Abstract
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
Retrospective cohort analysis of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998–2009 and evaluated at 18–22 months’ corrected age.
SETTING
22 academic neonatal intensive care units.
PARTICIPANTS
Inclusion criteria were: birth weight 401–1500 g; survival to 12 hours; available for follow-up. Some conditions were excluded. 12 111 infants were included in analyses, 87% of those eligible.
EXPOSURES
Surgical procedures; surgery also classified by expected anesthesia type as major (general anesthesia) or minor surgery (non-general anesthesia).
MAIN OUTCOME 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 means of Bayley Scales of Infant Development, Second Edition, Mental Developmental Index and Psychomotor Developmental Index for patients born before 2006.
RESULTS
There were 2186 major, 784 minor and 9141 no surgery patients. 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% confidence interval 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% confidence interval 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 odds ratio for neurodevelopmental impairment was 1.56 (95% confidence interval 1.26–1.93) and the adjusted mean Mental Developmental Index and mean Psychomotor Developmental Index values 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 18–22 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.1–10 The toxic effects are widespread and affect both neurons and oligodendrocytes.11, 12 The doses used to produce neurotoxic effects 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 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).14–16 A study of infants who were born in 1985–1988 weighing <1000 g or who were <27 weeks’ gestational age found an adverse association of surgery requiring general anesthesia and moderate or severe disability at age 5 years, with adjusted odds ratio (AOR) = 10.1; 95% confidence interval (CI) = 2.3–44.17 However, a smaller study of infants born between 2001–2004 weighing <1250 g or <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.18 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 three-fold.19 Postoperative 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 if there were an increased adjusted risk for death or NDI at 18–22 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 (GDB).
Methods
Subjects
We studied VLBW infants enrolled in the NRN GDB from 1998 through 2009 who had birth weights (BW) of 401–1500 g, survived 12 hours and were available for follow-up assessments at 18–22 months’ CA. We excluded patients who had certain conditions (eTable 1); among the excluded patients were those with congenital heart defects (CHD) and those who had surgery for a patent ductus arteriosus (PDA), conditions associated with NDI.21–24 The follow-up evaluation included neurologic, hearing, vision and developmental assessment.25 Centers received local institutional review board approval for data collection.
Sample size
During 1998–2009, there were 12 111 infants of BW 401–1500 g with complete data who were included in the analyses, and 2970 of these had surgery during the initial hospitalization (eFigure).
Definitions
The primary outcome was death before follow-up assessment or NDI at 18–22 months’ CA. Because the NRN instrument used in neurodevelopmental assessment changed during the study period, NDI for infants born from 1998–2005 was defined as one or more of: Bayley Scales of Infant Development, Second Edition (BSID II) Mental Developmental Index (MDI) score <70 or Psychomotor Developmental Index (PDI) score <70; Gross Motor Function Classification System (GMFCS) ≥ level 2; moderate or severe cerebral palsy; bilateral blindness; or hearing impairment with hearing aids in both ears. For infants born from 2006–2009, NDI was defined as one or more of: Bayley Scales of Infant and Toddler Development, Third Edition (BSID III) cognitive composite score <80; GMFCS ≥ level 2; 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 two subgroups, major and minor surgery. The GDB 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, physiologic stress and postoperative analgesia. The GDB includes annotations regarding some circumstances under which surgery was performed, including general anesthesia used for procedures that are usually performed with non-general anesthesia.
Severe intracranial hemorrhage (ICH) was defined as parenchymal or intraventricular hemorrhage with ventricular dilatation, or cystic periventricular leukomalacia (cPVL). Bronchopulmonary dysplasia (BPD) was defined as requiring supplemental oxygen at 36 weeks. Necrotizing enterocolitis (NEC) was defined as modified Bell classification stage II A or higher.26
Analysis
Chi-square and Fisher’s 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, respectively, 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.27–30 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, 31 We 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 18–22 months’ CA, multivariable linear regression analyses were performed to determine separately for adjusted mean MDI and adjusted mean PDI 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. SAS Version 9.2 (Cary, NC) was used for statistical analyses.
Results
Patient characteristics
The analyses included 2186 patients with major surgery, 784 with minor surgery and 9141 patients with no surgery. The patients in these three categories differed in most characteristics (Table 1). The 4649 procedures that we classified as major or minor surgery (eTable 2) were unequally distributed among anatomical systems (eTable 3). Most subjects who had surgery had only a single exposure, but 1080 subjects had multiple exposures (eTable 3).
Table 1.
