Pat F. Bass III, MD, MS, MPH

Although many parents report food allergy in their children and the incidence of parental report has increased over time,

 the actual incidence of confirmed food allergy is much lower.

 However, food allergy still is estimated to impact 2% to 10% of pediatric patients, and its prevention is an important goal in pediatric practice because there is no current cure.

The pediatrician needs to be aware of changing practice recommendations related to the introduction of complementary foods for children. Although pediatricians who have been in practice for some time may have previously asked parents to delay the introduction of highly allergenic foods, emerging evidence now suggests just the opposite. Earlier introduction of highly allergenic foods may actually prevent food allergy.

Food allergies refer to reactions that occur as a result of immunologic reactions in response to certain foods. Food allergies are generally classified as either immunoglobulin (Ig)E mediated or non–IgE mediated and have different clinical presentations.

Whereas any food can theoretically lead to an allergic reaction, the most common offenders are:

Immunologic IgE-mediated reactions may present with the following symptoms:

·      Gastrointestinal anaphylaxis

Non–IgE-mediated food allergies are more likely to present with subacute, chronic symptoms that are isolated to the gastrointestinal tract or skin.

Based on the idea that delaying exposure to solid foods might prevent atopic dermatitis and other allergic disease, the American Academy of Pediatrics (AAP) recommended in 2000 that children at high risk for developing food allergies delay the introduction of certain foods

: delay cow’s milk until age 1 year; eggs until age 2 years; peanuts, tree nuts, and fish until age 3 years. Although not specifically recommended, many pediatricians incorporated these guidelines into their routine recommendations in some form or fashion for other lower-risk children.

In 2008, the AAP updated its policy statement that included recommendations for the prevention of atopic disease. The report concluded that there was insufficient data and evidence to justify delaying the timing of complementary foods beyond the age of 4 to 6 months and that there was no protective effect of any dietary intervention beyond this age impacting the development of atopic disease.

 the AAP summarizes additional research since the 2008 report, concluding that there is no evidence that delaying the introduction of highly allergenic foods such as peanuts, eggs, and fish beyond age 4 to 6 months prevents atopic disease.

 The report goes on to cite evidence that early introduction of peanuts may prevent peanut allergy.

The Learning Early About Peanut (LEAP) study was the first randomized controlled trial (RCT) to show that early exposure to peanut could prevent peanut allergy in high-risk infants.11 The authors believe that early exposure to peanut in the environment (ie, skin) leads to sensitization while early dietary exposure may lead to immune tolerance.

In this study, high-risk infants from the United Kingdom (UK), defined as having severe eczema, egg allergy, or both, were randomized into 2 groups of peanut exposure and then stratified based on pinprick testing (children with a response greater than 4 mm were excluded): early (aged between 4 and 11 months), or delayed (avoidance until age 5 years).

Only 1.7% of participants with early peanut exposure developed peanut allergy after age 5 years whereas 13.7% of participants randomized to avoidance as a prevention strategy developed peanut allergy. The 11.8% absolute difference in risk of peanut allergy (95% confidence interval [CI], 3.4-20.3; 

<0.001) represents a greater than 85% relative risk (RR) reduction. The LEAP study demonstrated that early peanut exposure decreases peanut allergy in both sensitized infants and nonsensitized infants.

In a follow-up study known as LEAP-On, both the avoidance and consumption groups were asked to avoid peanut for 1 year at the conclusion of LEAP. Peanut allergy continued to be more common in the original avoidance group compared with the early exposure group (18.6% vs 4.8% of children, respectively; 

Early introduction of peanut was also found to prevent peanut allergy in the Enquiring About Tolerance (EAT) RCT.

 In this study, exclusively breastfed infants were randomized to receive early introduction of peanut or 5 other allergenic foods (cooked egg, cow’s milk, sesame, whitefish, or wheat) at age 3 months, or continue exclusive breastfeeding until age 6 months. Infants in the early introduction group were less likely to develop peanut allergy compared with children randomized to UK Department of Health advice to delay food introduction to age 6 months (0% vs 2.5%, respectively; 

=0.003). A meta-analysis of the LEAP and EAT studies determined with “moderate certainty” that early introduction of peanut decreased the risk of peanut allergy (RR, 0.29; 95% CI, 0.11-0.74).

In 2017, the National Institute of Allergy and Infectious Diseases (NIAID)-sponsored expert panel on peanut allergy issued a 3-tiered recommendation for the introduction of peanut into an infant’s diet. The guideline provides the option for assessments that may be performed in a primary care practice or for referral for specialty care (Table).

