Editor-in-Chief: Lawrence F. Nazarian, Rochester, NY Associate Editors: Tina L. Cheng, Baltimore, MD Joseph A. Zenel, Sioux Falls, SD Editor, In Brief: Henry M. Adam, Bronx, NY Consulting Editor, In Brief: Janet Serwint, Baltimore, MD Editor, Index of Suspicion: Deepak M. Kamat, Detroit, MI contents Consulting Editor Online and Multimedia Projects: Laura Ibsen, Portland, OR Editor Emeritus and Founding Editor: Pediatrics in Review Vol.32 No.7 July 2011 Robert J. Haggerty, Canandaigua, NY Managing Editor: Luann Zanzola Medical Copy Editor: Deborah K. Kuhlman Editorial Assistants: Kathleen Bernard, Melissa Schroen Editorial Office: Department of Pediatrics Articles University of Rochester School of Medicine & Dentistry 267 Breastfeeding: More Than Just Good Nutrition 601 Elmwood Avenue, Box 777 Rochester, NY 14642 Robert M. Lawrence, Ruth A. Lawrence [email protected] Editorial Board Hugh D. Allen, Columbus, OH Hal B. Jenson, Kalamazoo, MI Margie Andreae, Ann Arbor, MI Donald Lewis, Norfolk, VA Normal Pubertal Development: Richard Antaya, New Haven, CT Gregory Liptak, Syracuse, NY 281 Part II: Clinical Aspects of Puberty Denise Bratcher, Kansas City, MO Michael Macknin, Cleveland, OH George Buchanan, Dallas, TX Susan Massengill, Charlotte, NC Brian Bordini, Robert L. Rosenfield Brian Carter, Nashville, TN Jennifer Miller, Gainesville, FL Joseph Croffie, Indianapolis, IN Blaise Nemeth, Madison, WI B. Anne Eberhard, New Hyde Park, NY Mobeen Rathore, Jacksonville, FL Philip Fischer, Rochester, MN Renata Sanders, Baltimore, MD 293 Focus on Diagnosis: The D-test Rani Gereige, Miami, FL Thomas L. Sato, Milwaukee, WI Lindsey Grossman, Springfield, MA Sarah E. Shea, Halifax, Nova Scotia Kamakshya P. Patra Patricia Hamilton, London, United Kingdom Andrew Sirotnak, Denver, CO Jacob Hen, Bridgeport, CT Nancy D. Spector, Philadelphia, PA Jeffrey D. 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Breastfeeding: More Than Just Good Nutrition Robert M. Lawrence, MD, Objectives After completing this article, readers should be able to: FAAP,* Ruth A. Lawrence, MD, DD (HON), FAAP† 1. Discuss the nutritional benefits of breastfeeding and its effects on growth and development. 2. Delineate the advantages to the baby of breastfeeding. Author Disclosure 3. Describe the benefits to the mother of breastfeeding. Drs Lawrence and 4. Explain the role that breastfeeding plays in the bonding process. Lawrence have 5. List the differences in composition of human milk, colostrum, cow milk, and formula. disclosed no financial 6. Describe the effects of maternal infection and medication on human milk and infant relationships relevant health. to this article. This 7. List the few contraindications to breastfeeding. commentary does not 8. Review the use of human milk in feeding preterm babies. contain a discussion 9. Discuss current recommendations for breastfeeding, including the role of hospitals in of an unapproved/ promoting the practice. investigative use of a commercial Introduction product/device. Over the past 50 to 60 years, human milk has been described and recognized as the best first food for human infants; breast is best! Human milk provides substantial nutritional, cognitive, emotional, and immunologic benefits for the infant. Such ongoing acclamation is based on the observations and experiences of mothers, families, midwives, doulas, nutritionists, nurses, physicians, and scientists. Over the past 30 years, scientific study and research have accumulated and now constitute a large body of evidence Abbreviations documenting the actual benefits of breastfeeding for the AAP: American Academy of Pediatrics infant and the mother. This article examines and references AHRQ: Agency for Healthcare Research and Quality much of this evidence-based data in describing human milk ARV: antiretroviral and how it contributes to the health and well-being of infants BFHI: Baby Friendly Hospital Initiative and mothers. CI: confidence interval CMV: cytomegalovirus Current Evidence: Health Benefits of DHA: docosahexaenoic acid Breastfeeding FFA: free fatty acid The Agency for Healthcare Research and Quality (AHRQ) GBS: group B Streptococcus Report on Breastfeeding in Developed Countries summa- GI: gastrointestinal rizes evidence (published in English through May 2006) on HIV: human immunodeficiency virus breastfeeding in maternal and infant health. (1) More than HTLV: human T-lymphotrophic virus 9,000 abstracts were considered, and data from more than Ig: immunoglobulin 400 individual studies were included after evidence-based NEC: necrotizing enterocolitis review of meta-analyses, updated systematic review of the RID: relative infant dose data, and newly performed systematic reviews. It is important TB: tuberculosis to emphasize that this report included data from developed TH: T-helper cell countries only. Table 1 presents definitions of breastfeeding WHO: World Health Organization that are particularly useful in “quantification” as standard WNV: West Nile virus definitions used in clinical studies. Nineteen specific outcomes were reviewed by the AHRQ

*Clinical Associate Professor, Pediatric Immunology and Infectious Diseases, University of Florida – Health Science Center, Gainesville, FL. †Professor, Department of Pediatrics and Obstetrics/Gynecology; Director, Human Lactation Study Center, University of Rochester School of Medicine, Rochester, NY.

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mia, infant mortality, and sudden Table 1. Breastfeeding Definitions infant death syndrome as well as cognitive development and the risk Any Breastfeeding of cardiovascular disease. Factors • Full Breastfeeding studied in mothers were: return to –Exclusive: Human milk only; no other nutrients, supplements, or liquids prepregnancy weight and incidence –Almost Exclusive: No milk other than human milk; minimal amounts of of type 2 diabetes, osteoporosis, other substances provided infrequently • Partial Breastfeeding postpartum depression, breast can- –High Partial: Nearly all feedings are human milk (>80%) cer, and ovarian cancer. –Medium Partial: A moderate amount of feedings are human milk in For infants, the meta-analyses or combination with other nutrient foods and nonhuman milk (20% to 80% of systematic reviews strongly favored nutritional intake is human milk) breastfeeding over not breastfeed- –Low Partial: Very few feedings are human milk (<20% of nutritional intake) –Token: Breastfeeding is primarily for comfort (minimal % of total nutritional ing for a reduced risk of acute otitis intake) media, GI infections, asthma (regard- less of whether there was a family Never Breastfed history of asthma), type 2 diabetes, • Infant has never ingested any human milk leukemia, and sudden infant death Modified from Lawrence RM, Pane CA. Human breast milk: current concepts of immunology and syndrome. The meta-analysis of infectious diseases. Pediatr Adolesc Health Care. 2007;37:1-44. GI infections reported a crude odds ratio for 14 cohort studies of 0.36 (95% confidence interval [CI] research team, including 13 for term infants and six for 0.32 to 0.41) strongly favoring breastfeeding mothers. The outcomes for infants were: incidence of (ever) in reducing the risk of GI infection in infants acute otitis media, atopic dermatitis, gastrointestinal younger than 1 year of age (Fig. 1). Another analysis (GI) infections, lower respiratory tract infections, reported on two case-control studies demonstrating a asthma, obesity, type 1 and 2 diabetes, childhood leuke- summary odds ratio of 0.54 (95% CI 0.36 to 0.80) again favoring breastfeeding. A sep- arate analysis demonstrated that infants breastfeeding exclusively for greater than 3 months’ or greater than 6 months’ duration had sig- nificant reductions in the risk of acute otitis media compared with infants who were never breastfed. The analysis of infants developing atopic dermatitis (who had a family history of atopic disease) demon- strated that the risk for atopic der- matitis was lower in infants breast- fed exclusively for longer than 3 months compared with children who were breastfed for less than 3 months. An analysis examining lower respiratory tract infections The relationship between breastfeeding (BF) and infant outcomes: meta- Figure 1. showed an overall reduced risk of ,acute otitis media؍adjusted odds ratio, AOM؍analysis (MA) results. adjOR hospitalization due to lower respi- lower respiratory؍gastrointestinal, LRTI؍family history, GI؍diabetes mellitus, FH؍DM sudden infant death syndrome. Adapted with ratory tract infections in infants؍odds ratio, SIDS؍tract infection, OR Ͻ permission from Figure 4 in Ip S, Chung M, Raman G, et al. A summary of the Agency for ( 1 year of age) who were breast- Healthcare Research and Quality’s Evidence Report on Breastfeeding in Developed fed exclusively for 4 months or Countries. Breastfeed Med. 2009;4:S17–S30, published by Mary Ann Liebert, Inc., New longer compared with infants who Rochelle, NY. were never breastfed (Fig. 1).

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These high-quality, evidence- based data from the AHRQ Report support breastfeeding as provid- ing significant health benefits to both the mother and infant, even in developed countries. A larger body of evidence from developing coun- tries examines the benefits of breastfeeding in locales where the risk of infection in infants and chil- Figure 2. The relationship between breastfeeding (BF) and maternal outcomes: Meta- dren is high due to poor sanitation, odds ratio. Adapted with permis- low water quality, contaminated؍adjusted odds ratio. OR؍analysis (MA) results. adjOR sion from Figures 2 and 3 in Ip S, Chung M, Raman G et al. A summary of the Agency for food sources, and other variables. Healthcare Research and Quality’s Evidence Report on Breastfeeding in Developed This benefit is well documented for Countries. Breastfeed Med. 2009;4:S17–S30, published by Mary Ann Liebert, Inc., New diarrheal disease, respiratory infec- Rochelle, NY. tions, and otitis media. Beyond the evidence-based The report presented two meta-analyses and a system- medicine measures is the realm of attachment and bond- atic review demonstrating a reduced risk of breast cancer ing between infant and mother and the psychological associated with breastfeeding primarily in premenopausal and developmental benefits of breastfeeding for the women. One meta-analysis that included 45 studies mother and infant. How these spheres are influenced by showed a 4.3% reduction in risk for each year of breast- breastfeeding has been studied extensively in many dif- feeding. A second meta-analysis that included 23 studies ferent countries and cultures. Close and frequent contact demonstrated a 28% reduced risk of breast cancer for between the mother and infant, especially skin-to-skin 12 months or more of breastfeeding. The AHRQ team contact, affects the mother’s attachment to the infant performed a meta-analysis of 9 “fair” quality studies positively. The positive feelings affected by the close that included 4,387 cases of ovarian cancer and more (skin-to-skin) and frequent early contact facilitate suc- than 10,000 controls. This new meta-analysis showed cessful breastfeeding, longer duration of breastfeeding, an association between breastfeeding and a reduced risk and more attachment behavior (fondling, kissing, and of ovarian cancer. Cumulative lifetime breastfeeding caressing the infant). Recognition of these effects has led duration of more than 12 months was associated signif- to more direct contact between the infant and his or her icantly with a decreased risk of ovarian cancer compared parents in the delivery and postpartum areas. Such rec- with never breastfeeding. This benefit was not seen for ognition has supported the recommendation to allow cumulative duration of breastfeeding of less than 12 placement of the infant in direct skin-to-skin contact months (Fig. 2). Additional data are needed to confirm a with the mother in the first hour after birth to encourage dose-response relationship between breastfeeding and a successful breastfeeding. The multiple contributory fac- reduced risk of ovarian cancer. tors to infant development makes it difficult to demon- The analysis for type 2 diabetes, involving two very strate a causative connection between early skin-to-skin large cohort studies, showed that breastfeeding was as- contact or breastfeeding and overall infant and child sociated with a reduced risk of developing type 2 diabetes development, emotional stability, personality, attach- in women who did not have a history of gestational ment, or person-to-person interactions. diabetes. Each additional year of lifelong breastfeeding was associated with a 4% to 12% risk reduction in the Breastfeeding to Avoid Allergy two different cohorts. Breastfeeding did not appear to The impact of different methods of feeding infants on the lead to a reduced risk of developing type 2 diabetes in onset of allergy has been researched. A meta-analysis of women who had gestational diabetes. The studies on 18 prospective studies involving term infants who had a return to prepregnancy weight, osteoporosis, and post- family history of atopy found a reduction of 42% (95% partum depression were unable to demonstrate an asso- CI, 8% to 59%) in the risk of atopic dermatitis for infants ciation between breastfeeding and these specific maternal breastfed for at least 3 months compared with those who health outcomes due to methodologic issues and the were breastfed for less than 3 months. (1) effect of other contributing factors or confounders. Studies on asthma were less definitive. The AHRQ

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Table 2. Comparison of Human Milk, Cow Milk, and Infant Formula

Component Human Milk Similac®/Enfamil® Formulas Cow Milk Calories (kcal/L) 747 700 701 Protein (g/100 mL) 1.1 1.5 2.8 Casein 3.7 25.0 Taurine (mM/100 mL) 25 to 30 Added artificially <1.0 Phenylalanine (mg/100 mL) 48 390 mM/100 mL 172 Tyrosine 61 179 Fat (g/1,000 mL) 4.5 2.6 4.4 Cholesterol (mg/L) 139 0 120 Carbohydrate (g/1,000 mL) 6.8 7.2 4.7 Minerals ash (weight %) 0.2 0.33 0.7 Calcium (mg/dL) 34 55 118 Phosphorus (mg/dL) 14 44 93 Calcium/phosphorus ratio 2.4:1 1.2:1 1.3:1 Sodium (g/L) 0.512 (7 mL Eq/L) 1.1 (6 mL Eq/L) 0.768 g/L Vitamin D 4 to 40 IU/L 400 IU 47 to 100 IU Vitamin K 0.9 to 6.9 mg/L 4 mg/100 kcal 19 mg/L

Similac® is a product of Abbot Laboratories, North Chicago, IL, Enfamil® is a product of Mead Johnson & Co, Evansville, IN. Data from American Academy of Pediatrics. Pediatric Nutrition Handbook. 6th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009; Walker WA, Watkins JB. Nutrition in Pediatrics. Boston, MA: Little, Brown and Co; 1985; and Jensen RG. Handbook of Milk Composition. New York, NY: Academic Press; 1995. reported that breastfeeding for at least 3 months was produced by the second 24 hours, 400 g by the third calculated to provide a 27% (95% CI, 8% to 41%) reduc- 24 hours, and 1,100 g/24 hours by the fourteenth day tion in the risk of asthma in children who had no family (800 to 1,000 mL). Human milk and cow milk differ history of asthma compared with children who were not substantially in their composition (Table 2).The proteins breastfed. Children who had a family history of asthma differ in quality and quantity. In its unaltered form, cow had a 40% risk (95% CI, 18% to 57%) reduction in the milk contains too much protein, too much casein, too occurrence of asthma before 10 years of age if breastfed much sodium, and too much phosphorus and has too for 3 months compared with those not breastfed. The high a solute load for a human infant. Formulas have risk for children older than 10 years is less clear. Exclusive been designed to improve these issues. Cow milk does breastfeeding for the first 6 months is recommended by not contain any taurine, an amino acid that has high the American Academy of Pediatrics (AAP) for many concentrations in human milk and is essential to infant reasons, including reducing the risk of allergy. Further brain growth. The profile of amino acids in cow milk if supplementation is necessary, an amino acid-based differs significantly from human milk, especially phenyl- formula is recommended (hypoallergenic formula). alanine and tyrosine, which are at high concentrations in cow milk and formula and contribute to problems in Physiologic Consequences of the Differences phenylketonuria. between Colostrum and Mature Milk The effect of higher protein in infant formula recently The milk available in the breast after 16 weeks’ gestation has been questioned by investigators of the obesity epi- is called prepartum milk. When the infant delivers and is demic. It has been suggested that a constant intake of placed at the breast (or is allowed to find his or her way) high protein in infancy stimulates the metabolic rate to suckle, the milk is colostrum for the next few days. and contributes to the long-term obesity of formula-fed A gradual change from this transition milk to mature infants. After processing, cow milk and infant formulas milk usually occurs by 14 days. Postpartum colostrum contain no cells, no enzymes, and no antibodies or other is called “the first immunization” because it contains active protective agents and do not support the mainte- high concentrations of antibodies and other infection- nance of physiologic flora of the infant’s GI tract. protective elements, including cells. Colostrum is high in Docosahexaenoic acid (DHA) has received consider- total protein, low in carbohydrate, and lower in fat than able attention because studies in preterm infants have mature milk. The amount of milk produced in the first demonstrated improved visual acuity and auditory acuity 24 hours after birth is approximately 50 g, with 190 g in those fed human milk compared with those fed regular

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preterm formula. When DHA was added to formula, the ulation of B cells for antibody production, and limited acuity improved but did not reach the scores achieved by numbers of mature functioning T cells. In addition, breastfed infants. DHA and omega-3 fatty acids derived function of the classical and alternative pathways of com- from bacterial culture are added to many formulas, plement formation and activation is decreased. Immuno- although a benefit has not been proven. globulin (Ig) production is limited in amount and reper- Vitamin concentrations in human and cow milk are toire, including poor isotype switching, limited IgG comparable, except for vitamin C, which is significantly subclass production, and low serum IgA concentrations higher in human milk (100 mg/d). Vitamins in infant through 7 to 8 years of age. formula exceed the concentrations found naturally. Vita- min D has become an important issue because the vita- Bioactive Factors min D generated in human skin from exposure to sun- Human milk not only bolsters the infant’s immature shine has diminished through the use of sunscreen, immune response by providing numerous bioactive fac- wearing of clothing to shade from the sun, pollution of tors that dynamically affect the innate, adaptive, and the air by industrial waste, and migration of dark-skinned mucosal immunity against specific infectious agents but populations to climates with less sun. Pregnant women also by influencing immune system development and have been documented in recent decades to pass less maturation of the mucosal barrier. A very clear dose- vitamin D to the fetus, so newborns lack sufficient stores response relationship has been documented between the at birth. As a result, breastfed infants now are given amount (full [exclusive], partial, token) and duration of 400 U daily from birth. Investigative work continues on breastfeeding and the benefits gained by the infant and the benefits of providing pregnant and lactating women mother. (See Table 1 for the definitions.) Most bioactive with 1,000 U of vitamin D daily. Most, but not all, infant factors exert their effects at the level of the mucosal formulas contain 400 U of vitamin D in 26 to 32 oz of immune system. Igs are the best recognized and studied reconstituted formula. bioactive components in human milk. Igs in human milk Vitamin K content presents an important issue for the are predominantly secretory IgA, with much smaller newborn who is born with low concentrations, even amounts of IgM and IgG. Colostrum contains higher when the mother receives extra doses at the time of amounts of Igs and immunologically competent mono- delivery. Hemorrhagic disease of the newborn, with GI nuclear cells than transitional or mature milk. The Igs or intracranial hemorrhage and generalized bleeding, can function by binding directly to specific microbial anti- present early or up to several weeks after birth and is due gens, blocking binding and adhesion to host cells, to relative deficiencies of vitamin K-dependent coagula- enhancing phagocytosis, and modulating local immune tion factors. Such deficiency has resulted in all newborns response. Table 3 in the online edition of this article lists receiving 1 mg of vitamin K intramuscularly at birth, specific antibodies that have been identified in human regardless of the proposed mode of feeding. If vitamin K milk. is administered orally, multiple doses should be pro- The actual antibodies against specific microbial agents vided. Formula has extra vitamin K, so an infant who present in an individual woman’s milk depends on her receives 26 to 32 oz per day of formula receives 4 mg of exposure and response to the particular agents. Not vitamin K orally daily. Concentrations in human milk and every mother has antibodies in her milk against every cow milk are lower. microbe. The predominant action of Igs in human milk is seen at the mucosal level of the infant’s mouth, Immunologic Considerations of Human Milk nasopharynx, and GI tract, where they bind to and block Neonates and infants are immunologically immature the infectious entry of microbial agents through the and at increased risk for infection. Such developmental mucosal barrier. Although best recognized and remem- immune defects are only some of the factors that place bered in association with “specific” protection against infants at greater risk of infection. In the first 6 postnatal individual infectious agents, Igs provide only a small months, phagocyte function is immature, with limited portion of the overall immunologic benefit of human ability to migrate to the site of infection, and reserve milk. production of phagocytes in response to infection is Other important individual bioactive proteins include limited. Cell-mediated immunity develops throughout lactoferrin, lysozyme, alpha-lactalbumin, and casein. childhood. Defects are particularly apparent in the first Lactoferrin exerts its effects via iron chelation, which 6 months after birth, including decreased cytokine pro- contributes to limiting bacterial growth, blocking adsorp- duction, decreased natural killer cell function, poor stim- tion and penetration of viruses and adhesion of bacteria,