Characteristics of Subjects
| Characteristic | Major Surgerya ( n=2186) |
Minor Surgery (n=784) |
No Surgery (n=9141) |
P Value |
|---|---|---|---|---|
| Birth year | ||||
| 1998–2001, No. (column %) | 667 (30.5) | 314 (40.1) | 3204 (35.1) | |
| 2002–2005, No. (column %) | 913 (41.8) | 288 (36.7) | 3506 (38.4) | <.001 |
| 2006–2009, No. (column %) | 606 (27.7) | 182 (23.2) | 2431 (26.6) | |
| Birth weight, mean (SD), g | 731.6 (143.2) | 748.0 (146.5) | 770.2 (158.4) | <.001 |
| <500 g, No. (column %) | 77 (3.5) | 22 (2.8) | 413 (4.5) | |
| 500–999 g, No. (column %) | 2055 (94.0) | 741 (94.5) | 8377 (91.6) | <.001 |
| 1000–1500 g, No. (column %) | 54 (2.5) | 21 (2.7) | 351 (3.8) | |
| Gestational age, median (IQR), wk | 25 (2) | 25 (3) | 26 (3) | <.001 |
| <26 wk, No. (column %) | 1347 (61.6) | 395 (50.4) | 4229 (46.3) | |
| 26–28 wk, No. (column %) | 765 (35.0) | 320 (40.8) | 4060 (44.4) | <.001 |
| 29–30 wk, No. (column %) | 60 (2.7) | 56 (7.1) | 635 (7.0) | |
| >30 wk, No. (column %) | 14 (0.6) | 13 (1.7) | 217 (2.4) | |
| Gender male, No. (column %) | 1228 (56.2) | 497 (63.4) | 4364 (47.7) | <.001 |
| Multiple birth cohort, No. (column %) | 480 (22.0) | 207 (26.4) | 2,215 (24.2) | .02 |
| Small-for-gestational-age, No. (column %) |
274 (12.5) | 146 (18.6) | 1456 (15.9) | <.001 |
| 5-min Apgar score, median (IQR) | [n=2166] 7 (3) |
[n=778] 7 (2) |
[n=9030] 7 (2) |
<.001 |
| Caucasian, No./column total (%) | 1171/2179 (53.7) | 426/781 (54.5) | 4832/9095 (53.1) | .69 |
| Antenatal corticoid steroid exposure, No./column total (%) |
1747/2174 (80.4) | 641/781 (82.1) | 7304/9118 (80.1) | .42 |
| Postnatal corticosteroid exposure, No./column total (%) |
717/2173 (33.0) | 219/784 (27.9) | 1292/9102 (14.2) | <.001 |
| Severe intracranial hemorrhage and/or cystic periventricular leukomalacia, No./column total (%) |
586/2182 (26.9) | 163/773 (21.1) | 1773/8610 (20.6) | <.001 |
| Bronchopulmonary dysplasia, No./column total (%) |
1294/1837 (70.4) | 276/511 (54.0) | 2452/6517 (37.6) | <.001 |
| Sepsis and/or meningitis, No./column total (%) |
1348/2184 (61.7) | 368/781 (47.1) | 2740/8295 (33.0) | <.001 |
| Necrotizing enterocolitis, No./column total (%) |
664/2184 (30.4) | 282/784 (36.0) | 389/9139 (4.26) | <.001 |
| Patent ductus arteriosus, excluding those surgically closed, No./column total (%) |
1047/2186 (47.9) | 362/784 (46.2) | 3366/9125 (36.9) | <.001 |
| Seizures, No./column total (%) | 333/2186 (15.2) | 82/784 (10.5) | 726/9137 (8.0) | <.001 |
| Caregiver highest educational level: | ||||
| ≤9 y, No./column total (%) | 137/2009 (6.8) | 58/672 (8.6) | 628/8071 (7.8) | |
| 10–12 y, No./column total (%) | 302/2009 (15.0) | 96/672 (14.3) | 1,217/8071 (15.1) | |
| >12 y, No./column total (%) | 1156/2009 (57.5) | 393/672 (58.5) | 4671/8071 (57.9) | .55 |
| Unknown, No./column total (%) | 414/2009 (20.6) | 125/672 (18.6) | 1555/8071 (19.3) |
With or without additional minor surgical procedure
Unadjusted outcomes
Unadjusted associations of the 3-level surgery exposure and, respectively, death or NDI; NDI among survivors; mean scores for BSID II MDI and PDI and BSID III cognitive composite score; GMFCS level ≥2; moderate or severe cerebral palsy; blindness; and deafness (Table 2) exhibit a progressively greater incidence of the respective adverse outcome from the no surgery, to the minor surgery, and to the major surgery subgroups.
Table 2.
Unadjusted Associations of Neurodevelopmental Outcomes with Patient Subgroups
| Outcome | Major Surgerya | Minor Surgery |
No Surgery | P Value |
|---|---|---|---|---|
| Death or neurodevelopmental impairment, column No./column total (%) |
1401/2186 (64.1) |
480/784 (61.2) |
4364/9141 (47.7) |
<.001 |
| Neurodevelopmental impairment, column No./column total (%) |
818/1603 (51.0) |
179/483 (37.1) |
1541/6318 (24.4) |
<.001 |
| BSID II MDI, mean (SD) | [n=1109] 71.3 (18.0) |
[n=376] 77.0 (17.2) |
[n=4525] 82.3 (17.4) |
<.001 |
| BSID II PDI, mean (SD) | [n=1109] 74.2 (19.3) |
[n=372] 80.4 (17.5) |
[n=4504] 87.1 (16.8) |
<.001 |
| BSID III Cognitive composite score, mean (SD) |
[n=469] 82.7 (15.8) |
[n=103] 88.9 (11.9) |
[n=1771] 92.2 (14.0) |
<.001 |
| GMFCS ≥ 2, column No./column total (%) | 242/1602 (15.1) |
30/482 (6.2) |
194/6313 (3.1) |
<.001 |
| Cerebral palsy, moderate or severe, column No./column total (%) |
238/1600 (14.9) | 32/482 (6.6) |
198/6311 (3.1) |
<.001 |
| Blindness, column No./column total (%) | 84/1600 (5.3) |
4/481 (0.8) |
24/6310 (0.4) |
<.001 |
| Deafness, column No./column total (%) | 112/1597 (7.0) |
12/482 (2.5) |
155/6302 (2.5) |
<.001 |
BSID II- Bayley Scales of Infant Development, Second Edition; BSID III - Bayley Scales of Infant Development, Third Edition; GMFCS – Gross Motor Function Classification System; MDI – Mental Developmental Index; PDI – Psychomotor Developmental Index
With or without additional minor surgical procedure
Multivariable logistic regression analyses
In a multivariable logistic regression analysis of the primary outcome in which all surgery patients were considered together as a risk factor (Table 3, Model 1), patients who had 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 increased risk for NDI among all survivors who had surgery (eTable 4, Model 2).