Six RCTs have been published since 2008 looking at the introduction of egg to prevent egg allergy.

One example is the Prevention of Egg Allergy with Tiny Amount Intake (PETIT) study.

 The PETIT study, which was stopped early due to benefit, demonstrated that ingesting heated egg powder daily from age 6 months lowered the rate of egg allergy compared with infants who avoided egg completely until age 1 year (9% vs 38%, respectively; 

Although there are differences in these studies related to the types of patients enrolled, mechanisms used to prevent allergy, and in the assessed outcomes/results that can make drawing conclusions difficult,

 Ierodiakonou and colleagues performed a meta-analysis of 5 studies that included nearly 2000 infants and found “moderate certainty” that introduction of egg between age 4 to 6 months reduced the risk of egg allergy (RR, 0.56; 95% CI, 0.36-0.87).

The pediatrician needs to be aware of changing recommendations and the changing environment for the prevention of food allergy. With significant changes in recommendations over the last 20 years and more likely to come over the next several years, the pediatrician must examine his or her current recommendations for the introduction of highly allergenic foods into a child’s diet based on that child’s risk and determine how he or she will communicate these changes to parents going forward.

1. Peters RL, Koplin JJ, Gurrin LC, et al; HealthNuts Study. The prevalence of food allergy and other allergic diseases in early childhood in a population-based study: HealthNuts age 4-year follow-up. 

2. Verrill L, Bruns R, Luccioli S. Prevalence of self-reported food allergy in U.S. adults: 2001, 2006, and 2010. 

3. Venter C, Pereira B, Grundy J, et al. Incidence of parentally reported and clinically diagnosed food hypersensitivity in the first year of life. 

4. EggesbÃ¸ M, Botten G, Halvorsen R, Magnus P. The prevalence of CMA/CMPI in young children: the validity of parentally perceived reactions in a population-based study. 

5. Chafen JJ, Newberry SJ, Riedl MA, et al. Diagnosing and managing common food allergies: a systematic review. 

6. Du Toit G, Sampson HA, Plaut M, Burks AW, Akdis CA, Lack G. Food allergy: update on prevention and tolerance. 

7. Burks AW, Tang M, Sicherer S, et al. ICON: food allergy. 

8. Committee on Nutrition; American Academy of Pediatrics. Hypoallergenic infant formulas. 

9. Greer FR, Sicherer SH, Burks AW, American Academy of Pediatrics Committee on Nutrition; American Academy of Pediatrics Section on Allergy and Immunology. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. 

10. Greer FR, Sicherer SH, Burks AW; Committee on Nutrition, Section on Allergy and Immunology. The effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, hydrolyzed formulas, and timing of introduction of allergenic complementary foods. 

11. Du Toit G, Roberts G, Sayre PH, et al; LEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy. 

. 2015;372(9):803-813. Erratum in: Randomized trial of peanut consumption in infants at risk for peanut allergy. 

12. Du Toit G, Sayre PH, Roberts G, et al; Immune Tolerance Network LEAP-On Study Team. Effect of avoidance on peanut allergy after early peanut consumption. 

13. Perkin MR, Logan K, Tseng A, et al; EAT Study Team. Randomized trial of introduction of allergenic foods in breast-fed infants. 

14. Ierodiakonou D, Garcia-Larsen V, Logan A, et al. Timing of allergenic food introduction to the infant diet and risk of allergic or autoimmune disease: a systematic review and meta-analysis. 

15. Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: summary of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. 

16. Palmer DJ, Metcalfe J, Makrides M, et al. Early regular egg exposure in infants with eczema: a randomized controlled trial. 

17. Bellach J, Schwarz V, Ahrens B, et al. Randomized placebo-controlled trial of hen’s egg consumption for primary prevention in infants. 

18. Palmer DJ, Sullivan TR, Gold MS, Prescott SL, Makrides M. Randomized controlled trial of early regular egg intake to prevent egg allergy. 

19. Wei-Liang Tan J, Valerio C, Barnes EH, et al; Beating Egg Allergy Trial (BEAT) Study Group. A randomized trial of egg introduction from 4 months of age in infants at risk for egg allergy. 

20. Natsume O, Kabashima S, Nakazato J, et al; PETIT Study Team. Two-step egg introduction for prevention of egg allergy in high-risk infants with eczema (PETIT): a randomised, double-blind, placebo-controlled trial. 

21. Perkin MR, Bahnson HT, Logan K, et al. Association of early introduction of solids with infant sleep: a secondary analysis of a randomized clinical trial. 

22. Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. 

23. Section on Breastfeeding. Breastfeeding and the use of human milk. 

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In 2016 and 2017, the US Food and Drug Administration (FDA) issued a warning and subsequent labeling change for anesthetic drugs with concerns that repeated or lengthy use of sedation and general anesthesia in children aged younger than 3 years may impact brain development.

 Although not calling for delay of medically necessary procedures, the FDA did state that healthcare providers should consider delaying elective procedures when medically appropriate.

Prior to the late 1980s, the concept of neonatal pain during procedures was not acknowledged and thought to be a behavioral reflex rather than a conscious experience of pain. However, multiple studies subsequently demonstrated neonates did respond to painful stimuli and that these stimuli could be managed. Further failure to manage pain can lead to both short- and long-term complications.

 These warnings need to be considered within that context.

This article will review both animal and human studies so that pediatricians can have informed discussion with parents and caregivers whose children may be faced with procedures requiring sedation or general anesthesia.

Multiple animal studies have demonstrated significant long-term and possible permanent damage to the developing brain in the areas of behavior, learning, and memory following administration of anesthetic agents. Pathophysiologic mechanisms for the neurodevelopmental effects include increased apoptosis of neurons, glia, and oligodendrocytes; impaired neurogenesis; synaptic and axonal dysgenesis; perturbed neurotrophic signaling; mitochondrial dysfunction; and neuroinflammation.

A 2003 study administering midazolam, isoflurane, and nitrous oxide (a triple cocktail commonly used in pediatric anesthesia) to 7-day old rat pups demonstrated apoptotic neurodegeneration and deficits in hippocampal synaptic function following 6 hours of anesthesia. The baby rats demonstrated immediate, persistent, and ongoing deficits in learning, working memory, and reference memory as evidenced by performance in several different maze activities.

 In animal studies, there appears to be a direct correlation with time under anesthesia and abnormalities seen in the brain.

Several studies have demonstrated that xenon, nitrous oxide, or midazolam administered alone were not associated with neurodegeneration. Administered with other agents, xenon or nitrous oxide may also attenuate the impact of other anesthetics. A 2007 study showed nitrous oxide or xenon alone did not cause cell death and that xenon reduced isoflurane-induced cell death.

 Other rodent studies have demonstrated similar results with xenon and nitrous oxide attenuating neurodegeneration and hypoxia making it worse.

Jevtovic-Todorovic’s 2003 study examined both single exposures as well as continuous infusion of anesthetic agents and found that rat pups suffered no immediate or long-term neurodegeneration with administration of nitrous oxide or midazolam alone, but combination with isoflurane was associated with increased cell death and neurodegeneration.

 Other studies have found conflicting results with only administration of midazolam but that the administration of melatonin prior to anesthesia has an attenuating effect on neurodegeneration.

Given that outcomes in rats may not truly represent outcomes in humans, studies have also been performed in primates. A 2012 study administered intravenous ketamine for 5 hours to rhesus neonates (day 6 of life) or to pregnant rhesus females at 120 days’ gestation (full-term is 165 days). Pregnant rhesus females were delivered via cesarean delivery 3 hours following infusion. Both fetal and neonatal brains exposed to ketamine experienced significantly more brain apoptosis compared with controls. Fetal exposure led to 2.2 times more neurodegeneration compared with neonatal exposure.10 Other rhesus monkey studies with ketamine also have demonstrated neurodegeneration and poor long-term outcomes.

Because common anesthetics such as ketamine and isoflurane demonstrated neurodegeneration, other investigators examined other anesthetic agents in nonhuman primates. Propofol anesthesia was delivered to fetal rhesus macaques at gestational age 120 days, or rhesus neonates using the same protocol as described above. Compared with isoflurane, propofol infusion for 5 hours led to less neurodegeneration in both fetal rhesus macaques and rhesus neonates. Unlike ketamine exposure, neurodegeneration was similar in both fetal and neonatal rhesus monkeys.

Although it’s clear that administration of anesthetics leads to neurodegeneration in rats and primates, children receive lower doses (in terms of mg/kg) and are generally exposed for much shorter durations of time, and the animals were not undergoing a painful surgical procedure. Similarly, these experimental studies did not monitor the animals as closely as a child undergoing surgery would be monitored.

There is also the question of whether adverse developmental outcomes in rats are similar, meaningful, and equivalent to poor developmental outcomes in children. However, better-controlled studies in progressively larger animals (sheep, pigs, monkeys) did not account for all the developmental issues seen post-anesthesia.