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and enhancing intestinal cell growth and repair. Lyso- mation of toxic oxygen radicals. Various enzymes in zyme binds to endotoxin, increases macrophage activa- human milk break down inflammatory molecules: cata- tion, and contributes to bacterial cell wall lysis. Lactalbu- lase destroys hydrogen peroxide, histaminase destroys min transports calcium and enhances the growth of histamine, and arylsulfatase degrades leukotrienes. Vari- Bifidobacterium, and a modified lactalbumin (in the gut) ous soluble receptors in human milk (IL-1Ra, STNF- affects immune modulation. Casein limits adhesion of alpha R1 and R2) bind to specific cytokines, blocking bacteria and facilitates the growth of Bifidobacterium. their inflammatory action. Carbohydrates are an important nutritional component Vitamins A, C, and E, which are present in higher in human milk, and the specific carbohydrates lactose, concentrations in human milk than in cow milk, scavenge oligosaccharides, and glycoconjugates act as bioactive oxygen radicals. Catalase and glutathione peroxidase as factors. Oligosaccharides act as prebiotics, enhancing the well as lactoferrin serve multiple purposes and have anti- growth of specific probiotic bacteria in breastfed infants, oxidant properties. Prostaglandins in human milk limit and both oligosaccharides and glycoconjugates bind superoxide production. The sum total of these anti- specific microbial antigens. inflammatory effects of human milk occurring at the Lipids in the form of triglycerides, long-chain polyun- mucosal level limits damage to the mucosal barrier and saturated fatty acids, and free fatty acids (FFAs) have a facilitates its ongoing growth and development to fur- lytic effect on many viruses and are active against Giardia ther enhance human milk’s protection of the infant. as well. Nucleotides, nucleosides, and nucleic acids com- prise more than 15% of the nonprotein nitrogen in Infant Microflora, Probiotics, and Prebiotics human milk. Nucleotides serve many crucial roles in The concept that “normal” intestinal microflora influ- energy metabolism, nucleic acid production, and signal ence the development of the local mucosal immunity and transduction, processes of increased importance during even “prime” systemic immunity is being supported by the cellular activation and replication related to an active new research. Pathogen-associated molecular patterns in immune response. Research related to the “essential” the microflora are recognized by toll-like receptors and nature of nucleotides in protection against infection has may contribute to the expression of toll-like receptors on led to the addition of nucleotides to some infant formu- intestinal epithelial cells as well as lead to “program- las. Cytokines and soluble receptors of cytokines are ming” of systemic T-helper cell type 1 (TH1), TH2, and other examples of bioactive factors that serve several TH3-like T-cell responses. Probiotic bacteria are organ- functions. Cytokines can act as functional growth fac- isms that live symbiotically in the intestine, conferring tors and have both inflammatory and anti-inflammatory additional benefits on the host, which include competi- effects in different situations. tion with pathogenic organisms, strengthened tight Hormones and growth factors, including erythropoi- junctions between cells, production of antimicrobial bac- etin, epidermal growth factor, insulin, insulin-like teriocidins, increased mucin production, stimulated peri- growth factor, nerve growth factor, and transforming stalsis, increased production of specific nutrients (argi- growth factor-alpha, stimulate the growth and matura- nine, glutamine, small-chain fatty acids), and enhanced tion of the GI tract and, to a degree, systemic growth. development of the mucosal immune system. These bioactive factors are less specific than Igs, but by Prebiotics usually are nondigestible oligosaccharides acting in concert with multiple factors, they provide the that, after fermentation, lower the pH of the local envi- major portion of protective effects from human milk. rons and increase the amount of available FFAs. Prebiot- ics enhance the growth of probiotic bacteria in the intes- Anti-inflammatory Factors tine. Oligosaccharides are the third most common The concept of immune protection without an extensive component in human milk in terms of quantity. Cow and potentially damaging inflammatory response is gain- milk and formula contain less than one tenth of the ing in significance in general medicine and in breastfeed- oligosaccharides in human milk by weight. The micro- ing medicine. Many of the same protective bioactive flora of breastfed infants include Lactobacillus bifidus factors act at the mucosal level without stimulating and Bifidobacterium, which comprise up to 95% of the a significant inflammatory response, which indirectly culturable organisms. The remaining small portion of decreases inflammation and possible local tissue damage. bacteria include Streptococcus, Bacteroides, Clostridium, Certain factors limit further inflammatory stimulation: Micrococcus, and Enterococcus as well as Escherichia coli lactoferrin blocks activation of complement, and lyso- and other organisms in even smaller numbers. The zyme inhibits neutrophil chemotaxis and limits for- microflora of formula-fed infants are composed primarily

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of gram-negative organisms (coliforms, Bacteroides, Clos- on transmission have documented approximately a 30% tridium, Enterobacter, and Enterococcus) in much larger transmission rate in breastfed infants, 10% rate in numbers than in breastfed infants and include very small “mixed-feeding” infants, and 0% rate in exclusively amounts of Lactobacillus and Bifidobacterium. Lactoba- formula-fed infants. Researchers estimate that 1 mL of cillus and Bifidobacterium ferment oligosaccharides, pro- human milk can contain 1,000 T cells infected with ducing various acids, including FFAs, which lower the HTLV-1. Epidemiologic studies from areas of Japan that pH in the intestine and limit the growth of potential have high rates of HTLV-1 have reported significant pathogens such as E coli, Bacteroides, and Staphylococcus. reductions in transmission of the virus from mother to New molecular techniques that analyze stool by detect- infant with avoidance of breastfeeding or limiting breast- ing ribosomal RNA sequences of microbes are expanding feeding to less than 6 months’ duration. the understanding of GI microflora and factors influenc- HIV-1 infection in the mother is another chronic ing intestinal and immunologic development at the level infection that can be transmitted readily via human milk of the gut. Multiple studies have suggested a protective to the infant. In the United States and other areas of the role of specific intestinal microflora against the risk of world where HIV perinatal transmission prevention is developing necrotizing enterocolitis (NEC) in preterm highly successful and safe alternatives to breastfeeding and very low-birthweight infants. are available, acceptable, feasible, affordable, sustainable, and safe, mothers who have HIV infection have been Infectious Disease Considerations advised not to breastfeed their infants. In areas of the Despite all the evidence for the immunologic benefits of world where there is an increased risk of infectious dis- human milk and the protection afforded infants against eases, nutritional deficiencies, and significant morbidity specific organisms and separate clinical illnesses, data also and mortality for infants who are not breastfed and document the transmission of specific infections through replacement feeding is not available, exclusive breast- human milk or direct contact with an infected maternal feeding by an HIV-positive mother can afford the infant breast. Although only a few infections are transmitted the best chance of survival. HIV DNA is detectable easily easily through human milk (human immunodeficiency in human milk and can be categorized as cell-free and virus [HIV-1], human T-lymphotrophic viruses 1 and 2 cell-associated virus. Factors associated with an increased [HTLV-1 and -2], and cytomegalovirus [CMV]), these risk of HIV transmission via breastfeeding include mixed viruses are important because of their potential for caus- feeding versus exclusive breastfeeding, duration of ing morbidity or mortality in the infant. In addition, breastfeeding, maternal illness and high viral loads, other infections that are uncommonly transmitted by lower CD4 lymphocyte counts in the mother, and mas- human milk or breast contact should be considered in titis or nipple lesions in the mother. Recent studies have specific situations. documented that effective antiretroviral (ARV) treat- Transmission of infection through human milk is ment of the HIV-positive mother along with exclusive exceedingly rare compared with the more common breastfeeding can lead to lower transmission rates for mechanisms of transmission for neonates and infants. infants and lower mortality for both mothers and infants. Prenatal infection is congenital, occurring across the Prophylactic ARV treatment of the infant along with placenta; perinatal infection is due to passage through exclusive breastfeeding also has been associated with the birth canal; and postnatal infection occurs via air- decreased HIV transmission to the infant. Additional borne, droplet, or contact transmission other than with carefully controlled research on exclusive breastfeeding, the breast. The predominant modes of transmission and ARV therapy, and optimizing the infant’s nutrition and the usual timing of infection are important consider- growth are needed before an optimal regimen can be ations in different clinical situations. (2) Review of the devised. considerations for transmission via human milk for Latent CMV infection or even recent CMV infection selected organisms can be divided into bacterial, viral, in a breastfeeding mother is not a contraindication to and other. See Tables 4 and 5 in the online edition of this breastfeeding. Postnatal CMV infection via human milk article for summaries of the considerations for selected occurs readily, but viral presence is rarely, if ever, clini- bacteria and viruses. cally significant in the term infant. In fact, breastfeeding has been described as “natural CMV immunization” in Viral Infections the term infant. Preterm, low-birthweight, and very low- Chronic infection of the mother with HTLV-1 or -2 is birthweight infants are at risk for clinically significant considered a contraindication to breastfeeding. Studies postnatal CMV infection via breastfeeding. This post-

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natal infection is more likely to occur between 3 and mission via respiratory droplets, which is the same for 12 weeks postpartum, when virolactia occurs commonly. breastfeeding or formula-fed infants in contact with their Pasteurization and freezing-thawing milk can decrease mothers. TB mastitis or TB lesions of the breast are rare. the CMV load in human milk. A reasonable protocol has Breastfeeding or use of expressed human milk from the been outlined for protecting susceptible infants while mother who has TB can continue once the mother is using human milk in nurseries that include preterm and receiving appropriate antituberculous therapy and the very low-birthweight infants. (3) The protocol includes infant is receiving isoniazid prophylactically. screening mothers for CMV before providing human Staphylococcus or group A Streptococcus infection of milk to their infants, pasteurizing or freezing-thawing the breast can interfere with breastfeeding. Breastfeeding human milk from CMV-positive mothers before its use, or use of expressed human milk can continue when the and observing infants in the nursery for evidence of acute mother is physically comfortable with the process, after CMV infection.No prospective, controlled trials docu- a temporary suspension during the mother’s initial ment the protective effects of such a protocol. 24 hours of effective antibacterial therapy. Prophylactic West Nile virus (WNV) is the only other virus for antibiotic therapy for the infant in conjunction with the which there has been evidence for transmission via maternal treatment often allays additional fear. human milk with any frequency. Several studies docu- In general, the same antibiotics used to treat a specific ment the presence of WNV DNA as well as IgM and IgG infection in the mother are used and are safe in the infant antibodies against WNV in human milk, but no clear and in the mother’s milk. Antibiotics do enter human evidence documents clinically significant illness in infants milk, but usually in very low concentrations, exposing exposed through breastfeeding by mothers who have the infant to a daily dose well below the commonly used WNV infection. The concern about viruses such as her- therapeutic dose prescribed for infants and children. The pes simplex virus, varicella-zoster virus, vaccinia virus exceptions to this principle are doxycycline or tetracy- (smallpox vaccine virus), or variola virus (smallpox virus) cline because of a concern for dental staining or altered is transmission through contact with skin lesions that bone growth in the infant (short duration of therapy in contain the virus on the mother’s nipple or breast, not the mother [Ͻ3 wk] generally is considered acceptable) through virus excreted in the milk. Temporary avoidance and erythromycin, which has been associated with the of breastfeeding and milk from the mother’s breast that occurrence of infantile hypertrophic pyloric stenosis in has an identified lesion due to one of these viruses may be young infants. Quinolone use has been increasing in reasonable. Prophylactic antiviral treatment for the infant children due to the absence of significant adverse effects, along with maternal antiviral treatment usually is ade- and the use of levofloxacin or ofloxacin in breastfeeding quate to allow breastfeeding to continue. mothers appears to be without significant concerns, Viruses commonly transmitted via the respiratory other than the potential for changing the gut flora of the route (influenza, respiratory syncytial virus, severe acute infant and perhaps bacterial overgrowth with a resistant respiratory syndrome-associated coronavirus) are not pathogen. transmitted through human milk. Most frequently, by Additional considerations for group B Streptococcus the time a specific respiratory illness is diagnosed in the (GBS) infection or colonization of the mother and trans- mother, the infant has already been exposed via respira- mission to the infant include adherence to proposed tory secretions. There is no reason to suspend breastfeed- guidelines for prevention of GBS disease in the infant, ing or the use of expressed human milk, except when the frequent and “back and forth” nature of colonization severe disease in the mother prevents the ability to obtain in mother-infant dyads, the difficulty in eradicating col- human milk. The numerous bioactive factors (not Igs if onization in the mother or infant, and the fact that it is early in the maternal infection) in human milk can transmission of GBS from mothers to infants occurs with provide the infant some ongoing protection. and without evidence of mastitis in the mother. Acquisi- tion of GBS infection via breastfeeding or human milk Bacterial Infections remains uncommon compared with transmission via The concern about bacterial infections in the mother close direct contact between mothers and infants. Close is infection of the nipple or breast (mastitis or breast adherence to the guidelines for prevention of early GBS abscess) that introduces the bacteria into the milk or disease in the infant is effective and important. directly into the infant’s mouth. (See Table 4 for selected Other recommendations to decrease possible GBS bacterial infections in the mother.) The risk of pulmo- transmission between mother and infant via human milk nary tuberculosis (TB) in the mother is related to trans- include careful instruction of mothers and medical staff

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on the appropriate techniques for expression, collection, Breastfeeding and Maternal Medications and storage of expressed milk and on the signs and The risk of maternal medication to the breastfed infant symptoms of mastitis to facilitate early recognition and is a frequent question for the physician. The answer initiation of effective interventions. Breastfeeding or the depends on a number of factors that involve the infant, use of expressed human milk can continue after a tem- including gestational age at birth, current age, weight, porary suspension during the initial 24 hours of anti- feeding pattern, and total oral intake, and the mother, bacterial treatment for the mother. Preventive or early such as medication dose and dosing pattern, route of empiric antimicrobial therapy for the infant may be indi- administration, drug absorption, peak plasma concentra- cated in specific clinical situations, along with the contin- tion and timing of that peak, volume of distribution, uation of breastfeeding. molecular size of the drug, degree of ionization, pH, solubility in water or lipids, degree to which the drug is Fungal Infections protein bound, and oral bioavailability. Candida infection of the breast and mucocutaneous A number of questions must be clarified to make an Candida infection in the infant are the only pertinent informed decision about the use and the potential risk of fungal infections related to breastfeeding and human the medication. If the drug passes into the milk, what is milk. In general, antifungal therapy administered simul- the concentration in the milk? Is it absorbed by the infant taneously to the infant and the mother is the most or is it not orally bioavailable as are many drugs that are effective and appropriate treatment because of the ease effective only by the intravenous or intramuscular routes? of colonization or recolonization in both mother and Is the infant able to detoxify and excrete the drug or does infant. Numerous topical and systemic therapies are it accumulate in the infant’s system? The milk/plasma effective. Occasionally, persistent or recurrent Candida ratio has been determined for a number of drugs by infection adversely affects ongoing breastfeeding. Can- measuring the concentration in the milk and maternal dida infection of the breast is overdiagnosed. Consulta- plasma simultaneously. A single point in time milk/ tion with a professional or physician who has extensive plasma ratio does not give an accurate determination of experience supporting and caring for the breastfeeding how much the infant will receive. A concentration mea- mother-infant dyad can facilitate effective treatment and sured in the milk at the time of feeding is the only reliable ongoing breastfeeding. measure of what the infant receives. Parasitic Infections Despite these questions, reliable measures of many common medications have been documented. Consider- Transmission of parasites through breastfeeding or human milk is not a significant concern. Although hook- able research has resulted in valuable estimations of the worm infection occurs commonly in young children, and safety of many, but not all, drugs. The determination of transmammary spread of helminths has been described the relative infant dose (RID) has been used to standard- in veterinary medicine, little substantiated evidence sup- ize the method that estimates the amount of a given drug ports the presence of hookworms in human milk or that the infant receives. The formula is: significant infection in the infant due to a hookworm RID (%)ϭabsolute infant dose (mg/kg per day)Ϭ passed via human milk. Giardiasis in infants younger than maternal dose (mg/kg per day ϫ100) 6 months of age is rare, and given the various factors active against Giardia in human milk, transmission via These calculations assume average metabolism and a this route is highly unlikely. There is no evidence for maternal dose in the usual therapeutic range. The accept- transmission of malaria via human milk, but the mother able RID of a drug is 10% or less for term infants, who and infant both need to be protected from contact with have a clearing capacity about one third that of the adult. infected mosquitoes. Maternal treatment or prophylaxis Preterm infants are less efficient at clearing drugs, with for malaria during breastfeeding can be accomplished capacity only 5% of the adult capacity at 24 to 28 weeks’ safely with various agents, such as chloroquine, quinine, gestation and only 10% at 28 to 34 weeks’ gestation. pyrimethamine-sulfadoxine, tetracycline, mefloquine, After 7 months of age, however, the infant can handle and primaquine, with some attention to the age of the most drugs at adult concentrations. The RID is avail- child, the duration of exposure, and short periods of able for many medications from reference data banks “pumping and dumping” of expressed milk during the such as the Library of Medicine data bank at http:// use of mefloquine. Transmission of Toxoplasma gondii or toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT. Other Trichomonas via human milk has not been demonstrated. resources are Medications and Mother’s Milk (4) and the

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University of Rochester Breastfeeding and Human Lac- in human milk, using a medication in the same classifica- tation Study Center Drug Line (585/275-0088). tion of drugs that have the lowest RID, avoiding long- The AAP Committee on Drugs has published catego- acting preparations of medications, scheduling dosing ries of drugs and their safety for use while breastfeeding. so the medication concentration in the milk is lowest If the drug is prescribed normally for term or preterm when the infant feeds, taking the medication immedi- infants, it is considered safe via human milk. If the infant ately after breastfeeding or breastfeeding just before the also needs a drug such as an antibiotic, it must be next dose when the medication is taken several times a administered directly to the infant. If the medication is day, and observing the infant for changes in behavior not bioavailable orally, the infant cannot absorb it from while administering the medication to the mother. the stomach. Large molecules such as insulin, heparin, and many Igs do not pass into milk from maternal Use of Human Milk in Preterm Infants plasma. All of the benefits of human milk are magnified in the Drugs of abuse or street drugs are considered contra- preterm infant. If the infant can receive oral feeding, indicated, and breastfeeding is not recommended. For a mother’s milk is the safest and best tolerated of all the mother actively participating in a methadone mainte- available feedings. Human milk can be introduced earlier nance program, the potential benefits of breastfeeding than the foreign protein of formula. All of the infection and human milk for the mother and infant should be protection qualities and the antibodies found naturally in considered strongly. Breastfeeding can be recommended human milk protect against infection, especially NEC. in certain situations in which there has been good pre- The limitations are the ability of the mother to pump her natal care, maternal compliance with a drug addiction milk and make it available. Milk banks are available recovery program before birth, and negative maternal throughout the country that can provide pasteurized urine toxicology screens for 12 weeks before and at human milk from approved donors. The concerns of the delivery. Women who have been stable on a methadone neonatologist stem from the inability to measure the maintenance program should be permitted to breastfeed. volume consumed when the infant is at the breast and the Evidence suggests that methadone-exposed infants may need for additional calories in the limited volumes toler- have less severe symptoms of neonatal abstinence syn- ated by extremely immature infants. The quick solution drome when maintained after delivery on human milk. is to add concentrated formula from powder or liquid Immunosuppressant drugs, such as methotrexate, are made from bovine milk, known by the misnomer contraindicated. However, some newer antimetabolites “human milk supplementer.” This preparation contains or cancer drugs have very short half-lives. A drug is none of the protective factors of human milk and inter- considered to clear the body within 5 times the half-life. feres with those present in any human milk provided. If the half-life is 2 hours, it will clear in 10 hours, during One commercially available supplementer made exclu- which time the mother can pump and discard her milk. sively from human milk has been shown to promote The infant can be fed previously pumped milk or a growth in preterm infants as well as protect against suitable substitute during that interim period. infection, especially NEC. Radioactive compounds have been studied widely. Because women today commonly are deficient in vita- The clearance half-life has been measured for most of the min D, even while taking prenatal vitamins during preg- radioactive compounds used diagnostically or therapeu- nancy, their infants have inadequate stores at birth, espe- tically. The same formula (5ϫhalf-lifeϭclearance time) cially if born preterm. Vitamin D supplementation is can be used to determine how long a mother needs to required if the preterm infant is receiving mother’s milk pump and discard her milk. However, when the half-life (400 U daily). is longer than 3 days, it is impractical to have a mother Ideally, preterm nurseries have nursing staff who are pump and discard for 15 days or longer, although this also certified lactation consultants and can assist mothers determination is an individual decision. Radioactive iodine who wish to pump and provide their milk. The consul- falls in this category. Iodine 131 in therapeutic doses takes tants can advocate for the mother who is ready and eager 3 to 5 weeks to clear the maternal system. to feed her preterm infant at the breast. All neonatal In summary, drugs that are administered routinely to intensive care units should provide electric breast pumps infants are safe to prescribe for the breastfeeding mother. and private accommodations to pump. Freezers and Important considerations for minimizing the amount of refrigerators should be designated for sole storage of medication to which the breastfeeding infant is exposed human milk. Pumped milk should be stored in freezer- include choosing the drug present in the lowest amount safe containers that can be sealed and labeled with name,

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unit number, date, and time of collection, so milk can be age. The Healthy People 2020 goals for breastfeeding were fed sequentially, beginning with the antibody-rich colos- released in late 2010 (http://www.healthypeople.gov/ trum. Most neonatal intensive care units have feeding 2020/topicsobjectives2020/overview.aspx?topicidϭ26) protocols geared to the gestational age and weight of the and show some changes. Anticipated rates are changed, infant. Mother’s milk can be used if these guidelines are and methods to reduce barriers are included. The goals followed. are: At the time of discharge, some preterm infants still ● need added calories, which can be provided by “bioen- Infants ever breastfed: 82% ● gineering,” in which the mother pumps 5 mL of milk Infants breastfeeding at 6 months: 60.6% ● from the breast first (and saves it frozen for weeks to be Infants exclusively breastfed through 3 months: 46.2% ● used later). She then feeds just the hind milk, which is Infants exclusively breastfed through 6 months: 25.5% higher in calories and fat than the foremilk. Some nurs- The WHO multicenter growth reference was conducted eries have the ability to measure the caloric content of in six countries (Brazil, Ghana, India, Norway, Oman, mother’s milk from a sample taken from each pumping and the United States) between 1997 and 2003. The for 24 hours. The average caloric measure is 20 kcal/oz, study consisted of a longitudinal follow-up of 882 infants with a range of 15 to 24 kcal/oz. The milk can be from birth to 24 months of age and a cross-sectional supplemented as necessary or, in the case of high-calorie study of 6,669 children ages 18 to 71 months. Children producers, not at all. The initial milk produced by moth- included in the study were healthy infants living in socio- ers who deliver preterm has been demonstrated to be economic situations favorable to growth, who were higher in protein, calcium, sodium, and calories for the breastfed exclusively for at least 4 months and were first few weeks. Although an advantage to the infant, lack introduced to complementary foods at 6 months of age, of bedside technology does not permit factoring in this with breastfeeding continuing up through 12 months of nutrient variation in the feeding orders. age. The tables and charts (www.who.int/childgrowth/ Current Recommendations en) created through this study depict normal human growth under optimal environmental conditions. The The World Health Organization (WHO), United Nations curves for the six different countries were virtually super- Children’s Fund, AAP Section on Breastfeeding, Amer- imposable on each other for height and weight growth ican College of Obstetricians and Gynecologists, Amer- through 60 months of age. These standards now identify ican Academy of Family Physicians, Academy of Breast- breastfeeding as the biologic norm for growth and devel- feeding Medicine, and many other health organizations opment and add further evidence for the recommenda- recommend exclusive breastfeeding for the first 6 post- tions of exclusive breastfeeding through 4 to 6 months natal months. Numerous obstacles to the initiation and of age. continuation of breastfeeding remain within health-care Pediatricians and other health-care professionals settings, the workplace, communities, and the media. across the United States should continue to recommend The goals for Healthy People 2010 for breastfeeding the use of human milk for all infants, with few exceptions in the United States were: 1) initiation of any breastfeed- (Table 6). A balanced presentation of up-to-date infor- ing in 75% of infants in the early postpartum period, mation on the benefits and process of breastfeeding 2) continuation of any breastfeeding in 50% of infants should be provided to all parents to assist them in making at 6 months of age, 3) continuation of any breastfeeding an informed decision for the feeding of their infants. in 25% of infants at 1 year of age, 4) exclusive breast- Pediatricians and other health-care professionals should feeding in 40% of infants at 3 months of age, and 5) exclu- adopt and promote the “Ten Steps to Successful Breast- sive breastfeeding in 17% of infants at 6 months of age. feeding” in all maternity services and facilities providing The Centers for Disease Control and Prevention have care to infants and children (Table 7). reported preliminary survey data on breastfeeding rates in the United States for infants born in 2006. Although rates have improved since 1999, they still fall below the In-hospital Breastfeeding Policies: Early and Healthy People 2010 goals. For infants born in 2006, Frequent Contact of Mother and Infant 74% initiated breastfeeding, 43% continued breastfeed- Hospital management of the mother-infant dyad who ing at 6 months, and 23% continued at 12 months of age. plan to breastfeed are clearly spelled out by the WHO- An estimated 33% of infants were exclusively breastfed UNICEF ten steps that have been endorsed by the AAP through 3 months of age and 14% through 6 months of (Table 7). The AAP did take exception to the recommen-