Table 3.
Model 1: Multivariable Logistic Regression Analysis of the Primary Outcome Death or Neurodevelopmental Impairment with Two-Level Surgery Predictor Variable
| Variablea | Adjusted Odds Ratio | ||
|---|---|---|---|
| Estimate | 95% CI | ||
| Surgery vs no surgery | 1.29 | 1.08 | 1.55 |
| Number of surgeries (for each additional surgery) |
1.23 | 1.13 | 1.34 |
| Birth weight (for each 250 g increase in weight) |
0.70 | 0.60 | 0.81 |
| Small-for-gestational-age | 1.35 | 1.17 | 1.56 |
| Male | 1.63 | 1.42 | 1.88 |
| Multiple birth cohort | 1.30 | 1.15 | 1.48 |
| Caucasian | 0.75 | 0.67 | 0.84 |
| 5-min Apgar score ≤ 3 | 1.22 | 1.00 | 1.49 |
| Antenatal corticosteroid exposure |
0.84 | 0.72 | 0.98 |
| Postnatal corticosteroid exposure |
1.64 | 1.38 | 1.95 |
| Seizures | 2.93 | 2.31 | 3.71 |
| Severe intracranial hemorrhage and/or cystic periventricular leukomalacia |
2.12 | 1.78 | 2.54 |
| Bronchopulmonary dysplasia (supplemental O2 at 36 wk) |
1.47 | 1.25 | 1.72 |
| Sepsis and/or meningitis | 1.26 | 1.07 | 1.49 |
| Necrotizing enterocolitis (Bell stage ≥ IIA) |
1.26 | 0.83 | 1.92 |
| Patent ductus arteriosus, excluding surgically closed patients |
1.07 | 0.95 | 1.21 |
| Caregiver highest educational level: |
|||
| 10–12 y vs ≤9 y | 0.86 | 0.69 | 1.07 |
| >12 y vs ≤9 y | 0.62 | 0.51 | 0.76 |
| Birth year: | |||
| 2002–2005 vs 1998–2001 | 1.26 | 1.10 | 1.43 |
| 2006–2009 vs 1998–2001 | 0.64 | 0.55 | 0.76 |
| Inborn | 0.77 | 0.62 | 0.95 |
| Propensity score- surgeryb AOR per 10% increase in the predicted probability |
1.02 | 0.92 | 1.14 |
Neonatal Research Network center variable is also included in the model.
Included in the PS model were BW, SGA, sex, race, 5-minute Apgar score, ICH, BPD, sepsis and/or meningitis, NEC, PDA, multiple birth cohort, antenatal corticosteroid exposure (ANS), PNS, highest level of education attained by primary caregiver, birth year, and center.
In a multivariable logistic regression analysis of the outcome death or NDI when surgery procedures are classified as major or minor (Table 4, Model 3), patients who had 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 also compared 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 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 had major surgery compared with those who either had no surgery or minor surgery (eTable 5, Model 4). eTable 6 presents evidence that the PS achieved balanced distribution of covariates among the surgery groups.
Table 4.
Model 3: Multivariable Logistic Regression Analysis of the Primary Outcome Death or Neurodevelopmental Impairment with Three-Level Surgery Predictor Variable
| Variablea | 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 |
| Number 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 |
| Small-for-gestational-age | 1.45 | 1.25 | 1.68 |
| Male | 1.74 | 1.49 | 2.03 |
| Multiple birth cohort | 1.33 | 1.18 | 1.51 |
| Caucasian | 0.73 | 0.65 | 0.82 |
| 5-min Apgar score ≤ 3 | 1.17 | 0.96 | 1.42 |
| Antenatal corticosteroid exposure |
0.84 | 0.72 | 0.98 |
| Postnatal corticosteroid exposure |
1.63 | 1.37 | 1.93 |
| Seizures | 2.88 | 2.27 | 3.65 |
| Severe intracranial hemorrhage and/or cystic periventricular leukomalacia |
1.99 | 1.68 | 2.37 |
| Bronchopulmonary dysplasia (supplemental O2 at 36 wk) |
1.41 | 1.21 | 1.64 |
| Sepsis and/or meningitis | 1.18 | 1.02 | 1.38 |
| Necrotizing enterocolitis (Bell stage ≥ IIA) |
1.12 | 0.76 | 1.65 |
| Patent ductus arteriosus, excluding surgically closed patients |
1.09 | 0.96 | 1.22 |
| Caregiver highest educational level: |
|||
| 10–12 y vs ≤9 y | 0.86 | 0.69 | 1.08 |
| >12 y vs ≤9 y | 0.62 | 0.51 | 0.76 |
| Birth year: | |||
| 2002–2005 vs 1998–2001 | 1.18 | 1.03 | 1.36 |
| 2006–2009 vs 1998–2001 | 0.60 | 0.50 | 0.71 |
| Inborn | 0.77 | 0.63 | 0.95 |
| Propensity scoreb, minor surgery AOR per 10% increase in the predicted probability |
0.88 | 0.72 | 1.07 |
| Propensity scoreb, major surgery AOR per 10% increase in the predicted probability |
1.07 | 0.98 | 1.18 |
Neonatal Research Network center variable is also included in the model.
