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SPECIAL ARTICLE
A History of Pediatric Specialties
This is the seventh article in our series on the history of pediatric specialties. Drs. Kleinman and Barness describe the historyof artificial feeding, discoveries of micronutrients, definition of nutritional requirements and the affirmation of human breast milk as the ideal infant feeding. Dr. Finberg describes the studies of electrolyte metabolism and effective fluid therapy, which hasresulted in a dramatic reduction in the mortality of diarrheal disease. These are great stories of major contributions fromPediatrics. Alvin Zipursky Editor-in-Chief
History of Pediatric Nutrition and Fluid Therapy
RONALD E. KLEINMAN, LEWIS A. BARNESS, AND LAURENCE FINBERG
Department of Pediatrics, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, U.S.A. [R.E.K.]; Department of Pediatrics, University of South Florida, School of Medicine, Tampa, Florida 33606, U.S.A. [L.A.B.]; and Departments of Pediatrics, University of Californiaat San Francisco, School of Medicine, Stanford University School of Medicine, San Francisco, California94143, U.S.A. [L.F.]
A HISTORY OF PEDIATRIC NUTRITION
1
Many of the individual nutrients in the human diet have beenrecognized for hundreds of years. However, identifying thedaily requirements for these nutrients and their role in humanmetabolism and homeostasis are recent developments. Al-though, historically, the major focus in pediatric nutrition hasbeen growth, attention to the relationship between dietarynutrients and other health outcomes, such as host defense,psychomotor development, and long-term health, has occurredonly recently and has led to major advances in our understand-ing of the importance of nutrition in infancy and childhood.Several of the important advances in our understanding of therole of micronutrients and macronutrients in the health anddevelopment of infants and children are described below, alongwith historically relevant events in the history of infant feed-ing, childhood nutrition, and public health and fluid therapy.The history of infant feeding and formula development is givenspecial emphasis because in many ways it is synonymous withthe early history of the science of pediatric nutrition and alsobecause of its importance in the practice of pediatrics in thepast century. Each of the topics discussed in this review couldserve as the basis for a full historical review by itself, andbecause of space limitations, many topics are not even dis-cussed. Thus many, and perhaps most, of the individuals whohave contributed in a very important way to the development of our understanding of the science of pediatric nutrition have notbeen mentioned. For this we apologize.
Energy.
We have only recently begun to unravel the com-plex central and peripheral signaling pathways and chemicalmessengers that govern energy intake and expenditure inhealthy and compromised infants and children. The techniqueof indirect calorimetry pioneered by Voit in the last half of the19th century and applied to infants by Forster in 1877 [as
Received November 19, 2001; accepted April 23, 2003.Correspondence: Laurence Finberg, M.D., 152 Lombard Street, #602, San Francisco,CA 94111, U.S.A.; e-mail: finberg@itsa.ucsf.edu
1
A History of Pediatric Nutrition section authored by Drs. R. Kleinman and L. Barness.
DOI: 10.1203/01.PDR.0000088018.17598.C5
0031-3998/03/5405-0762PEDIATRIC RESEARCH Vol. 54, No. 5, 2003Copyright © 2003 International Pediatric Research Foundation, Inc.
Printed in U.S.A.
762
reviewed by Thompson
et al.