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instructed to delay pacifier use until Table 6. Contraindications to Breastfeeding breastfeeding is well-established, usually about 3 to 4 weeks after Infant Conditions birth. • Classic galactosemia (galactose 1-phosphate uridyltransferase deficiency) Every effort should be made at • Maple syrup urine disease birth and while in the hospital to • Phenylketonuria (partial breastfeeding is possible with careful monitoring) keep mother and infant in proximity. Maternal Conditions Labor-delivery-recovery-postpartum • Human immunodeficiency virus 1 infection (if replacement feeding is rooms allow care for the dyad to con- acceptable, feasible, affordable, sustainable, and safe) tinue in the same room. Birth centers • Human T-lymphotropic virus 1 and 2 infection (varies by country; in Japan, and rooming-in provide the best breastfeeding is initiated) environment in which to establish • Tuberculosis (active, untreated pulmonary tuberculosis, until effective maternal treatment for the initial 2 weeks or the infant is receiving isoniazid) lactation. The infant should be put • Herpes simplex virus infection on a breast (until the lesions on the breast are to breast as soon as possible after cleared) delivery, ideally in fewer than 30 min- • Medications (those of concern) utes or, as recommended in the –Most medications are considered safe because little gets into the milk United States, within the first hour –A few select compounds drugs of abuse and some radioactive compounds that have long half-lives require cessation of lactation after birth. When a mother has her baby nearby, the proximity offers her an opportunity to learn her baby’s cues before they are discharged from dation on pacifier use with the following footnote: “The the hospital. The Baby Friendly Hospital Initiative (BFHI) AAP does not support a categorical ban on pacifiers due promotes the ten steps, and The Joint Commission has to their role in sudden infant death syndrome risk reduc- introduced them in their review of hospitals that provide tion and their analgesic benefit during painful procedures delivery services. This support, as recommended by the when breastfeeding cannot provide the analgesia.” (6) BFHI, should continue through infancy until weaning. Pacifier use in the hospital in the neonatal period should Weaning involves the introduction of safe and appro- be limited to specific medical indications, such as pain priate complementary foods to the infant, beginning at reduction or for calming in a drug-exposed infant. 6 months of age. Weaning is a process, and breastfeed- Mothers of healthy term breastfed infants should be ing continues with the introduction of other foods. The overall duration of breastfeeding varies significantly according to Table 7. Ten Steps to Successful Breastfeeding the mother’s and family’s beliefs and cultural practices. The end of Every facility providing maternity services and care for newborn infants should: breastfeeding is most frequently 1. Have a written breastfeeding policy that is communicated routinely to all “decided” by the mother and infant health-care staff. 2. Train all health-care staff in skills necessary to implement this policy. (together or separately), and there 3. Inform all pregnant women about the benefits and management of is no predetermined ideal time for breastfeeding. stopping breastfeeding. 4. Help mothers initiate breastfeeding within 30 minutes of birth. 5. Show mothers how to breastfeed and how to maintain lactation even if they should be separated from their infants. Human Milk Banks 6. Give newborns no food or drink other than human milk, unless medically Human milk banking operates in indicated. many countries. Ten approved 7. Practice rooming-in, that is, allow mothers and infants to remain together not-for-profit banks are members 24 hours a day. of the Human Milk Banking 8. Encourage breastfeeding on demand. Association of North America 9. Give no artificial teats or pacifiers (also called dummies or soothers) to breastfeeding infants. (www.HMBANA.org). All the 10. Foster the establishment of breastfeeding support groups and refer mothers banks follow the association to them on discharge from the hospital or clinic. guidelines for collecting and pas- From Evidence for the Ten Steps to Successful Breastfeeding. (5) teurizing human milk. Women who donate milk are carefully

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3. Lawrence RM. Cytomegalovirus in human breast milk: risk to Summary the premature infant. Breastfeed Med. 2006;1:99–107 4. Hale TW. Medications and Mother’s Milk. 12th ed. Amarillo TX: • Ample evidence documents the clear benefits of Pharmasoft Publishing; 2010 5. breastfeeding for both the mother and the infant. Division of Child Health and Development, Family and Repro- • Among the very few contraindications to ductive Health, World Health Organization. Evidence for the Ten breastfeeding are galactosemia, medications or drugs Steps to Successful Breastfeeding. Geneva, Switzerland: World Health of concern, and HIV and HTLV infection. Organization; 1998. Accessed April 2011 at: http://www.who. • Pediatricians should recognize that human milk is int/child_adolescent_health/documents/9241591544/en/ 6. superior to formula in optimizing each infant’s American Academy of Pediatrics. Tayloe DT. AAP endorse- potential for early growth and development. ment to the WHO/UNICEF ten steps to successful breastfeed- • Pediatricians should recommend exclusive/full ing. Accessed May 2011 at: http://www.aap.org/breastfeeding/ breastfeeding as superior to formula feeding through files/pdf/TenStepswosig.pdf the first 6 postnatal months and the subsequent timely introduction of adequate, safe, and appropriate complementary foods in combination Suggested Reading with continued breastfeeding as optimal nutrition in American Academy of Pediatrics Section on Breastfeeding. Policy the first postnatal year. statement: breastfeeding and the use of human milk. Pediatrics. • Pediatricians should be knowledgeable about 2005;115:496–506 important issues concerning breastfeeding and the Briggs GE, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lacta- management of the breastfeeding mother-infant tion. 8th ed. Philadelphia, PA: Lippincott, Williams & Wilkins; dyad in situations of infant prematurity or illness 2010 and maternal illness, infection, and medication Centers for Disease Control and Prevention. Breastfeeding Among exposure. U.S. Children Born 1999 – 2006, CDC National Immunization • Families should be provided with appropriate Survey. March 16, 2010. Accessed April 2011 at: http://www. information about breastfeeding and infant feeding cdc.gov/breastfeeding/data/NIS_data/index.htm before as well as throughout the pregnancy and de Onis M, Garza C, Onyango AW, Rolland-Cachera MF and infancy. le Comite de nutrition de la Societe Francaise de Pediatrie. • Mothers should receive ongoing support for WHO growth standards for infants and young children. Arch breastfeeding in the hospital, in medical offices and Pediatr. 2009;16:47–53. Accessed April 2011 at: www.who. facilities, and throughout communities, paralleling int/childgrowth/en the BFHI. Ip S, Chung M, Raman G, Chew P, et al. Breastfeeding and • Ongoing lifelong education about support for and Maternal and Infant Health Outcomes in Developed Countries. management of the breastfeeding mother-infant Evidence Report/Technology Assessment No. 153. AHRQ Publi- dyad is essential for pediatricians in the 21st cation No. 07-E007. Rockville, MD: Agency for Healthcare century. Research and Quality; 2007 Ito S. Drug therapy for breastfeeding women. N Engl J Med. 2000;343:118–126 tested and screened. Milk is available by doctor’s Lawrence RA, Lawrence RM. Breastfeeding: A Guide for the Medi- prescription for a fee that covers processing, shipping, cal Profession. 7th ed. Philadelphia, PA: Elsevier Mosby; 2010 and handling. Donors are not paid. At least one for- Lawrence RM, Lawrence RA. Breast milk and infection. Clin profit milk bank has investigated the variations in Perinatol. 2004;31:501–528 Lawrence RM, Pane CA. Human breast milk: current concepts of human milk and has produced a concentrated fluid immunology and infectious diseases. Curr Probl Pediatr Adolesc human milk supplementer made only of human milk. Health Care. 2007;37:1–44 The company also provides regular human milk, the National Library of Medicine Lactation Data Base. Accessed April calorie and protein content of which is available at 20, 2011 at: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen? 24, and 26 kcal/oz. This milk is also available for a fee. LACT United States Department of Health and Human Services. Healthy People 2010: Conference Edition – Volumes I and II. Washing- ton, DC: United States Department of Health and Human References Services, Public Health Service, Office of the Assistant Secretary 1. Ip S, Chung M, Raman G, Trikalinos TA, Lau J. A summary of for Health; 2000:47–48 the Agency for Healthcare Research and Quality’s Evidence Report on Breastfeeding in Developed Countries. Breastfeed Med. 2009;4: S17–S30 2. American Academy of Pediatrics. Pickering LK, Baker CJ, Kim- Resource berlin DW, Long SS, eds. Red Book: 2009 Report of the Committee Breastfeeding and Human Lactation Study Center located at the on Infectious Diseases. 28th ed. Elk Grove Village, IL: American University of Rochester, School of Medicine. Phone Number: Academy of Pediatrics; 2009 585–275-0088

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PIR Quiz Quiz also available online at http://pedsinreview.aappublications.org.

1. Skin-to-skin contact between an infant and mother in the first hour after birth has been associated with: A. Calmer personality. B. Earlier attachment. C. Faster infant development. D. Greater emotional stability. E. More successful breastfeeding.

2. The most definitive studies showing a reduction in atopic dermatitis following at least 3 months of breastfeeding involved: A. Children younger than 10 years of age who had a family history of asthma. B. Children older than 10 years of age who had with a family history of asthma. C. Children who had no family history of asthma. D. Infants who had a family history of atopy. E. Infants who had no family history of atopy.

3. Vitamin K has been administered routinely to newborns for many years. Which of the following vitamins has also been recommended for supplementation from birth? A. A. B. B. C. C. D. D E. E.

4. In the United States, infection with which of the following viruses is a contraindication to breastfeeding? A. Cytomegalovirus. B. Human immunodeficiency virus. C. Respiratory syncytial virus. D. Varicella-zoster virus. E. West Nile virus.

5. The earliest age at which most infants can metabolize drugs at adult rates is: A. 1 week. B. 1 month. C. 4 months. D. 8 months. E. 1 year.

HealthyChildren.org Parent Resources from AAP The reader is likely to find material to share with parents that is relevant to this article by visiting this link: http://www.healthychildren.org/English/ages-stages/baby/ breastfeeding/Pages/default.aspx.

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Normal Pubertal Development: Part II: Clinical Aspects of Puberty Brian Bordini, MD,* Objectives After completing this article, readers should be able to: Robert L Rosenfield, MD* 1. Describe the usual sequence of pubertal development in boys and girls. 2. Describe how linear growth during puberty is related to pubertal stage. Author Disclosure 3. Identify pubertal abnormalities that require further evaluation. Drs Bordini and Rosenfield have Part I of this article, which deals with the endocrine basis of puberty, was published in the disclosed no financial June 2011 issue of Pediatrics in Review. relationships relevant to this article. This Stages of Puberty and Their Evaluation commentary does not Sexual Maturity Rating (SMR) staging of sexual development, also known as Tanner staging, contain a discussion provides a means of discretely documenting a child’s progression through puberty by inspec- tion. Separate scales are used for breast (female), genital (male), and pubic hair (both sexes) of an unapproved/ development (Figs. 1 and 2). (1)(2)(3) By definition, SMR stage 1 is prepubertal. Pubertal investigative use of a development of the gonads is indicated specifically by thelarche (breast stage 2) in girls (Fig. 1) commercial and testicular enlargement (genital stage 2) in boys (Fig. 2). Pubertal development is ongoing product/device. at stage 3, nearly complete by stage 4, and complete and adultlike at stage 5. The limitation of the SMR system is that defining early breast and testicular develop- mental stages accurately requires palpation, not just visual inspection. (4)(5) Inspection of breast development does not enable the distinction between breast tissue development and fat deposition (adipomastia), which is a common confounder. The distinction is best made by palpation of the subareolar breast bud. Direct measurement of testicular size by palpation is likewise preferable to the SMR genital staging system, which relies on a “gestalt” visual estimation of testicular enlargement (a follicle-stimulating hormone [FSH] effect on the seminiferous tubules) that is confounded easily by penile size, which varies constitutionally and is stimulated by androgen and obscured by obesity. A testicular long diameter of Ͼ15/16 in (volume Ͼ3.0 mL, direct determination of which requires an orchidometer measurement (6))† indicates entry into puberty and is the key feature of genital stage 2 (Fig. 2). (7)(8)(9)(10) Mature pubertal testicular development (stage 5) is indicated by attainment of a testicular long diameter of 1.5 to 2.0 in (12 to 27 mL). (3)(9)(11) Testicular volume determined by ultrasonography is about half of that deter- mined by orchidometry but correlates highly. (10) Pubarche is not specific evidence of pubertal function of the gonads because these changes may result from either gonadal or adrenarchal androgen production. Although pubic hair stage 2 may indicate early sexual hair growth, it also may result from generalized hypertrichosis. Thus, pubic hair stage 2 is a less accurate indicator of pubertal androgen production than pubic hair stage 3, the appearance of frank sexual hair (Fig. 1). (4) Although pubic hair stages 2 to 4 Abbreviations may result solely from adrenarchal androgens in both sexes, the development of a “male escutcheon” (stage 6, Fig. 2), ie, sexual BMI: body mass index hair extending up the linea alba, specifically suggests a concen- DHEAS: dehydroepiandrosterone sulfate tration of androgen above that normally found in females. FSH: follicle-stimulating hormone HPG: hypothalamic-pituitary-gonadal PCOS: polycystic ovary syndrome Normal Age of Attainment and Sequence of SD: standard deviation Pubertal Milestones SMR: Sexual Maturity Rating The normal age of onset of puberty traditionally is con- sidered to be between 8.0 and 13.0 years in the general

*Section of Adult and Pediatric Endocrinology, The University of Chicago Pritzker School of Medicine, Chicago, IL. †orchidometer dimensionsϭellipsoid of revolution: volumeϭ0.52ϫlengthϫ(0.64ϫlength)2.

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utes to the trend by an average of about 0.5 years in girls (Fig. 3). (4) There is more debate about the trend and effect of obesity in boys. The more recent epide- miologic studies of boys in the United States are inadequate to gauge puberty onset adequately because boys’ genital development was evaluated by inspection for SMR staging rather than palpa- tion. SMR data suggest that obe- sity delays the onset of male puberty, (16) but data obtained by orchidometry indicate that obe- sity advances the onset of puberty about 0.5 years. (9) Figure 1. Stages of breast and pubic hair development. Stage 1 is prepubertal. Breast stages (left panel): 2–a subareolar breast bud, 3–elevation of the breast contour and The sequence of progression enlargement of the areolae, 4–the areolae form a secondary mound above the contour of through the pubertal stages is pre- the breast, 5–mature female breast with recession of the secondary mound and a dictable. Female puberty typically dependent breast contour. Pubic hair stages (right panel): 2–sparse, fine, straight pubic begins with thelarche, which may hair; 3—long, dark, curly hair; 4–pubic hair resembles adult pubic hair in quality but not be asymmetric and ordinarily pre- distribution, having not yet spread to the thighs; 5–pubic hair has adult quality and cedes the onset of sexual hair by distribution, with spread to the medial thighs. Males go through the same pubic hair about 1.0 to 1.5 years (Table 1) stages and on to stage 6 (male escutcheon, an inverted triangular extension of pubic (Fig. 4), (4)(11) although pubarche hair up the midline) at maturity (Fig. 2). Modified from Rosenfield, et al. (2008) (1) may occur first or simultaneously. Copyright © 2005, Elsevier. A photographic atlas of pubertal stages with full descriptions (17) Menarche occurs approxi- is available from the American Academy of Pediatrics. (3) mately 2.5 years (usual range, 0.5 to 3.0 years) after thelarche, at population of girls and 9.0 and 14.0 years in boys. (12) an average age of 12.6 years in white girls and 12.1 years Current best estimates of the ages of attainment of the in African American girls of normal weight, with Mexican key milestones in pubertal development of normal girls American girls being intermediate. (4) The pubertal and boys in the general population, based on data col- growth spurt (Fig. 4) commences with early puberty and lected from 1988 to 1994, indicate that these milestones occurs over 2 to 3 years, with peak height velocity being remain appropriate (Table 1). (4) Fewer than 5% of the achieved before puberty is complete. (11)(18) general population of normal-weight girls in the United Male puberty typically begins with testicular enlarge- States enter puberty before 8.0 years of age. However, ment. (7) Pubarche characteristically follows, with most thelarche in normal-weight girls occurs about 1 year earlier boys attaining SMR 3 pubic hair within 1.0 to 1.5 years in non-Hispanic African American and Mexican American after testicular enlargement (Table 1) (Fig. 4). (11) The girls than in non-Hispanic white girls. Consequently, breast pubertal growth spurt occurs during genital stages 3 and development is normal during the seventh year in these 4, during which time spermarche occurs. (19) Further minority groups, about 15% of whom experience thelarche masculinization, including facial hair appearance and by 8.0 years of age. Sexual (stage 3) pubic hair, on the other voice change, occur during genital stage 4. hand, occurs in fewer than 5% of girls younger than 8.0 Normal variations in pubertal progression include years of age, regardless of ethnicity. asymmetric breast or testicular development (including a However, there is considerable uncertainty about the one-stage advance of unilateral development at onset) current exact range of normal. The trend toward earlier and gynecomastia (breast tissue development in boys). age of puberty onset in girls appears to have been con- Pubertal gynecomastia occurs in approximately 50% of tinuing over the past several decades, (13)(14)(15) but boys, begins after the onset of genital development (most methodologic obstacles have hindered establishing the often at pubic hair stage 3 to 4) and usually lasts less than extent of this finding definitively. Excess adiposity contrib- 1 year. (20)

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explains the typical height discrep- ancy between males and females. Plotting growth on appropriate growth curves is important for diag- nosis of growth disorders. Ordinary growth charts, which are based on cross-sectional data, are useful for identifying deviations in growth patterns that signify pathology in prepubertal children. (21) How- ever, they provide average ranges for growth and do not reflect the shape of the growth curve during puberty, when children are enter- ing and leaving their growth spurt at diverse ages. Therefore, longitu- dinal growth charts are necessary for interpreting growth after 9 years Figure 2. Genital stages in males. Stage 1 is prepubertal. Stage 2 is characterized by in relation to sexual maturity enlargement of the testes and scrotum but no enlargement of the penis. Stage 3 involves (Fig. 4). (11)(18) The arrest of a continued enlargement of the testes and scrotum along with penile growth, first in length previously normal pubertal growth and later in diameter. Stage 4 involves continued growth of the testes, scrotum, and rate in an adolescent is abnormal penis, with enlargement of the glans. Stage 5 is mature male genitalia, which are shown and demands thorough evaluation with mature pubic hair (stage 6, PH6). Modified from Rosen DS. (2) A photographic atlas for endocrine, metabolic, and sys- with full descriptions of pubertal stages is available from the American Academy of Pediatrics. (3) temic disorders. Because height largely is deter- mined genetically, a “target height” of healthy children can be Linear Growth in Relation to Puberty crudely estimated based on parental heights, adjusting Before puberty, growth velocity gradually decelerates for the average differences between men and women: slightly (Fig. 4). (11)(18) Production of sex hormones at target heightϭaverage of the parents’ heights plus puberty (both estrogen and testosterone) stimulates 6.5 cm for boys or minus 6.5 cm for girls. Height growth both directly and indirectly by augmenting potential is determined more accurately from bone age. growth hormone production. The pubertal growth spurt (22) Because the degree of bone maturation is inversely corresponds more closely to pubertal stage rather than to proportional to the amount of epiphyseal cartilage chronologic age per se (Fig. 4). growth remaining and the fraction of final height The pubertal growth spurt in girls begins at breast and achieved at each level of bone age is known, adult height pubic hair stage 2. Girls then typically achieve an average can be predicted by dividing a child’s current height by peak height velocity of 8.25 cm/y at approximately this fraction. (22) For example, at a bone age of 10 years, breast and pubic hair stage 3, about 1 year before men- normal girls have achieved 86.2% of adult height (boys, arche. Although linear growth slows after menarche, girls 78.4%), with a predictive accuracy of 1.25 in (standard attain an average of another 7 cm thereafter, and growth deviation [SD]), whether they are 9 or 11 years old. At a is approximately 99% complete at a bone age of 15 years. bone age of 13 years, normal girls have achieved 95.8% of The pubertal growth spurt begins an average of adult height (boys, 87.6%), with a predictive accuracy of 2 years later in boys than girls. Linear growth accelerates 0.67 in (SD), whether they are 12 or 14 years old. in boys beginning at genital and pubic hair stage 2. (11) Interpretation of bone age for height prediction pur- Boys achieve an average peak height velocity greater than poses is performed best by a pediatric endocrinologist. girls of 9.5 cm/y at genital and pubic hair stages 3 to 4. Growth is approximately 99% complete at a bone age of Normal Menstrual Cycle 17 years. The combination of a longer period of prepu- The menstrual cycle should be considered equivalent to bertal growth and greater pubertal peak height velocity an examination’s vital signs. (23) Because of immaturity

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Adolescent behavior must be under- Table 1. Current Best Estimates for Age of Onset stood in the context of individual of Pubertal Milestones in Normal Children in susceptibility, family upbringing and † the United States General Population interactions, peer group interac- tions, changes in brain maturation, Age of Onset and adolescents’ reaction to their Stage Mean Range (5th to 95th) perceptions of the bodily changes and to the sexual urges that are Girls Breast Buds (B2) 10.2 8.2 to 12.1* the direct consequences of puberty. Pubic Hair (PH3) 11.6 9.3 to 13.9** Simply because a problem is dis- Menarche 12.6 11.0 to 14.1*** played during adolescence does not mean that it is a direct consequence Boys of puberty. Testes length 2.6 cm (4 cc) (G2) 11.5 9.5 to 13.3 Pubic Hair (PH3) 12.6 10.7 to 14.5 Many behavioral problems that Testes length 3.8 cm (12 cc) (G5) 14.0 11.5 to 16.5 emerge during adolescence have earlier roots. Although the preva- B2ϭbreast stage 2, G2/5ϭgenital stage 2/5, PH3ϭpubic hair stage 3 †Overweight girls’ puberty is about 0.5 years earlier lence of depression increases during *Thelarche is normal in the 7th year in non-Hispanic African American and Mexican American girls. puberty, many children who develop **Pubarche is approximtely 0.5 to 1.0 years earlier in non-Hispanic African American and Mexican American girls. depression during adolescence have ***Menarche is approximately 0.5 years earlier in non-Hispanic African American and intermediate in had preexisting symptoms of psy- Mexican American girls. Female and PH3 data are for normal-body mass index children from Rosenfield, et al.(4) chological distress. Similarly, most Male genital data based on Tanner and Davies. (11) delinquent teenagers have had an- tecedent problems at home and school. of the hypothalamic-pituitary-gonadal (HPG) axis, about Girls who mature early in Western cultures are more 50% of menstrual cycles are anovulatory or have attenuated popular. However, they have more emotional problems; ovulation (24) during the first 2 years after menarche. This lower self-image; and higher rates of depression, anxiety, “physiologic adolescent anovulation” accounts for the and disordered eating than their peers. Early maturation greater menstrual irregularity and longer average inter- appears to be a particular risk factor for problem behavior menstrual length in the early postmenarchal years com- among girls who have had a history of difficulties before pared with adults. However, about 50% of anovulatory adolescence, when they have more opposite-sex friend- cycles are of normal length, so menstrual regularity is ships and relationships, and when they attend coeduca- greater than ovulatory frequency would suggest. In no tional schools. Early maturing boys also are more popu- circumstance is the adage truer that menstrual regularity lar, but they are at higher risk for engaging in antisocial does not assure ovulatory normalcy. Although the time and aggressive behaviors and precocious sexual activity, required for menstrual cyclicity to mature varies consider- particularly when they forge friendships with older peers. ably, menstrual regularity approximates adult standards in Short-term administration of testosterone or estrogen two thirds of girls within 1 year of menarche. By 2 years after has minimal effects on behavior or mood in adolescents. menarche, only 10% of girls have an average cycle length (26)(27) Thus, variation in hormone concentrations shorter than 21 days or longer than 45 days. By 5 years after accounts for only a small fraction of adolescents’ affective menarche, the menstrual cycle is within the adult normal issues; social influences account for considerably more. range (average cycle length, 22 to 42 days), with at least Although there is little evidence that psychological diffi- 75% of cycles being ovulatory. culties stem directly from hormonal changes during nor- mal puberty, it is likely that the bodily changes of The Relationship Between Puberty and adolescence play a role in the development of a negative Adolescent Behavior body image when they occur out of synchrony with Despite the popular concept that adolescence is inher- sociocultural norms. ently a period of turmoil, most teenagers do not develop Problems with initiating and maintaining sleep are significant social, emotional, or behavioral difficulties. common in adolescents and contribute a small amount (25) Occasional experimentation and risk-taking are nor- to poor school performance. (28) Insufficient sleep mal, as are withdrawal from and conflict with parents. might be due to environmental factors (eg, social and