Included in the PS model were BW, SGA, sex, race, 5-minute Apgar score, ICH, BPD, sepsis and/or meningitis, NEC, PDA, multiple birth cohort, ANS, PNS, highest level of education attained by primary caregiver, birth year, and center.
We performed a sensitivity analysis in which patients who had surgery for retinopathy of prematurity (ROP) 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 ROP sufficiently severe to warrant surgery had a high probability before surgery of having impaired vision and thus NDI. The exclusion of ROP surgery patients did not qualitatively change the primary outcome death or NDI calculated using Model 3. A second sensitivity analysis was performed in which we excluded 123 severe ICH patients 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 adverse risk for this group of procedures and also that the association between general anesthesia and the primary outcome is dependent on the specific surgical procedure, i.e., effect modification. One possible explanation for the effect modification is the length of the procedure and exposure to anesthesia associated with various procedures.
Bayley II MDI and PDI
Among those 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), major surgery patients 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 1.5–5.6) less than that for those who had minor surgery. The adjusted mean value for PDI for major surgery patients 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 5.
Models 5 and 6: Multivariable Linear Regression Analyses for Mean BSID II MDI and Mean PDI with Three-Level Surgery Predictor Variables
| Model 5 for Mean Mental Developmental Index |
Model 6 for Mean Psychomotor Developmental Index |
|||||
|---|---|---|---|---|---|---|
| Variablea | Estimate | 95% CI | Estimate | 95% CI | ||
| No surgery vs major surgery | 3.3 | 1.4 | 5.1 | 3.6 | 1.8 | 5.4 |
| Minor surgery vs major surgery | 3.6 | 1.5 | 5.3 | 3.1 | 1.0 | 5.2 |
| No surgery vs minor surgery | −0.3 | −2.3 | 1.6 | 0.5 | −1.5 | 2.5 |
| Number of surgeries (for each additional surgery) |
−0.9 | −1.6 | −0.1 | −1.5 | −2.3 | −0.7 |
| Birth weight (for each 250 g. increase in weight) |
3.4 | 2.2 | 4.5 | 2.1 | 0.9 | 3.2 |
| Small-for-gestational-age (no vs yes) |
1.9 | 0.7 | 3.1 | 3.5 | 2.3 | 4.7 |
| Male (no vs yes) | 6.1 | 4.9 | 7.2 | 3.9 | 2.8 | 5.1 |
| Multiple birth cohort (no vs yes) | 3.0 | 2.0 | 4.0 | 2.3 | 1.3 | 3.3 |
| Caucasian (yes vs no) | 5.1 | 4.2 | 6.0 | −0.4 | −1.3 | 0.5 |
| 5-min Apgar score ≤ 3 (no vs yes) | 1.5 | −0.2 | 3.2 | 1.0 | −0.7 | 2.7 |
| Antenatal corticosteroid exposure (yes vs no) |
1.2 | −0.04 | 2.4 | 1.3 | 0.090 | 2.52 |
| Postnatal corticosteroid exposure (no vs yes) |
1.9 | 0.6 | 3.2 | 3.27 | 2.0 | 4.6 |
| Seizures (no vs yes) | 7.5 | 5.5 | 9.5 | 8.4 | 6.4 | 10.4 |
| Severe intracranial hemorrhage and/or cystic periventricular leukomalacia (no vs yes) |
5.1 | 3.7 | 6.5 | 9.1 | 7.7 | 10.5 |
| Bronchopulmonary dysplasia (no vs yes) | 2.4 | 1.2 | 3.6 | 3.1 | 1.9 | 4.3 |
| Sepsis and/or meningitis (no vs yes) | 1.3 | 0.1 | 2.5 | 0.9 | −0.3 | 2.1 |
| Patent ductus arteriosus, excluding surgically closed patients (no vs yes) |
1.2 | 0.3 | 2.18 | 1.0 | 0.02 | 1.9 |
| Necrotizing enterocolitis (Bell stage ≥ IIA) (no vs yes) |
0.6 | −2.2 | 3.5 | 0.2 | −2.6 | 3.1 |
| Caregiver highest educational level: |
||||||
| 10–12 y vs ≤9 y | 2.9 | 1.1 | 4.7 | 1.1 | −0.7 | 2.9 |
| >12 y vs ≤9 y | 7.0 | 5.4 | 8.5 | 2.6 | 1.1 | 4.2 |
| Birth year, 1998–2001 vs 2002–2005 | 0.5 | −0.4 | 1.5 | −0.1 | −1.03 | 0.9 |
| Inborn (yes vs. no) | 1.8 | 0.2 | 3.4 | 1.2 | −0.4 | 2.9 |
| Propensity scoreb, minor surgery AOR per 10% increase in the predicted probability |
1.0 | −0.4 | 2.3 | 1.2 | −0.1 | 2.6 |
| Propensity scoreb, major surgery AOR per 10% increase in the predicted probability |
−0.5 | −1.2 | 0.3 | −0.4 | −1.1 | 0.3 |
Neonatal Research Network center variable is also included in the models.