(1)] was exploited by Rubner andHeubner in Europe and Lusk (all of whom studied with Voit)and Howland in the United States in the early 20th century, toprovide the
fi
rst widely cited reference values for energyexpenditure in infants and children. Atwater, who also workedwith Voit, used calorimetry to provide estimates of the energyvalue of fat, carbohydrate, and protein, thus allowing recom-mendations to be made regarding dietary intake related toenergy expenditure. Harris and Benedict (2) developed predic-tive equations for energy expenditure based on age, weight,and height. Revised equations have been developed byScho
fi
eld (3) and others. Talbot (4), in Boston, publishedenergy expenditure data in the 1930s that contributed signi
fi
-cantly to the recommendations made by the Food and Agri-culture Organization and the World Health Organization forenergy requirements in childhood. The methodological errorsinherent in these measurements of energy expenditure and theirapplicability to infants in particular were not addressed untilthe advent of the doubly labeled water technique to measureenergy expenditure in free-living individuals developed byLifson in the early 1950s and
fi
rst adapted in humans bySchoeller and van Santen (5) in the 1980s. Many investigators,including Shepherd, Butte, Lucas, Sinclair, Putet, Heim, Rob-erts, Schanler, Dewey, and others, have since provided accu-rate and precise determinations of energy expenditure in preg-nant women, premature and mature infants, and children. Themost recent recommendations from the Institute of Medicineregarding energy intakes in infancy and childhood use data forenergy requirements derived by these investigators and others,and these newest values are in fact lower than previousrecommendations.
Macronutrients and micronutrients.
The interaction be-tween iron and Hb, and the harmful effects of persistentanemia, have long been appreciated. In 1928 Mackay added toour understanding of the role of iron in human health, when hereported that supplementing the diet of infants with iron re-duced the incidence of respiratory and diarrheal disease. Sincethen, these
fi
ndings have been largely con
fi
rmed, in spite of methodological challenges to the original research (6, 7). Onthe basis of these
fi
ndings, along with the observation that ironde
fi
ciency was (and still remains) the most prevalent singlenutrient de
fi
ciency, infant formulas were forti
fi
ed with iron. Inthe 1970s Murray
et al.
(8) found increased rates of infectionin anemic Somali subjects who were given iron supplements,thus causing concern that supplementing infant formulas withiron could make children more susceptible to infection (9).Miller, however, showed in rats, that administration of iron toinfected iron-de
fi
cient animals resulted in an increased deathrate, but this was not the case in iron-suf
fi
cient animals. TheAmerican Academy of Pediatrics Committee on Nutrition con-cluded the evidence was insuf
fi
cient to warrant changing rec-ommendations for the use of iron-forti
fi
ed formulas (10) andhas reaf
fi
rmed those recommendations repeatedly.Along with the pioneering work of Oski
et al.
(11), Siimes
et al.
(12), and others on the consequences of iron de
fi
ciency,we now better understand at the cellular and molecular levelhow iron participates in brain function. Studies have shownthat persistent iron de
fi
ciency in infancy (even in the absenceof anemia) may have deleterious effects on psychomotor de-velopment. Lozoff
et al.
(13), Walter
et al.
(14), Hurtado
et al.
(15), and many others con
fi
rmed and extended these
fi
ndings.The importance of early iron status (along with other environ-mental factors) on long term development was establishedwhen it was shown that, even after iron nutriture was restoredto acceptable levels, infants who were severely anemic hadworse psychomotor developmental outcomes 10 y after treat-ment than their iron-suf
fi
cient counterparts (16). Althoughthere is still debate about the optimal levels of iron forti
fi
cationof infant formulas, iron forti
fi
cation of commercially producedinfant cereals is now common, and iron-rich complementaryfoods are encouraged to reduce the still-high prevalence of ironde
fi
ciency in both developed and developing nations. Theidenti
fi
cation of iron-binding ligands (as well as other mineral-binding ligands) in human milk that enhance the absorption of iron from breast milk, along with other recently elucidatedcomponents of the biology of iron absorption, storage, andrelease are also major, recent advances in the science of humannutrition (17).
HFE,
the candidate gene responsible for hered-itary hemochromatosis, was identi
fi
ed in 1996 (18). Althoughhereditary hemochromatosis is not a disorder of infancy andchildhood, this discovery will ultimately lead to importanttreatments for this disorder and potentially other disorders of iron disposition that affect infants and children.The importance of zinc was realized rather late in compar-ison to other nutrients (19). In 1961, Prasad
et al.