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and early puberty. The red blood cell mass increases further when the growth spurt begins, with adult males ultimately attaining hemo- globin values slightly higher (range, 13.5 to 17.5 g/dL [135 to 175 g/L]) than those of females (12.0 to 15.5 g/dL [120 to 155 g/ L]), which remain nearly at mid- childhood values. (30) The total alkaline phosphatase concentration elevates transiently to as high as 525 U/L (8.8 ␮kat/L) (girls) and 585 U/L (9.8 ␮kat/L) (boys), re- flecting the high osteoblastic activity of rapid bone growth. (30) Bone-specific alkaline phosphatase peaks at pubertal stage 3 in both girls (average, 80 ␮g/L) and boys Figure 3. Relationship of body mass index (BMI) status to the prevalence of pubertal ␮ milestones. Stage 2 breast development differs significantly according to BMI status from (100 g/L). (31) Total cholesterol ages 8.0 through 9.6 years. Similarly, pubarche in girls differs significantly by BMI status peaks in early puberty; low-density from ages 8.0 through 10.2 years. Menarche differs significantly by BMI status from ages lipoprotein cholesterol peaks in 10.6 through 12.9 years. There was no evidence of an association between excess later puberty. (32) High-density li- adiposity and pubarche in boys. Modified from Rosenfield et al. (4) poprotein cholesterol concentra- tions remain relatively constant, academic pressures), but intrinsic factors clearly play an although boys have a slight decrease from early to mid- important role. A 50% decline in the intensity of deep puberty. Triglycerides tend to rise slightly. Blood pres- (slow wave, delta) sleep occurs during adolescence, and sure gradually increases. (33) It is important to assess 50% of this change occurs between 12 and 14 years of blood pressure in relation to sex-specific, height- and age. (29) Recent evidence indicates that this change is age-matched normal values, using the 95th percentile as related to age and sex, beginning earlier in girls, but not a criterion for separating normal from those who require to pubertal stage. It has been proposed that this shift is a evaluation (Table 2). Serum concentrations of renin and manifestation of the widespread synaptic pruning that is aldosterone decrease considerably and those of thyroid related to the emergence of adult cognitive capacity. hormones, calcium, and phosphate all decrease slightly The causal direction of the link between pubertal throughout childhood to reach adult values when development and the quality of family relationships has puberty is complete. come into question. Several studies have indicated that family dynamics may affect the timing and course of Recognizing Disorders of Puberty puberty, with earlier and faster maturation observed Pubertal disorders can be recognized when puberty (or among adolescents raised in homes characterized by menses) is too early, too much, too late, or too little. more conflict and among girls from homes in which the Although it is beyond the scope of this review to deal biologic father is not present. comprehensively with disorders of puberty, the general principles involved in recognizing and differentiating Effects of Puberty on Other Body Systems these conditions from normal are discussed. In addition to the classic pubertal changes, the sex ste- roid changes of puberty bring about physiologic altera- Puberty Too Early: Premature (Precocious) tions in a wide variety of systems. In both sexes, the Puberty hemoglobin concentration increases slightly from an Thelarche or pubarche before 8.0 years of age in girls and average of 12.5 g/dL (125 g/L) in 2 to 6 year olds to an pubarche or genital development before 9.0 years in boys average of 13.5 g/dL (135 g/L) during late childhood is considered to be premature, (12) except in the case of

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Figure 4. Relationship of key pubertal stages to pubertal growth velocity. Top panel: After a slight deceleration in growth, female puberty begins with breast development. Pubic hair development soon follows, and linear growth accelerates. Girls achieve peak height velocity approximately 1 year before menarche. Note that the current estimates for attainment of pubertal milestones in normal-weight girls (Table 1) are about 0.25 years (pubic hair stage 3) to 0.5 years (breast stage 2) earlier than these 1985 estimates from Tanner and Davies (1985). (11) Bottom panel: After a slight deceleration in growth, male puberty begins with testicular enlargement to genital stage 2 (volume >3 mL). Pubic hair development soon follows, and linear growth accelerates. Boys achieve peak height velocity before entering genital stage 5 (testis volume 12 mL). Note that the current estimates for pubic hair stage 3 milestones (Table 1) are 0.5 year earlier than these 1985 estimates. Modified from Bock and Rosenfield (18) and Tanner and Davies. (11)

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a few months or it may persist in Table 2. 95th Percentile of Blood Pressure (BP) for proportion to somatic growth until Girls and Boys Ages 1 to 17 Years by normal true puberty begins at a nor- Percentiles of Height mal age. Premature thelarche usu- ally is due to minimal activation of 95th Percentile 95th Percentile the hypothalamic-pituitary-ovarian Systolic BP (mm Hg) Diastolic BP (mm Hg) axis with predominant FSH secre- Height tion, (35)(36)(37) but estrogen Percentile: 5% 50% 95% 5% 50% 95% formation in excess adipose tissue Girls and exogenous estrogen exposure, Age (yr) such as from topical tea tree oil, 1 101 104 107 57 58 60 should be considered. 3 104 107 110 65 66 68 Premature thelarche occasion- 5 107 110 113 69 71 73 7 110 113 116 73 74 76 ally is the first sign of progressive 9 114 117 120 75 77 79 true sexual precocity, indicating the 11 118 121 124 78 79 81 need for close observation of puber- 13 121 125 128 80 82 84 tal development, height velocity, 15 124 128 131 82 83 86 and bone age. Breast development 17 126 129 132 83 84 86 in a boy before puberty (that is, Boys unaccompanied by pubertal geni- Age (yr) tal and pubic hair development) is 1 98 102 106 55 57 59 abnormal, and a feminizing disor- 3 104 109 113 63 65 67 der such as a neoplasm must be 5 108 112 116 69 71 74 7 110 115 119 74 76 78 ruled out. 9 113 117 121 76 79 81 Premature pubarche is charac- 11 116 121 125 78 80 83 terized by slowly progressive pubic 13 121 126 130 79 82 84 or axillary hair development and 15 127 131 135 81 83 86 may be accompanied by increased 17 132 136 140 85 87 89 body odor or mild acne. This devel- Data from Horan. (33) opment is not accompanied by breast or testicular enlargement or a pubertal growth spurt. Premature pubarche may be idiopathic, due to non-Hispanic African American and Mexican American apparent sexual hair follicle hypersensitivity to the nor- girls, in whom thelarche is normal in the seventh year mal traces of androgen of early adrenarche, or due to (Table 1). A clinically significant excess of sex hormone premature adrenarche or anabolic steroid exposure. Pre- output is suggested if puberty advances rapidly or is mature adrenarche ordinarily is diagnosed when prema- accompanied by a growth spurt. Sexually precocious ture pubarche is accompanied by a mild elevation of children are at risk for the premature epiphyseal fusion plasma dehydroepiandrosterone sulfate (DHEAS), typi- that leads to the paradox of short adult stature despite tall cally to 40 to 130 ␮g/dL (1.1 to 3.5 ␮mol/L), which is stature in childhood. above the upper limit for normal preadrenarchal children Most sexual precocity does not have a serious cause and in the range for normal early pubertal children. (38) that needs to be treated. Two extreme variants of normal The DHEAS elevation seems to be caused usually by are common, particularly in girls, in whom they account early maturation of the zona reticularis of the adrenal for more than 15% of office visits (34): idiopathic prema- cortex. Premature adrenarche occasionally may be a pre- ture thelarche and idiopathic premature pubarche/ cursor of polycystic ovary syndrome (PCOS) or, rarely, adrenarche. may be the first evidence of a virilizing disorder. Close Idiopathic premature thelarche may begin unilaterally observation of pubertal development, height velocity, or bilaterally. This change occurs in isolation; affected and bone age is indicated. girls do not have pubic hair development or a pubertal Complete precocious puberty results from early acti- growth spurt. The breast development may regress after vation of the HPG axis, with gonadotropins stimulating

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sex hormone production. The condition is five times cation for an evaluation to rule out estrogen excess, more common in girls than in boys, and 90% of cases in androgen deficiency, or liver dysfunction. girls are idiopathic. Conversely, complete precocious puberty is idiopathic in only 50% of boys. Consequently, Puberty Too Late: Delayed Puberty organic central nervous system disorders, of virtually any Delayed puberty is defined as lack of breast development cause, are more prevalent in precocious boys than in by age 13.0 years in girls and lack of pubertal testicular precocious girls. An activating mutation of GPR54, a key development (genital stage 2) by age 14.0 years in boys factor in the hypothalamic signaling system regulating (Table 1). The delay is accompanied by slowing of linear pubertal GnRH release, has been reported to cause pre- growth velocity, and sometimes the accompanying short mature puberty. (39) stature is the primary complaint. Precocity in the 6- to 8-year age range usually is not Most delayed puberty does not have a serious cause rapidly progressive and may not require specific treat- because it is due to an extreme variant of normal, known ment. Overweight and obesity may be the underlying as constitutional delay of pubertal growth and devel- cause in many such cases. However, rapidly progressive opment, which is seen more commonly in boys. This precocity, particularly if before 6 years of age or if asso- condition results from unexplained delay in the onset ciated with vaginal bleeding at breast stage 2, requires of pubertal HPG activation, ie, prolongation of the investigation and treatment. physiologic gonadotropin deficiency of childhood. Once Other causes of precocious puberty include puberty begins, its course and tempo are normal, and gonadotropin-independent precocious puberty, which catch-up growth to target height occurs. If puberty does results from intrinsic adrenal or gonadal disorders or not begin in a boy by 18 years of age, it is pathologic. In exogenous hormones. The most common of these con- the meantime, the self-image of many constitutionally ditions are nonclassic congenital adrenal hyperplasia delayed boys benefits significantly from short physiologic (which is mildly virilizing), McCune-Albright syndrome (low-dose) courses of androgen replacement therapy (which typically feminizes girls), and “testotoxicosis” under the care of a pediatric endocrinologist. (primary Leydig cell hyperplasia, which causes moderate Delayed puberty also can be caused by a variety of masculinization in boys); neoplasms are rare possibilities chronic endocrine, metabolic, and systemic disorders. to consider. Undernutrition underlies the delayed puberty of disad- Vaginal bleeding in the absence of breast develop- vantaged populations. Screening tests for general health ment is not likely to be hormonally mediated. Alter- (eg, complete blood count, comprehensive metabolic nate causes, such as foreign body, abuse, or genital tract panel, erythrocyte sedimentation rate, and thyroid func- neoplasm, should be explored. tion tests) are indicated, as are gonadotropin concentra- tions to assess the possibility of hypogonadism. Puberty Too Much: Sex Steroid Excess Disorders Hirsutism, excessive sexual hair development in a female Puberty Too Little: Hypogonadism (as distinguished from a generalized excess of body hair Hypogonadism is suspected when the patient experi- or hypertrichosis), is a normal variant when mild and ences too little pubertal development, micropenis, or isolated. However, when accompanied by menstrual cryptorchidism. Obesity is a common confounder in the abnormality or when severe, hyperandrogenism must be diagnosis of micropenis because a prominent suprapubic considered, and PCOS accounts for about 85% of these fat pad obscures penile development (“pseudomicro- cases. (40) PCOS is a disorder of otherwise unexplained penis”), but normalcy of penile development is demon- hyperandrogenic anovulation that manifests typically strable by palpation of the full length of the penile in the perimenarchal stage of development. PCOS gen- corpus. Failure of the testes to descend is a risk factor for erally is due to functional ovarian hyperandrogenism. infertility and testicular malignancy. (41) These risks About 50% of affected girls are obese, and 50% of these appear to increase with the severity of the cryptorchidism have metabolic syndrome. and time to orchiopexy beyond infancy. Retractile testes During puberty, most boys develop transient gyneco- were believed to be spared these risks, but recent studies mastia. However, a mid-adolescent female degree of suggest that about one third of retractile testes ascend to breast development in a boy (“macromastia”) can be become cryptorchid and lose germ cells. Accordingly, expected to persist. Although usually an extreme variant health supervision visits should include assurance of the of normal, this degree of breast development is an indi- scrotal position of the testes.

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Primary hypogonadism is hypergonadotropic, with tumor, trauma, or autoimmune disease). Gonadotropin FSH, in particular, being elevated. Secondary (pituitary) deficiency should also be suspected if there are other or tertiary (hypothalamic) hypogonadism is indicated by pituitary hormone deficiencies. absolutely or inappropriately low luteinizing hormone Girls are particularly vulnerable to the reproductive values. The bone age is important in determining effects of undernutrition and stress. Anorexia nervosa is whether gonadotropin concentrations are appropriate. the prototypic form of eating disorders and is a common Because neuroendocrine puberty may not begin until the cause of hypogonadotropism in teenagers. This syn- bone age reaches a pubertal level, prepubertal gonado- drome of undernutrition is due to voluntary starvation tropin values do not necessarily rule out primary hypo- associated with a particular psychological dysfunction gonadism before this stage of bone age. After a pubertal that results in amenorrhea. (42) Experimentally, the bone age is achieved, prepubertal gonadotropin concen- gonadotropin deficiency has been corrected by opioid trations rule out primary hypogonadism. antagonists. At the other extreme, after 18.0 years of age, hypo- The weight changes leading to cessation or restora- gonadotropic hypogonadism is indicated by lack of ele- tion of menstrual cycles are in the range of 10% to 15% of vated gonadotropin values, not necessarily by low values. body weight. Recovery of menses is associated with In between, it may be difficult to differentiate constitu- attainment of sufficient mental health to achieve a critical tionally delayed puberty from hypogonadotropic hypo- amount of body fat, which typically entails reaching a gonadism unless there are clues to specific conditions. body mass index (BMI) within the normal range. The age of onset and severity determine the manifes- Athletic amenorrhea is a related disorder that refers to tations of hypogonadism. Congenital hypogonadism the hypothalamic anovulation resulting from the low may cause disorders of sexual differentiation in genetic body fat stores associated with excessive exercise and males. Complete hypogonadism that is present prepu- obsession with weight control. The female athletic triad bertally causes sexual infantilism in both sexes, and consists of menstrual disturbance, eating disorder, and puberty will never occur. Less severe hypogonadism or osteoporosis. (1) Primary or secondary amenorrhea, oli- hypogonadism that manifests in the early teenage years gomenorrhea, or excessively frequent periods due to slows or arrests the pubertal progression. luteal insufficiency are common. The BMI does not In cases of untreated severe hypogonadism, epiphy- accurately reflect body fat stores in athletes, which is the seal closure is delayed, resulting in taller stature than critical factor related to the menstrual disorders. Leptin would be expected from the family target height. Hypo- concentrations are decreased significantly and are a major gonadism after complete puberty has been attained contributor to the gonadotropin deficiency. (43) causes menstrual disturbance in females and impotence and gynecomastia in males. Primary (hypergonadotropic) hypogonadism usually Menstrual Disorders is due to the gonadal dysgenesis that results from sex Although menstrual irregularities are common in adoles- chromosomal errors in cell division. In girls, the com- cents, they are too often mistakenly disregarded. (23) mon cause is Turner syndrome, which is due to a defi- Any disorder that can affect female puberty can cause the ciency of genes on the X chromosome. Short stature following types of menstrual dysfunction: primary amen- typically is present from early childhood. Many affected orrhea (failure of menses to begin by 15.0 years of age or girls otherwise lack the Turner phenotype, which in- within 3 years of thelarche), secondary amenorrhea (ces- cludes webbed neck, cubitus valgus, and other typical sation of menstrual periods for 90 days or more after features. In boys, the common cause is Klinefelter syn- initially menstruating), oligomenorrhea or amenorrhea drome, which is due to an extra X chromosome. The (infrequent periods or no periods within any year after testes are inappropriately small for the degree of mascu- initially menstruating), or dysfunctional uterine bleeding linization, and affected boys often have a history of (anovulatory bleeding that is excessive in amount or learning disabilities. frequency). Even within the first year after menarche, Gonadotropin deficiency may be due to molecular evaluation should be considered for an unusual degree of defects in HPG signaling pathways, such as in the menstrual irregularity, such as missing a period for 90 kisspeptin-GPR54 system. The deficiency may be either days for even one cycle, bleeding more often than at congenital (which should be suspected if anosmia or 21-day intervals, or bleeding for more than 7 days or midline craniofacial defects are associated) or acquired requiring pad or tampon changes more than every 1 to 2 (which commonly is a consequence of undernutrition, hours. By 2 postmenarchal years, failure to establish or

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sustain menstrual cyclicity that is normal by adult stan- References dards carries about a two-thirds risk of persistent oligo- 1. Rosenfield RL, Cooke DW, Radovick S. The ovary and female ovulation. (44) Thus, failure to establish normal adult maturation. In: Sperling M, ed. Pediatric Endocrinology. 3rd ed. cyclicity by this time is a strong indication for investiga- Philadelphia, PA: Elsevier; 2008:530–609 2. Rosen DS. Physiologic growth and development during adoles- tion. cence. Pediatr Rev. 2004;25:194–200 Pregnancy is always the first consideration. Most men- 3. Herman-Giddens ME, Bourdony CJ, Dowshen SA, Reiter EO. strual disorders are due to anovulatory disorders; PCOS, Assessment of Sexual Maturity Stages in Girls and Boys. Elk Grove nutritional disturbance, and hyperprolactinemia are the Village, IL: American Academy of Pediatrics; 2010 most common conditions. Prolactin excess is accompa- 4. Rosenfield RL, Lipton RB, Drum ML. Thelarche, pubarche, nied by galactorrhea in about 50% of cases and may cause and menarche attainment in children with normal and elevated body mass index. Pediatrics. 2009;123:84–88 a hypogonadotropic or a hyperandrogenic picture. 5. Lee PA, Guo SS, Kulin HE. Age of puberty: data from the Unique causes to consider in the differential diagnosis of United States of America. APMIS. 2001;109:81–88 dysfunctional uterine bleeding are sexual abuse, genital 6. Prader A. Testicular size: assessment and clinical importance. tract or feminizing neoplasm, and bleeding diathesis. Triangle. 1966;7:240–243 Unique causes to consider in the case of primary amen- 7. Biro FM, Lucky AW, Huster GA, Morrison JA. Pubertal staging orrhea are delayed puberty, aplasia of the genital tract, in boys. J Pediatr. 1995;127:100–102 8. Mul D, Fredriks AM, van Buuren S, Oostdijk W, Verloove- and disorders of sex development. Inspection of the Vanhorick SP, Wit JM. Pubertal development in The Netherlands external genitalia, which is recommended as part of the 1965–1997. Pediatr Res. 2001;50:479–486 routine annual comprehensive physical examination of 9. Sorensen K, Aksglaede L, Petersen JH, Juul A. Recent changes children and adolescents at all ages, is likely to detect the in pubertal timing in healthy Danish boys: associations with body latter conditions; an internal pelvic examination seldom mass index. J Clin Endocrinol Metab. 2010;95:263–270 10. Goede J, Hack WW, Sijstermans K, et al. Normative values for is necessary for diagnosis. (45) Nevertheless, normal testicular volume measured by ultrasonography in a normal popu- external genitalia do not exclude a disorder of sex devel- lation from infancy to adolescence. Horm Res Paediatr. 2011; Epub opment. Complete androgen insensitivity presents as a April 5: DOI:10.1159/000326057 well-developed normal female who has primary amenor- 11. Tanner JM, Davies PS. Clinical longitudinal standards for rhea and scanty pubic hair, often associated with an height and height velocity for North American children. J Pediatr. inguinal hernia, and whose evaluation reveals her to be a 1985;107:317–329 12. Carel JC, Eugster EA, Rogol A, et al. Consensus statement on genetic male with cryptorchid testes and male testoster- the use of gonadotropin-releasing hormone analogs in children. one concentrations. Pediatrics. 2009;123:e752–e757 13. Euling SY, Selevan SG, Pescovitz OH, Skakkebaek NE. Role of environmental factors in the timing of puberty. Pediatrics. 2008; 121(suppl):S167–S171 14. Parent AS, Teilmann G, Juul A, Skakkebaek NE, Toppari J, Summary Bourguignon JP. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and All of the following are based on strong research changes after migration. Endocr Rev. 2003;24:668–693 evidence: 15. Biro FM, Galvez MP, Greenspan LC, et al. Pubertal assessment • Breast development before 8.0 years of age is unusual in the general population of normal-weight method and baseline characteristics in a mixed longitudinal study of girls in the United States, but breast development is girls. Pediatrics. 2010;126:e583–e590 normal in the seventh year in girls of minority 16. Lee JM, Jacuritu N, Appuglies D, Corwyn RF, Bradley RH, ethnic status (non-Hispanic African American and Lumeng JC. Body mass index and timing of pubertal initiation in Mexican American). boys. Arch Pediatr Adolesc Med. 2010;164:139–144 • Obesity advances the onset of puberty in girls. 17. Biro FM, Huang B, Daniels SR, Lucky AW. Pubarche as well as • Pubertal development in boys is 1 to 2 years later thelarche may be a marker for the onset of puberty. J Pediatr Adolesc than in girls, on average. Gynecol. 2008;21:323–328 • Missing a menstrual period for 90 or more days or 18. Bock RD, Rosenfield RL. Course-of-growth norms for longi- having an average cycle length less than 21 days is tudinal height velocity. Hummanbiol Budapest. 1994;25:575–586 abnormal for a girl of any age, and an average cycle 19. Nielsen CT, Skakkebaek NE, Richardson DW, et al. Onset of length of more than 45 days by 2 years after the release of spermatozoa (spermarche) in boys in relation to age, menarche is a risk factor for ongoing oligo- testicular growth, pubic hair, and height. J Clin Endocrinol Metab. anovulation. 1986;62:532–535 • Pubertal growth and development and menstrual 20. Biro FM, Lucky AW, Huster GA, Morrison JA. Hormonal cyclicity are sensitive indicators of general health. studies and physical maturation in adolescent gynecomastia. J Pedi- atr. 1990;116:450–455