Included in the PS model were BW, SGA, sex, race, 5-minute Apgar score, ICH, BPD, sepsis and/or meningitis, NEC, PDA, multiple birth cohort, ANS, PNS, highest level of education attained by primary caregiver, birth year, and center.
Discussion
VLBW infants who underwent surgical procedures during their postnatal hospitalizations had increased adjusted risk of death or NDI at 18–22 months’ CA, and survivors had increased adjusted risk of NDI. Classification to major or minor surgery groups based on expected type of anesthesia also resulted in increased adjusted risk of death or NDI for those classified as major, but not for those classified as minor surgery patients. 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 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, an observation of effect modification that suggests a relatively low adverse risk 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 physiologic alterations or effects of pharmacologic agents other than anesthetics administered to surgery patients. The adjusted means for the BSID II MDI and PDI scores at age 18–22 months were less for patients who had major surgery than for those who had minor 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 previously demonstrated to 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 PDA because the procedure in VLBW infants has been associated with subsequent NDI or neurosensory impairment, 23, 24 we retained patients who had PDA 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 study of NRN patients, surgery for NEC was a significant independent risk factor for MDI scores <70, PDI scores <70 and NDI compared with infants who had medically treated NEC and infants without NEC.32 However, surgical NEC patients also had poorer growth than others. 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, neonates with NEC or intestinal perforation who were treated by laparotomy under general anesthesia were compared with those treated by peritoneal drain placement without general anesthesia.33 The AOR for NDI or death by treatment group was not significant. In another NRN retrospective cohort analysis, 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.34
Other retrospective analyses 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 age 5 years.35–46 The observed outcome measures ranged from individual neurodevelopmental testing at 18–22 months to learning disabilities identified during childhood and school achievement assessed by group testing at 19 years. Most,35–43 but not all,44–46 studies reported worse neurodevelopmental or achievement outcomes for patients who had surgery than for others, and some reported increasing risk with multiple surgical exposures. 35, 38, 40
It is difficult to determine if 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-analysis of 7 selected observational studies of the effect of anesthesia with or without surgery in children ages 0–4 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.47 Included among the studies selected for the meta-analysis was one that reported no increase in adjusted neurodevelopmental risk for preterm infants who received prolonged sedation and/or opioids for mechanical ventilation and/or surgery.48 Another included study examined sedation and analgesia drugs following surgery for CHD and found no association between dose and duration of sedation/analgesia drugs and adverse neurodevelopmental outcomes.49
Both major surgery and ICH, which includes cPVL, are significant independent predictors of death or NDI and NDI among survivors (Table 4 and eTable 5). There are likely multiple pathways to NDI in preterm infants, as suggested previously by the detection of cPVL by ultrasound in only a minority of infants with abnormal neurodevelopmental outcomes.50
For the present analysis, the type of anesthesia was not documented, and 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 shown to potentiate the neurotoxic effects of anesthetic agents in developing mice;51 potentiation in infants has not been studied. 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 18–22 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 control trials examining the potential adverse neurodevelopmental effects of general compared with spinal anesthesia for surgery, although at least one trial is underway for a selected procedure, inguinal herniorrhaphy.52 It is currently not feasible, however, to conduct a trial of general versus non-general 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 about specific agents and the doses and duration of administration to determine if 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.53, 54 Finally, postponement of elective procedures until young patients are older may be considered, especially if the procedure represents a second or subsequent anesthesia.
Conclusions
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.
Supplementary Material
Acknowledgments
Funding Source: This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
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 Sponsor: While NICHD staff had input into the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication; the comments and views of the authors do not necessarily represent the views of the NICHD. NCRR and NCATS staff did not have input into this study.
Footnotes
Disclosures
The authors declare no conflicts of interest, including relevant financial interests, activities, relationships, and affiliations.
Authors’ Contributions:
Frank H. Morriss, Jr.: Dr. Morriss conceived and designed the initial study plan, interpreted the results, drafted the manuscript, and approved the final manuscript as submitted.
Shampa Saha: Dr. Saha, Research Statistician at RTI International, acquired data, carried out the analyses, contributed to the drafting of the manuscript and approved the final manuscript as submitted.
Edward F. Bell: Dr. Bell, the Principal Investigator of the University of Iowa Neonatal Research Network grant, participated in the conception, design, and acquisition of data for the study, critically reviewed and revised the manuscript and approved the final manuscript as submitted.