(20) pursuedthe hypothesis that zinc de
fi
ciency was a major cause of adolescent nutritional dwar
fi
sm, a condition found mostly inMiddle Eastern countries. This line of investigation promptedmore research into the role of zinc in growth and development.In 1974, Moynihan (21) discovered that acrodermatitis entero-pathica, a genetic disorder that was often fatal, was caused byzinc de
fi
ciency. Zinc ligands and cellular zinc transportershave now been described by Cousins (22), Lonnerdal
et al.
(23), and a number of other investigators, informing our un-derstanding of the pathogenesis of this disorder. The absenceof zinc from early parenteral nutrition regimens and the sub-sequent development of symptoms of zinc de
fi
ciency in pa-tients supported by these solutions reemphasized the criticalrole of zinc in human nutrition. During the 1970s and 1980s,Hambidge and others (24, 25) showed that zinc de
fi
ciency inchildren resulted in stunting. This led to studies by Bhutta
et al.
(26), Black (27), and others that showed that daily supplementsof zinc in the diets of zinc-de
fi
cient children in developingcountries enhanced linear growth, reduced the risk of acutediarrhea, and reduced the prevalence of pneumonia andmalaria.We now know that zinc, like iron, also participates incognitive functioning. During the 1960s and 1970s, McLardy(28) as well as Hu and Friede (29) reported on components of the brain that are particularly enriched with zinc. During thesame period, Henkin
et al.
(30) showed that severe zincde
fi
ciency impaired the neuromotor and cognitive performanceof adults. Concurrently, Hambidge
et al.
(31) reported thatoffspring of pregnant mothers with acrodermatitis entero-pathica had a high incidence of brain malformations. Morerecently, Sandstead
et al.
(32) have demonstrated that zinc
763
HISTORY OF NUTRITION AND FLUID THERAPY
supplementation of de
fi
cient children has improved neuropsy-chological functioning.Over 40 y ago Menkes
et al.
(33) reported the signs andsymptoms of what proved to be a genetically determinedcopper-de
fi
ciency syndrome. Graham and Cordano (34) andGraham (35) were instrumental in describing the consequencesof copper de
fi
ciency in infants with malnutrition. In the past15 y, membrane-localized copper transporters and genes re-lated to them have been discovered, with important implica-tions for the identi
fi
cation and treatment of patients withdiseases characterized by excessive copper accumulation.The work of Eijkman and Hopkins led to the discovery of vitamins, earning them the Nobel Prize in 1929. In 1912 theterm
“
vitamines
”
was coined by Funk. The
“
e
”
in the word wasdropped when it was discovered that not all vitamins areamines. Early in the 20th century a number of vitamins weresynthesized, including thiamine by Williams in 1936. In 1953Snyderman and colleagues (36) described the consequences of vitamin B
6
de
fi
ciency, including growth failure and seizures,which occurred in infants exclusively fed a formula de
fi
cient inpyridoxine. During this same period of the 1950s
–
1960s thedevelopment of megaloblastic anemic in infants breast-fed byexclusively vegan mothers was recognized to be a consequenceof vitamin B
12
de
fi
ciency, a vitamin synthesized in nature byfungi, algae, and bacteria. Vitamin K was synthesized byFieser in 1939, and approximately 20 y later it was establishedthat hemorrhagic disease of the newborn could be preventedand treated with vitamin K administration. In 1961 The Amer-ican Academy of Pediatrics Committee on Nutrition publishedits
fi
rst recommendations for the universal administration of vitamin K in the newborn period to prevent hemorrhagicdisease of the newborn (37).Although vitamins were only recently identi
fi
ed and named,the relationship between foods rich in speci
fi
c vitamins anddiseases has been appreciated since antiquity. In ancient Egypt,night blindness was cured by eating liver, which is rich invitamin A. In 1933, several thousand years later, Blackfan, astudent of Howland, and Wolbach described the pathobiologyof vitamin A de
fi
ciency. The recent discovery that vitamin A isimportant in epithelial cell growth and integrity has led to animportant advance in the protection against measles (38) andagainst acute diarrheal illness by providing vitamin A supple-ments to children at risk for vitamin A de
