiMaggio  C, Sun  LS, Kakavouli  A, Byrne  MW, Li  G.  A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children. J Neurosurg Anesthesiol. 2009;21(4):286-291.
PubMed   |  Link to Article
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;113(5):1143-1151.
PubMed   |  Link to Article
Ing  C, DiMaggio  C, Whitehouse  A,  et al.  Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130(3):e476-e485. doi:10.1542/peds.2011-3822.
PubMed   |  Link to Article
Block  RI, Thomas  JJ, Bayman  EO, Choi  JY, Kimble  KK, Todd  MM.  Are anesthesia and surgery during infancy associated with altered academic performance during childhood? Anesthesiology. 2012;117(3):494-503.
PubMed   |  Link to Article
Walker  K, Badawi  N, Halliday  R,  et al.  Early developmental outcomes following major noncardiac and cardiac surgery in term infants: a population-based study. J Pediatr. 2012;161(4):748-752.e1. doi:10.1016/j.jpeds.2012.03.044.
PubMed   |  Link to Article
Kalkman  CJ, Peelen  L, Moons  KG,  et al.  Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology. 2009;110(4):805-812.
PubMed   |  Link to Article
Bartels  M, Althoff  RR, Boomsma  DI.  Anesthesia and cognitive performance in children. Twin Res Hum Genet. 2009;12(3):246-253.
PubMed   |  Link to Article
Hansen  TG, Pedersen  JK, Henneberg  SW,  et al.  Academic performance in adolescence after inguinal hernia repair in infancy. Anesthesiology. 2011;114(5):1076-1085.
PubMed   |  Link to Article
DiMaggio  C, Sun  LS, Ing  C, Li  G.  Pediatric anesthesia and neurodevelopmental impairments. J Neurosurg Anesthesiol. 2012;24(4):376-381.
PubMed   |  Link to Article
Rozé  JC, Denizot  S, Carbajal  R,  et al.  Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants. Arch Pediatr Adolesc Med. 2008;162(8):728-733.
PubMed   |  Link to Article
Guerra  GG, Robertson  CM, Alton  GY,  et al; Western Canadian Complex Pediatric Therapies Follow-up Group.  Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth. 2011;21(9):932-941.
PubMed   |  Link to Article
Hamrick  SE, Miller  SP, Leonard  C,  et al.  Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants. J Pediatr. 2004;145(5):593-599.
PubMed   |  Link to Article
Yuede  CM, Olney  JW, Creeley  CE.  Developmental neurotoxicity of alcohol and anesthetic drugs is augmented by co-exposure to caffeine. Brain Sci. 2013;3(3):1128-1152.
PubMed   |  Link to Article
A multi-site randomized controlled trial comparing regional and general anesthesia for effects on neurodevelopmental outcome and apnea in infants (GAS). http://clinicaltrials.gov/ct2/show/NCT00756600?term=NCT00756600&rank=1. Accessed November 6, 2012.
Reddy  SV.  Effect of general anesthetics on the developing brain. J Anaesthesiol Clin Pharmacol. 2012;28(1):6-10.
PubMed   |  Link to Article
Costantine  MM, Weiner  SJ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.  Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants. Obstet Gynecol. 2009;114(2, pt 1):354-364.
PubMed   |  Link to Article

Correspondence

CME


You need to register in order to view this quiz.
Submit a Comment

Multimedia

Supplement.

eTable 1. Conditions excluded from analysis

eTable 2. Procedures classified as major or minor

eTable 3. Distribution of surgical procedures between patient subgroups

eTable 4. Model 2: multivariable logistic regression analysis of the secondary outcome neurodevelopmental impairment among survivors at 18-22 months’ corrected age with two-level surgery predictor variable

eTable 5. Model 4: multivariable logistic regression analysis of the secondary outcome neurodevelopmental impairment among survivors at 18-22 months’ corrected age with three-level surgery predictor variable

eTable 6. Demonstration of propensity score achievement of balanced distribution of covariates

eFigure. Patient flow diagram

Supplemental Content
JAMA Pediatrics Journal Club Slides:

Morriss Jr FH, Saha S, Bell EF, et al. Surgery and Neurodevelopmental Outcome of Very Low-Birth-Weight Infants. JAMA Pediatr. Published online June 16, 2014. doi:10.1001/jamapediatrics.2014.307.

Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

1,834 Views
3 Citations

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Related Multimedia

Author Interview

audio player

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
×