Tarah T. Colaizy: Dr. Colaizy contributed to the acquisition of data and interpretation of the neurodevelopmental outcomes, revision of the manuscript, and approved the final manuscript as submitted.
Barbara J. Stoll: Dr. Stoll contributed to the acquisition of data, participated in the design of the study, reviewed and revised the manuscript and approved the final manuscript as submitted.
Susan R. Hintz: Dr. Hintz contributed to the acquisition of data, participated in the design of the study, reviewed and revised the manuscript and approved the final manuscript as submitted.
Seetha Shankaran: Dr. Shankaran contributed to the acquisition of data, participated in the design of the study, reviewed and revised the manuscript and approved the final manuscript as submitted.
Betty R. Vohr: Dr. Vohr contributed to the acquisition of data, participated in the design of the study, reviewed and revised the manuscript and approved the final manuscript as submitted.
Shannon E. G. Hamrick: Dr. Hamrick participated in the design of the study, reviewed and revised the manuscript and approved the final manuscript as submitted.
Athina Pappas: Dr. Pappas participated in the design of the study, reviewed and revised the manuscript and approved the final manuscript as submitted.
Patrick M. Jones: Dr. Jones participated in the design of the study, reviewed and revised the manuscript and approved the final manuscript as submitted.
Waldemar A. Carlo; Dr. Carlo contributed to the acquisition of data, reviewed and revised the manuscript and approved the final manuscript as submitted.
Abbot R. Laptook; Dr. Laptook contributed to the acquisition of data, reviewed and revised the manuscript and approved the final manuscript as submitted.
Krisa P. Van Meurs; Dr. Van Meurs contributed to the acquisition of data, reviewed and revised the manuscript and approved the final manuscript as submitted.
Pablo J. Sánchez: Dr. Sánchez contributed to the acquisition of data, reviewed and revised the manuscript and approved the final manuscript as submitted.
Ellen C. Hale: Ms. Hale contributed to the acquisition of data, reviewed and revised the manuscript and approved the final manuscript as submitted.
Nancy S. Newman: Ms. Newman contributed to the acquisition of data, reviewed and revised the manuscript and approved the final manuscript as submitted.
Abhik Das: Dr. Das, Senior Research Statistician at RTI International, participated in the design of the study, supervised the analysis, participated in the drafting of the manuscript and approved the final manuscript as submitted.
Rosemary D. Higgins: Dr. Higgins, Program Scientist for the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network, participated in the design of the study, participated in the drafting of the manuscript and approved the final manuscript as submitted.
Data Access, Responsibility, and Analysis:
Data collected at participating sites of the NICHD Neonatal Research Network (NRN) were transmitted to RTI International, the data coordinating center (DCC) for the network, which stored, managed and analyzed the data for this study. On behalf of the NRN, Drs. Abhik Das (DCC Principal Investigator) and Shampa Saha (DCC Statistician) had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.
We are indebted to our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. The following investigators, in addition to those listed as authors, participated in this study:
NRN Steering Committee Chairs: Alan H. Jobe, MD PhD, University of Cincinnati (2003–2006); 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; Victoria E. Watson, MS CAS.
Case Western Reserve University, Rainbow Babies & Children's Hospital (U10 HD21364, M01 RR80) – Michele C. Walsh, MD MS; Avroy A. Fanaroff, MD; Deanne E. Wilson-Costello, MD; Bonnie S. Siner, RN; Harriet G. Friedman, MA.
Cincinnati Children's Hospital Medical Center, University Hospital, and Good Samaritan Hospital (U10 HD27853, 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; Kristin Kirker, CRC.
Duke University School of Medicine, University Hospital, Alamance Regional Medical Center, and Durham Regional Hospital (U10 HD40492, 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; Melody B. Lohmeyer, RN MSN.
Emory University, Children’s Healthcare of Atlanta, Grady Memorial Hospital, and Emory University Hospital Midtown (U10 HD27851, M01 RR39) – David P. Carlton, MD; Ira Adams-Chapman, MD.
Eunice Kennedy Shriver National Institute of Child Health and Human Development–Linda L. Wright, MD; Elizabeth M. McClure, MEd; Stephanie Wilson Archer, MA.
Indiana University, University Hospital, Methodist Hospital, Riley Hospital for Children, and Wishard Health Services (U10 HD27856, 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; 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; 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, 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; Nicholas H. St. John, PhD.
Tufts Medical Center, Floating Hospital for Children (U10 HD53119, 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; Ana Brussa, MS OTR/L.
University of Alabama at Birmingham Health System and Children’s Hospital of Alabama (U10 HD34216, 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; 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; Wade Rich, BSHS RRT.
University of Iowa Children's Hospital (U10 HD53109, M01 RR59) – John A. Widness, MD; Michael J. Acarregui, MD; Karen J. Johnson, RN BSN; Diane L. Eastman, RN CPNP MA.
University of Miami, Holtz Children's Hospital (U10 HD21397, 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; Arielle Riguad, MD.
University of New Mexico Health Sciences Center (U10 HD27881, U10 HD53089, 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; Rebecca Montman, BSN.
University of Rochester Medical Center, Golisano Children’s Hospital (U10 HD40521, M01 RR44, 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; 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; Kimberly Yolton, PhD.