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21. Rosenfield RL. Essentials of growth diagnosis. Endocrinol Control in Children–1987. Task Force on Blood Pressure Control Metab Clin N Am. 1996;25:743–758 in Children. National Heart, Lung, and Blood Institute, Bethesda, 22. Bayley N, Pinneau S. Tables for predicting adult height from Maryland. Pediatrics. 1987;79:1–25 skeletal age: revised for use with the Gruelich-Pyle hand standards. 34. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Second- J Pediatr. 1952;40:432–441 ary sexual characteristics and menses in young girls seen in office 23. American Academy of Pediatrics Committee on Adolescence; practice: a study from the Pediatric Research in Office Settings American College of Obstetricians and Gynecologists Committee Network. Pediatrics. 1997;99:505–512 on Adolescent Health Care, Diaz A, Laufer MR, Breech LL. 35. Lucky AW, Rich BH, Rosenfield RL, Fang VS, Roche-Bender Menstruation in girls and adolescents: using the menstrual cycle as N. A useful test to discriminate true precocious puberty from a vital sign. Pediatrics. 2006;118:2245–2250 premature thelarche and adrenarche. J Pediatr. 1980;97:214–216 24. Zhang K, Pollack S, Ghods A, et al. Onset of ovulation after 36. Pescovitz OH, Hench KD, Barnes KM, Loriaux DL, Cutler menarche in girls: a longitudinal study. J Clin Endocrinol Metab. GB, Jr. Premature thelarche and central precocious puberty: the 2008;93:1186–1194 relationship between clinical presentation and the gonadotropin 25. Steinberg L, Morris AS. Adolescent development. Annu Rev response to luteinizing hormone-releasing hormone. J Clin Endo- Psychol. 2001;52:83–110 crinol Metab. 1988;67:474–479 26. Finkelstein JW, Susman EJ, Chinchilli VM, et al. Estrogen or 37. Klein KL, Mericq V, Brown-Dawson JM, Larmore KA, testosterone increases self-reported aggressive behaviors in hypogo- Cabezas P, Cortinez A. Estrogen levels in girls with premature nadal adolescents. J Clin Endocrinol Metab. 1997;82:2433–2438 thelarche compared with normal prepubertal girls as determined by 27. Susman EJ, Finkelstein JW, Chinchilli VM, et al. The effect of an ultrasensitive recombinant cell bioassay. J Pediatr. 1999;134: sex hormone replacement therapy on behavior problems and 190–192 moods in adolescents with delayed puberty. J Pediatr. 1998;133: 38. Rosenfield RL. Identifying children at risk of polycystic ovary 521–525 syndrome. J Clin Endocrinol Metab. 2007;92:787–796 28. Dewald JF, Meijer AM, Oort FJ, Kerkhof GA, Bogels SM. The 39. Teles MG, Bianco SD, Brito VN, et al. A GPR54-activating influence of sleep quality, sleep duration and sleepiness on school mutation in a patient with central precocious puberty. N Engl performance in children and adolescents: a meta-analytic review. J Med. 2008;358:709–715 Sleep Med Rev. 2010;14:179–189 40. 29. Feinberg I, Higgins LM, Khaw WY, Campbell IG. The ado- Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med. lescent decline of NREM delta, an indicator of brain maturation, is 2005;353:2578–2588 linked to age and sex but not to pubertal stage. Am J Physiol Regul 41. Thorup J, McLachlan R, Cortes D, et al. What is new in Integr Comp Physiol. 2006;291:R1724–R1729 cryptorchidism and hypospadias–a critical review on the testicular 30. Mayo Medical Laboratories 2010 Reference Laboratory Services dysgenesis hypothesis. J Pediatr Surg. 2010;45:2074–2086 for Health Care Organizations. Rochester, MN: Mayo Clinic. 42. American Academy of Pediatrics Policy Statement. Iden- Accessed April 2011 at: www.mayomedicallaboratories.com tifying and treating eating disorders. Pediatrics. 2003;111: 31. Tobiume H, Kanzaki S, Hida S, et al. Serum bone alkaline 204–211 phosphatase isoenzyme levels in normal children and children with 43. Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin growth hormone (GH) deficiency: a potential marker for bone in women with hypothalamic amenorrhea. N Engl J Med. 2004; formation and response to GH therapy. J Clin Endocrinol Metab. 351:987–997 1997;82:2056–2061 44. Southam A, Richart E. The prognosis for adolescents 32. Hickman TB, Briefel RR, Carroll MD, et al. Distributions and with menstrual abnormalities. Am J Obstet Gynecol. 1996;94: trends of serum lipid levels among United States children and 637–645 adolescents ages 4–19 years: data from the Third National Health 45. Braverman PK, Breech L. American Academy of Pediatrics. and Nutrition Examination Survey. Prev Med. 1998;27:879–890 Clinical report–gynecologic examination for adolescents in the 33. Horan M. Report of the Second Task Force on Blood Pressure pediatric office setting. Pediatrics. 2010;126:583–590

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PIR Quiz Quiz also available online at http://pedsinreview.aappublications.org.

6. Normal pubertal development varies according to a child’s weight and ethnicity. Which of the following clinical findings indicates premature pubertal development? A. Penile enlargement in a 10-year-old African American male of normal weight. B. Stage 3 pubic hair in a 7-year-old Mexican American girl of normal weight. C. Testicular enlargement in a 9-year-old white boy who is obese. D. Thelarche in a 7-year-old African American girl of normal weight. E. Thelarche in a 9-year-old white girl who is obese.

7. You are seeing a 13-year-old girl who experienced menarche 3 months ago. Her physical examination shows that the areolae form a secondary mound above the contour of her breasts. Her pubic hair is curly and coarse and covers the lower portion of her mons pubis. Which of the following is the most accurate description of her Sexual Maturity Rating? A. Breast: stage 2, pubic hair: stage 3. B. Breast: stage 3, pubic hair: stage 3. C. Breast: stage 3, pubic hair: stage 4. D. Breast: stage 4, pubic hair: stage 4. E. Breast: stage 4, pubic hair: stage 5.

8. Which of the following is a true statement regarding normal pubertal development? A. Behavioral changes in adolescence are a direct manifestation of increases in sex hormone concentrations. B. Bone age is an accurate determinant of height potential in boys and girls. C. Most girls miss periods for 90 days within 1 year of menarche. D. Pubertal gynecomastia is rare and should prompt an investigation. E. The pubertal growth spurt in girls typically occurs within 2 to 3 months after menarche.

9. Which of the following patients should undergo an evaluation to rule out organic pathology as a cause for abnormal pubertal development at this time? A. A 6-year-old white girl who has unilateral thelarche, normal growth velocity, and no pubic hair development. B. A 7-year-old Mexican American boy who has breast development and testicular enlargement. C. A 13-year-old African American girl who has a recent growth spurt and no menarche. D. A 13-year-old white boy who has no testicular enlargement and normal growth velocity. E. A 16-year-old African American girl who has excessive pubic hair and normal menstrual cycles.

HealthyChildren.org Parent Resources from AAP The reader is likely to find material to share with parents that is relevant to this article by visiting this link: http://www.healthychildren.org/English/ages-stages/gradeschool/ puberty/pages/default.aspx.

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The D-test Kamakshya P. Patra, MD*

Introduction ence of inducible clindamycin resis- Traditionally, clindamycin has been tance. His medication is switched to used to combat both methicillin- oral trimethoprim-sulfamethoxazole, sensitive and methicillin-resistant and he experiences a dramatic resolu- Staphylococcus aureus (MSSA and tion of the skin lesions. Follow-up eval- Author Disclosure MRSA) infections because of its low uation reveals no recurrence. Dr Patra has disclosed no financial cost, oral form, optimum bioavail- relationships relevant to this article. ability, excellent tissue penetration, Inducible Macrolide This commentary does not contain a nonrenal clearance, antitoxin effect, Resistance discussion of an unapproved/ and ease of transition from inpatient Three mechanistically similar classes investigative use of a commercial to outpatient management. Over of antibiotics—macrolides (eg, the years, many published reports erythromycin), lincosamide (eg, clin- product/device. documented clinical failures of clin- damycin,) and streptogramin B (eg, damycin in treating S aureus infec- quinupristin)—share a common tions caused by strains that initially binding site on the 23S rRNA sub- demonstrated in vitro sensitivity to unit of the 50S ribosome on bacteria. clindamycin but were resistant to Because of this common site, micro- erythromycin. This outcome was at- organisms may exhibit cross- tributed to macrolide-inducible re- resistance to these agents. This ge- sistance to clindamycin. Routine an- netic makeup of the bacterium that is tibiotic testing can be misleading in associated with cross-resistance is these cases, indicating sensitivity to also called the macrolides, lincos- clindamycin that turns to resistance. amide, and streptogramin B class of

antibiotics (MLSB) phenotype. The Case Study phenotype results from modification A 12-year-old boy presents with eczema of the binding site for these antibiot- complicated by secondary infection. ics via enzymatic methylation of the The culture from a skin lesion grows adenine residue of the 23S rRNA MRSA that is sensitive to clindamy- subunit of 50S ribosome. This meth- cin, vancomycin, and trimethoprim- ylase enzyme is encoded by the erm sulfamethoxazole but resistant to genes. The genetic expression of MLS Abbreviations erythromycin. The boy is treated with B oral clindamycin for 10 days, and the resistance may be constitutive (“al- CLSI: Clinical Laboratory skin lesions resolve. However, 2 weeks ways on,” the MLSBc phenotype) or Standards Institute later, he develops cellulitis at the same inducible (the MLSBi phenotype). site, with purulent drainage. He is Unlike the constitutive genotype, MLSB: macrolides, lincosamide, and streptogramin admitted to the hospital for failed out- the inducible genotype requires the B class of antibiotics patient therapy and is treated with presence of an inducer for erm gene intravenous vancomycin. Repeat cul- expression. When the phenotype is MLSBc: constitutive cross-resistance tures from the site grow MRSA that constitutive (MLSBc), routine in to MLSB antibiotics has exactly the same sensitivity pattern vitro susceptibility tests exhibit resis- MLSBi: inducible cross-resistance as the previous isolate, except that it is tance to all three antibiotic families. to MLSB antibiotics MRSA: methicillin-resistant resistant to clindamycin. A D-test of On the other hand, when the bacte- Staphylococcus aureus the previous isolate confirms the pres- rium has the inducible genotype MSSA: methicillin-sensitive (MLSBi), in vitro tests demonstrate Staphylococcus aureus *Pediatric Resident, Louisiana State University, resistance to erythromycin but sensi- Shreveport, LA. tivity to clindamycin. This dissoci-

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presence of the MLSBi phenotype. A good response occurs if resistant mutants do not emerge or are elimi- nated before full-blown infection ensues. In serious or invasive infections, a positive D-test result should pre- clude the use of clindamycin. A large microbial burden in deep-seated and invasive infections amplifies the pos- sibility of resistant mutants, resulting in treatment failure. Clindamycin, in view of its unique pharmacokinetic properties, is an excellent empiric therapeutic option for treating minor skin and soft-tissue infections. The clinician faces a clinical conundrum as to whether to switch to another antibiotic or continue clindamycin if the D-test result is positive. Close Figure. Positive and negative D-test results. follow-up evalution and monitoring for potential failure or recrudescence ated resistance is attributed to the ence of D-shaped blunting of the is warranted when using clindamycin disparity in the inducing capacities circular zone of growth inhibition for minor infections caused by of erythromycin and clindamycin around the clindamycin disk on the D-test-positive strains. (erythromycin is a good inducer and side facing the erythromycin disk is a The proportion of S aureus strains clindamycin is a poor inducer). positive result. This pattern indicates that have inducible clindamycin re-

However, MLSBi strains have a high the presence of inducible clindamy- sistance varies widely by geographic rate of spontaneous mutation (both cin resistance, mediated by erm region, patient age, methicillin sus- in vivo and in vitro) to constitutive genes. ceptibility, and the passage of time. resistance, which could occur in the Negative D-test result: A circular Cross-sectional studies of pediatric midst of clindamycin therapy. Rou- zone of growth inhibition 21 mm or patients from different hospitals have tine antibiotic susceptibility tests fail greater in diameter with no blunting reported a very broad range of to detect the MLSBi strains. The around the erythromycin disk is a MLSBi prevalence, from 8% of D-test, a simple test also known as negative test result. The result indi- community-acquired MRSA isolates the double-disk diffusion method, is cates pure macrolide resistance with in Houston to 94% of MRSA isolates employed to identify MLSBi resis- retained clindamycin susceptibility. in Chicago. The presence of comor- tance. The erythromycin resistance in this bidity (eg, diabetes, cystic fibrosis, case is attributed to a macrolide- immunodeficiency, postsurgical sta- The D-test specific efflux mechanism, mediated tus) is highly predictive of the organ- In this test, two disks containing by the msr A gene. ism producing a positive D-test re- erythromycin (2 ␮g) and clindamy- sult. Periodic surveillance of the cin (15 ␮g) are placed 15 mm apart Clinical Relevance relative frequency of inducible resis- (edge-to-edge distance) on a A positive D-test result simply im- tance can help in tailoring empiric Mueller-Hilton agar plate inoculated plies the genetic potential of the therapy for suspected S aureus infec- with a standardized suspension (0.5 MLSBi strains to develop resistance tions. McFarland inoculum) of the S aureus to clindamycin during the course of isolate. After overnight incubation at therapy via spontaneous mutation to Guideline: Using the D-test

37.0°C, the test is read and inter- the MLSBc phenotype. However, a Beginning in 2004, the Clinical Lab- preted as follows (Figure): possibility of adequate response to oratory Standards Institute (CLSI) Positive D-test result: The pres- clindamycin remains, despite the recommended the use of the D-test

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for detection of inducible clindamy- appropriate antibiotic therapy and aureus isolates. J Clin Microbiol. 2006; cin resistance in all staphylococcal may contribute to avoidable failures 44:2481–2484 of pharmacotherapy. Prunier AL, Malbruny B, Laurans M, isolates. The recommendation sug- Brouard J, Duhamel JF, Leclercq R. gested that all laboratories report High rate of macrolide resistance in D-test-positive isolates as being resis- Staphylococcus aureus strains from pa- tant to clindamycin. CLSI also sug- tients with cystic fibrosis reveals high Suggested Reading proportions of hypermutable strains. gested that a comment be added: Frank AL, Marcinak JF, Mangat PD, et al. J Infect Dis. 2003;187:1709–1716 “This isolate is presumed to be Clindamycin treatment of methicillin- Sattler CA, Mason EO, Jr, Kaplan SL. Pro- resistant based on detection of in- resistant Staphylococcus aureus infections spective comparison of risk factors and ducible clindamycin resistance. Clin- in children. Pediatr Infect Dis J. 2002; demographic and clinical characteristics 21:530–534 of community-acquired, methicillin- damycin may still be effective in some Lewis JS, Jorgensen JH. Inducible clinda- resistant versus methicillin-susceptible patients.” mycin resistance in staphylococci: Staphylococcus aureus infection in chil- Despite the above guidelines, use should clinicians and microbiologists be dren. Pediatr Infect Dis J. 2002;21: of the D-test still is not universal. concerned? Clin Infect Dis. 2005;40: 910–917 280–285 Siberry GK, Tekle T, Carroll K, Dick J. Physicians in primary care and spe- NCCLS (CLSI). Performance Standards for Failure of clindamycin treatment of cialty settings must be aware of Antimicrobial Susceptibility Testing. methicillin-resistant Staphylococcus au- whether a D-test has been performed Wayne, PA: NCCLS (CLSI); 2004: reus expressing inducible clindamycin to determine the presence of induc- M100–S14 resistance in vitro. Clin Infect Dis. 2003; Patel M, Waites KB, Moser SA, Cloud GA, 37:1257–1260 ible clindamycin resistance in S au- Hoesley CJ. Prevalence of inducible clin- Woods CR. Macrolide-inducible resistance reus isolates. Varying use of the damycin resistance among community- to clindamycin and the D-test. Pediatr D-test may cause delay in initiating and hospital-associated Staphylococcus Infect Dis J. 2009;28:1115–1118

Corrections In the In Brief article entitled “Balance and Vertigo in Children” in the February issue (Pediatr Rev. 2011;32:84–85), the next-to-last sentence in the third column on page 84 should read, “The attack is induced by head movements or positional changes.” This condition is very similar to benign paroxysmal positional vertigo in adults and may be the same condition. Current thinking is that the pediatric disorder is a migraine equivalent, whereas the adult condition is attributed to calcium crystals in the semicircular canals, although the cause of the pediatric disorder is not clear. In the Visual Diagnosis case published in the June issue (Pediatr Rev. 2011;32:253–255), the correct designation for the third author is Kenneth Cochran, RN.

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Likelihood Ratio in Diagnosis Stephanie Crewe, MD,* Peter C. Rowe, MD†

Case Study disease probability (pretest probabil- You are evaluating an 18-year-old ity) and generates the probability of girl who has dysuria. Using your un- disease after the test (posttest proba- derstanding of the epidemiology of uri- bility). Practitioners and patients nary tract infections (UTIs) in adoles- are most interested in the posttest cents, your knowledge of the signs and probability because this knowledge symptoms of UTI, and your clinical can help in deciding whether a diag- judgment of how ill she appears, you nosis can be confirmed and treat- arrive at a pretest estimation that she ment initiated, if a diagnosis can be has a 40% probability of having a UTI. ruled out and treatment withheld, or You wonder how much the probability if further tests are needed. (2) of UTI will change if the urinalysis An effective and practical (if Author Disclosure shows white blood cells (WBCs) in the underused) approach to evaluating Drs Crewe and Rowe have disclosed urine. test results is the likelihood ratio no financial relationships relevant to (LR). LRs provide a reasonable esti- mate of the degree to which a test this article. This commentary does Evaluating Diagnostic Test result will change the probability of not contain a discussion of an Results Diagnostic tests are used in practice an individual patient having a dis- unapproved/investigative use of a to enhance clinical decision making ease. (2) They provide a summary of commercial product/device. and especially to revise probabilities how many times more (or less) in individual patients. (1) A diagnos- likely patients who actually have the tic test is often ordered to modify the disease are to demonstrate a particu- practitioner’s initial estimation of lar result compared with patients who do not have disease. Simply stated, an LR is the percentage of ill people who have a given test result *Assistant Professor, Division of Adolescent divided by the percentage of well in- Medicine, VCU Health Systems, Richmond, VA. † dividuals who have the same result. Professor of Pediatrics, Department of Pediatrics, ϫ Division of General and Adolescent Medicine, Johns (3) LRs can be calculated from a 2 2 Hopkins University School of Medicine, Baltimore, MD. table, as shown in Figure 1. Al-

Disease

Positive Test Present Absent Result a b

Negative Test Result cd

a ϩ cbϩ d Sensitivity ϭ a/(aϩc) Specificity ϭ d/(bϩd) LR for a positive test ϭ [a/(aϩc) Ϭ b/(bϩd)] or sensitivity Ϭ (1-specificity) LR for a negative test ϭ [c/(aϩc) Ϭ d/(bϩd)] or (1-sensitivity) Ϭ specificity.

Figure 1. General calculation of likelihood ratios.