 As a result, the pediatrician needs to acknowledge preclinical data indicating the possibility that anesthesia may be neurotoxic and potentially damaging to pediatric development.

A variety of studies have attempted to examine neurotoxicity in children following anesthesia.

The Western Australian Pregnancy Cohort (Raine) study was originally designed to examine the effects of prenatal ultrasound on 2608 infants born between 1989 and 1992.

 Detailed demographics and medical history were collected prenatally and included assessments at ages 1, 2, 3, 5, 8, 10, 13, and 16 years. In this group, 321 children were exposed to anesthesia before age 3 years and 2287 children were unexposed.

NEUROPSYCHOLOGIC AND FUNCTIONAL TESTING at the 10-year follow-up visit was the primary outcome for this study and utilized validated and reliable tests:

Cognition: Symbol Digit Modality Test (SDMT); Raven’s Colored Progressive Matrices (CPM)

Language: Clinical Evaluation of Language Fundamentals (CELF); Peabody Picture Vocabulary Test (PPVT)

Gross/Fine Motor Function: McCarron Assessment of Neuromuscular Development (MAND)

Behavioral problems: Child Behavior Checklist (CBCL)

Anesthesia was associated with significantly worse scores in tests of receptive, expressive, total language  cognition, and abstract reasoning measured by CPM. Differences were not seen between exposed and unexposed children in behavior and motor function domains. After adjusting for confounders, anesthesia before age 3 years was associated with increased risk of disability in receptive language (CELF), expressive language (CELF), total language (CELF) and abstract reasoning (CPM).

The Mayo Anesthesia Safety in Kids (MASK) study

 examined whether (unexposed, singly exposed, and multiply exposed children born in Olmsted County, Minnesota, from 1994 to 2007) children requiring general anesthesia before age 3 years suffered adverse neurodevelopment outcomes. In the cohort, 997 children underwent neuropsychologic testing (full-scale intelligence quotient [IQ] standard score of the Wechsler Abbreviated Scale of Intelligence) at ages 8 to 12 years or 15 to 20 years. Results demonstrated the IQ did not vary significantly across groups. However, processing speed and fine motor abilities did vary significantly in the multiply exposed compared with singly exposed children. Parents of multiply exposed children also reported more problems with behavior and reading. It is important to note that all the differences seen were secondary outcomes and should be interpreted with caution.

Interestingly, one of the tests administered to rhesus monkeys, the Operant Test Battery (OTB), can be and was also administered to children in the MASK study. The OTB examines aspects of learning, motivation, impulse control, and short-term memory. Children exposed to general anesthesia did not experience similar deficits on OTB tasks that were previously observed in nonhuman primates.

The Pediatric Anesthesia Neurodevelopment Assessment (PANDA) study

 looked at 105 sibling pairs born within 3 years of each other with one of the children undergoing inguinal hernia repair under general anesthesia before age 3 years and the other not having any anesthesia exposure before age 3 years. The goal was to determine if a single anesthesia exposure before age 3 years in otherwise healthy children was associated with impaired neurocognitive development and abnormal behavior between ages 8 to 15 years. Children prospectively underwent a neurocognitive and behavior battery that included measures of IQ; expressive and receptive language; verbal reasoning; memory; attention; executive function; motor skills; academic skills; adaptive skills; and parental rating.

Clinical data from the surgical procedure and anesthesia were retrospectively abstracted from hospital records. Mean duration of anesthesia was 84 minutes with a range of 20 to 240 minutes. Mean age of IQ testing was 10.6 for children receiving anesthesia and 10.9 for those not. The IQ scores were not statistically or clinically different between the 2 groups (difference, 0.2 IQ points).

 Similarly, there were no significant differences in the secondary outcomes of mean scores of memory, attention, visuospatial function, executive function, language, motor and processing speed, or behavior.

It is important to note that this study utilized similar comprehensive neuropsychologic assessments and did not find similar secondary outcomes as the MASK study did.

 Thus, among healthy children undergoing a single anesthesia expo- sure before age 3 years, significant neurodevelopment differences were not seen.

 is the only completed randomized controlled trial (RCT) of anesthesia-induced neurotoxicity.

 This international open-label trial randomized 772 children aged younger than 5 years undergoing inguinal herniorrhaphy to either an awake-regional anesthesia group or to a sevoflurane-based general anesthesia group in a 1:1 fashion. The primary outcome measure was full-scale IQ (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III), and assessors were blinded to treatment arm. Secondary outcomes at age 2 years included cognitive scores on the Bayley Scales of Infant and Toddler Development and various measures of language, memory, attention, executive function, motor skills, academic skills, adaptive skills, and parental ratings at age 5 years.