fi
ciency.In 1753, Lind discovered that eating citrus fruits preventedscurvy. British sailors have been called
“
limeys
”
since theBritish government began administering lemon or lime juice toall sailors soon after Lind
’
s discovery. A number of papersappeared in the literature as early as 1898 on the associationbetween boiling milk and the appearance of scurvy in infants.In 1932, Waugh and King, at the University of Pittsburgh, andSzent-Gyorgyi, a Hungarian scientist, isolated and synthesizedascorbic acid, or vitamin C. Beginning in 1948, infant formulaswere forti
fi
ed with ascorbic acid, and the incidence of scurvywas dramatically reduced (39).Public health reports in the
fi
rst decades of the 20th centuryshow that in some sections of New York City, as many as 90%of black children showed signs of rickets before 15 mo of age(39). The high prevalence of rickets seen among all childrenwas in large part a result of the industrialization of the largeurban cities, with signi
fi
cant air pollution and children workingindoors at very young ages. Smith reported in 1893 on thevalue of cod liver oil in the prevention of rickets. In 1918,Mellanby cured puppies of rickets by feeding them cod liver oil(36). This was followed by the work of Acker and Snow on theincreased frequency of rickets in children with dark skin.Subsequently, milk products and infant formulas have beenforti
fi
ed with vitamin D, and rickets has largely been eradi-cated in the developed world for the last half of the 20thcentury. However, anecdotally rickets is reemerging as a publichealth problem for the 21st century (40), perhaps in partbecause of efforts to limit sun exposure in young infants andchildren in the absence of dietary supplementation of vitaminD. DeLuca (41) and others signi
fi
cantly informed our under-standing that vitamin D is a hormone synthesized from pre-cursors in the skin through the action of sunlight and convertedto the biologically active metabolites in the liver and kidneys.During the past 50 y signi
fi
cant work has been accomplishedin understanding the physiology of bone growth and homeosta-sis. The recent development of noninvasive methods of exam-ining bone mineralization, including imaging techniques aswell as serum and urine biochemical measures, has allowedmore accurate determinations of sex-speci
fi
c daily require-ments of calcium, phosphorus, and magnesium at differentages. Very recently, recommendations for daily calcium intakehave been increased as a result of work showing a relationshipbetween calcium intake and bone mineral density. The work of Wosje and Specker (42) and many others has shown thetemporal relationship between increases in dietary calcium andincreases in bone mass and mineral density and the bone siteswhere this is occurring. Interventions to improve bone mineralcontent and density with the biologically active forms of vitamin D and pharmacologic agents are major achievementsof the past 15 y and are used in children with chronic illnessand in those taking medications that interfere with bone min-eralization and remodeling.Vitamin E de
fi
ciency is rare in a healthy human population.However, in pediatric patients with chronic illness or prema-ture birth that results in fat maldigestion or malabsorption,vitamin E de
fi
ciency may result in severe neurologic de
fi
cits.Oski and Barness (43) and others were among the
fi
rst to reporton the requirement for supplemental vitamin E to preventhemolysis associated with oxidants such as iron in prematureinfants.The association between folic acid supplementation in thediet of pregnant women and a lowered risk of spina bi
fi
da andother neural tube defects has been another major public healthadvance. The US Centers for Disease Control and Preventionissued recommendations for folic acid intake during pregnancyin 1992 in response to landmark studies showing that theincidence of neural tube defects was lower in infants born towomen who consumed between 400
g and 4000
g of folicacid per day (44). Since 1998, all enriched-grain productsmanufactured in the United States must be forti
fi
ed with 140
g of folic acid per 100 g of grain.
764
KLEINMAN
ET AL.
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