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though posttest probabilities can be- calculated, the Fagan nomogram (Fig. 2) is a convenient tool that shows how a test that has a known LR can change the pretest probabil- ity. (4) An LR greater than 1 increases the probability that the target disorder is present, and the higher the LR, the greater this increase. Conversely, an LR less than 1 decreases the proba- bility of the target disorder, and the smaller the LR, the greater the de- crease in probability. (5) LRs of dif- ferent sizes have different clinical im- plications; the further the LR is from 1.0, the greater its effect on the prob- ability of disease. (3) For example, an LR greater than 10 or less than 0.1 generates large and often conclusive changes from pretest to posttest probability. On the other hand, LRs of 1 to 2 and 0.5 to 1 alter probability to a small (and rarely important) de- gree. (4) LRs offer several advantages in the clinical setting compared with other statistical methods of assessing the properties of diagnostic tests. (1) They are useful across an array of Figure 2. Nomogram for pre- and posttest probabilities and likelihood ratios. A line disease frequencies and allow the test can be drawn from the pretest probability estimate on the left side of the figure results to be applied to a specific pa- through the likelihood ratio to identify the posttest probability of disease. Modified tient. Not only can LRs be used for from Jaeschke et al. (5) Used with permission of the Massachusetts Medical Society. dichotomous results, but they can be applied to tests involving multiple levels of results. This property en- Urinary Tract Infection ables clinicians to interpret and use a (culture-proven) full range of diagnostic test out- comes. (3) Urine Test Present Absent Ն White blood cells 50 17 4 Case Continuation White blood cells Ͻ50 7 32 A recent study demonstrated the util- ity of urgent urine microscopy for im- 24 36 proving the diagnosis of UTI, particu- larly when there are more than 50 Sensitivity ϭ a/(aϩc) ϭ 17/24 ϭ 0.708 Specificity ϭ d/(bϩd) ϭ 32/36 ϭ 0.889 WBCs per high-power field (hpf). (6) LR for a positive test ϭ [a/(aϩc) Ϭ b/(bϩd)] ϭ 17/24 Ϭ 4/36 Ϸ 6.4 Using the study results (Figure 3), the LR for a negative test ϭ [c/(aϩc) Ϭ d/(bϩd)] ϭ 7/24 Ϭ 32/36 Ϸ 0.33 calculated sensitivity of more than 50 WBCs for diagnosing UTI is Figure 3. Calculation of likelihood ratios for urine microscopy. (6) 0.708 and specificity is 0.889. The LR

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of a positive test is approximately 6.4; the LR of a negative test is approxi- mately 0.33. Using the Fagan nomo- gram and a pretest probability of 40%, note how much a positive or negative result on this test changes the posttest probability (Fig. 4). The LR for a pos- itive test increases the posttest probabil- ity of UTI to approximately 80%, while a negative test reduces the posttest probability to below 20%. Your patient has a positive urine microscopy showing more than 50 WBCs/hpf. Knowing that the post- test probability is approximately 80%, you feel comfortable treating with an- tibiotics rather than simply waiting until the culture results return. (1) References 1. Schechter M, Sheps S. Diagnostic testing revisited: pathways through uncertainty. Can Med Assoc J. 1985;132:755–760 2. Akobeng A. Understanding diagnostic tests 2: likelihood ratios, pre- and post-test probabilities and their use in clinical prac- tice. Acta Paediatr. 2006;96:487–491 3. Grimes D, Schultz K. Refining clinical diagnosis with likelihood ratios. Lancet. 2005;365:1500–1505 4. Fagan T. Nomogram for Bayes theorem [letter]. N Engl J Med. 1975;293:257 5. Jaeschke R, Guyatt G, Sackett D, for the Figure 4. Effects of a likelihood ratio of a positive and a negative test for urinary Evidence-Based Working Group. Users’ white blood cells on the posttest probability of your patient having a urinary tract guides to the medical literature. III: How to infection. The pretest probability is 40%. use an article about a diagnostic test, B: What are the results and will they help me in caring for my patients? JAMA. 1994;271:703–707 6. Leman P. Validity of urinalysis and mi- croscopy for detecting urinary tract infec- tion in the emergency department. Eur J Emerg Med. 2002;9:141–147

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Case 1: Leg Cramps, Hand Spasms, Diarrhea, and Substantial Weight Loss in a 12 Year Old Case 2: Hypothermia, Hypoglycemia, and Hyperbilirubinemia in a Neonate Case 3: Recurrent Fevers, Abdominal Pain, and Cervical Lymphadenopathy in a 7 Year Old The reader is encouraged to write Case 1 Presentation transferrin saturation of 3% (0.3), possible diagnoses for each case before turning to the discussion. A 12-year-old previously healthy boy and serum ferritin less than 5 ng/mL presents with leg cramps for 2 weeks (11.23 pmol/L) (21 to 275 ng/mL and spasms of his hands since yester- [47.2 to 617.9 pmol/L]). ESR is day. He also complains of nausea, 46 mm/h and CRP is 9.5 mg/dL Ͻ Author Disclosure bloating, epigastric pain, and recur- (normal 0.05 mg/dL). His serum 25-hydroxyvitamin D concentration Drs Patra, Thomas, Dariya, Herbst, rent watery and loose stools for 1 month. Currently, he is taking lanso- is low at 5.7 ng/mL (14.2 nmol/L) Martin, Drury-Brown, Hill, Kerrigan, prazole for epigastric pain without (normal, 32 to 100 ng/mL [79.9 to Jung-Wu, Tetteh, and Dickson have any relief. He also has a history of 249.6 nmol/L]) and serum parathy- disclosed no financial relationships involuntary weight loss of 10 lb over roid hormone, urine calcium, and relevant to these cases. This 2 months. The family history con- creatinine values are within normal commentary does not contain a tains no findings of note. limits. His tetany and hypocalcemia resolve with calcium replacement. discussion of an unapproved/ On physical examination, the Additional evaluation leads to the investigative use of a commercial boy’s weight is 36 kg (25th percen- tile) and height is 140 cm (10th per- diagnosis. product/device. centile) and he exhibits a positive Trousseau sign and negative Chvos- tek sign. Remaining physical signs, Case 2 Presentation including on abdominal examina- A 1-month-old boy is admitted for Frequently Used Abbreviations tion, are normal. evaluation of hypothermia and leth- ALT: alanine aminotransferase Laboratory evaluation shows hypo- argy. He was born at 34 weeks’ ges- AST: aspartate aminotransferase calcemia (total calcium of 5.3 mg/ tation to a G1 18-year-old woman fol- BUN: blood urea nitrogen dL [1.3 mmol/L], ionized calcium lowing an uncomplicated pregnancy CBC: complete blood count of 2 mg/dL [0.5 mmol/L], and and delivery and had spent 1 week CNS: central nervous system corrected calcium of 6.1 mg/dL in the neonatal intensive care unit for CSF: cerebrospinal fluid [1.5 mmol/L]) as well as hypoalbu- transient hypothermia, hypoglycemia, CT: computed tomography minemia (3 g/dL [30 g/L]). Serum and hyperbilirubinemia requiring ECG: electrocardiography magnesium measures 1.6 g/dL. phototherapy. The hyperbilirubinemia ED: emergency department CBC shows Hgb of 9.3 g/dL (93 g/ was attributed to breastfeeding and EEG: electroencephalography L), Hct of 29% (0.29), WBC count of he was switched to formula feeding ϫ 3 ␮ ϫ 9 ESR: erythrocyte sedimentation 9.9 10 / L (9.9 10 /L), platelet before discharge. A thorough evalu- ϫ 3 ␮ ϫ 9 rate count of 471 10 / L (471 10 / ation for infection yielded negative GI: gastrointestinal L), mean corpuscular volume of results. GU: genitourinary 67 fL, and reticulocyte count of 1% Two weeks after discharge, he is Hct: hematocrit (0.01). Results of the iron studies are readmitted for intermittent hypogly- Hgb: hemoglobin consistent with iron deficiency ane- cemia. Home glucose meter readings MRI: magnetic resonance imaging mia, with a serum iron concentration range from 32 to 89 mg/dL (1.8 to ␮ ␮ WBC: white blood cell of 6 g/dL (1.07 mol/L) (31 to 4.9 mmol/L), despite feedings of 144 ␮g/dL [5.5 to 25.8 ␮mol/L]), 3 to 4 oz every 2 to 3 hours. He has a

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rectal temperature of 35.2°C, scleral sodes, with chills before the onset of tinal parasites performed before en- icterus, and jaundice to the lower fevers. Recurrent fever episodes have doscopy were negative. The serum abdomen. He does not have hepato- been so debilitating that he has immunoglobulin E (IgE) concentra- splenomegaly, and he has normal missed many school days, prompting tion was normal, and radioimmune male genitalia. an investigation for neglect. He has absorption studies for a panel of food His serum glucose concentration had many evaluations in the past, allergens were negative. Evaluation is 36 mg/dL (2.0 mmol/L), total none of which have determined the for celiac disease (duodenal biopsy, bilirubin is 13.3 mg/dL (227.5 cause of his fevers. antigliadin, and antitransglutaminase ␮mol/L), and direct bilirubin is His weight and height are at 95th antibodies) was negative. Results of 3.1 mg/dL (53.0 ␮mol/L). Results percentile. His temperature is the inflammatory bowel disease of additional laboratory tests are as 40.3°C, heart rate is 81 beats/min, (IBD) serology 7 panel were strongly follows: negative full sepsis evalua- respiratory rate is 22 breaths/min, indicative of Crohn disease (CD). tion (blood, urine, and CSF cul- blood pressure is 110/58 mm Hg, The boy was treated with balsalazide, tures); negative urine and serum and oxygen saturation is 98% in room calcium, vitamin D, and pred- studies for cytomegalovirus; normal air. He appears well but tired. Physi- nisolone, which resulted in resolu- CBC, peripheral smear, and reticulo- cal findings are unremarkable except tion of the symptoms, weight gain, cyte count; normal serum electrolyte for enlarged bilateral posterior cervi- and normalization of abnormal labo- values; nonreactive hepatitis A, B, cal lymph nodes, with the largest be- ratory values. and C studies; normal serum gamma ing 1 cm. glutamyl transpeptidase, total pro- Laboratory results show a WBC Differential Diagnosis tein, albumin, alkaline phosphatase, count of 9.6ϫ103/␮L (9.6ϫ109/L) Hypocalcemia at this age has myriad ammonia, and lactic acid values; nor- (69% neutrophils, 19% lymphocytes, causes, including hypovitaminosis D, mal urine organic and amino acids; 10% monocytes, and 2% eosino- malabsorption, hyperphosphatemia, and normal plasma amino acids. phils). Liver function tests and hypomagnesemia, hypoparathyroid- Maximal concentrations of serum urinalysis results are normal. The an- ism, and poor diet as well as disorders AST and ALT are 249 and 139 U/L, tinuclear antibody as well as Epstein- of liver and kidney. Hypoalbumine- respectively. Abdominal ultrasonog- Barr virus and human immunodefi- mia, anemia, and gastrointestinal raphy yields normal results. Addi- ciency virus antibodies are negative. symptoms were clues suggesting ma- tional imaging and laboratory studies ESR is 24 mm/hr and C-reactive labsorption. This boy’s clinical pre- reveal the cause of his hypoglycemia, protein is 9.52 mg/dL. Additional sentation and laboratory evaluation, hypothermia, and hyperbiliru- laboratory evaluation reveals his including serologic markers, led to binemia. diagnosis. the diagnosis of CD.

The Condition Case 3 Presentation Case 1 Discussion CD is an idiopathic chronic inflam- A 7-year-old boy is transferred from Abdominal CT scan was obtained matory disease of the bowel that can another facility to rule out lymphoma because of abdominal pain of long affect any part of the digestive tract, because of a 2-day history of temper- duration and showed thickening of from mouth to anus, and has an an- atures up to 40.6°C and an enlarged the wall of the terminal ileum (Fig. nual incidence of approximately 3 to posterior cervical lymph node. He 1). Endoscopy revealed hypertro- 5 per 100,000. Around 30% of pa- does not have runny nose, cough, phied mucosa at the greater curva- tients are diagnosed before 20 years nausea, vomiting, or diarrhea. He has ture of the stomach, rectosigmoid of age. As per the Montreal classifica- had recurrent episodes of high fever junction, and distal splenic flexure. tion, patients may be classified by (temperatures of 40.0 to 40.6°C) Biopsies from the esophagus, stom- age, location (ileum, colon, ileocolic, over the past 6 years, beginning at 6 ach, duodenum, jejunum, and termi- or upper GI tract), and disease be- months of age, occasionally accom- nal ileum yielded numerous eosino- havior (inflammatory, stricturing, or panied by abdominal pain. The fre- phils (15/high-power field) (Fig. 2). penetrating). (1) Fewer than one quency of fever has been increasing Gastric and duodenal biopsies were third of patients present with the over the past 3 years, now occurring negative for Helicobacter pylori, and triad of abdominal pain, diarrhea, nearly every month. He is usually there was no evidence of cryptitis or and weight loss. Extraintestinal drowsy and sleepy during fever epi- abscess. Serial stool analyses for intes- symptoms are more common in CD

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budesonide. Aminosalicylates such as olsalazine, sulfasalazine, and balsala- zide are prodrugs that have an active 5-ASA moiety. Budesonide is effec- tive only in disease confined to the ileum and ascending colon. Cortico- steroid enemas are used for treating CD that involves the distal colon. Severe disease necessitates therapy with prednisone. Those who have corticosteroid-dependent or refrac- tory disease need thiopurines (aza- thioprine or 6-mercaptopurine). Thiopurine methyltransferase geno-

Figure 1. CT scan of abdomen showing thickening of the terminal ileum. than in ulcerative colitis (UC) and flammation helps to discriminate CD account for approximately 20% of from UC. In this patient, biopsy clinical manifestations. Oral aph- showed only eosinophilia and did not thous ulcers, erythema nodosum, pe- reveal the characteristic granulomas. ripheral arthritis, nephrolithiasis, IBD is characterized by an overpro- cholelithiasis, clubbing, and episcle- duction of eotaxin 1 (a chemokine ritis are more frequent in CD. Peri- responsible for recruitment of eosin- anal fistula, abscess, and skin tags ophils in tissues). The degree of eo- suggest the diagnosis of CD. sinophilia is inversely proportional to Perturbation in calcium homeo- the prognosis. Gastrointestinal eo- stasis is a well-known complication of sinophilia also can result from pri- CD, and approximately one third of mary GI eosinophilia, hypereosino- patients have hypovitaminosis D. philic syndrome, parasitic infestation, Hypocalcemia is more prevalent in allergic disorders, gastroesophageal association with long-standing cases, reflux, Helicobacter pylori infection, winter season, dark skin complexion, drug reactions, celiac disease, lupus upper GI involvement, high ESR, erythematosus, malignancy, and or- low body mass index, hypoalbumin- gan transplantation. emia, inadequate nutritional supple- IBD 7 is a comprehensive sero- mentation, and concomitant gluco- logic test that helps to identify IBD corticoid therapy. and differentiate between UC and Endoscopic hallmarks of CD are CD. It includes seven tests, of which skip lesions, cobblestoning, aph- anti-Saccharomyces cerevisiae anti- thous ulcers, strictures, fistula, ulcer- body, anti-OMPc (antibody to outer ation of ileocecal valves, and rectal membrane protein), and anti- Figure 2. Micrographs of the stomach sparing. These findings, however, CBir1(antibody to flagellin) are the (A), small intestine (B), and large intes- occur in only 64% of cases. The his- serologic markers for CD. tine (C) showing increased eosinophils in tologic finding of noncaseating gran- the lamina propria. The eosinophils are ulomas is diagnostic of CD, but these Treatment readily identified by their characteristic are seen in only 28% of cases. In Mild cases of CD are treated with red-staining cytoplasmic granules. pathologic specimens, transmural in- aminosalicylates or enteric-coated (Original magnification: X400.)

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type or enzyme activity should be (Kamakshya P. Patra, MD, Vedanta ties (such as agenesis of the corpus evaluated before beginning therapy Dariya, MD, Wanda Thomas, MD, callosum and absence of the septum with thiopurines because this status John Herbst, MD, Louisiana State pellucidum), and pituitary hypopla- can affect response and toxicity. University Health Sciences Center, sia with associated hypopituitarism. Methotrexate is used in patients who Shreveport, LA) Generally, two of the three condi- develop resistance or toxicity to aza- tions must be present for diagnosis. thioprine and 6-mercaptopurine. The disorder is equally prevalent in Infliximab (a monoclonal anti- Reference males and females. Most cases are body to tumor necrosis factor) is 1. Silverberg MS, Satsangi J, Ahmad T, et sporadic, but familial cases have been used in patients who have suboptimal al. Toward an integrated clinical, molecular described. For unknown reasons, and serological classification of inflamma- responses to conventional therapy. tory bowel disease: report of a working party cases occur more often in infants Adverse reactions include infusion of the 2005 Montreal World Congress of born to young mothers. reaction, reactivation of latent tuber- Gastroenterology. Can J Gastroenterol. Clinical features in infancy may culosis, opportunistic infections, de- 2005;19(suppl A):5–36 include respiratory distress on the myelinating disease, development of first postnatal day, metabolic acido- autoantibodies, and T-cell lym- sis, hypotonia, severe hypoglycemia, phoma. Metronidazole or cipro- Case 2 Discussion hypogenitalism, and midline CNS floxacin is used as initial therapy for Additional laboratory test results in- defects. As many as two of three pa- perirectal fistulas. Nonhealing cases cluded the following: serum cortisol tients develop endocrine deficits require thiopurines or infliximab. at 10:20 PM was 1.1 ␮g/dL ranging from isolated GHD to pan- Surgery is indicated when there is (30.3 nmol/L) (normal PM range, hypopituitarism; progressive loss of perforation, stricture, intractable 2to10␮g/dL [55.2 to 275.9 nmol/ endocrine function may occur over bleeding, abscess, or disease refrac- L]), thyroid-stimulating hormone time. Both cholestatic and nonchole- tory to medical treatment. Nutri- was 6.25 mIU/mL (normal range, static jaundice have been associated tional rehabilitation and psychosocial 0.6 to 10.0 mIU/mL), and free with the condition. Hyperbiliru- therapy are important adjunctive thyroxine was 0.8 ng/dL (10.3 binemia resolves in most cases once treatments. pmol/L) (normal range, 0.6 to hormonal replacement therapy is ini- CD is a chronic disorder that in- 1.75 ng/dL [7.7 to 22.5 pmol/L]). tiated. Neurologic deficits are com- volves remissions and intermittent Brain MRI revealed an ectopic poste- mon but highly variable, ranging disease flares. Onset before 20 years rior pituitary gland and pituitary from severe intellectual disability to of age is associated with a poorer gland hypoplasia, absence of the an- mild focal deficits. prognosis. Because extensive and terior portion of the septum pelluci- long-standing disease increases the dum, and hypoplasia of the left optic Diagnosis risk for malignancy, screening is rec- nerve and optic chiasm. These find- Hypoglycemia and hypothermia ommended for older patients. ings are consistent with septo-optic (with or without hyperbilirubinemia) dysplasia (SOD), also known as De in the newborn period always should Lessons for the Clinician Morsier syndrome. raise concern for sepsis, and a thor- ● Tetany can be an initial presenta- The patient was treated initially ough evaluation and appropriate tion of CD. A high degree of sus- with hydrocortisone, and levothy- treatment should ensue. picion is required because CD has roxine was added subsequently. Be- Causes of hypoglycemia in the protean manifestations. cause of persistent hypoglycemia, newborn period include hyperinsu- ● Diagnosing CD can be a challenge growth hormone deficiency (GHD) linemia (as occurs in infants born because often endoscopy and bi- was diagnosed clinically, and growth to mothers who have toxemia or ges- opsy may not yield characteristic hormone treatment was instituted. tational diabetes mellitus), limited findings. A combination of clinical glycogen stores (from prematurity, manifestations, laboratory studies The Condition intrauterine growth restriction, star- that include serologic markers, and SOD is a rare condition occurring in vation, and perinatal stress), in- imaging studies may help establish 1 in 10,000 live births. It is highly creased glucose use (seen in hypo- the diagnosis. heterogeneous and defined loosely thermia, polycythemia, and sepsis), ● Gastrointestinal eosinophilia can by the triad of optic nerve hypoplasia, endocrinopathies (such as adrenal be a histologic finding in CD. midline neuroradiologic abnormali- insufficiency or GHD), decreased

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glycogenolysis, diminished gluco- outcome in infants who have biliary consider the diagnosis when evalu- neogenesis, and inborn errors of atresia. ating an infant who has hypoglyce- metabolism. mia and hypothermia. Evaluation for hypoglycemia Management ● Unexplained hypoglycemia should should be performed when the pa- Once the diagnosis of SOD is con- be evaluated. Urgent treatment is tient is symptomatic (blood glucose firmed, appropriate treatment should essential to prevent adverse neuro- Ͻ50 mg/dL [2.8 mmol/L]) and be initiated. Urgent treatment of hy- logic outcomes. should include assessment of serum poglycemia may require intravenous ● It is essential that treatment with glucose and insulin, cortisol, growth dextrose. Therapy with hydrocorti- glucocorticoid be initiated before hormone, lactic acid, free fatty acids, sone and growth hormone may be thyroid hormone replacement so and beta-hydroxybutyrate as well as a necessary for long-term maintenance adrenal crisis is not precipitated. complete metabolic panel that in- of euglycemia. Thyroid hormone re- Treatment with other pituitary cludes liver function tests. In addi- placement must be instituted as soon hormones, such as growth hor- tion, plasma concentrations of am- as the diagnosis of thyroid hormone mone and antidiuretic hormone, monia, an acyl-carnitine profile, and deficiency is established; long-term then can be instituted as needed. urine organic acids should be mea- treatment with thyroid hormone, in- ● Hyperbilirubinemia (cholestatic and sured. The newborn screen results volving careful monitoring of con- noncholestatic) often is present in should be reviewed. centrations and titration of dosage, infants who have hypopituitarism. At 2 weeks of age, any infant who offers the best outlook for physical ● Neonatal cholestasis is always has jaundice should be evaluated by growth and neurodevelopmental pathologic and requires further measuring total serum bilirubin and progress. Because treatment with evaluation. conjugated bilirubin. Elevation of thyroid hormone can precipitate ad- conjugated bilirubin in infancy is renal crisis in patients who have un- (Julie Martin, MD, Marcie Drury- defined as a serum concentration treated adrenal insufficiency, replace- Brown, MD, Ivor Hill, MD, Wake greater than 1.0 mg/dL (17.1 ment of glucocorticoid must precede Forest University Health Sciences, ␮mol/L) if the total bilirubin is less thyroid hormone treatment. Contin- Winston-Salem, NC; James Kerri- than 5.0 mg/dL (85.5 ␮mol/L) or ued assessment and appropriate gan, MD, East Tennessee Children’s more than 20% of the total bilirubin treatment of other hormonal defi- Hospital, Knoxville, TN) if the total bilirubin is greater than ciencies, such as diabetes insipidus 5.0 mg/dL (85.5 ␮mol/L). and hypogonadism, is essential. Af- Although a large number of con- fected infants also need evaluation by Case 3 Discussion ditions are associated with conju- specialists in ophthalmology, neurol- The boy’s immune evaluation showed gated hyperbilirubinemia, relatively ogy, and childhood development. serum IgA of 84 mg/dL (840 mg/L) few account for the majority of cases. This patient was treated with thy- (normal, 33 to 202 mg/dL [330 to Idiopathic neonatal hepatitis syn- roid hormone, hydrocortisone, and 2,020 mg/L]), IgG of 669 mg/dL drome and biliary atresia account for growth hormone. His hypoglycemia, (6.7 g/L) (normal, 633 to 70% to 80% of cases, and alpha-1- hypothermia, and hyperbiliru- 1,280 mg/dL [6.3 to 12.8 g/L]), antitrypsin deficiency accounts for binemia resolved, and the serum and IgM of 62 mg/dL (620 mg/L) another 5% to 15%. The initial step in transaminase values normalized. His (normal, 48 to 207 mg/dL [480 to evaluation should be to identify growth is being monitored, as are his 2,070 mg/L]). His IgD concentra- treatable disorders of neonatal developmental progress, visual func- tions, however, were significantly el- hepatitis syndrome, such as sepsis, tion, and signs of possible diabetes evated at 335 mg/dL (3,350 mg/L) other neonatal infections (such as insipidus and hypogonadism. The (normal, 4 to 41 mg/dL [40 to TORCH infections), hypothyroid- latter condition typically is not diag- 410 mg/L]). Thus, a diagnosis of ism, panhypopituitarism, and in- nosed until the expected time of pu- hyperimmunoglobulin D syndrome born errors of metabolism (galac- bertal development. (HIDS) was established. tosemia). The next step is directed Hereditary periodic fever syn- at evaluation of possible extrahepatic Lessons for the Clinician dromes (HPFSs), or human auto- biliary atresia because surgical in- ● Hypopituitarism in infancy is a po- inflammatory syndromes, represent a tervention within the first 2 post- tentially life-threatening but treat- group of disease processes that result natal months results in improved able condition. It is important to in recurrent episodes of fever, usually