University of Texas Southwestern Medical Center at Dallas, Parkland Health & Hospital System and Children's Medical Center Dallas (U10 HD40689, 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; 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, RNBSN; 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; Sharon L. Wright, MT.
University of Utah Medical Center, Intermountain Medical Center, LDS Hospital, and Primary Children's Medical Center (U10 HD53124, 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; Kimberlee Weaver-Lewis, RN BSN.
Wake Forest University Baptist Medical Center, Brenner Children's Hospital, and Forsyth Medical Center (U10 HD40498, 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; 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; Geraldine Muran, RN BSN.
Yale University, Yale-New Haven Children’s Hospital, and Bridgeport Hospital (U10 HD27871, UL1 RR24139, M01 RR125, 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; Joanne Williams, RN BSN.
Contributor Information
Shampa Saha, Email: saha@rti.org.
Edward F. Bell, Email: edward-bell@uiowa.edu.
Tarah T. Colaizy, Email: tarah-colaizy@uiowa.edu.
Barbara J. Stoll, Email: Barbara.Stoll@oz.ped.emory.edu.
Susan R. Hintz, Email: srhintz@stanford.edu.
Seetha Shankaran, Email: sshankar@med.wayne.edu.
Betty R. Vohr, Email: BVohr@wihri.org.
Shannon E. G. Hamrick, Email: sehamri@emory.edu.
Athina Pappas, Email: apappas@med.wayne.edu.
Patrick M. Jones, Email: Patrick.M.Jones@uth.tmc.edu.
Waldemar A. Carlo, Email: WCarlo@peds.uab.edu.
Abbot R. Laptook, Email: ALaptook@WIHRI.org.
Krisa P. Van Meurs, Email: vanmeurs@leland.stanford.edu.
Pablo J. Sánchez, Email: Pablo.Sanchez@nationwidechildrens.org.
Ellen C. Hale, Email: ehale@emory.edu.
Nancy S. Newman, Email: nxs5@case.edu.
Abhik Das, Email: adas@rti.org.
Rosemary D. Higgins, Email: higginsr@mail.nih.gov.
References
- 1.Ikonomidou C, Bosch F, Miksa M, et al. Blockade of glutamate receptors triggers apoptotic neurodegeneration in the developing brain. Science. 1999;283(5398):70–74. doi: 10.1126/science.283.5398.70. [DOI] [PubMed] [Google Scholar]
- 2.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. doi: 10.1523/JNEUROSCI.23-03-00876.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.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. doi: 10.1213/ane.0b013e318172ba0a. [DOI] [PubMed] [Google Scholar]
- 4.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. doi: 10.1213/ane.0b013e318167ad77. [DOI] [PubMed] [Google Scholar]
- 5.Brambrink AM, Evers AS, Avidan MS, et al. Isoflurane-induced neuroapoptosis in the neonatal rhesus macaque brain. Anesthesiology. 2010;112(4):834–841. doi: 10.1097/ALN.0b013e3181d049cd. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.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. doi: 10.1097/ALN.0b013e3181d3e0c2. [DOI] [PubMed] [Google Scholar]
- 7.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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.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. doi: 10.1016/j.ntt.2011.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.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. doi: 10.1097/ALN.0b013e318209aa71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.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. doi: 10.1016/j.ntt.2011.06.003. [DOI] [PubMed] [Google Scholar]
- 11.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. doi: 10.1002/ana.23652. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Creeley CE, Dikranian KT, Dissen GA, Back SA, Olney JW, Brambrink AM. Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. Anesthesiology. 2013 Oct 23; doi: 10.1002/ana.23652. [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.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. doi: 10.1097/ALN.0b013e31821b5729. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.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. doi: 10.1097/00000542-200408000-00004. [DOI] [PubMed] [Google Scholar]
- 15.Williams RK. The pediatrician and anesthesia neurotoxicity. Pediatrics. 2011;128(5):e1268–e1270. doi: 10.1542/peds.2011-2489. [DOI] [PubMed] [Google Scholar]
- 16.Rappaport B, Mellon RD, Simone A, Woodcock J. Defining safe anesthesia in children. N Engl J Med. 2011;364(15):1387–1390. doi: 10.1056/NEJMp1102155. [DOI] [PubMed] [Google Scholar]
- 17.The 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. doi: 10.1111/j.1440-1754.1996.tb00916.x. [DOI] [PubMed] [Google Scholar]
- 18.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. doi: 10.1016/j.jpeds.2011.09.009. [DOI] [PubMed] [Google Scholar]
- 19.Morriss FH. Increased risk of death among uninsured neonates. Health Serv Res. 2013;48(4):1232–1255. doi: 10.1111/1475-6773.12042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Boghossian NS, Page GP, Bell EF, et al. Late-onset sepsis in very low birth weight infants from singleton and multiple-gestation births. J Pediatr. 2013;162(6):1120–1124. doi: 10.1016/j.jpeds.2012.11.089. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.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. doi: 10.1056/NEJMoa067393. [DOI] [PubMed] [Google Scholar]
- 22.Owen M, Shevell M, Majnemer A, Limperopoulos C. Abnormal brain structure and function in newborns with complex congenital heart defects before open heart surgery: a review of the evidence. J Child Neurol. 2011;26(6):743–755. doi: 10.1177/0883073811402073. [DOI] [PubMed] [Google Scholar]