 Median duration of anesthesia was 54 minutes with an average of less than 34 minutes. Mean FSIQ were equivalent for the awake-regional anesthesia group and the sevoflurane-based general anesthesia group. Likewise, differences in secondary outcomes were not clinically significant.

Certain medical, socioeconomic, or psychosocial comorbidities may confer higher risk and may not be easily studied. Children with congenital heart disease will often experience significantly more exposure to anesthesia than described in the MASK, PANDA, and GAS studies. It is not feasible to perform a GAS-like RCT in these groups. As a result, less rigorous observational and nonrandomized designs will be implemented and the results are subject to bias and residual confounding. However, several such studies of cardiac patients have shown inverse associations in children’s IQ scores at age 4 to 5 years.

 Importantly some of the studies in congenital heart patients have not shown adverse outcomes for several years identifying the importance of long-term follow-up.

Whereas animal and retrospective studies demonstrating possible neurotoxic and developmental impacts following anesthesia should concern the pediatrician, data from the MASK, PANDA, and GAS studies provide strong evidence that a one-hour or less single exposure to general anesthesia is not associated with an increased risk of neurodevelopmental deficit in later childhood.

 Given that more than half of all pediatric procedures in children aged younger than 3 years last less than one hour should also be reassuring.

However, there are many practical questions that remain unanswered: Is it better to have all planned procedures for an individual patient coordinated under one anesthetic procedure/exposure or should the procedures for a given individual be separated as several short anesthetic exposures? There is no good answer to this question as it has not been addressed in animal or human studies. Similarly, recommendations for particular mixtures of anesthetic agents are not possible based on the current state of knowledge.

The pediatrician needs to be aware of ongoing research and development so that he or she can be aware and recommend adjuvants in development that might prevent anesthesia-associated neurotoxicity; report findings to the FDA that may be related to anesthetic exposure; and have appropriate discussions with patients’ parents and caregivers regarding anesthesia.

1. US Food and Drug Administration. FDA Drug Safety Communication: FDA approves label changes for use of general anesthetic and sedation drugs in young children. Available at: 

https://www.fda.gov/drugs/drug-safety-andavailability/fda-drug-safety-communication-fda-approves-label-changes-use-general-anesthetic-and-sedation-drugs

. Updated April 27, 2017. Accessed September 4, 2019.

2. Hall RW, Anand KJ. Pain management in newborns. 

3. Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. 

4. 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. 

5. Wise-Faberowski L, Zhang H, Ing R, Pearlstein RD, Warner DS. Isoflurane-induced neuronal degeneration: an evaluation in organotypic hippocampal slice cultures. 

. 2005;101(3):651-657, table of contents.

6. Ma D, Williamson P, Januszewski A, et al. Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain. 

7. Shu Y, Patel SM, Pac-Soo C, et al. Xenon pretreatment attenuates anesthetic-induced apoptosis in the developing brain in comparison with nitrous oxide and hypoxia. 

8. Yon JH, Carter LB, Reiter RJ, Jevtovic-Todorovic V. Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. 

9. Young C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. 

10. Brambrink AM, Evers AS, Avidan MS, et al. Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. 

11. 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. 

12. Slikker W Jr, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. 

13. Creeley C, Dikranian K, Dissen G, Martin L, Olney J, Brambrink A. Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. 

14. Bellinger DC, Calderon J. Neurotoxicity of general anesthetics in children: evidence and uncertainties. 

15. Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. 

16. Warner DO, Zaccariello MJ, Katusic SK, et al. Neuropsychological and behavioral outcomes after exposure of young children to procedures requiring general anesthesia: the Mayo Anesthesia Safety in Kids (MASK) Study. 

17. Warner DO, Chelonis JJ, Paule MG, et al. Performance on the Operant Test Battery in young children exposed to procedures requiring general anaesthesia: the MASK study. 

18. Sun LS, Li G, Miller TL, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. 

19. McCann ME, de Graaff JC, Dorris L, et al; GAS Consortium. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. 

20. Diaz LK, Gaynor JW, Koh SJ, et al. Increasing cumulative exposure to volatile anesthetic agents is associated with poorer neurodevelopmental outcomes in children with hypoplastic left heart syndrome. 

21. 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. 

Pediatricians need to have informed discussions with parents and caregivers about procedures for their children requiring sedation or general anesthesia. This evidence can help with those decisions.

Looking at anesthetic neurotoxicity in pediatric sedation

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