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caused by a disturbance in the mech- headache. Other common symptoms condition may be that episodes are anisms that control and mediate in- include abdominal pain, diarrhea, nau- precipitated by vaccinations and mild flammation. These disorders typically sea, vomiting, and arthralgia. Up to viral infections. are suspected after infectious causes 90% of patients have lymphadenopa- HIDS can be diagnosed when the have been ruled out. thy during fever episodes, usually in patient presents with the previously HPFSs are inherited disorders. Pa- the cervical region. Among the cutane- described symptoms and has an ele- tients usually present with high tem- ous manifestations are erythematous vated serum IgD concentration peratures, along with nonspecific con- macular rashes, papules, and urticaria. (Ͼ13 mg/dL [130 mg/mL]). Be- stitutional symptoms such as joint More than two thirds of patients expe- cause IgD values sometimes can be pain, fatigue, abdominal pain, and rience the first episode of fever before normal in the condition, if the pa- rash. Symptoms usually resolve on res- their first birthdays. tient presents with clinical features olution of fever, which may take days The most common characteristic strongly suggestive of HIDS, genetic to weeks without any medical inter- of HIDS is significantly elevated se- testing can be performed. During the ventions. Familial Mediterranean fever rum IgD concentrations. However, attacks, patients usually have elevated (FMF) is by far the most common serum IgD values may be normal un- acute-phase reactants. Some patients HPFS. til age 3 years. The prevalence of can present with elevated serum IgA FMF is an autosomal recessive dis- HIDS is higher in individuals of values. Because patients have an in- order caused by a mutation in the Dutch or French origin, but the dis- ability to metabolize mevalonic acid, Mediterranean fever (MEFV) gene on order can be found in individuals of mevalonic acid can be detected in the chromosome 16, which encodes the other European ethnic groups. urine. This situation can be assessed protein pyrin. Pyrin is involved in reg- HIDS follows an autosomal reces- by determining the ratio of meval- ulating interleukin-1-beta (IL-1␤). sive inheritance pattern, and the ge- onic acid to creatinine in urine. Affected patients usually present with netic defect is found on chromosome However, this finding should not be abdominal, chest, and joint pains, 12, specifically in the q24 chromo- used as a confirmatory test; rather, it symptoms that sometimes lead to un- some region. Patients who have should be considered as supporting necessary laboratory and radiographic HIDS have reduced activity of me- evidence for the diagnosis. Cur- evaluation and even laparotomy. valonic kinase, an enzyme that me- rently, studies are evaluating leuko- Amyloidosis is a common complica- tabolizes mevalonic acid, an interme- triene E4 concentrations in urine as tion of FMF, sometimes resulting in diate product of cholesterol and another diagnostic tool for HIDS. renal failure. isoprenoid biosynthesis. It is pro- Another periodic fever syndrome is posed that the decrease in isoprenoid Treatment tumor necrosis factor (TNF) receptor- end-products leads to increased pro- There is no known definitive therapy 1-associated periodic fever (TRAPS), duction of IL-1␤, leading to in- for HIDS. However, colchicine, non- which is also known as familial Hiber- creased inflammation and fever. Al- steroidal anti-inflammatory drugs, nian fever. The mode of transmission is though patients who have FMF and immune globulin intravenous, cyclo- autosomal dominant with incomplete TRAPS develop amyloidosis, pa- sporine, glucocorticoids, statins, and penetrance. The defect occurs in the tients who have HIDS very rarely anticytokine therapies such as IL-1 gene encoding for the TNF receptor. develop this complication. receptor antagonists and TNF-␣ an- Affected patients usually present with tagonists have been tried with some fevers for at least 5 days and up to Diagnosis success. 2 weeks. The fever typically is accom- The median period from onset of panied by conjunctivitis and periorbital disease to diagnosis is usually 10 Lessons for the Clinician edema, sometimes with joint pain, years because the disease is not sus- ● An accurate and detailed history in rash, and abdominal pain. pected until the history reveals a cy- patient who experiences prolonged clical pattern of fever over time. It is fever may prevent unnecessary lab- The Condition important, however, to diagnose the oratory evaluation. HIDS was described first in 1984 by condition earlier rather than later be- ● It is important to consider heredi- Jos van der Meer in the Netherlands. cause early detection can prevent un- tary fever syndromes in the differ- (1) HIDS is characterized by recurrent necessary extensive evaluations and ential diagnosis when a patient temperatures up to 39.0°C, accompa- missed school days for patients and presents with frequent unexplained nied by chills, lymphadenopathy, and workdays for parents. A clue to the episodes of fever.

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● Early diagnosis of periodic fever Harbor-UCLA Medical Center, Da- periodic fever: a new syndrome. Lancet. syndromes is important to monitor vid Geffen UCLA School of Medicine, 1984;323:1087–1090 for and prevent complications. Torrance, CA) To view Suggested Reading lists for Reference these cases, visit http://pedsinreview. (Sandy Jung-Wu, MD, Beatrice 1. Van der Meer JWM, Vossen JM, Radl J, aappublications.org and click on “In- Tetteh, MD, Patricia Dickson, MD, et al. Hyperimmunoglobulinaemia D and dex of Suspicion.”

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In Brief

Tumor Markers in Infancy and Childhood Rosanna Ricafort, MD Tumor markers are substances found in neoplastic conditions are associated The Children’s Hospital abnormal amounts in the blood, urine, with an elevation in serum bHCG, most at Montefiore or tissues that can be used in the commonly, chronic renal insufficiency. Bronx, NY diagnosis, staging, treatment, and sur- The use of bHCG as a tumor marker is veillance of patients who have cancer. based on its association with tropho- The two most common tumor markers blastic differentiation in malignant Author Disclosure in pediatric oncology, ␣-fetoprotein germ cell tumors such as choriocarci- Drs Ricafort and Adam have (AFP) and ␤-human chorionic gonado- nomas and embryonal carcinomas. disclosed no financial relationships tropin (bHCG), can aid in the treatment Although evidence-based clinical relevant to this In Brief. This of children who have either known practice guidelines exist for using tu- cancer or genetically predisposed can- mor markers as screening tools for sev- commentary does not contain a cer syndromes. eral cancers in adults, most notably, discussion of an unapproved/ AFP is a glycoprotein normally syn- breast and colorectal cancers, such investigative use of a commercial thesized by the fetal yolk sac, liver, and mass screening guidelines do not exist product/device. intestine that serves as a fetal type of for the pediatric population. Cancer binding protein. Reference values for surveillance protocols in pediatrics are serum AFP in the neonatal period and limited to patients who have genetic Alpha 1-Fetoprotein (AFP) Reference infancy up to 2 years of age have been syndromes that predispose to cancer. Values in Infants up to 2 Years of established from normal term babies Beckwith-Wiedemann syndrome, the Age. Blohm ME, Vesterling-Ho¨rner D, who did not have additional factors best described of several overgrowth Calaminus G, Go¨bel U. Pediatr associated with AFP elevation. Espe- syndromes that are associated with an Hematol Oncol. 1998;15:135–142 cially in the first few postnatal months, increased incidence of childhood can- Alpha-Fetoprotein and Beta-Human the range of values is broad. Initially, cer, carries about an 8% risk of intra- Chorionic Gonadotropin: Their Clini- AFP has a half-life of less than 1 week; abdominal cancers in early childhood, cal Significance as Tumour Markers. later, the half-life appears to be longer. most commonly, Wilms tumor and Gregory JJ, Jr, Finlay JL. Drugs. 1999; Elevations of serum AFP can be seen in hepatoblastoma. Although surveillance 57:463–467 association with certain nonneoplastic guidelines vary, the general practice is Diagnostic Value of Alpha 1- conditions, most commonly in acute to screen with abdominal/pelvic ultra- Fetoprotein and Beta-Human Chori- liver disease, such as extrahepatic bili- sonography and serum AFP measure- onic Gonadotropin in Infancy and Childhood. Schneider DT, Calaminus ary atresia and hepatitis. In addition, ments every 3 to 4 months until age 4 G, Go¨bel U. Pediatr Hematol Oncol. hereditary disorders such as ataxia tel- years for hepatoblastoma, with pelvic 2001;18:11–26 angiectasia and tyrosinemia can be as- ultrasonographic imaging continued The Prognostic Value of Tumor Markers sociated with serum AFP elevation. The until age 8 years for Wilms tumor. in Newly Diagnosed Patients With use of AFP as a tumor marker is based Initial diagnostic evaluation of chil- Primary Central Nervous System on its association with epithelial liver dren in whom a malignant germ cell Germ Cell Tumors. Kim A, Ji L, Bal- tumors (hepatoblastoma and hepato- tumor or liver tumor is suspected in- maceda C, et al. Pediatr Blood Can- cellular carcinoma) and certain malig- cludes quantitative measurement of se- cer. 2008;51:768–773 nant germ cell tumors (yolk sac tumors rum AFP and bHCG. Liver function tests Timing and Magnitude of Decline in [also known as endodermal sinus tu- always should accompany AFP assess- Alpha-Fetoprotein Levels in Treated mors] and embryonal carcinomas). ment to exclude nonmalignant hepatic Children with Unresectable or Met- astatic Hepatoblastoma are Predic- bHCG is a glycoprotein produced diseases that can be associated with tors of Outcome: A Report from the physiologically by the trophoblasts of elevated AFP concentrations. For a child Children’s Cancer Group. Van Torn- the placenta to stimulate hormonal who has a liver mass, quantification of out JM, Buckley JD, Quinn JJ, et al. production and maintain pregnancy. serum AFP aids in the diagnosis. The J Clin Oncol. 1997;15:1190–1197 Aside from pregnancy, only a few non- most common primary malignant liver

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tumor in childhood, hepatoblastoma, is mount. A patient who has an intracra- Serum tumor marker surveillance is associated with higher AFP values than nial germ cell tumor associated with a valuable tool in assessing patients for hepatocellular carcinoma, which is elevated AFP or bHCG in the serum or relapse of malignant germ cell tumors more common in adolescents. Liver me- CSF should be treated, even in the and liver tumors. In general, low-risk tastases from other malignant tumors, presence of contradicting histology, for patients who are treated with surgery such as neuroblastoma, or benign con- a nongerminomatous germ cell tumor, alone are followed more frequently ditions, such as hepatic hemangioma, which has a poorer prognosis than a than those who receive adjuvant che- are not associated with elevated AFP pure germinoma and, thus, requires motherapy, with the aim of detecting concentrations. more aggressive therapy. relapse early to allow timely interven- When a young child who has a liver Although the initial concentration tion. A consistent increase in serum mass is unable to undergo a diagnostic of tumor markers at diagnosis has been tumor markers in some cases can pre- biopsy because of respiratory compro- investigated as a prognostic indicator, a cede a clinically apparent relapse. Most mise, abdominal compartment syndrome, more common trend is to follow tumor practice guidelines advocate for at or uncorrectable coagulopathy, a mark- marker rate and magnitude of decline least monthly serum tumor marker edly elevated serum AFP value is specific as an indicator of response to therapy. screening during the first year after enough to allow for hepatoblastoma- Persistence, a secondary increase, or therapy, followed by more extended directed emergent therapy. Of note, consistent prolongation beyond the es- intervals thereafter for approximately hepatoblastoma accompanied by low AFP timated half-life of tumor marker se- 5 years. values (Ͻ100 ng/mL) is associated with rum values may indicate residual or Unlike in the adult population, the presence of unfavorable small cell recurrent malignancy. The half-life of population-wide tumor marker screen- undifferentiated histology and a poor AFP is estimated at 7 days and bHCG at ing of pediatric patients for malignant prognosis. Also, although hepatocellular 3 days. A transient elevation in AFP may tumors is not appropriate. Elevations in carcinoma typically is associated with not necessarily herald persistent active AFP and bHCG need to be evaluated in lower AFP values than hepatoblastoma, a tumor; liberation of AFP from dying clinical context to distinguish malig- less common fibrolamellar variant of tumor cells may cause a reversible in- nant from nonmalignant sources. In hepatocellular carcinoma secretes high crease immediately following the initi- pediatric oncology practice, these tu- amounts of AFP. ation of chemotherapy. Liver dysfunc- mor markers aid in the prognosis and AFP and bHCG measurements from tion related to therapy also may cause treatment of patients who have secret- serum, cerebrospinal fluid (CSF), or se- an increase in AFP. In hepatoblastoma, ing malignant tumors, most commonly, rous effusions can aid in establishing serum AFP values generally normalize intracranial and peripheral malignant the diagnosis of germ cell tumors. In within 4 to 6 weeks following a com- germ cell tumors and the primary liver certain well-defined clinical settings, plete surgical resection; persistence of tumors hepatoblastoma and hepatocel- elevated tumor markers can allow for elevated AFP beyond this period war- lular carcinoma. the diagnosis of malignant germ cell rants careful evaluation for residual or tumors without the need for histologic metastatic disease. Comment: Urine vanillylmandelic confirmation. In mixed germ cell tu- Among children who have initially acid and homovanillic acid, metabolites mors, the presence of elevated serum unresectable or metastatic hepatoblas- of norepinephrine and dopamine, are AFP or bHCG concentrations should toma at diagnosis in whom primary tumor markers for neuroblastoma, the elicit a careful, meticulous review of surgery is delayed, the decline of tumor most common cancer of infancy and the histology for elements of yolk sac markers following neoadjuvant chemo- the most common extracranial solid tumor or choriocarcinoma, respectively. therapy before surgical resection has tumor of childhood. Studies in Japan, In large immature teratomas that lack been demonstrated to have prognostic Great Britain, Germany, and Canada morphologic evidence of yolk sac tu- value. An decline of at least 1 log from have investigated screening programs, mor, elevated serum AFP values should baseline is associated with improved usually at 6 months of age, to detect prompt immunohistochemistry analysis survival. In malignant nonseminoma- undiagnosed neuroblastomas. The Na- of the tumor for microscopic foci of tous germ cell tumors, AFP and bHCG tional Cancer Institute has determined malignant yolk sac elements. are excellent tumor markers for moni- that such screening does not result in Because biopsy technique may allow toring the response to therapy. Tumor decreased mortality. Aside from false- for only a small sampling of an intra- marker decline has been evaluated as a positive results, most tumors identified cranial germ cell tumor, serum and CSF potential prognostic marker to guide by mass screening programs are early- assessment for AFP and bHCG is para- further therapy in such patients. stage neuroblastomas, which have a

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high likelihood of spontaneous regres- ten to treatment that is more likely to prostate-specific antigen as a screen sion. In other words, most of the tumors be toxic than beneficial. The ability to for prostate cancer. found would have disappeared without screen does not mean that all screening ever becoming symptomatic, but their should be undertaken, an issue raising identification leads to the enormous controversy for our colleagues in adult Henry M. Adam, MD anxiety associated with cancer and of- medicine about the use, for example, of Editor, In Brief

In Brief

Pheochromocytoma Sadiqa Edmonds, MD Pheochromocytoma, a rare disease oc- The Table summarizes four familial Daniel M. Fein, MD curring more often in adults than in syndromes commonly associated with Alison Gurtman, MD children, accounts for only about 1% of pheochromocytoma. Von Hippel-Lindau Children’s Hospital at Montefiore pediatric hypertension and often is as- syndrome (VHL), a neurocutaneous syn- Bronx, NY sociated with a variety of genetic syn- drome associated with 20% of all dromes. The National Registry of Child- pheochromocytomas, carries a 10% to Author Disclosure hood Cancers reports an incidence of 20% risk of developing pheochromo- Drs Edmonds, Fein, Gurtman, and 0.11 benign and 0.02 malignant pheo- cytoma. The tumors can be bilateral or chromocytomas per 1 million children. extra-adrenal, but only 5% associated Adam have disclosed no financial Eighty-five percent of pheochromocy- with VHL are malignant. relationships relevant to this In Brief. tomas are located in the adrenal Multiple endocrine neoplasia (MEN) This commentary does not contain a glands; the rest develop in the extra- types IIA and IIB are associated with discussion of an unapproved/ adrenal parasympathetic and sympa- pheochromocytoma. MEN IIA manifests investigative use of a commercial thetic paraganglia. Most tumors are with parathyroid hyperplasia, adrenal product/device. less than 5 cm in size, and 25% to 33% medullary hyperplasia or pheochromo- are bilateral. Approximately 10% of cytoma, and medullary thyroid car- intra-adrenal and 40% of extra-adrenal cinoma. MEN IIB is characterized by Phaeochromocytoma in Children. Armstrong R, Sridhar M, Greenhalgh pheochromocytomas are malignant. In neuromas, medullary carcinoma, and KL, et al. Arch Dis Child. 2008;93: childhood, these tumors are more prev- pheochromocytoma. The risk of pheo- 899–904 alent in boys than girls, but during chromocytoma in MEN IIA is about Clinical Problem Solving: A Crisis in adolescence this trend reverses, possi- 50% and in MEN IIB is higher. Late Pregnancy. Desai AS, Chutkow bly because of hormonal influences. Neurofibromatosis type 1, an auto- QA, Edelman E, et al. N Engl J Med. In children 18 years of age and somal dominant syndrome associated 2009;361:2271–2277 younger, about 60% of pheochromo- with cafe´ au lait macules, Lisch nod- Adrenal Dysfunction. Speiser PW. In: cytomas have an associated germline ules, neurofibromas, optic gliomas, and McInerny TK, Adam HM, Campbell mutation, and in children younger than axillary or inguinal freckling, carries a DE, Kamat DM, Kelleher KJ, eds. 10 years, this number increases to 70%. 1% risk of pheochromocytoma. In fa- American Academy of Pediatrics Familial genetic syndromes predispose milial paraganglioma syndrome, which Textbook of Pediatric Care. Elk Grove to the development of pheochromocy- is also autosomal dominant, paragan- Village, IL: American Academy of toma by altering sympathetic neuronal gliomas develop in the head, neck, Pediatrics; 2009:1808–1818 cell precursor apoptosis. A family his- chest, abdomen, and pelvis; about 20% A Current Review of the Etiology, Di- agnosis and Treatment of Pediatric tory of genetic syndromes is common of affected patients develop a pheo- Pheochromocytoma and Paragangli- but not equivocal in affected children. chromocytoma. oma. Waguespack SG, Rich T, Grubbs Many associated syndromes are auto- Pheochromocytomas become symp- E. J Clin Endocrinol Metab. 2010;95: somal dominant, but spontaneous mu- tomatic from the increased secretion of 2023–2037 tations occur. norepinephrine (predominant in chil-

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high likelihood of spontaneous regres- ten to treatment that is more likely to prostate-specific antigen as a screen sion. In other words, most of the tumors be toxic than beneficial. The ability to for prostate cancer. found would have disappeared without screen does not mean that all screening ever becoming symptomatic, but their should be undertaken, an issue raising identification leads to the enormous controversy for our colleagues in adult Henry M. Adam, MD anxiety associated with cancer and of- medicine about the use, for example, of Editor, In Brief

In Brief

Pheochromocytoma Sadiqa Edmonds, MD Pheochromocytoma, a rare disease oc- The Table summarizes four familial Daniel M. Fein, MD curring more often in adults than in syndromes commonly associated with Alison Gurtman, MD children, accounts for only about 1% of pheochromocytoma. Von Hippel-Lindau Children’s Hospital at Montefiore pediatric hypertension and often is as- syndrome (VHL), a neurocutaneous syn- Bronx, NY sociated with a variety of genetic syn- drome associated with 20% of all dromes. The National Registry of Child- pheochromocytomas, carries a 10% to Author Disclosure hood Cancers reports an incidence of 20% risk of developing pheochromo- Drs Edmonds, Fein, Gurtman, and 0.11 benign and 0.02 malignant pheo- cytoma. The tumors can be bilateral or chromocytomas per 1 million children. extra-adrenal, but only 5% associated Adam have disclosed no financial Eighty-five percent of pheochromocy- with VHL are malignant. relationships relevant to this In Brief. tomas are located in the adrenal Multiple endocrine neoplasia (MEN) This commentary does not contain a glands; the rest develop in the extra- types IIA and IIB are associated with discussion of an unapproved/ adrenal parasympathetic and sympa- pheochromocytoma. MEN IIA manifests investigative use of a commercial thetic paraganglia. Most tumors are with parathyroid hyperplasia, adrenal product/device. less than 5 cm in size, and 25% to 33% medullary hyperplasia or pheochromo- are bilateral. Approximately 10% of cytoma, and medullary thyroid car- intra-adrenal and 40% of extra-adrenal cinoma. MEN IIB is characterized by Phaeochromocytoma in Children. Armstrong R, Sridhar M, Greenhalgh pheochromocytomas are malignant. In neuromas, medullary carcinoma, and KL, et al. Arch Dis Child. 2008;93: childhood, these tumors are more prev- pheochromocytoma. The risk of pheo- 899–904 alent in boys than girls, but during chromocytoma in MEN IIA is about Clinical Problem Solving: A Crisis in adolescence this trend reverses, possi- 50% and in MEN IIB is higher. Late Pregnancy. Desai AS, Chutkow bly because of hormonal influences. Neurofibromatosis type 1, an auto- QA, Edelman E, et al. N Engl J Med. In children 18 years of age and somal dominant syndrome associated 2009;361:2271–2277 younger, about 60% of pheochromo- with cafe´ au lait macules, Lisch nod- Adrenal Dysfunction. Speiser PW. In: cytomas have an associated germline ules, neurofibromas, optic gliomas, and McInerny TK, Adam HM, Campbell mutation, and in children younger than axillary or inguinal freckling, carries a DE, Kamat DM, Kelleher KJ, eds. 10 years, this number increases to 70%. 1% risk of pheochromocytoma. In fa- American Academy of Pediatrics Familial genetic syndromes predispose milial paraganglioma syndrome, which Textbook of Pediatric Care. Elk Grove to the development of pheochromocy- is also autosomal dominant, paragan- Village, IL: American Academy of toma by altering sympathetic neuronal gliomas develop in the head, neck, Pediatrics; 2009:1808–1818 cell precursor apoptosis. A family his- chest, abdomen, and pelvis; about 20% A Current Review of the Etiology, Di- agnosis and Treatment of Pediatric tory of genetic syndromes is common of affected patients develop a pheo- Pheochromocytoma and Paragangli- but not equivocal in affected children. chromocytoma. oma. Waguespack SG, Rich T, Grubbs Many associated syndromes are auto- Pheochromocytomas become symp- E. J Clin Endocrinol Metab. 2010;95: somal dominant, but spontaneous mu- tomatic from the increased secretion of 2023–2037 tations occur. norepinephrine (predominant in chil-