- 23.Madan JC, Kendrick D, Hagadorn JI, Frantz ID., 3rd 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. doi: 10.1542/peds.2007-2781. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A. Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms. J Pediatr. 2007;150(3):229–234. doi: 10.1016/j.jpeds.2006.11.039. [DOI] [PubMed] [Google Scholar]
- 25.Vohr BR, Stephens BE, Higgins RD, et al. Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes. J Pediatr. 2012;161(2):222–228. doi: 10.1016/j.jpeds.2012.01.057. e3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am. 1986;33(1):179–201. doi: 10.1016/S0031-3955(16)34975-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Rosenbaum PR. Propensity score. In: T Colton, P Armitage., editors. Encyclopedia of Biostatistics. Vol. 5. New York: Wiley; 1998. pp. 3551–3555. [Google Scholar]
- 28.Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55. [Google Scholar]
- 29.D’Agostino RB, Jr, D’Agostino RB. Estimating treatment effects using observational data. JAMA. 2007;297(3):314–316. doi: 10.1001/jama.297.3.314. [DOI] [PubMed] [Google Scholar]
- 30.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. doi: 10.1093/ije/dyn079. [DOI] [PubMed] [Google Scholar]
- 31.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. doi: 10.1001/archpediatrics.2010.20. [DOI] [PubMed] [Google Scholar]
- 32.Hintz SR, Kendrick DE, Stoll BJ, et al. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics. 2005;115(3):696–703. doi: 10.1542/peds.2004-0569. [DOI] [PubMed] [Google Scholar]
- 33.Blakely ML, Tyson JE, Lally KP, et al. Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants: outcomes through 18 months adjusted age. Pediatrics. 2006;117(4):e680–e687. doi: 10.1542/peds.2005-1273. [DOI] [PubMed] [Google Scholar]
- 34.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. doi: 10.1542/peds.2007-0423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.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. doi: 10.1097/01.anes.0000344728.34332.5d. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.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. doi: 10.1097/ALN.0b013e3181adf481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.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. doi: 10.1213/ANE.0b013e3181f2ecdd. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.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. Erratum in Pediatrics. 2012. 129(3):595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.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. doi: 10.1097/ANA.0b013e3181a71f11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.DiMaggio C, Sun LS, Li G. Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling cohort. Anesth Analg. 2011;113(5):1143–1151. doi: 10.1213/ANE.0b013e3182147f42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130:e476–e485. doi: 10.1542/peds.2011-3822. [DOI] [PubMed] [Google Scholar]
- 42.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. doi: 10.1097/ALN.0b013e3182644684. [DOI] [PubMed] [Google Scholar]
- 43.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. doi: 10.1016/j.jpeds.2012.03.044. [DOI] [PubMed] [Google Scholar]
- 44.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. doi: 10.1097/ALN.0b013e31819c7124. [DOI] [PubMed] [Google Scholar]
- 45.Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12(3):246–253. doi: 10.1375/twin.12.3.246. [DOI] [PubMed] [Google Scholar]
- 46.Hansen TG, Pedersen JK, Henneberg SW, et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology. 2011;114(5):1076–1085. doi: 10.1097/ALN.0b013e31820e77a0. [DOI] [PubMed] [Google Scholar]
- 47.DiMaggio C, Sun LS, Ing C, Li G. Pediatric anesthesia and neurodevelopmental impairments: a Bayesian meta-analysis. J Neurosurg Anesthesiol. 2012;24(4):376–381. doi: 10.1097/ANA.0b013e31826a038d. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Rozé JC, Denizot S, Carbajal R, et al. Prolonged sedation and/or analgesia and 5-year neurodevelopment outcome in very preterm infants: results from the EPIPAGE cohort. Arch Pediatr Adolesc Med. 2008;162(8):728–733. doi: 10.1001/archpedi.162.8.728. [DOI] [PubMed] [Google Scholar]
- 49.Guerra GG, Robertson CM, Alton GY, et al. Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth. 2011;21(9):932–941. doi: 10.1111/j.1460-9592.2011.03581.x. [DOI] [PubMed] [Google Scholar]
- 50.Hamrick SE, Miller SP, Leonard C, et al. Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia. J Pediatr. 2004;145(5):593–599. doi: 10.1016/j.jpeds.2004.05.042. [DOI] [PubMed] [Google Scholar]
- 51.Yuede CM, Olney JW, Creeley CE. Developmental neurotoxicity of alcohol and anesthetic drugs is augmented by co-exposure to caffeine. [Accessed November 12, 2013];Brain Sci. 2013 3:1128–1152. doi: 10.3390/brainsci3031128. www.mdpi.com/journal/brainsci. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52. [Accessed November 6, 2012];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.
- 53.Reddy SV. Effect of general anesthetics on the developing brain. J Anaesthesiol Clin Pharmacol. 2012;28(1):6–10. doi: 10.4103/0970-9185.92426. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Costantine MM, Weiner SJ for the. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units Network (MFMU). Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: A meta-analysis. Obstet Gynecol. 2009;114(2, pt 1):354–364. doi: 10.1097/AOG.0b013e3181ae98c2. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.