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about the pharmacologic agent of choice Table. Familial Syndromes Associated With has not been reached, but the preferred Pheochromocytoma method is alpha-adrenergic blockade with the nonselective irreversible medi- Risk of Syndrome Pheochromocytoma Genetic Mutation cation phenoxybenzamine. Administra- tion should begin 2 weeks before surgery Von Hippel-Lindau syndrome 10% to 20% Chromosome 3p25.5 to allow for correction of hyperten- Multiple endocrine neoplasia >50% RET gene on 10q11.2 syndrome sion, starting at a low dose and titrating Neurofibromatosis type 1 1% NF1 gene on 17q11.2 upward, while monitoring for adverse Familial paraganglioma 20% SDHB/SDHD gene on 11q23 effects such as abdominal pain, nasal syndrome congestion, and orthostasis. Selective alpha-1-adrenergic blockers are typically avoided preoperatively because they of- dren), epinephrine, and dopamine. Chil- lished which of these tests is superior. ten result in incomplete alpha-adrenergic dren often have sustained hyperten- For children who have episodic symp- blockade. sion as their primary sign, which may toms, the best time to assess concen- Once alpha-adrenergic blockade be severe enough to cause encephal- trations is during or immediately after has been obtained, beta-adrenergic opathy or cardiac failure. Children are an episode, when hormone values are blockade is instituted to blunt reflex less likely than adults to present with highest. Borderline elevations typically tachycardia. Beta-adrenergic antago- the classic triad of tachycardia, head- are false-positive findings. nists never should be started alone ache, and diaphoresis. Associated find- Diagnostic imaging can start with because blockage of the vasodilatory ings can include visual changes, nau- ultrasonography in symptomatic pa- effects of beta-adrenergic receptors sea, vomiting, constipation, diarrhea, tients. Computed tomography (CT) scan leads to unopposed alpha-adrenergic orthostatic hypotension, urinary symp- and magnetic resonance imaging (MRI) activity and worsening hypertension. toms, psychiatric disturbances, and with contrast both have high sensitiv- Increased salt intake and intravenous weight loss. Although patients have ity. Iodinated contrast media can con- fluids for volume expansion complete presented with symptomatic pheochro- tribute to a hypertensive crisis, so it the typical preoperative regimen. mocytomas after glucocorticoid ther- is prudent to avoid using contrast in Alternative regimens for preoperative apy, this outcome is uncommon in pe- patients who have significant hyper- management include administration of diatrics. All reported cases have been tension. MRI is a better choice for calcium channel blockers, such as nicar- adults. The mechanism is still being locating extra-adrenal tumors. A less dipine, and inhibition of catecholamine debated. sensitive but more specific method of synthesis using the tyrosine hydroxyl- In addition to the effects of hor- diagnosis is a 131Ior123I-metaiodo- ase inhibitor alpha-methyl-para-tyrosine mones released by the pheochromocy- benzylguanidine (MIBG) scan. MIBG is (metyrosine). These agents typically are toma, the mass effect of the tumor may a radioiodine-labeled norepinephrine reserved for patients who have refractory cause abdominal pain and distention or analog that is taken up by tumor cells hypertension despite combined alpha- back pain. Laboratory abnormalities can but not by healthy adrenal medullary and beta-adrenergic blockade or for include increased erythrocyte sedimen- cells. The test is useful for discovering those experiencing intolerable adverse tation rate, polycythemia, leukocytosis, multiple tumors if CT scan or MRI is effects. and hyperglycemia. Panic attacks, thy- positive. Functional positron emission Laparoscopy often is used for resec- rotoxicosis, intracranial lesions, reno- tomography is another diagnostic tool tion of both benign and malignant vascular disease, and sympathomimetic that is especially useful when the diag- tumors smaller than 10 cm. Total adre- drug use are in the differential diag- nosis is equivocal. nalectomy is performed for unilateral nosis. Although surgery is the preferred treat- tumors located in the adrenal gland. The diagnosis depends on demon- ment option, tumor resection should not Patients who have bilateral pheochro- strating both catecholamine excess be attempted without preoperative med- mocytomas more frequently undergo and evidence of a tumor on imaging. ical preparation to oppose catecholamine- bilateral cortical-sparing adrenalecto- Measuring fractionated metanephrines, induced cardiovascular effects (immedi- mies to prevent the need for lifelong the metabolites of catecholamines, in ate and anticipated physiologic changes corticosteroid replacement. Monitoring urine or plasma is the most sensitive during surgery) as well as to assure is required during surgery because hyper- test. However, no consensus has estab- volume expansion. Universal consensus tension can occur from manipulation of

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the tumor and immediately after tumor who have no underlying genetic condi- and pathology classes hearing about removal. Adjunctive therapy, such as tion, annual follow-up is likely to be pheochromocytoma than essential hy- high-dose 131I-MIBG, may be used in sufficient after the first 6 months. How- pertension. Although pheochromo- patients who develop metastatic disease. ever, lifelong follow-up is required be- cytoma is in the differential diagnosis, Removal of a benign pheochromo- cause tumors can recur, particularly we hope that in the midst of an epi- cytoma should result in resolution of with familial pheochromocytomas that demic of childhood obesity and associ- symptoms. Hypertension beyond 24 hours are part of a genetic syndrome. ated hypertension, it is not still topping after resection raises concern for re- the list. tained tumor. Initial follow-up consists of Comment: When I was in medical monthly blood pressure and urinary cat- school (granted, a long time ago), we Henry M. Adam, MD echolamine measurements. In patients actually spent more time in physiology Editor, In Brief

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Caring for Abused Children Marilyn A. Fisher, MD, MS*

Objectives After completing this article, readers should be able to: 1. Recognize the primary reason for parental conflict of interest regarding continuation versus withdrawal of life-sustaining medical treatment after severe child abuse. 2. Realize that brain death is ethically indistinguishable from cardiopulmonary death. 3. State ethical arguments for and against covert surveillance in suspected cases of factitious disorder by proxy. Author Disclosure 4. Understand dilemmas encountered by health-care professionals regarding Dr Fisher has disclosed no financial the reporting and conviction of perpetrators of violence affecting children. relationships relevant to this article. 5. Be aware of the difficulty in balancing beneficence and nonmaleficence to This commentary does not contain a the child when determining whether he or she will be served best by foster discussion of an unapproved/ care placement. investigative use of a commercial product/device. Introduction rectives, parents or guardians must Suspected or confirmed child abuse decide on his or her behalf. Consid- is devastating for families and their eration of likely harms and benefits of children. Treatment of children who acute and chronic treatment, degree are abused or exposed to violence and duration of pain and suffering, may be distressing, but clinicians anticipated level of functioning, and must be adept in dealing with the expected duration of life are neces- ethical dilemmas inherent in provid- sary to determine the child’s best in- ing care to such children to make terest. (1) If, after careful consider- the best medical decisions on their ation, it is determined that the child behalf. would be reasonably expected to lead Severe, Permanent Incapacity a life consisting of little or no plea- sure but only of permanent or pro- In the wake of severe injury from longed suffering and ongoing bur- child abuse, a child may require life- dens of survival or if the child is in a sustaining medical treatment persistent vegetative state and has lit- (LSMT). The decision as to whether tle interest in living or dying, it may to continue LSMT must be deter- mined for the abused child just as for be reasonable to consider discontin- any critically ill child. If the child will uation of LSMT to allow death to be severely and permanently disabled occur. but is not brain-dead, a determina- Seeking the parents’ input and tion may need to be made about taking into consideration their life whether continuation of LSMT is in values in terms of the best interest of the child’s best interest. Because a the child are important in making child has never possessed decision- this decision. In the case of child making capacity to make advance di- abuse, clinicians must listen carefully to the parents’ thought processes be-

*Associate Professor of Pediatrics, Albany Medical cause it is their reasoning, more than Center, Albany, NY. their final conclusion, that is most

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important. If the child is expected to should be discontinued in the brain- and social attention, it is important die following withdrawal of LSMT, it dead child. LSMT should not be to the parent to remain undiscov- is possible that a legal charge of as- continued in any dead patient, re- ered. If FDBP is discovered, the par- sault may be changed to manslaugh- gardless of the circumstances leading ent may face separation from his or ter or murder. Thus, the outcome of to death. Parents, however, may be her child and loss of attention. the parents’ decision may alter the compassionately offered some input Therefore, most perpetrators of legal charges filed against them, a as to when and under what circum- FDBP are careful not to be discov- guardian, relative, or acquaintance. stances such LSMT is discontinued. ered. FDBP is most likely to occur at (2)(3) Parents’ desire to decide in the Because the chance of criminal pros- home, but when it occurs in the hos- best interest of the severely abused ecution is so high in death following pital, it happens when no health-care child may, therefore, be compro- child abuse, the AAP recommends professional is present. mised by an attempt to protect them- that the medical examiner be in- Because this condition is so diffi- selves or others from increased legal volved before forgoing LSMT. (2) cult to diagnose unequivocally, prosecution. health-care professionals have used If health-care practitioners sus- Organ and Tissue Donation covert surveillance to aid in making pect that parents are experiencing a State and federal laws require that the diagnosis. Principal methods of conflict of interest in deciding about parents or legal guardians be given covert surveillance include hidden their child’s best interest, additional the opportunity to donate their dead video cameras as well as one-way mir- resources may be sought. The hospi- child’s organs or tissues. Even par- rors in the hospital room. Arguments tal ethics committee, attorneys, ad- ents suspected of abuse retain the against and for covert surveillance are ministrators, social workers, and cul- right to make this decision on behalf ethically charged. tural and religious leaders may be of their dead child, unless their legal helpful in resolving the conflict. Be- rights as parents have already been Arguments Against Covert cause stripping parents of their legal removed. The AAP recommends Surveillance custody and decision-making rights, that the medical examiner be encour- Covert surveillance may reveal sensi- even when they are no longer physi- aged to attend the organ/tissue pro- tive information irrelevant to the cally caring for their child, may be curement procedure to have the op- child’s illness. Such disclosure may time-consuming and require court portunity to collect any possible cause shame or harm to the involved intervention, the American Academy additional criminal evidence. (2) parties. If the parent learns that he or of Pediatrics (AAP) recommends she has been observed secretly and that a guardian ad litem be appointed Covert Surveillance for his or her privacy violated without to assist with medical decision- Factitious Disorder by Proxy consent, he or she may lose all trust in making in each case of child abuse Factitious disorder by proxy the physician as well as in health-care requiring LMST in which the parent (FDBP), a type of child abuse in professionals in general. Such loss of may have conflict of interest in decid- which a caretaker, usually a parent, trust may cause the parent to avoid ing whether to continue LSMT. (2) takes action so a child appears to be health-care professionals in the fu- Thus, in the field of child abuse, pa- or actually becomes ill, results in ture, setting up the child for subse- tient (parental) autonomy can be eventual death in up to 10% of chil- quent insufficient care. The parent outweighed by beneficence and non- dren as well as in significant long- may question the physician’s honesty maleficence toward the child. (4) term physical and psychological mor- and whether the physician’s actions bidity for the child. are in the best interest of the child or Brain Death FDBP may be suspected when a of the child-parent dyad. Deteriora- If a child is determined to be brain reasonable medical evaluation reveals tion in the parent-physician relation- dead, whether abused or not, prepa- no primary disease in the child, but ship may make the parent unwilling ration should be made to remove the the child has events requiring medi- to participate in any physician- child’s body from LSMT because cal attention, usually occurring solely mandated program designed to re- brain death is recognized as legally in the presence of the parent, which duce risk to children suspected of and ethically equivalent to cardiopul- cannot be explained otherwise. On being abused. Thus, the use of covert monary death. Parental agreement removal from the parent, signs of surveillance to try to diagnose FDBP should not be sought with regard to FDBP disappear. To continue to may indirectly threaten the parent- whether mechanical life support reap the benefits of extensive medical child relationship by limiting paren- e74 Pediatrics in Review Vol.32 No.7 July 2011 Downloaded from http://pedsinreview.aappublications.org. Provided by Health Internetwork on July 1, 2011 ethics for the pediatrician

tal commitment to a healing pro- best interests. When they enlist the is encroaching on the resources of gram. Subsequent removal of the help of a physician, they are seeking the health-care system. Such a parent child from the home may result in a attention for themselves rather than a clearly is not aligned with the physi- long trail of foster homes and associ- cure for the child’s condition. They cian in serving as a fiduciary for the ated risks. have not sought the physician’s child. It may be ethically inexcusable to counsel to have him or her spy on If the parent-physician relation- use the child as bait during covert them covertly in an attempt to ship has been formed with a goal of surveillance in the case of suspected achieve a diagnosis. It is unfortunate, providing health care in the best in- FDBP, due to the risk of harm to the in the parents’ eyes, that the consci- terest of the child, but the parent is child during the actual surveillance. entious physician is obligated, legally secretly acting against the best inter- If health-care professionals suspect and ethically, to investigate any sus- est of the child, the relationship be- FDBP so strongly that they consider picions. tween the parent and the physician is the use of covert surveillance, it As society leaders, physicians fraudulent. Therefore, covert surveil- might be preferable to remove the should hold themselves to high stan- lance of parental activities will not child immediately from the likely dards and not stoop to deceitful cause much more damage than al- source of abuse to guarantee his or means of making diagnoses. Accep- ready has affected the parent- her safety. Physicians willing to per- tance of such behavior may under- physician relationship, which is built form covert surveillance have been mine the virtue of being a physician. on a precarious structure of parental criticized as being so focused on falsehoods. catching the parents in the process of Arguments for Covert If FDBP occurs in the hospital perpetrating FDBP that they lose Surveillance under surveillance, not only is the sight of their fiduciary responsibility Covert surveillance is consistent with child subject to less severe and to protect the child at all times. (5) the physician’s role as a fiduciary, en- lengthy trauma than if he or she were Many parents involved in FDBP trusted with the care of another. As enduring these events at home, but are wary of video cameras and one- primary fiduciaries, parents usually the diagnosis is determined. (7) Ben- way mirrors and are unlikely to per- enlist and entrust physicians to cure efits to the child from diagnosing form their actions in a hospital. and protect the best interests of their FDBP include immediate protection Therefore, practically speaking, use children by treating their ailments. from further events and minimizing of secret surveillance bears great risk Parents who abuse their children may the subsequent risk of death or mor- and lends little benefit. FDBP may be not be capable of making important bidity from parental actions. Despite treated based on clinical suspicion decisions regarding the children’s suspicions of FDBP, most clinicians without the deleterious effects of di- best interests. Therefore, the physi- generally require evidence of paren- agnosis via covert surveillance. The cian whom the parents have enlisted tal attempts to harm their child be- clinician may simply tell parents sus- to care for their children may be the fore barring them access to the child. pected of being involved in FDBP only fiduciary. (7) Thus, covert surveillance helps to that their only options are to partici- Under the guise of promoting the protect the long-term interests of the pate in a recovery program or to refer child’s best interests, the parent in- child. the child to Child Protective Ser- volved in FDBP may have sought Although covert surveillance of vices. The physician who positions medical assistance for the child to call parents interacting with their chil- himself or herself on the side of attention to himself or herself. A par- dren violates their right to privacy, working with the parent to keep cus- ent who commits FDBP has, thus, may extinguish the trust they have tody of the child, rather than as an established a false relationship with for the physician, and may not yield adversary willing to spy on the fami- the physician. Although he or she any answers regarding the cause of ly’s activities, demonstrates respect appears to have enlisted and is sup- the child’s illness, such surveillance for the parents, maintains their trust, porting the physician in trying to de- does not disrespect the parents. In- and minimizes risk to the child of termine the source of the child’s stead, it may identify the abusing another FDBP event. (6) illness, this parent actually is with- parent as needing help. The applica- Parents who practice FDBP are holding information from the physi- tion of covert surveillance is justified not appropriate surrogate decision- cian that could help determine why because of the physician’s fiduciary makers for their children and are not the child is ill. In addition, the parent responsibility to protect the best in- attempting to protect their children’s is manipulating the child’s health and terest of the child. Protecting the

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child should be the priority, and diatrician and the child’s family, may the abused child to the parental making a diagnosis is germane to that need to decide whether it is in the home for more abuse. function. child’s best interest to remain in such an environment, whether the envi- Foster Care Placement Violence ronment can be improved, or Child abuse and neglect frequently Children who witness physical vio- whether the child should be up- result from such adversities as pov- lence between their parents have rooted and placed in a foster home erty, mental illness, caregiver sub- psychological outcomes similar to free of the predilection for violence. stance abuse, transitions between those of children who have been The physician is legally and ethi- caregivers, and domestic violence. physically abused. Even when there is cally mandated to report violence di- For each household referred to the no direct physical abuse of children rected against children to protect child welfare authorities, it must be being raised in a violent household, them. (14) The pediatrician may sus- determined whether the child’s in- such children have physiologic neuro- pect abuse based on physical find- terests are served best by his or her endocrine alterations that result in ings; the adverse psychosocial effects remaining at home or by placement elevated resting heart rate, elevated of a violent environment that does in foster care. The key ethical di- blood pressure, other findings consis- not cause obvious physical findings lemma in choosing whether a child tent with a chronic “fight-or-flight” in the child may be more difficult to should be in foster placement or re- response, (8) and somatic symptoms recognize. The pediatrician may be main at home with his or her parents such as headache. Similarly, such chil- less inclined to report these cases, lies in balancing beneficence and dren have a high risk of adverse even if he or she is aware of the nonmaleficence to the child. A sec- psychosocial outcomes, including ad- presence of violence in the child’s ondary dilemma is determining allo- justment disorders and posttraumatic environment. Physicians may fail to cation of social resources, such as fos- stress disorder. report violent households, which ter care, to optimize community Adverse outcomes may be inter- may harm the child, due to their own outcomes. nalized within the child in the form desire not to damage the patient- Depending on the individual fam- of social isolation, lack of emotional physician relationship and to con- ily’s circumstances, the child’s best attachment, and cognitive inatten- tinue to provide treatment for the interest may be met by remaining at tion with poor academic perfor- child and family. Failure to report home, provided certain dangerous mance. Children may present with violence affecting children allows conditions are corrected. If the par- externalized, aggressive, and violent more opportunities for children to ents are willing to correct the envi- behavior. Very young children have experience adverse effects. ronment within their home, benefits limited understanding of conflict and In the emergency department, the could include stability in terms of the fewer strategies for coping with it. physician’s office, or court, often child maintaining psychological at- (9) Therefore, it is the youngest chil- within earshot of the parent, the tachments, consistency of rules and dren exposed to violence at home child may be asked questions about expectations of behavior, consistency who are at greatest risk for adverse being the deliberate or inadvertent of provision of physical care, mainte- psychosocial outcomes. target of violence. The child may be nance of familial and ethnic identity, Violence affecting children also inclined to deny that any violence and more effective use of social re- may occur in the form of teen dating occurs at home to appease his or her sources. Therefore, reasonable ef- violence; bullying; and exposure to parent and avoid later punishment. forts should be exerted, when appro- firearms, (10) television shows, mov- He or she should be allowed to an- priate, to preserve and repair families ies, (11) video games, and music. swer without the parent being pres- to make the parental home as ideal as (12) Media violence has been ent. He or she should be assured that possible for the child. (15) strongly associated with aggressive honest answers are in his or her own When the parental home is not behavior, desensitization to violence, best interest and that he or she will be remediable and continues to be dan- fear of being harmed, and night- protected from parental retaliation. gerous for a child, foster care must be mares. (13) Once abuse is reported, lawyers rep- used, even on a temporary basis. Fos- When a child is exposed to re- resenting the alleged abusive parents ter care is intended to provide the peated violence at home, and if the may be aware of the abuse, but still child with safety as well as psycholog- violence cannot be eliminated, au- may argue in favor of the innocence ical, physical, and cognitive nurtur- thorities, in conjunction with the pe- of their clients, thus risking return of ing to allow the child to heal. How- e76 Pediatrics in Review Vol.32 No.7 July 2011 Downloaded from http://pedsinreview.aappublications.org. 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ever, foster care is associated with ment may be less attentive in relative developmentally appropriate and less certain risks. Due to the high work- foster care than in nonrelated foster cognitively stimulating than that force turnover in the child welfare care. Relative foster caregivers have a which they would have received in system, youth in foster care may suf- high incidence of incomplete high the parental home. (17) This differ- fer adverse effects such as lack of sta- school education, similar to that of ence may occur because the average bility and loss of trusting relation- the investigated parents, increasing foster family provides care for five or ships with child welfare workers. (16) the risk of poor academic achieve- more children simultaneously, Insufficient numbers of suitable fos- ment of the child. Both related and stretching both financial resources ter homes result in placement with nonrelated foster caregivers have a and time available for each child’s relatives, (15) a delay of long-term higher incidence of serious physical care. Without adequate knowledge placement, or frequent changes of illness compared with investigated of and skills in child development, foster homes for any given child. (17) parents, often due to their greater enough time to attend to the child’s Repeated foster home and school age, which may impede their ability physical and developmental needs, changes compound the adverse con- to care for the foster child in an ex- good mental and physical health, and sequences that previous stress and emplary manner. financial and other resources neces- inadequate parenting had on the Although nonrelated foster par- sary to build a safe and nurturing child’s neurodevelopment and ability ents generally are older and have environment for the child, foster care to cope. Repeated separation of the higher levels of education, higher in- may not be superior to the high-risk child from his or her primary pillars comes, a spouse to help with child- home being investigated. of psychological support (first, the care, and better mental health, they The authorities of the child wel- parents and later, a variety of foster generally provide a learning environ- fare and judicial systems have the dif- parents) may result in attachment ment for the foster child that is less ficult role of weighing the alterna- disorders and an inability to trust and love. Frequent school changes and the termination of foster care at 18 Summary years of age may leave the child un- prepared for adult life (inadequate • Multiple ethical dilemmas in the field of child abuse create challenges to independent living skills, inadequate making decisions that are in the best interest of the child. The clinician must have command of these ethical issues to render the most appropriate employment skills and plans, inade- and compassionate care to the child. quate coaching regarding the pursuit • Withdrawal of LSMT may be ethically permissible, with the intention of of higher education, lack of financial allowing death to occur, for the child who has suffered severe and aid). (15) permanent brain damage and who may have no interest in whether he or Placement of a child in the foster she lives or dies or who is expected, if medical technology is continued, to live a life of pain and suffering. care of a relative offers the advantages • Parents may have conflicts of interest regarding whether to continue LSMT of maintaining his or her family and because if the child dies, they may be legally charged with manslaughter or ethnic roots and having a more con- murder. Therefore, the clinician must listen to the reasoning process that sistent group of caregivers. Such fac- parents use in reaching their decision. tors could ease the child’s transition • Appointment of a guardian ad litem, as well as use of ethics consultants and other resources, can help to ensure that the treatment decision is in the back to the parental home when its best interest of the child. deficiencies are corrected. A lower • A brain-dead child is legally and ethically indistinguishable from a child incidence of untreated mental illness who suffers a cardiorespiratory death. is seen in foster caregivers who are • Covert surveillance in suspected factitious disorder by proxy has been relatives compared with parents criticized for revealing irrelevant and embarrassing information as well as being deceitful and deleterious to the parent-physician relationship, whose homes have been investigated potentially dangerous to the child, likely to be nondiagnostic, not serving by child welfare workers. Foster care the purpose for which the parents sought the physician’s counsel, and with a relative, however, may result harmful to the role of the physician. However, its use is justifiable because in unplanned, inadvertent, and po- of the physician’s fiduciary responsibility to protect the best interest of the tentially unsafe return of the child to child. • Although the intention of foster care is to place children in a safe, healing his or her parental home. Social sup- home, certain risks inherent in foster placement create a challenge in port resources may be less available, determining which home situation is in the best interest of the child. and supervision of the home environ-

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